THER 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., 1960Ether: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-597-84416-X 1. Ether-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 ether. 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 ETHER ....................................................................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Ether.............................................................................................. 5 E-Journals: PubMed Central ....................................................................................................... 65 The National Library of Medicine: PubMed ................................................................................ 71 CHAPTER 2. ALTERNATIVE MEDICINE AND ETHER ....................................................................... 91 Overview...................................................................................................................................... 91 National Center for Complementary and Alternative Medicine.................................................. 91 Additional Web Resources ........................................................................................................... 96 General References ..................................................................................................................... 160 CHAPTER 3. DISSERTATIONS ON ETHER ....................................................................................... 161 Overview.................................................................................................................................... 161 Dissertations on Ether ............................................................................................................... 161 Keeping Current ........................................................................................................................ 164 CHAPTER 4. PATENTS ON ETHER .................................................................................................. 165 Overview.................................................................................................................................... 165 Patents on Ether......................................................................................................................... 165 Patent Applications on Ether..................................................................................................... 196 Keeping Current ........................................................................................................................ 234 CHAPTER 5. BOOKS ON ETHER ...................................................................................................... 235 Overview.................................................................................................................................... 235 Book Summaries: Online Booksellers......................................................................................... 235 Chapters on Ether ...................................................................................................................... 245 CHAPTER 6. PERIODICALS AND NEWS ON ETHER ........................................................................ 247 Overview.................................................................................................................................... 247 News Services and Press Releases.............................................................................................. 247 Academic Periodicals covering Ether......................................................................................... 248 CHAPTER 7. RESEARCHING MEDICATIONS .................................................................................. 251 Overview.................................................................................................................................... 251 U.S. Pharmacopeia..................................................................................................................... 251 Commercial Databases ............................................................................................................... 265 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 269 Overview.................................................................................................................................... 269 NIH Guidelines.......................................................................................................................... 269 NIH Databases........................................................................................................................... 271 Other Commercial Databases..................................................................................................... 273 APPENDIX B. PATIENT RESOURCES ............................................................................................... 275 Overview.................................................................................................................................... 275 Patient Guideline Sources.......................................................................................................... 275 Finding Associations.................................................................................................................. 281 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 283 Overview.................................................................................................................................... 283 Preparation................................................................................................................................. 283 Finding a Local Medical Library................................................................................................ 283 Medical Libraries in the U.S. and Canada ................................................................................. 283 ONLINE GLOSSARIES................................................................................................................ 289 Online Dictionary Directories ................................................................................................... 289
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ETHER DICTIONARY.................................................................................................................. 291 INDEX .............................................................................................................................................. 371
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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 ether is indexed in search engines, such as www.google.com or others, a nonsystematic 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 ether, 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 ether, 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 ether. 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 ether, 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 ether. 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 ETHER Overview In this chapter, we will show you how to locate peer-reviewed references and studies on ether.
The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and ether, 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 “ether” (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: •
Rapid Dissolution of Gallstones by Methyl Tert-Butyl Ether Source: Journal of Lithotripsy and Stone Disease. 3(1): 62-65. January 1991. Summary: Dissolution of gallbladder or bile-duct stones has received increasing interest in the past decade. This article reviews the rapid dissolution of gallstones by methyl tertbutyl ether (MTBE). MTBE is an ether that remains liquid at body temperature and has dissolved multiple human gallstones implanted in dog gallbladders, within 4 to 6 hours and without serious side effects. This article reports on initial studies of MTBE in humans. The authors describe two patients in whom MTBE was used to dissolve cholesterol gallstones in the gallbladder and bile duct within hours. 6 figures. 12 references.
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Dissolution of Gallbladder Stones with Methyl tert-Butyl Ether and Stone Recurrence: A European Survey Source: Digestive Diseases and Sciences. 43(5): 911-920. May 1998. Contact: Available from Plenum Publishing Corporation. 233 Spring Street, New York, NY 10013. (212) 620-8468. Fax (212) 807-1047. Summary: Since there are now several ways to treat symptomatic gallstone disease, physicians can select a treatment on the basis of the patient's comfort; the practicability, effectiveness, and side effects of the technique; and the relative costs. In a study undertaken to assess the present status of contact dissolution with methyl tert-butyl ether at 21 European hospitals; 803 patients were selected for contact litholysis of cholesterol gallstones using methyl tert-butyl ether. Percutaneous (through the skin) transhepatic puncture of the gallbladder was performed under x-ray or ultrasound guidance. Dissolution rate, side effects, and treatment times of 268 patients from a single center were compared with those of 535 patients from the other 20 centers and 264 patients were followed for 5 years to monitor for stone recurrence. Physicians were asked how they assessed the method's cost, the discomfort to the patients, and the staffing situation. Patients were asked to indicate their acceptance on an analog scale. Puncture was successful in 761 patients (94.8 percent) and prophylactic administration of antibiotics was not necessary. Stones were dissolved in 724 patients (95.1 percent). In 315 patients (43.5 percent), sludge remained in the gallbladder. The most severe complication was bile leakage, which led 12 patients (1.6 percent) to have elective cholecystectomy. No toxic injuries due to ether were reported. The recurrence rate over 5 years was about 40 percent for single stones and about 70 percent for multiple ones. Some 70 to 90 percent of the centers found the puncture to be simple and not distressing for patients, and the relation between expenditure and therapeutic success to be acceptable. The acceptance of contact litholysis by the patients was excellent. The authors conclude that contact litholysis, when performed by an experienced team, provides real advantages in the treatment of gallstone disease. The method is technically simple and well accepted by the patients, and it can be easily applied in community hospitals. Contact litholysis may be of particular value in patients who are not suitable for anesthesia or surgery. 5 figures. 4 tables. 36 references. (AA-M).
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Commentary: Rapid Dissolution of Gallstones in Humans Using Methyl Tert-Butyl Ether Source: Journal of Lithotripsy and Stone Disease. 3(1): 58-61. January 1991. Summary: This article comments on the first report of the clinical use of methyl tertbutyl ether (MTBE) to dissolve gallbladder and bile duct gallstones (simultaneously published with this commentary). The author presents a brief history of the use of dissolution therapy, the introduction of ether solvents, the use of an automatic infusionaspiration pump, and a comparison of dissolution therapy to laparoscopic cholecystectomy. An annotated bibliography of 6 related items is appended. 19 references.
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Federally Funded Research on Ether The U.S. Government supports a variety of research studies relating to ether. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.2 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to ether. 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 ether. The following is typical of the type of information found when searching the CRISP database for ether: •
Project Title: A NOVEL TECHNOLOGY FOR MTBE REMOVAL FROM DRINKING WATER Principal Investigator & Institution: Tennakoon, Charles L.; Lynntech, Inc. College Station, Tx 77840 Timing: Fiscal Year 2003; Project Start 15-SEP-2003; Project End 31-AUG-2005 Summary: (Applicant?s abstract): Some 18 billion pounds of MTBE was produced in 1995, making it the second most widely produced organic chemical in the United States. Despite its advantages in reducing air pollution, it has now been found that both ground water surface water sources are being contaminated with MTBE. The most serious contamination to date occurred in ground ware supplies in California, where 20 production wells are closed due to high MTBE contamination. USEPA currently classifies MTBE as a possible carcinogen in its largest directive this year and has decided to phase out the use of MTBE in gasoline. In the coming years, this nation faces a formidable task of ensuring that our drinking water supplies are free of MTBE. MTBE is not readily amenable to treatment by conventional techniques. It is high solubility in water (50g/L) limits adsorption on to activated carbon. Other oxidative techniques produce bromate ions far exceeding the allowed maximum concentration level (MCL) of 10mg/L in drinking water. Hence, efficient non-oxidative alternatives to remove MTBE from water are highly desirable and are urgently needed. The aim of this proposal is to develop a cartridge filter using a remarkably effective separation technology developed at Lynntech. Based upon the Phase I results, this technology would lead to the development of a cartridge that could supply MTBE safe drinking water for more than six months to household of four. Projected sale price of such a cartridge is about $25.00. During the Phase II, practical issues related to long-term stability, regenerability and reusability of the absorbent, large scale manufacturing, and production will be addressed. Phase II will also include designing and assembling prototype cartridges for further evaluation and demonstration to potential industrial partners. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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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Project Title: A UNIFIED APPROACH TO (+) AND (-) SPIROXINS AE Principal Investigator & Institution: Moniz, Georgr A.; Chemistry and Chemical Biology; Harvard University Holyoke Center 727 Cambridge, Ma 02138 Timing: Fiscal Year 2002; Project Start 17-SEP-2002 Summary: (provided by applicant) This proposal will detail studies directed towards the total synthesis of (+)- and (-)-Spiroxins A-E, new members of the bisnaphthospiroketal class of natural products. Spiroxin A has been shown to possess very promising biological activity, exhibiting antitumor activity in nude mice against ovarian carcinoma (59 percent inhibition after 21 days) at 1mg/kg dosing and cytotoxicity with a mean IC50 value of 0.09 mg/mL against a panel of 25 diverse cell lines. The mechanism of this activity is not known, nor are the biological activities of spiroxins B-E. The spiroxins are therefore very attractive targets for synthesis and analog preparation. Furthermore, the absolute stereochemistry of these natural products is not known, nor are the relative stereochemistries of Spiroxins D and E. The syntheses proposed herein would therefore also serve to provide critical stereochemical information by accessing the unnatural enantiomers and diastereomers which may themselves possess important biological activity. The proposed synthetic route is convergent, incorporates new methodology for the asymmetric preparation of naphthoquinols, and expands the utility of existing biaryl ether-forming methodologies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ANESTHETIC BINDING SITES ON THREE-HELIX BUNDLE PROTEINS Principal Investigator & Institution: Johansson, Jonas S.; Assistant Professor; Anesthesia; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 01-MAR-2002; Project End 28-FEB-2007 Summary: The proposed research has the long-range goal of providing an understanding of how the inhaled general anesthetics interact with proteins, from structural and dynamic points of view, at the molecular level. This will be achieved using approaches developed in this laboratory to detect anesthetic binding to protein targets. The primary experimental focus will be synthetic three-alpha-helix bundles that can be structurally modified by established techniques. These synthetic proteins serve as simplified models for the bundles of transmembrane alpha-helices that are ubiquitous structural components of ion channels and neurotransmitter receptors in the central nervous system, and are the favored targets for general anesthetics at present. The current structural understanding of membrane proteins precludes their use to precisely examine anesthetic- protein complexation. However, the proposed use of simplified, well-defined, models of the transmembrane domains of native proteins lend themselves to the direct determination of the structural features of anesthetic binding sites using various spectroscopic approaches and X-ray crystallography. This will provide a detailed frame to evaluate hydrophobic, polar, and protein cavity contributions to anesthetic binding, providing insight into the relative importance of specific molecular interactions for anesthetic complexation. This information will provide guidelines for the structural composition of in vivo binding sites for volatile general anesthetics. The consequences of anesthetic binding to protein targets will be determined using measures of protein dynamics such as fluorescence anisotropy and protein thermodynamic stability, with the goal of furthering our understanding of how a bound anesthetic might alter protein function. The proposed studies build on the reported findings on halothane binding to dimeric four-alpha-helix bundles to (i) define the structure of the anesthetic
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binding site, and (ii) obtain atomic-level X-ray crystal structures of protein with bound anesthetic. Ultimately, the use of such model systems will provide fundamental information concerning how these important clinical compounds interact with potential target sites in the central nervous system at the molecular level, and will establish a framework for testing such associations, with natural membrane proteins. A precise structural description of the anesthetic binding site on this model system will allow a focused search of the Protein Data Bank for potential binding sites on existing- and future entries. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ANESTHETIC CONSEQUENCES
RENAL
METABOLISM--MECHANISMS
AND
Principal Investigator & Institution: Kharasch, Evan D.; Professor; Anesthesiology; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 01-MAY-1999; Project End 30-APR-2004 Summary: (Adapted from the Investigator's Abstract) The overall long-term objective of the proposed research is to enhance the clinical safety and efficacy of currently used fluorinated volatile anesthetics, to improve the development of future anesthetics, and to develop in vitro nephrotoxicity models which translate directly to clinical application. The immediate goals are to elucidate mechanisms of anesthetic nephrotoxicity, assess human risk, prevent clinical toxicity, and modernize in vitro screening methods for new anesthetic development. Two issues which drive this research are: 1) Certain fluorinated anesthetics cause nephrotoxicity, which is intrinsically linked to their metabolism by cytochrome P450. Nevertheless, the historically accepted explanation that hepatic P450catalyzed anesthetic defluorination and systemic fluorosis causes renal insufficiency is now clearly invalid and unapplicable to modern anesthetics, and 2) Sevoflurane, the most recently approved anesthetic, undergoes chemical degradation in clinical anesthesia machines and exposes patients to fluoromethyl-2,2- difluoro-1(trifluoromethyl)vinyl ether. This fluoroalkene causes profound proximal renal tubular necrosis in rats. In humans, some evidence suggests dose-related clinically significant sevoflurane fluoroalkene nephrotoxicity, however data are very contradictory and the controversy remains unresolved. The potential risk to humans remains ambiguous, in part because the biochemical mechanism of fluoroalkene toxicity in rats and its relevance to humans is unknown. The central hypothesis to he tested in this investigation is that intrarenal metabolism is the critical etiologic factor responsible for the organ-specific nephrotoxicity of certain fluorinated anesthetics and the tubular necrosis caused by fluoroalkene anesthetic degradation products, and that species and drug specific differences in intrarenal anesthetic metabolism confers similar differences in nephrotoxicity. This hypothesis will be tested using complementary in vivo and in vitro approaches in both animal models and humans. Rat studies will evaluate anesthetic metabolism and toxicity using subcellular fractions, isolated proximal tubular segments, and whole animal models. Human studies will evaluate hepatic and renal metabolism in vitro, cultured human kidney cells, and clinical investigations in surgical patients. If intrarenal, rather than hepatic bioactivation underlies anesthetic nephrotoxicity, then screening mechanisms to identify such anesthetics and prevent their toxicity can be revised and future anesthetics more rationally developed. Identifying intrarenal pathways responsible for fluoroalkene breakdown product nephrotoxicity and their interspecies differences will permit adequate assessment of human anesthetic risks. More broadly, resulting biochemical and clinical insights will be
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applicable to the numerous other nephrotoxic haloalkenes that are ubiquitous environmental contaminants. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: APPLICATIONS CYCLIZATIONS
OF
ELECTRON
TRANSFER
INITIATED
Principal Investigator & Institution: Floreancig, Paul E.; Chemistry; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2007 Summary: The purpose of this proposal is to continue the development of the electron transfer initiated cyclization reaction and to use this methodology for the synthesis of biologically important structures. In this reaction the photoinitiated single electron oxidation of alkylarenes substituted at the homobenzylic position with an electron donating substituent produces radical cations containing substantially weakened and polarized benzylic carbon-carbon bonds. Appended nucleophiles, such as hydroxyl, ether, and amide groups can displace benzylic radicals, resulting in a cyclization reaction. The mild reaction conditions and unique chemoselectivity exhibited by single electron transfer make this reaction a potentially very powerful new method for constructing organic molecules. Specific goals for the project include: A thorough study of the types of cation stabilizing substituents, aromatic leaving groups, and nucleophiles tolerated by this reaction. This study includes the development of new heterogenerative cascade reactions. The development of a chemically initiated variant of the reaction. The development of an electron transfer initiated cyclorelease reaction from a polymer support. Employment of the reaction as the key step in brief total syntheses of potent antitumor and immunosuppressant agents from the pederin and mycalamide family, and the use of these sequences in the synthesis of analogs. The proposed program provides both new methodology for organic synthesis and efficient routes to challenging and medicinally important structures. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: APPLICATIONS REARRANGEMEN
OF
THE
STEREORETENTIVE
O
AND
C
Principal Investigator & Institution: Rovis, Tomislav; Chemistry; Colorado State University Fort Collins, Co 80523 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2006 Summary: (provided by applicant) The overall goal of this research is to develop stereoselective methods for the formation of sterically congested carbon-carbon bonds in order to provide rapid, efficient, and selective routes to biologically active molecules. These types of bonds are found in numerous natural product targets. The structurally related class of tetramic acid macrolactams, characterized by a polysubstituted bicyclo (3.3.0 core and a tetramic acid moiety connected within a macrolactam, are accessible by this methodology. They are of fundamental interest since members of this class exhibit a diverse biological activity profile. Cylindramide exhibits cytotoxicity against B16 melanoma cells. Geodin A is a potent nematocidal agent. Alteramide A shows cytotoxicity against murine leukemia P388 cells, murine lymphoma L1210 cells, and the human epidermoid carcinoma KB cells in vitro. Discodermide inhibits the in vitro proliferation of cultured murine P388 leukemia cells and has some antifungal activity. Aburatubolactam A was found to inhibit superoxide anion generation while aburatubolactam C induces apoptosis. The central approach of this research is to convert
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chiral vinyl ethers into the corresponding carbon-carbon bonds with retention of stereochemistry. This strategy takes advantage of the multitude of ways to control carbon-oxygen bond stereochemistry to translate it into carbon-carbon bond stereochemistry. Specifically, the goals of this research are: 1) develop and explore the scope of the stereoretentive O to C rearrangement of vinyl acetals; 2) apply this insight to the development of a general vinyl ether O to C rearrangement and investigate its limits; 3) explore new methods for the stereodefined generation of vinyl ethers in order to expand the scope of the stereoretentive O to C rearrangement of vinyl acetals and ethers; 4) extend these studies to the stereoretentive replacement of chiral ethers with other nucleophiles; 5) develop a mechanistic understanding of these reactions; 6) couple the stereoretentive O to C rearrangement with a subsequent transformation to facilitate the rapid assembly of oligopyrans relevant to the ladder toxin family of natural products; 7) implement these methods in the stereoselective synthesis of tetramic acid macrolactams such as cylindramide. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ARENE ACTIVATION BY TRANSITION METALS Principal Investigator & Institution: Pearson, Anthony J.; Rudolph and Susan Rense Professor and c; Chemistry; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2002; Project Start 01-JUL-1986; Project End 31-MAR-2005 Summary: (provided by applicant) The objectives of the proposed research are to use in organic synthesis the ability of transition metals to activate aromatic substrates toward nucleophilic addition. Two main areas of endeavor will be studied: (1) Chromium tricarbonyl complexes of alkoxybenzene derivatives, in which the alkoxy group is chiral, will be used as substrates for asymmetric carbon nucleophile addition reactions. The outcome of this protocol is the formation of chiral substituted cyclohexenones in high enantiomeric excess. (2) Cyclopentadienylruthenium complexes of chloroarenes will be used to effect nucleophilic aromatic substitution as a key step in the total synthesis of the aglycone of ristocetin A, which is a complex peptido aryl ether related to the important glycopeptide antibiotics vancomycin and teicoplanin. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ASSESMENT OF A CHRONIC SUBCUTANEOUS GLUCOSE SENSOR Principal Investigator & Institution: Ward, W Kenneth.; Legacy Health System 1919 Nw Lovejoy St Portland, or 97209 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2004 Summary: (provided by applicant): In the United States, diabetes mellitus is the leading cause of end-stage kidney failure, blindness in adults under age 65, and is the second leading cause (after trauma) of limb amputation. Poorly-controlled glucose levels are the major cause of these complications, but tight glycemic control is difficult to safely achieve using present technology. While a continuously-functioning glucose sensor would assist in safely achieving tight glucose control, such devices are typified by instability and loss of output over time due to the formation of foreign-body scar tissue, which eventually surrounds the sensors. Miniaturized sensors could be implanted under the skin with minimal discomfort. It is possible that the surrounding scar capsule could be made much more "friendly" to a glucose sensor by the slow release of growth factor compounds from the sensor surface. The hypothesis is that such compounds would reduce the scar fibrosis and generate many blood vessels in the capsule. These
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blood vessels are important to the long-term function of the sensor given its need for continuous glucose and oxygen delivery. A study will initially be performed in order to ascertain the optimal dosage of the growth factor. Then the growth factor (or saline control) will be slowly released over one month from miniaturized pumps into the tissue, which directly contacts the sensor. The thickness of the capsule and the formation of new blood vessels will measured by standard histologic staining techniques and by endothelial Factor Vifi immunohistochemistry. Another major problem of glucose sensors is short-term drift. It is frequently observed but poorly understood. It now appears that it may be possible to obtain stable readings from simultaneous recordings of multiple sensor electrodes. The technique which will be used to separate the accurate electrode signals from the inaccurate (outlying) signals is from the field of median statistics and is called the ZMAD method of Rousseeauw. The ZMAD data processing will be performed prospectively and continuously. In addition, the sensors and their transmitters will be miniaturized with the help of a biotelemetry company, MiniMitter. The body can be hostile to compounds which coat implanted devices. We will compare two promising polyurethanes as sensor coats: a carbonate based- vs. ether-based polymer. We will compare their long term function in studies using rabbits, which will be also be used to ascertain the effect of the growth factors and the real-time data processing. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ASYMMETRIC SYNTHESIS OF MEDIUM RING POLYETHERS Principal Investigator & Institution: Crimmins, Michael T.; George & Alice Welsh Professor; Chemistry; University of North Carolina Chapel Hill Aob 104 Airport Drive Cb#1350 Chapel Hill, Nc 27599 Timing: Fiscal Year 2002; Project Start 01-FEB-2000; Project End 31-JAN-2004 Summary: This new program will focus on the development of a novel strategy for the enantioselective synthesis of complex medium ring ether marine natural products. A practical asymmetric aldol addition followed by a ring closing metathesis reaction will be used to construct six to nine membered cyclic ethers. The ring closing metathesis reaction of medium rings can be effected without cyclic constraints by exploiting the gauche effect of adjacent oxygen substituents. This effect will be explored in a tandem ring opening-ring closing metathesis reaction for the simultaneous production of two medium-sized cyclic ethers. The methods for medium ring ether synthesis will be utilized in the synthesis of a variety of novel, pharmacologically active marine natural products such as isolaurallene, pannosallene, brevetoxin A, mucocin and gigantecin. Since many of the polyether toxins and the cytotoxic annonaceous acetogenins are available in very small quantities, chemical synthesis offers one solution to the supply problem for further studies on the mechanism of action and chemical modification of the toxins and antitumor agents, leading ultimately to improvements in public health. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: BIOMATERIALS THAT PROMOTE HEALING & PREVENT INFECTION Principal Investigator & Institution: Bryers, James D.; Professor; None; University of Connecticut Sch of Med/Dnt Bb20, Mc 2806 Farmington, Ct 060302806 Timing: Fiscal Year 2002; Project Start 10-SEP-2002; Project End 31-AUG-2005 Summary: (provided by applicant): Several prokaryotic and eukaryotic intra- and intercellular processes are initiated and controlled by a communication pathway from
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stimulus, to cell surface receptor, to cell nucleus, to mRNA, to cytokine signaling agents and higher tissue response. We recognize that both prokaryotic and eucaryotic biological processes can be influenced through cell membrane receptor mechanisms. With NIH support, we will develop model cardiovascular biomaterials that (a) use surface-tethered ligands to promote macrophage adhesion and instigate a healing cascade [1-2], while (b) releasing bioactive molecules specifically selected to negate bacterial receptor-mediated adhesion. We have developed poly(ether urethane) materials, modified with poly(ethylene glycol) tethers that (1) eliminate random protein adsorption and (2) allow for surface modifications by cell adhesion promoting peptides and monoclonal antibody fragments. While all treatments promoted macrophage adhesion, some also promoted macrophage activation. Results also indicate that both peptide- and Mab-decorated PEU surfaces significantly enhanced bacterial adhesion and biofilm formation versus base material. Consequently, for biomaterials to attract macrophage without promoting bacterial infection, a means to negate bacterial adhesion is needed. Thus, we will over a three (3) year period, develop model biomaterials that biologically prevent bacterial colonization. Objectives are: 1. We will isolate and characterize the cognate receptor(s) that the bacterium, Staphylococcus epidermidis (SE), employs to bind to fibronectin (FN)-coated surfaces - i.e., FN binding receptors (FN-BR) - and we will generate monoclonal antibodies (Mabs) to the entire receptor and its FN-binding domains. 2. A single chain variable fragment (scFV) antibody will be engineered from the variable heavy and light binding domains of the monoclonal antibody (MabFNBR) produced above. We will verify that the scFV antibody (FVFNBR) has the ability to bind to the SE FNBR receptor and block SE bacterial adhesion. 3. PEU materials will be fabricated containing one of the bacterial adhesion receptor blocking molecules (the MabFNBR or scFV antibody FVFNBR). Rates of bacterial anti-adhesion molecule release as a function of the amount of therapeutic agent loaded and biomaterial preparation will be determined. SE bacterial attachment studies will be carried out as a function of the specific biomaterial preparation in question and fluid phase cell concentration; under controlled hydrodynamic conditions. We will quantify macrophage adhesion, cytokine production, and macrophage activation; both with and without the presence of bacteria. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BIOTHERMODYNAMIC STUDIES OF THE SOLVATION AND CLUSTERING OF NONIONIC AMPHIPHILES Principal Investigator & Institution: Davis, Michael I.; University of Texas El Paso El Paso, Tx 79968 Timing: Fiscal Year 2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CHARACTERIZATION PLASMENYLCHOLINES
OF
PHOTOOXIDIZED
Principal Investigator & Institution: Thompson, David H.; Professor; Chemistry; Purdue University West Lafayette West Lafayette, in 479072040 Timing: Fiscal Year 2002; Project Start 01-SEP-2000; Project End 30-JUN-2003 Summary: The primary objectives of the proposed research are to quantify the formation rates of photooxidized plasmenylcholines and characterize their impact on membrane fluidity and lipidmediated membrane fusogenicity. An interdisciplinary project is
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proposed involving lipid synthesis, HPLC analysis with electrochemical & mass spectrometric detection, vesicle leakage, and EPR lipid diffusion experiments aimed at understanding the effects of photooxidation on membrane permeability. Water-soluble and membrane-soluble sensitizers, incorporated within guest membrane vesicles, will be illuminated under aerobic conditions to determine the effects of sensitizer localization on the lipid photooxidation rate. Results from these experiments will be compared with observations made using chemical oxidants. Labeled plasmenylcholines will be synthesized for 13C NMR experiments using methodology developed by Rui & Thompson [Chem. Eur. J. 1996 2 1505]. HPLC analysis and membrane fusion fluorescence assays will be used to monitor the rates of lipid photooxidation, vesicle lipid mixing, and vesicle contents mixing as a function of irradiation time & sensitizer type. Physical characterization of the membrane structures, before and after triggering, will also be performed using 31P NMR and EM techniques. These experiments will yield insights into the oxidative mechanisms of vinyl ether linked glycerophospholipids, such as plasmenylcholine and plasmenylethanolamine, that may be involved in reperfiision injury, multiple sclerosis, and other demyelinating disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CHEMICAL BASIS FOR POTASSIUM CHANNEL MODULATION Principal Investigator & Institution: England, Pamela M.; Pharmaceutical Chemistry; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2003; Project Start 15-JUL-2003; Project End 30-JUN-2007 Summary: (provided by applicant): Ion channels are a class of proteins that play critical role in cellular signaling by mediating the excitability of cells. This activity of ion channels is not static, but constantly changes in response to various intracellular and extracellular signals and, in recent years, many of the factors that directly modulate the activity of ion channels have begun to be identified. Understanding the chemical basis for how the activity of these proteins is modulated represents one of the most important areas of modern science as it impacts our understanding of how the nervous system works as well as our ability to pharmacologically manipulate it. The proposed research seeks to characterize several potential modes of modulation of the human ether-a-go-go related gene (HERG) ion channel, a voltage-gated potassium channel found in brain and heart. The activity of HERG channels is modulated by oxygen (02) and reactive oxygen species (ROS) in vitro and it has been proposed that HERG channels function as direct sensors of O2/ROS in vivo. The hypothesis that O2/ROS sensing by HERG channels is mediated by the reversible oxidation of methionine residues within the channel will be evaluated by characterizing the biophysical effects of site-specifically incorporating methionine sulfoxide into the channel on channel biophysics. HERG channel activity is also modulated by various classes of small molecules in vivo. In all but a few cases, the binding site(s) for these compounds have not been identified, however. The hypothesis that small molecules modulate the activity of HERG channels by binding to the Nterminal (PAS) domain will be evaluated using NMR spectroscopy (to detect structural perturbations associated with ligand binding) and electrophysiology (to define biophysical changes associated with ligand binding). Finally, HERG channel activity also appears to be modulated by various protein-protein interactions. To determine the site(s) in HERG that interact with other proteins, photoreactive amino acids capable of forming protein cross-links will be site-specifically incorporated into the HERG. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CONFORMATIONAL STUDY BY DYNAMIC NMR SPECTROSCOPY Principal Investigator & Institution: Noe, Eric A.; Jackson State University 1400 John R. Lynch St Jackson, Ms 39217 Timing: Fiscal Year 2002; Project Start 01-FEB-2002; Project End 31-DEC-2005 Summary: The proposed research involves the application of dynamic NMR spectroscopy and/or computational methods to studies of the conformational equilibria of a series of carboxylic acids, esters, and related compounds. The projects are expected to provide evidence that electron-releasing groups attached to the carbonyl group of an ester will increase the population of the E-isomers, and electron-withdrawing groups attached to the "ether" oxygen of an ester will also increase the stability of the E-isomers. Compounds to be studied include acetic acid, trifluoroacetic acid, oxalic, pyruvic acid, performic acid, and the cyanate esters of formic acid and acetic acid. Rotational barriers about the bond between oxygen and R' in RCO2 R' should affect the free-energy difference between E and Z conformations in esters, which a smaller barrier giving rise to a higher entropy and lower free energy. Studies of these barriers in several compounds, including tert-butyl formate and triphenylmethyl formate, are proposed. Esters occur widely in biological systems, and their properties are influenced by their conformations. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CORE--ENZYMES AND ANTIBODIES FACILITY Principal Investigator & Institution: Thomas, Paul E.; Professor; Univ of Med/Dent Nj-R W Johnson Med Sch Robert Wood Johnson Medical Sch Piscataway, Nj 08854 Timing: Fiscal Year 2002 Summary: The overall purpose of the Enzymes and Antibodies Facility Core is to provide expertise and facilities for the characterization of enzymes that are important in the biotransformation of environmental chemicals. The application provides a detailed list of specific services to be provided by the Enzymes and Antibodies Facility Core. The Enzyme and Antibody Facility Core was formed in October of 1996 by combining two pre-existing Cores, namely the Monoclonal Antibody Production and Assay Laboratory (which was directed by P.E. Thomas), and the Laboratory for Protein Purification and Characterization (which was directed by C.S. Yang). The new Core Facility is directed by Dr. Thomas, which provides continuity. Dr. Thomas will be assisted by Dr. Hong, who will oversee the Core Facility?s new role in providing expertise and resources for expressing recombinant enzymes, for analyzing genetic polymorphisms in xenobioticmetabolizing enzymes (XME?s) and for preparing DNA probes. The Enzyme and Antibody Facility Core is located in laboratories in three different buildings: the EOSHI building, the Laboratory for Cancer Research (located next to the EOSHI building) and Dr. Chada?s laboratory in the RWJMS (also located next to the EOSHI building). This Core Facility is readily accessible to members of the Center. The Enzyme and Antibody Facility Core has produced one of best, if not the best, inventory of monoclonal and polyclonal antibodies against various P450 enzymes and other xenobiotic-metabolizing enzymes (XME). The inventory is impressive not only in terms of the number of antibodies that have been prepared, but also for the degree to which these antibodies have been characterized with respect to their specificity and properties (such as whether they recognize the denatured P450 enzyme on western immunoblots, and whether they inhibit P450-dependent metabolism, a highly desirable property of such antibodies). The Enzyme and Antibody Facility Core has supported an impressive number and variety of research projects carried out by Center members. The facility was used to prepare
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recombinant P450 enzymes for studies of methyl-tert-butyl ether (MTBE) metabolism (for C.S. Yang and J.Y. Hong); to purify P450 enzymes, the inducible form of nitric oxide synthase and muconaldehyde cross-linked proteins (for P.E. Thomas, J. Laskin and G. Witz); to prepare monoclonal antibodies against heme oxygenase (for M. Iba); to provide antibodies for immunoquantitation and immunocytochemistry (for M. Iba, D. Morse, H. Lowndres, C.S. Yang, J. Landau, C. Gardner, D. Laskin and numerous outside investigators); to conduct antibody-inhibition experiments to identify the contribution of individual P450 enzymes to the metabolism of MTBE (for C.S. Yang and J.Y. Hong) and estradiol (for B.T. Zhu and A.H. Conney); and to screen for polymorphisms in the human genes encoding CYP2A6, CYP2E1, the pi and mu forms glutathione Stransferases and quinone oxidoreductase (for J.Y. Hong and S. Mohr). The Enzyme and Antibody Facility Core also provides training in a variety of immunochemical and molecular biology techniques. The Enzyme and Antibody Facility Core is used by members in each of the research cores (albeit to varying extent), and by numerous outside researchers. The application identifies a large number of future research projects that will be supported by the Enzyme and Antibody Facility Core. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CORE--OPTICS AND PHOTODYNAMIC THERAPY DOSIMETRY Principal Investigator & Institution: Potter, William R.; Roswell Park Cancer Institute Buffalo, Ny 14263 Timing: Fiscal Year 2002 Summary: The overall aim of Core B, the Optics and PDT Dosimetry Core, is to provide support for the light delivery for PDT both in the clinic and in the laboratory. This include the setup for the light delivery devices (lasers, fibers, beam splinters) for both clinical and laboratory photodynamic therapy. PDT in both the laboratory and clinic requires proper dosimetry. The Core provides equipment and personnel to support the research of the projects and works to maximize the yield of useful information. To perform this function it is necessity to understand the dosimetry of PDT. This leads an effort in modeling. The limited understanding of dosimetry as dependent on the light and a drug has been expanded through study of the QSAR data on the pyropheophorbide hexyl ether series to include a sensitive target for PDT. We intend to continue to study the dosimetry of PDT in an attempt to support and provide a testable model framework in which to understand the results of the other projects in the overall study of structure activity relationships. Core personnel will perform laser maintenance, calibration and dosimetric measurements required by the clinical and laboratory research activities of the projects. The specific aims of Core B are: i. Technical support for clinical and scientific lasers; ii. Measurement of photobleaching during therapy; iii. Measurement of the total attenuation of tumor and normal tissue in patients undergoing PDT for the treatment of skin tumors; iv. Study of the pharmacokinetics of pyropheophorbide hexyl ether and subsequent series and ALA; v. PS distributions in frozen sections of tumors and normal tissues; vi. Refining the analytic framework of PDT targeting and dosimetry. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: DEFECTIVE TRAFFICKING MECHANISMS IN A CARDIAC K+ CHANNEL Principal Investigator & Institution: Kupershmidt, Sabina; Pharmacology; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917
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Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: (provided by applicant): The Long QT Syndrome (LQTS) is a cardiovascular disorder characterized by an abnormality in cardiac repolarization leading to a prolonged QT interval on the ECG. Three of the five genetic loci known to cause the inherited form of the disease code for cardiac potassium channel subunits. One is the Human-ether-a-go-go-related-gene product (HERG) underlying the fast component of the cardiac delayed rectifier IKr. HERG-associated LQT mutations can result either in dysfunctional channels at the plasma membrane, or in incompletely processed channels retained in the endoplasmic reticulum (ER) and then targeted for degradation by ERresident quality control mechanisms. The forward trafficking of ion channels and other multimeric protein complexes can be regulated through assembly-dependent masking of specific ER retention motifs. One recently identified retention motif found in several membrane protein complexes, is 'RXR' where 'R' is arginine and 'X' can be any amino acid. Our preliminary data indicate that RXR is an important regulator of plasma membrane expression of HERG as well. We found that truncation of 147 amino acids from the distal C-terminus of HERG results in the loss of IKr However, IKr could be restored by deleting an RXR signal immediately upstream of the truncated C-terminus. The central hypothesis of our proposal is that the C-terminus of HERG influences IKr by controlling the rate of HERG trafficking through RXR ER retention signals. Thus, Cterminal LQT truncation mutations reduce the number of HERG channels at the membrane because they expose consensus RXRs recognized by the ER quality control system. To test this hypothesis, we have formulated three Specific Aims: 1. To test whether the exposure an RXR signal in HERG C-terminal LQT mutations leads to an IKr defect due to ER retention. We will determine the effect on HERG trafficking of eight RXR signals in the C-terminus. We will further test whether those RXRs cause defective trafficking of associated downstream LQT mutations. 2. To test if decoy peptides can rescue RXR-dependent ER retention mutants. Following up on our findings that RXRdependent intracellular retention of HERG can be reversed by treatment with specific peptides, we will develop peptide-based approaches to alleviate ER retention defects of HERG LQT mutations. 3. To identify the mechanism that permits HERG trafficking. We will investigate the role played by the HERG distal C-terminus in masking an upstream RXR, whether shielding of the RXR is accomplished by an intra- or an intermolecular mechanism. This study will explain important aspects of the biogenesis, intracellular processing, and trafficking of an important cardiac K+ channel. We will develop novel therapeutic strategies designed to correct intracellular processing steps of HERG and possibly other plasma membrane proteins that suffer from defects caused by the same mechanism. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DETERMINANTS OF CARDIAC REPOLARIZATION Principal Investigator & Institution: January, Craig T.; Professor of Medicine; Medicine; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2002; Project Start 01-APR-2000; Project End 31-MAR-2005 Summary: The rapidly activating delayed rectifier K- current (IKr), and the human ether-a-go-related gene (HERG) thought to encode it, play a key role in cardiac repolarization, and mutations in HERG cause congenital long QT syndrome (LQT-2). HERG, IKr and LQT-2 will be studied using molecular and electrophysiological techniques in transfected HEK293 cells and native rabbit myocytes. Specific aim 1 is to study cellular mechanisms of ion channel processing of HERG wild type and LQT-2 mutant channels. We have previously identified normal steps in the processing
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mechanism for HERG protein as well as abnormal processing for some LQT-2 mutants. We will extend these observations by testing three hypotheses: a) the failure of some LQT-2 mutants to function normally involves defects in multiple processing steps, b) coexpression of the minK or minK-related subunits modifies HERG wild type and LQT-2 protein trafficking, c) co-expression of wild type HERG protein with minK LQT mutations (LQT-5) alters the expression of HERG current. We will identify the steps where this occurs. Specific aim 2 is to study cell processes that modify HERG protein production and degradation. We will test the hypothesis that LQT-2 mutant proteins are degraded rapidly, compared with wild type HERG protein, which is of particular importance for newly described LQT-2 mutant channels that form functional channels. Such an increased turnover, if demonstrated, would be a novel mechanism for the expression of the LQT-2 phenotype. We will also test the hypothesis that N- linked glycosylation is a determinant of the stability of expressed HERG protein. We will test the effects of temperature as a determinant of the success and efficiency of trafficking of LQT-2 mutant channels to the surface membrane, and we will identify additional cell processes that might modify HERG protein trafficking. Specific aim 3 is to study the mechanisms of co- assembly of wild type HERG with LQT-2 mutant channel subunits. We will test the hypothesis that protein trafficking abnormalities alter expression of the dominant negative effect. We will test what role, if any, minK, minK-related, and minK mutant (LQT-5) channels have in modifying this. This research will increase our knowledge of molecular mechanisms of ion channel processing and function of HERG and more generally will have implications for all ion channels. More specifically it will have particular relevance to mechanisms of the human disease LQT-2. Elucidating mechanisms in these areas in important in developing new strategies for understanding normal and abnormal arrhythmogenesis and for new strategies for anti-arrhythmic therapies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TREATMENT
DEVELOPMENT
OF
AN
ORAL
DRUG
FOR
SMALLPOX
Principal Investigator & Institution: Painter, George R.; Chimerix, Inc. 4401 Eastgate Mall, Ste 1058 San Diego, Ca 92121 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 28-FEB-2008 Summary: (provided by applicant): An orally active antiviral drug for the treatment of smallpox infection resulting from biowarfare or bioterrorism is needed as an alternative therapy for the estimated 40 million Americans who cannot be safely vaccinated. Although Cidofovir (CDV, Vistide(r)) inhibits poxvirus replication in cell culture and in mouse models, it must be administered by intravenous infusion and has shown a high level of nephrotoxicity. Novel, lipid ether conjugates of CDV have recently been described that inhibit smallpox replication in cell culture, and prevent mortality in mouse models of poxvirus infection after oral dosing. In addition, tissue distribution experiments indicate that the lipid-CDV conjugates are not deposited in the kidney, suggesting the possibility of diminished nephrotoxicity. This proposal includes the work necessary to choose a development candidate for the treatment of smallpox from two lead lipid-CDV conjugates (HDP-CDV and ODE-CDV), and to file an IND and conduct a Phase I clinical trial to assess the safety, tolerability and pharmacokinetics of this candidate. Specific aims and milestones that represent critical activities and key decisions in this proposal are: 1. Synthesize and characterize adequate drug substance to complete Aims 2 through 4. Characterization will include preformulation studies. Alternative routes of synthesis will also be examined. 2. Compare the pharmacokinetics
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and organ distribution of HDP-CDV and ODE-CDV in mice after oral dosing. 3. Compare the toxicological profiles of oral HDP-CDV and ODE-CDV in a 14-day dose range finding study in mice. 4. Compare the oral efficacy of HDP-CDV and ODE-CDV in mice infected with vaccinia, cowpox and ectromelia virus. The data generated in aims 1 through 4 will be used to choose which candidate to carry into full development (first milestone). At this point a pre-IND meeting will be requested with the FDA to discuss the proposed development plans. 5. Complete absorption, distribution, metabolism and elimination studies necessary to file an IND. 6. Produce cGMP drug substance for use in toxicology studies and Phase I clinical trials. 7. Conduct GLP safety pharmacology and toxicology studies necessary to file an IND. 8. Evaluate the efficacy of the lead compound in the cynomolgus monkey model of smallpox infection in collaboration with USAMRIID. Under the animal efficacy rule (Federal Register 67:37988-98, 2002), this study could provide the efficacy data necessary for FDA approval. 9. Manufacture prototype formulations, and produce cGMP clinical trials material. A Phase I protocol will be finalized in collaboration with the NIAID, and an IND will be filed with the FDA (second milestone). Upon FDA approval, a Phase I trial will be initiated to evaluate the safety, tolerability and pharmacokinetics of a single, escalating dose in human volunteers. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DIMANDELIC ACID ETHERS AS TOPICAL MICROBICIDES FOR HIV Principal Investigator & Institution: Klotman, Mary E.; Professor and Chief; Medicine; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2002; Project Start 26-SEP-2001; Project End 31-JUL-2005 Summary: (provided by applicant): There are 16,000 new cases of HIV infection everyday with over 36.1 million people living with HIV/AIDS today. Worldwide, the vast majority of new infections with HIV are acquired through sexual transmission, the major route of transmission to the 16.4 million infected women. Compounds that are developed for topical use to prevent HIV transmission (microbicides) offer a promising and perhaps more easily realized alternative to development of an effective vaccine. However, recent disappointing experience with a widely used contraceptive, nonoxynol-9, emphasizes the need for extensive preclinical evaluation of compounds for antiviral efficacy and toxicity prior to their widespread use as a topical microbicide. This Program Project Grant will focus on the development of a novel class of candidate compounds based on the parent compound, sodium dimandelic acid ether (SAMMA). SAMMA has antiviral activity against laboratory-adapted and primary isolates of HIVas well as herpes simplex virus (HSV), the sexually transmitted disease that is a major cofactor for HIV, without apparent cytotoxicity. It inhibits sperm function and prevents fertilization in the rabbit. Through the rational design of compound derivatives synthesized by a core laboratory, critical structure/function relationships will be determined for this class of compounds in studies designed to define the full HIV (Projects 1 and 3) and HSV (Projects 2 and 3) inhibitory spectrum, cytotoxicity (Projects 1,2,3 and 4), mechanism(s) of inhibition (Projects 1 and 2) and contraceptive potential (Project 4). Mechanism studies will extend preliminary observations that the parent compound works at an early step in viral entry for both HIV and HSV by carefully studying viral and viral glycoprotein interactions with cell membrane ligands involved in attachment and entry (Projects 1 and 2). Initial cell interactions will be examined by using primary epithelial cells, T -cells, macrophages and dendritic cells. To more closely simulate the anatomical, physiologic and immunological environment of the genital
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mucosa, Project 3 will examine the efficacy in cervical lavage and seminal fluid as well as efficacy in human mucosal explant cultures and in a murine model of HSV. Lastly, through co-culture of HIV and HSV in primary cells and in the cervical mucosal explant culture, the added benefit of targeting both viruses with topical microbicides will be defined. The proposed comprehensive evaluation of this class of compounds will determine if it should progress to clinical evaluation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DISTINCTION AMONG EIGHT OPIATE DRUGS IN URINE BY GAS CHROMATOGRAPHIC Principal Investigator & Institution: Nowatzke, William; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002 Summary: Opiates are commonly abused substances, and forensic urine drug-testing for them involves an immunoassay screen and gas chromatographic/mass spectrometric (GC/MS) confirmation. There are also medical reasons to test urine for opiates, and confirmation procedures other than GC/MS are often used for medical drug-testing which are more compatible with the demands of clinical services and which identify a wider range of opiates than those in standard forensic batteries. One such procedure involves thin-layer chromatographic (TLC) analysis of opiate derivatives and can distinguish eight clinically encountered opiates, including morphine, acetylmorphine, hydromorphone, oxymorphone, codeine, dihydrocodeine, hydrocodone, and oxycodone. Medical drug-testing results are sometimes challenged by patients, causing physicians to request additional confirmation of the identified opiates. To our knowledge, no previous report examines all opiates specified above in a single GC/MS pr ocedure, but we find that they can be distinguished by GC/MS analyses of trimethylsilyl (TMS) ether derivatives, the mass spectra of which contain prominent molecular ions. Inclusion of deuterium-labeled internal standards permits quantitation of each of the eight opiates in urine. The GC/MS assay is linear over a concentration range which spans the TLC cutoff level, and coefficients of variation of 10% or less at concentrations below the TLC cutoff are achieved by for all opiates specified above except for oxymorphone and oxycodone, which exhibit coefficients of variation of 1819%. This procedure has proved useful as a third-stage identification step for medical drug-testing specimens in which results from prior immunoassay and TLC analyses were challenged. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: DNA CROSS-LINKING BY DIEPOXYBUTANE Principal Investigator & Institution: Tretyakova, Natalia Y.; Medicinal Chemistry; 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-2007 Summary: (provided by applicant): 1,2,3,4-Diepoxybutane (DEB) is an important metabolite of 1,3-butadiene, a major industrial chemical and environmental pollutant found in automobile exhaust and cigarette smoke. DEB is a bifunctional alkylating agent classified as "reasonably anticipated to be a human carcinogen" (U.S. Department of Health and Human Services). DEB is by far the most genotoxic metabolite of 1,3-BD, with mutagenic potency two orders of magnitude higher than that of butadiene monoepoxide. The cytotoxicity and genotoxicity of DEB is thought to be a result of its bifunctional nature. DEB can form DNA-DNA cross-links by simultaneously alkylating
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two nucleobases within the DNA duplex. Depending on their structure, the cross-linked lesions can induce cytotoxic or promutagenic effects. Although N7-G-N7-G DEB crosslinks were first isolated from DNA over 40 years ago, no detailed structural information for these lesions is available. Gel electrophoresis studies have provided evidence for DEB cross-linking at adenine nucleobases, but did not allow structural identification of these lesions. The overall goal of the proposed research is to evaluate the role of DNADNA cross-linking in the genotoxic effects of diepoxybutane and 1,3-butadiene. We will investigate DEB-induced DNA cross-linking by a combination of mass spectrometry, molecular biology, and molecular modeling. First, we will structurally characterize DEB-DNA cross-links and determine sequence preferences for their formation. Next, we will evaluate the hydrolytic stability of DEB-DNA cross-links and their recognition by the E. coli UvrABC repair complex. Finally, the formation of DEB-DNA cross-links in rodent tissues following DEB exposure will be quantified by capillary HPLC-ESIMS/MS methods. The results of this research will provide valuable information on the molecular mechanisms underlying the genotoxic activity of diepoxybutane. These findings will be extended to other bifunctional electrophiles to explain the observed differences in their biological activity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: EFFECTS OF COCAINE ON CARDIAC ION CHANNELS Principal Investigator & Institution: O'leary, Michael E.; Pathology, Anat/Cell Biology; Thomas Jefferson University Office of Research Administration Philadelphia, Pa 191075587 Timing: Fiscal Year 2002; Project Start 05-MAR-2002; Project End 29-FEB-2004 Summary: The experiments outlined in this proposal will examine the medical and health consequences of cocaine abuse, which has been identified as NIDA as a serious problem in this country. Since 1998 the use of cocaine in the US has risen, in part due to the low cost and ample supply. Paralleling this trend has been an increase in the rate of emergency room admissions related to cocaine use and cocaine-related deaths. The exact causes of the cocaine-related fatalities in most cases are not known but many are believed to result from cardiac arrhythmias, the leading cause of death associated with cocaine abuse. In humans, cocaine is known to increase heart rate and blood pressure, effects that are primarily attributable to the sympathomimetic actions of this drug. Cocaine also produces significant changes in cardiac electrophysiology, decreasing the conduction and slowing the repolarization following an action potential. These electrical disturbances are believed to result from a direct anesthetic effect of cocaine on cardiac ion channels. In this proposal, we will investigate the cocaine sensitivity of sodium and potassium channels important for initiating and terminating the cardiac action potential. Inhibiting these channels disrupts the coordinated electrical activity of the heart, a wellknown risk factor for the generation of ventricular arrhythmias. A combination of electrophysiology and molecular biology will be used to investigate the mechanisms of inhibition of these channels and to identity sites important for cocaine binding. The human cardiac sodium channel (hH1) and the human ether-a-g-go delayed rectifier potassium channel (HERG) will be expressed in mammalian cells and the resulting currents recorded using patch clamp techniques. Our data indicate that cocaine binding to these channels is state-dependent, with cocaine preferentially binding to the open and inactivated channels. Inactivation-deficient mutants of hH1 and HERG will be constructed to investigate the contribution of inactivation gating to cocaine binding and to facilitate the measurement of open-channel block. Additional mutants with the sixth transmembrane spanning segments, the putative anesthetic binding sites of these
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channels, will also be investigated. The proposed studies ill provide insight into the mechanisms underlying the cocaine-induced changes in cardiac electrophysiology and the cardiotoxic effects of this drug. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: FUNCTION
ENDOGENOUS
CANNABINOIDS
AND
BRAIN/IMMUNE
Principal Investigator & Institution: Martin, Billy R.; Louis/Ruth Harris Professor and Chair; Pharmacology and Toxicology; Virginia Commonwealth University Richmond, Va 232980568 Timing: Fiscal Year 2002; Project Start 15-SEP-1995; Project End 30-JUN-2007 Summary: (provided by applicant): There is now convincing evidence that an endogenous cannabinoid system exists in both the brain and periphery. The isolation and identification of endogenous cannabinoids, such as anandamide, 2-arachidonyl glycerol and noladin ether, have intensified efforts to understand the functional significance of endogenous cannabinoids. It was the discovery of the endocannabinoids that led to the formation of the current program project. Our major goal continues to be the establishment of the role of the endocannabinoid system in normal physiological processes as well as in disease states. This understanding is particularly relevant to the etiology of cannabis abuse as well as identification of therapeutic uses of cannabinoids. Cannabinoid research has produced tremendous advances in recent years; however, as is often the case, increased knowledge reveals the complexity of a biological system. We are now assured that endocannabinoids produce some of their effects through known cannabinoid receptors, yet they are also capable of acting at as-yet-unidentified sites. It is unclear whether endocannabinoids and the plant-derived tetrahydrocannabinoid (THC) activate endocannabinoids in an identical fashion. The synthesis, cellular uptake and metabolic degradation are all crucial for the actions of the endocannabinoids, but these processes are not yet fully understood. There are numerous suggestions that endocannabinoids are involved in neurodegenerative/neurological disorders, yet the mechanism responsible for these putative actions remain to be elucidated. The purpose of this proposal is to address the above questions using this multidisciplinary program that consists of five research projects and an administrative core. Each P.I. is an experienced researcher who will make a unique contribution. Professor Mechoulam proposes to isolate and identify other endogenous substances, conduct a synthetic program, and assess cannabinoids as neuroprotective and anti-inflammatory agents. Dr. Razdan will continue to provide novel and innovative probes to the other members of the program project. Research teams led by Drs. Martin and Pertwee will coordinate their pharmacological evaluations of endogenous ligands and their analogs in order to further the structure-activity relationships of agonists and antagonist at the CB1 receptor, establish the structure-activity relationships for non-CB1 cannabinoid receptors, investigate cannabinoid actions at vanilloid VR1 receptors and develop selective inhibitors for fatty acid amidohydrolase and the anandamide membrane transporter. Dr. Dewey will determine which signal transduction pathways are critical for endocannabinoid and exocannabinoid actions. This highly integrated research team will continue to work closely together toward the goal of defining the biological roles of endocannabinoids. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ENDOTHELIAL PLASMALOGENS
CELL
HYPOXIA
Studies
21
ROLE
OF
TOLERANCE:
Principal Investigator & Institution: Farber, Harrison W.; Professor; Medicine; Boston University Medical Campus 715 Albany St, 560 Boston, Ma 02118 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2007 Summary: (provided by applicant): We have demonstrated that endothelial cells (EC) are highly resistant to the injurious effects of acute and chronic hypoxia and have theorized that in EC, as in other hypoxia tolerant organisms or tissues, multiple factors contribute to their remarkable hypoxia tolerance. Among these potential factors are plasmalogens, a subset of "vinyl ether" phospholipids that are found within cellular membranes, constitute.18% of the total phospholipid mass in humans and have been identified as potent endogenous antioxidants. We have developed substantial evidence that plasmalogens exist in human and bovine pulmonary artery EC (HPAEC and BPAEC) and human brain microvascular EC and that increased plasmalogen levels correlate with resistance of human EC to the injurious effects of hypoxia and reactive oxygen species (ROS). Plasmalogen protection appears stress specific in that HPAEC with increased levels of plasmalogen are not protected against other common cellular stresses, such as heat shock or glucose deprivation. These findings suggest that plasmalogens can contribute to the protection of EC against specific cellular stresses; to investigate this hypothesis further, we will: 1) Define the role of plasmalogens in human EC survival during hypoxia: by establishing a relationship between plasmalogen levels and cell damage during exposure to hypoxia through modulation of plasmenylcholine content; by determining plasmalogen loss in normoxia and during exposure to hypoxia; by determining chemical breakdown, metabolic products of plasmalogens and/or plasmalogen-dependent eicosanoid products in normoxia and during hypoxia to determine if plasmalogens act as scavengers of ROS or as precursors for second messengers. 2) Define the stress-specific protection of increased human EC plasmalogen content: by comparing cell damage during exposure to hypoxia and other cellular stresses (exposure to ROS, change in redox potential, increased temperature, glucose depletion, etc): by determining the association between plasmalogens and cellular oxidants, cellular oxidases and antioxidants. Once the biochemistry of plasmalogens in EC has been clarified, studies to determine their biological importance can be undertaken. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ETHER LINKED LIPIDS AND SIGNALING IN BREAST TUMOR CELLS Principal Investigator & Institution: Wykle, Robert L.; Professor; Biochemistry; Wake Forest University Health Sciences Winston-Salem, Nc 27157 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-MAR-2005 Summary: (applicant's abstract): The membranes of mammalian cells are composed of an array of phospholipid species that are now recognized to function as a diverse source of lipid mediators. These mediators function as both intercellular and intracellular signals and are key components of numerous signaling cascades. The levels of etherlinked phospholipids vary greatly among cells; but, in a number of cells they are known to serve as an important reservoir of arachidonic acid and as a precursor of platelet activating factor (PAF), one of the most active mediators known. The ether bonds are not hydrolyzed by phospholipases, and distinct pathways are required for their synthesis and turnover. We recently completed an analysis of the subclass composition
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of the choline- and ethanolamine-containing phosphoglycerides (PC and PE) of four human breast tumor cell lines and found that the two cell lines that are estrogen receptor-positive (ER+), MCF-7 and T47D, contain only traces of alkyl or alk-1-enyl (plasmalogens) species in PC and similarly low levels in FE. In contrast the estrogen receptor-negative (ER-) cell lines, MDA 231 and MDA 435, contain 22 and 13 mol percent respectively of the alkyl subclass in PC and >30 mol percent plasmologen in the PE. Primary breast tumors contained higher ether content than the surrounding normal tissues. We have shown that the ER- MDA 231 cells can synthesize PAF. Breast tumor cells are known to contain phospholipase D that can be activated to convert PC to phosphatidic acid and diglycerides. PAF is known to promote cell growth and angiogenesis, whereas lyso PA promotes cell growth and tumor cell invasiveness; PA is believed to activate Raf1 and Ras. It is our hypothesis that the more invasive and metastatic ER- cells will produce alkyl-linked species of these mediators, along with PAF, and that they will be more persistent and potent mediators than their ester-linked counterparts and thus contribute to the aggressiveness of the ER- cells. Our specific aims are: (1) to measure the production of ether-linked mediators in estrogen receptorpositive and -negative breast tumor cells and compare our findings in more normal MCF I OA cells; (2) to determine the pathways by which alkyl acyl-GPC is converted to products in the breast tumor cells and to elucidate the mechanisms by which the pathways are controlled; and (3) to determine the action of ether-linked mediators on key signaling pathways of the estrogen receptor-positive and estrogen receptor-negative breast tumor cells and to measure their effect on cell growth. The proposed studies promise to advance our understanding of the role of the ether-linked lipids in tumor cells at the molecular level and could lead to new therapeutic approaches and targets. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ETHER PATHOPHYSIOLOGY
LIPIDS,
EICOSANOIDS
AND
LUNG
CELL
Principal Investigator & Institution: Henson, Peter M.; Professor; National Jewish Medical & Res Ctr and Research Center Denver, Co 80206 Timing: Fiscal Year 2002; Project Start 30-SEP-1985; Project End 31-AUG-2005 Summary: Lipid mediators include a wide variety of enzymatic and non- enzymatically derived oxidation products from phospholipids and unsaturated fatty acids. Here we will focus particularly on a newer arena of action for such molecules, namely suppression and resolution of pulmonary inflammation. Specific objectives include: Characterization of the nature and mechanism of action of oxidized phospholipids and PAF suppressing pro-inflammatory mediator production from macrophages in vitro and during resolution of pulmonary inflammation. Structural and functional investigation of the products resulting from oxidation of phospholipids along with a determination of the chemical mechanisms of oxidant action. The production of oxidized phospholipids in human pulmonary disease will be investigated by mass spectrometric analysis of materials exhaled from patients. Detailed study of cPLA2, an enzyme critically involved in the first step of lipid mediator production. Emphasis will be placed signal pathways leading to its phosphorylation, activation and translocation to the membrane. Analysis of the role played by a family of phospholipid scramblases in transbilayer movement of phospholipids across the cell membrane. Investigation of integration signaling via chemoattractant G protein-liked receptors and tyrosine phosphorylated membrane receptors such as FcgammaRIIa. In particular the studies will address the role of scaffold proteins and a possible central role in neutrophil signaling for the FcR gamma chain. The program brings together investigators
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experienced in cell biology, signal transduction, inflammation, pharmacology, physiology, lipid biochemistry, analytical chemistry, and clinical pulmonary medicine. This combination of structural, cellular, and physiologic approaches to a detailed analysis of the effects of lipid mediators in the lung is felt to represent an important step in developing the ability to selectively control pro- and anti-inflammatory lipid mediators, and thereby, influence the outcome of pulmonary inflammation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ETHER-LINKED DIGLYCERIDES AND PROTEIN KINASE C ISOTYPES Principal Investigator & Institution: Kester, Mark; Interim Chair and Professor; Pharmacology; Pennsylvania State Univ Hershey Med Ctr 500 University Dr Hershey, Pa 17033 Timing: Fiscal Year 2002; Project Start 01-JUN-2001; Project End 31-MAY-2005 Summary: Signaling mechanisms regulating vascular smooth muscle mitogenesis are being clearly elucidated and exploited for potential therapeutic benefit. To date however, there are still no effective therapeutics designed to control dysregulated vascular smooth muscle proliferation during inflammatory pathologies. Our laboratory is focused on identifying and characterizing endogenous lipid-derived second messengers that inhibit pro-mitogenic signaling cascades regulated through protein kinase C (PKC) and phosphoinositide-3-kinase (PI3K). Using in vivo and in vitro model systems, we have demonstrated that interleukin-1-generated ether-linked diglycerides (ether-DG) inhibit smooth muscle cell mitogenesis. These novel phospholipid-derived second messengers mimic the effect of interleukin-1 to inhibit cellular proliferation. As ether-DGs are analogues of diacylglycerol (DAG), a co- factor for growth factorstimulated PKC activation, we hypothesize that ether-DGs can competitively antagonize DAG-activated PKC as a mechanism to diminish smooth muscle mitogenesis. We now demonstrate that DAG analogues enhance PI3K activity. Thus, we also hypothesize that ether-DGs diminish cellular proliferation by competitively antagonizing DAGstimulated PI3K activity. In Specific Aim 1, the biochemical mechanisms by which etherDGs inhibit PKC delta and epsilon activation will be investigated in vascular smooth muscle cells. In Specific Aim 2, the role of ether-DGs to inhibit mitogenesis through PKC-dependent or -independent inhibition of P13K will be investigated. These studies will establish ether-DGs as potential therapeutics to limit abnormal vascular smooth muscle cell growth observed in atherosclerotic and restenotic lesions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: EVALUATION OF NM404 IN ENDOGENOUS BREAST CANCER MODELS Principal Investigator & Institution: Weichert, Jamey P.; Assistant Professor; Radiology; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2005 Summary: (provided by applicant): The overall goal of this proposal is to evaluate the tumor imaging characteristics of NM404, a new tumor-selective scintigraphic imaging agent, in two endogenous murine breast cancer models. One model will allow evaluation of uptake by hyperplastic and neoplastic lesions, the other will allow studies on metastatic lesions. NM404, a second-generation phospholipid ether analog, has displayed remarkable tumor selectivity in 21/21 xenographic primary and metastatic rodent tumor models, but has not been evaluated in a spontaneous mammary
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adenocarcinoma model. The prevailing hypothesis of this approach is that phospholipid ethers become trapped exclusively in tumor cell membranes because of their inability to become metabolized and cleared. Thus, the differential clearance rates of phospholipid ethers from normal cells versus tumor cells form the basis of this concept. The specific goals of this proposal are 1) to assess whether radioiodinated NM404 can noninvasively distinguish between hyperplastic and neoplastic breast lesions and 2) to evaluate its potential to accurately identify metastases. Lesion uptake will be quantitated by in vivo tissue distribution studies and subsequently by both scintigraphic, and high-resolution microPET imaging studies. These functional scintigraphic and PET images will be correlated anatomically with CT scans obtained on a high-resolution microCT scanner and with histopathology. Results obtained in a variety other tumor models indicate that NM404 is sequestered and selectively retained by viable tumor cells and therefore localizes in both primary and metastatic lesions regardless of location including those found in the lymph nodes. If it displays sufficient tumor cell selectivity in these endogenous breast cancer models, then it can potentially serve as an effective imaging agent capable of providing accurate and noninvasive diagnostic and staging information in human breast cancer patients. A physician-sponsored IND has been issued to evaluate radioiodinated NM404 in human prostate cancer patients. Positive results obtained from this exploratory grant are expected to stimulate rapid transition into human breast cancer patients. Moreover, sufficient tumor uptake and retention will stimulate a formal examination of this agent as a radiotherapeutic agent due to its extremely long tumor retention properties. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: FLUORESCENT CHEMOSENSORS FOR CARBOHYDRATES Principal Investigator & Institution: Heagy, Michael D.; Chemistry; New Mexico Inst of Mining & Technology 801 Leroy Pl Socorro, Nm 87801 Timing: Fiscal Year 2002; Project Start 01-SEP-1998; Project End 31-AUG-2005 Summary: (provided by applicant) Because of their potential for nondestructive detection and cell permeability, fluorescent chemosensors for carbohydrates can play a critical role in glycobiology. The objectives of this continuing research program involve the application of molecular clefts as fluorogenic sensors suitable for biological studies of monosaccharides and carbohydrate derivatives. The scope of these investigations build on previous results in which novel signal transduction mechanisms were identified and shown to proceed by substituent changes of the fluorophore component. In an effort to significantly augment the fluorescence signal intensity over conventional Photoinduced Electron Transfer (PET) fluorescence as well as red-shift this response to longer wavelength emission, new sensors are proposed which utilize Resonance Energy Transfer fluorescence (FRET). This research plan begins by investigating intermolecular energy transfer between two donor/acceptor Forster-pairs. Given the calculated distance of separation (14 Angstroms) for one saccharide complexed between two receptor components, well known donor/acceptor dyes that coincide with this Forster distance such as diethylaminocoumarin and fluorescein are incorporated into the sensor design. Subsequent plans utilize rigid aromatic diimide chromophores as nonfluorescent molecular scaffolds to which recognition groups are appended via benzylimide bonds. Cooperative binding of analyte between receptor sites is expected to decrease torsional motion and enhance energy transfer rates between coupled FRET cassettes. In addition to investigating simple monosaccharides via FRET based sensors, carbohydrate derivatives relevant to glucose metabolism and cell membrane carbohydrates are also targeted for fluorimetric detection. Specifically, glucose-6-
Studies
25
phosphate and N-acetylneuraminic acid via 2-point bifunctional binding sites from phenylboronic acid and guanidinium receptors. Second messenger myo-Inositoltriphosphate via bis- guanidinium groups and glucosamine sensing through crownether coordination are also included in these fluorometry studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: FORMULATION OF COMBINATION MICROBICIDES Principal Investigator & Institution: Rohan, Lisa C.; Magee-Womens Hlth Corp Pittsburgh, Pa Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Description (provided by applicant): The overall goal of this proposal is to develop a formulated combination microbicide which will prevent the spread of human immunodeficiency virus (HIV) both vaginally and rectally utilizing multiple protective factors which inactivate the virus at different stages in its replication cycle. Inhibition of HIV attachment to the CD4 cellular receptor will be accomplished by formulating plantderived flavonoids with sulfated polysaccharides (carrageenans). There will therefore be redundancy built into the microbicide to inhibit HIV binding to its cellular receptor. Virucidal compounds, which destroy the viral envelope, will also provide redundant protection from infection. Both the antiviral ether lipid 1-0-octylsn- glycerol and citric acid will destabilize the envelopes of viral particles. Furthermore, the HIV reverse transcriptase will be inactivated by both antiviral flavonoids and a non-nucleoside reverse transcriptase inhibitor (Dr. Parniak, Project 1). Herpes simplex virus (HSV) will also be targeted by flavonoids, carrageenans, 1-0-octyl-sn-glycerol and citric acid to reduce genital ulceration and consequently the transmission of HIV to a greater extent than inactivating HIV only. Methods will be developed to quantify antiviral agents at each step in the pre-formulation and formulation process and physical and chemical pre-formulation data including solubility, stability, partitioning, and permeability data will be developed as part of these studies. Once active agents have been selected, their compatibility and toxicity with normal vaginal microflora and local tissues in both the isolated and formulated state will be determined. Following the initial formulation and development of a combination microbicide product, the microbicide will be optimized to maximize each antiviral mechanism and minimize toxicity in an iterative manner. The final formulated product will undergo stability testing, and product assessments will be made to ensure that the product has appropriate physical, chemical, microbiological, and antiviral properties during its shelf life. This project contributes to the program by producing new combinations of formulated microbicides based upon inhibition of viral replication using multiple and redundant antiviral mechanisms. Formulated combination microbicides produced in this project will be evaluated in vitro against HIV (Dr. Parniak, Project 1; Dr. Gupta, Project 2) and normal vaginal flora (Microbiology Core, Dr. Hillier), and as well as in humans (Dr. Landers, Project 4). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: FUNGICIDAL AND NEUROTOXIC MARINE NATURAL PRODUCTS Principal Investigator & Institution: Rainier, Jon D.; Associate Professor; Chemistry; University of Utah Salt Lake City, Ut 84102 Timing: Fiscal Year 2003; Project Start 01-JAN-1998; Project End 31-DEC-2006 Summary: (provided by applicant): Natural products that have been isolated from the marine environment show promise as pharmacological agents. However, because of the supply problems associated with their isolation, a thorough evaluation of their
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properties requires their chemical synthesis. This proposal describes the chemical synthesis of three biologically important marine natural products. The first of these is gambierol, a marine ladder toxin associated with ciguatera poisoning. The second is armatol A, a polycyclic ether that has demonstrated interesting cytotoxicity in preliminary testing. The third is halichondrin B, a potent anticancer agent that has been recommended for preclinical trials in spite of its short supply. Gambierol, armatol A, and halichondrin B have in common a fused polycyclic ether skeleton. This proposal outlines the chemical synthesis of these agents centered around carbon-glycosides. As carbon-glycosides have been demonstrated to be important, not only in synthetic chemistry, but also in medicinal chemistry, we believe that this strategy might have broad implications. In addition, by coupling our carbon-glycoside forming chemistry with efficient annulation protocols, we believe that we will be able to efficiently generate polycyclic ethers including the natural products listed above. Furthermore, these efforts will undoubtedly lead to the generation of a number of interesting and biologically important analogs whose properties will be evaluated. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: RECEPTORS
GENERAL
ANESTHETIC
INTERACTIONS
WITH
GABA-A
Principal Investigator & Institution: Akabas, Myles H.; Associate Professor; Columbia University Health Sciences New York, Ny 10032 Timing: Fiscal Year 2002 Summary: (taken from the application): The gamma-aminobutyric acid Type A (GABAA) receptors form ligand-activated, anion-selective channels. They are the primary, fastacting, post-synaptic receptors for GABA, the major inhibitory neurotransmitter in the central nervous system. Current hypotheses suggest that GABA-A receptors may be a primary target for the actions of many general anesthetics. At low concentrations general anesthetics, such as propofol, etomidate, barbiturates and enflurane, potentiate GABA-induced currents, whereas at higher concentrations these anesthetics directly activate GABA-A receptors but do not appear to bind in the GABA binding sites. In order to understand the molecular basis of anesthetic action it is necessary to define the binding sites for these drugs, the conformational changes that occur following binding and the structure of the binding site. Mutations in the alpha-1 subunit of Ser270 (M2) and Ala291 (M3), residues near the extracellular ends of the M2 and M3 membranespanning segments, altered the efficacy of the inhaled ether anesthetics (enflurane and isoflurane) to potentiate GABA-induced currents. Whereas, mutations of the aligned residues in the beta subunits altered the efficacy of intravenous anesthetics (etomidate, barbiturates and perhaps propofol) to potentiate GABA-induced. It is uncertain whether these residues are part of anesthetic binding sites or are part of the transduction pathway. Cysteine substituted for these residues in the alpha-1 subunit were accessible to react with the negatively charged, sulfhydryl-specific reagent, pCMBS, applied extracellularly indicating that they are on the water-accessible surface of the protein. If these residues form a binding site(s) for anesthetics then anesthetics should protect the Cys-substituted mutants from modification by pCMBS. The ability of anesthetics to protect these Cys-substitution mutants will be determined. It was previously shown that Cys substituted for six of seventeen residues in the M3 segment were accessible to react with pCMBS. Reaction at four of the six positions was state dependent, it only occurred in the presence of GABA. It will be determined whether potentiating or directly activating concentrations of anesthetics induce changes in the accessibility of M3 segment substituted Cys mutants similar to those induced by GABA. Finally, if the M2
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and M3 membrane-spanning segments participate in forming an anesthetic binding site or interactions between them are important for transduction of anesthetic effects then they should be in close proximity. Disulfide bond formation will be used as a molecular ruler to determine the relative proximity, mobility and orientation of the M2 and M3 segments within a single subunit. The successful completion of this proposal could provide new insights into the binding and transduction of anesthetic effects in the GABA-A receptors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENERAL ANESTHETICS AND NACCHOR AGONIST AFFINITY Principal Investigator & Institution: Raines, Douglas E.; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-MAR-2005 Summary: (Verbatim from the applicant's abstract) The broad. Iong-term objective of this project is to define the molecular mechanisms by which general anesthetics act on protein targets in the CNS and periphery. This will guide the development of new anesthetic compounds possessing fewer side effects. The overall aim is to disentangle the effects of general anesthetics on agonist binding, channel gating kinetics, and agonist-induced desensitization in the best-characterized model ligand-gated ion channel (LGIC), the Torpedo nicotinic acetyicholine receptor (nAcChoR), and to identify the physicochemical features of anesthetics that govern their action on each kinetic step. The overall hypothesis is that general anesthetics act on the nAcChoR in a structurally specific manner because anesthetic binding affinity is strongly influenced by attractive electrostatic and repulsive steric interactions between anesthetics and their protein binding sites. The specific aims are: Aim 1: (1) to test the hypothesis that electrostatic (dipolar, quadrupolar, and/or hydrogen bonding) interactions between general anesthetics and the nAcChoR enhance binding to functionally important sites on this receptor and (2) to identify the kinetic step(s) leading to nAcChoR channel opening that are altered by general anesthetics to determine whether an anesthetic's molecular volume or chemical class governs its action. Aim 2: (1) to test the hypothesis that small general anesthetics increase nAcChoR's rate constant for desensitization by binding to a protein binding site that sterically limits the binding of large anesthetics and (2) to test the hypothesis that general anesthetics stabilize the open channel state and increase the rate constant for desensitization by binding to the same small receptor binding site. The proposed studies will lead to a better understanding of the fundamental interactions between anesthetics and their targets in the CNS and periphery. The nAcChoR was chosen as the experimental model because its function is far better defined than that of any other LGIC, allowing one to interpret anesthetic actions within the framework of a well-established and robust kinetic model. The method used to define anesthetic actions on the nAcChoR is a new rapid sequential mixing stopped-flow fluorescence assay developed and validated by the PI that can assess anesthetic actions on agonist binding, channel gating, and desensitization kinetics without the potentially confounding effects of anesthetic-induced channel blockade. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: GENETICS OF DROSOPHILA ETHER A GO GO RELATED GENE POTASSIUM CHANNELS Principal Investigator & Institution: Massa, Enrique; Associate Professor; Texas A&M University-Kingsville 700 University Blvd Kingsville, Tx 78363
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Timing: Fiscal Year 2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HUMAN BREAST CANCER CELL GROWTH INHIBITION BY VITAMIN E Principal Investigator & Institution: Kline, Kimberly; Professor; Human Ecology; University of Texas Austin 101 E. 27Th/Po Box 7726 Austin, Tx 78712 Timing: Fiscal Year 2002; Project Start 01-AUG-1994; Project End 31-JUL-2005 Summary: (Applicant's Abstract) Goals are to investigate the mechanisms of action of VES (vitamin E succinate; RRR-alpha-tocopheryl succinate), a potent inducer of apoptosis in human breast cancer cells but not normal mammary epithelial cells. The applicant's studies show that VES can restore both transforming growth factor-beta (TGF-beta) and Fas/CD95 impaired anti-proliferative and death signaling in human breast cancer cells that are resistant to these two important cell homeostatic signaling pathways. In this competing continuation application the applicant proposes to investigate critical signaling events involved in VES initiated apoptosis in human MDAMB-435 breast cancer cells. Normal human mammary epithelial cells (HMECs) and immortalized, non-tumorigenic human mammary epithelial MCF-10A cells which are insensitive to VES induced apoptosis but responsive to both TGF-beta and Fas induced cell fates will be studied for comparative purposes. Aim 1 will characterize components of the TGF-beta signal transduction pathway contributing to VES-induced apoptosis. Aim 2 will characterize Fas signal transduction events involved in VES induced apoptosis. Aim 3 will investigate the decision phase of apoptosis in VES treated cells with emphasis on Bax and mitochondrial mediated events that produce downstream execution phase mediators. Comparisons between VES and ligand (TGF-beta1 and antiFas agonistic antibody) mediated events in MDA-MB-435, HMECs and MCF-10A cells will address the molecular basis of VES's selective ability to induce apoptosis in cancer cells but not in normal or immortalized but non-tumorigenic cells. Expectations are that data generated will increase basic knowledge about TGF-beta and Fas signaling in normal and cancer cells and will provide a better understanding of how VES, a potent pro-apoptotic agent, induces cell death. Part of the significance of these mechanistic studies lies in the potential use of agents like VES for chemotherapy of human breast cancer. This possibility has been strengthened by the recent demonstration that a VES ether analog is a potent, orally active chemotherapeutic agent in a preclinical xenograft model of human breast cancer. Another aspect of the significance of these type studies lies in the belief that better understanding of signaling events will lead to the identification of critical intracellular signal transduction molecules which can be targeted for design of mechanism-based drugs to achieve improved cancer cell killing. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: HUMAN EXPLANT CULTURES AND A MOUSE TO EVALUATE SAMMA Principal Investigator & Institution: Cara, Andrea; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2002 Description (provided by applicant): Approximately 90% of new human immunodeficiency virus (HIV) infections are acquired through sexual contact. The development of safe, effective, and affordable topical microbicides for vaginal or rectal
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use could play a critical role in reducing HIV transmission rates worldwide. Clinical, epidemiological and molecular studies strongly support the role of herpes simplex virus (HSV) as a major cofactor for the transmission of HIV. Genital ulcers lead to breaks in the epithelial barrier and HSV induces the expression of pro-inflammatory cytokines that are known to enhance HIV replication. The goal of the proposed studies is to characterize the effects of sodium dimandelic acid ether (SAMMA) and its leading derivatives on HIV and HSV infection utilizing relevant biologic culture systems. SAMMA has excellent anti-mV and anti-HSV activity, while exhibiting no cytotoxicity in cell culture. While cell cultures may provide important information for the evaluation of microbicides, they may not adequately simulate events that occur in vivo. Human explant cultures (endocervical, ectocerivcal, vaginal and rectal), biologic fluids (cervicovaginal secretions and semen) and a mouse genital herpes model will be used in this Project to assess anatomic, physiologic, and immunologic factors that might impact on the activity of this novel class of compounds. Building on the in vitro cell culture data of Projects I, II and IV, the applicant will study the most active derivatives/isomers of SAMMA using biologic culture systems. In Aim 1, the most active derivatives will be evaluated for efficacy against HIV-1 infection of primary macrophages using human genital tract fluids and mucosal explant cultures. In Aim 2, mucosal explant cultures and a mouse model will be used to determine the efficacy of SAMMA to block HSV infection of epithelial cells. Inflammatory cells and cytokines will be measured to study the effects of SAMMA on the innate immune system (Aims 1,2 and 3). The interrelationship between HIV and HSV and the efficacy of SAMMA to inhibit dual infection will be studied in Aim 3. Efficacy and safety data in relevant biologic culture systems may provide compelling support for advancing SAMMA or one of its derivatives to clinical trials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: IN VITRO REFINEMENTS FOR CRYPTOSPORIDIUM PARVUM Principal Investigator & Institution: Upton, Steve J.; Professor; Division of Biology; Kansas State University 2 Fairchild Hall Manhattan, Ks 665061103 Timing: Fiscal Year 2002; Project Start 15-SEP-2002; Project End 31-AUG-2004 Summary: (provided by applicant): Over the last decade, our ability to cultivate the intestinal protozoan, Cryptosporidium parvum, in cell culture has increased by >500x. However, there still exist multiple fundamental problems associated with cultivating this parasite in vitro. One of these problems is the diversity of medium formulations currently in use, most of which are sub-optimal for growing the parasites in vitro. Formulations which result in the most extensive parasite development complete with both asexual and sexual stages rely on the investigatoradding5-6 key supplements and many laboratories fail to make the modifications resulting in sub-optimal data. The second of these problems, and more importantly, is our inability to produce high numbers of viable oocysts in vitro. Laboratories must either use vertebrate animals to produce oocysts or rely on commercial sources which are extremely expensive. Even excluding the expense, oocysts must be purified from feces at which time they are often exposed to a variety of chemical insults including reagents such as potassium dichromate and ether. In addition, microbial contamination is normally eliminated before the parasites are utilized by the addition of 10% (v/v) commercial bleach, which surface sterilizes the oocysts. Thus, any method where we can obtain sufficient numbers of oocysts in vitro without the need for animal propagation or coliform contamination would open up a variety of avenues that are currently unavailable. These avenues include1) providing opportunities to a wider variety of laboratories to work on the
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parasite at decreased expense, 2) developing gene knock-outs and allelic replacements that could be propagated indefinitely, 3) performing metabolic labeling studies and looking at incorporation of label into the purifiable oocysts, and 4) more easily studying parasite development in vitro following exposure of oocysts to disinfectants without pre-exposing oocysts to solvents or reagents beforehand. This R21 proposal will attempt to solve the two problems outlined above: 1) find a commercially available, artificial, serum-free medium that permits good parasite growth in vitro; and 2) develop a system whereby we can routinely, easily, cleanly, and inexpensively generate sufficient numbers of oocysts in vitro without the need for experimental animals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: INACTIVATION OF CYTOCHROMES P450 2E1 T303A Principal Investigator & Institution: Blobaum, Anna L.; Pharmacology; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-AUG-2005 Summary: (provided by applicant): The ethanol-inducible cytochrome P450 2E1 catalyzes the oxidation of a large number of drugs, hepatotoxic xenobiotics, and carcinogens. The primary goals of the proposed research are to gain a better understanding of the active site structure of P450 2E1 and to identify the critical amino acid residues in the active site of 2E1 that are involved in catalysis and substrate binding. High performance liquid chromatography (HPLC) and electrospray ionization liquid chromatography-mass spectrometry (ESI-LC-MS) will be used to determine the identities of the metabolites produced during the mechanism-based inactivation of cytochromes P450 2E1 and 2E1 T303A by tert-butyl acetylene (tBA) and tert-butyl 1methyl-2-propynyl ether (tBMP). LC-MS/MS (liquid chromatography-mass spectrometry/mass spectrometry) will be used to identify the tBA-modified polypeptide(s) and amino acid residue(s) in the P450 2E1 active site. NMR methodology and site-specific 2E1 mutants will be used to explore the novel mechanism for the inactivation of P450 2E1 T303A by tBA. Finally, ESI-LC-MS will be used to determine what effect alternate oxidants may have on the mechanism of inactivation of P450s 2E1 and 2E1 T303A by tert-butyl acetylenes. Understanding the active site structure of P450s and identifying the critical amino acid residues involved in catalysis and substrate binding will prove to be extremely valuable for developing techniques that can be used to selectively modulate the catalytic activity of these enzymes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: INHALED ANESTHETIC BINDING LOCATION AND CHARACTER Principal Investigator & Institution: Eckenhoff, Roderic G.; Associate Professor; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002 Summary: (taken from the application). Anesthetics are the most toxic of drugs administered by physicians, and yet we have little idea how they work. Improvement in the drugs can only occur with an enhanced understanding of their binding sites, and the atomic interactions responsible for binding. In this subproject, we intend to localize and characterize the important features of inhaled anesthetic binding sites. We hypothesize that protein internal cavities are essential for specific binding of anesthetics, and that their volume controls the effect the drugs will have on protein stability and dynamics. We also hypothesize that deep hydrophobic pockets are important, and that pocket/cavity polarity improves anesthetic binding affinity. We will test these
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hypotheses by graphically analyzing a subset of about 100 protein structures deposited with the Protein Data Bank for cavity and pocket features, and then correlating a subset of these with binding and stabilization using photolabeling fluorescence quenching and amide hydrogen exchange. Those proteins showing specific binding will be cocrystallized with the anesthetic to verify location of binding, and the atomic interactions responsible. These experiments with biological proteins build on our experience and success with peptide models. In collaboration with Project 2, designed cavities will be created and modified in both water soluble and membrane inserted helical peptide bundles, and then studied with photolabeling and amide hydrogen exchange to monitor the binding event Crystallization studies of these bundles for high resolution structural information will be conducted. Finally, many proteins exist for which no high-resolution structural detail is known (especially the large membrane proteins responsible for much CNS signaling), but photolabeling can assign location in the primary structure, and yield an idea of binding parameters. Halothane photolabeling, while useful, has limitations that dictate the development of novel photolabels based on the diazo- or diazirine group. In collaboration with Dr. William Dailey of the Department of Chemistry, we will design, synthesize and characterize new compounds to mimic an alkane, an ether, and a non-immobilizer compound to use on these complex proteins in the future. These studies will establish or refute the importance of pre-existing cavities or pockets in anesthetic binding, and thus establish the generality of important anesthetic-binding features. Further this work will provide a foundation for a unitary hypothesis of anesthetic-induced protein dysfunction: anesthetics stabilize the protein conformer with optimal cavity features, reducing flexibility and thereby hindering the shifts in conformational equilibria that underlie activity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: INHIBITION TUBERCULOSIS
OF
FATTY
ACID
BIOSYNTHESIS
IN
M.
Principal Investigator & Institution: Tonge, Peter J.; Associate Professor; Chemistry; State University New York Stony Brook Stony Brook, Ny 11794 Timing: Fiscal Year 2003; Project Start 01-MAY-1999; Project End 31-AUG-2004 Summary: The long term goal of this proposal is to generate novel inhibitors of fatty acid biosynthesis in Mycobacterium tuberculosis. It is hypothesized that such compounds will have antimycobacterial activity and will provide a appropriate starting point for generating drugs to treat multi-drug resistant tuberculosis. The proposal has two Aims. Specific Aim 1 focuses on the design and synthesis of inhibitors that target InhA, the enoyl reductase FASII enzyme. This enzyme is one of the putative targets for isoniazid, a frontline antituberculosis drug. Novel compounds will be synthesized based on the diphenyl ether skeleton of triclosan, an inhibitor of enoyl reductases in M. tuberculosis and other bacteria. Inhibitor design will utilize X-ray crystallography, Raman spectroscopy and computational approaches. Compounds will be tested using enzyme kinetics, the antimycobacterial activity will be assessed using MICs and the intracellular mode of action of the compounds will be evaluated using DNA microarrays and photoaffinity labeling. Specific Aim 2 will investigate the mechanism of action of isoniazid and will test the hypothesis that proteinprotein interactions within the mycobacterium modulate the sensitivity of InhA and other FASII enzymes to isoniazid. The FASII enzyme complex from M. tuberculosis will be purified and the activity and sensitivity of each enzyme component toward FAS inhibitors will be evaluated. Characterization of the FASII complex will reveal the identity of the dehydrase enzyme and the FASII complex will be reconstituted in vitro using
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recombinantly expressed proteins. In addition, pull-down experiments will be used to identify other InhA protein binding partners and characterization of the FASI enzyme complex from M. tuberculosis will be initiated. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: INTRACELLULAR ACTION OF SAMMA ON SPERM FUNCTION Principal Investigator & Institution: Zaneveld, Lourens J.; Professor; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2002 Summary: (Provided by applicant): Sodium dimandelic acid ether (SAMMA) is a noncytotoxic, contraceptive antimicrobial agent that appears to function by inhibiting sperm and viral function. The compound does not contain sulfur which differentiates it from most other non-cytotoxic "entry inhibitors" developed so far. SAMMA prevents fertilization in the rabbit when mixed with spermatozoa or placed vaginally as a gel before insemination; The compound also causes the dispersion of the acrosome from human spermatozoa. Physiologically, such dispersion (acrosome reaction) occurs when the spermatozoon approximates the oocyte, enabling sperm binding to and penetration of the layers surrounding the egg. Premature acrosomal loss, i.e., in the vagina, should render spermatozoa incapable of fertilizing. Therefore, the acrosomal loss-inducing capacity of SAMMA may be the primary reason for its contraceptive properties. Acrosomal loss of both capacitated and non-capacitated spermatozoa caused by modulators is usually calcium ion dependent and is mediated by signal transduction cascades involving one or more protein kinases; candidates include phospholipiddependent kinase (PKC), CAMP-dependent kinase (PKA), cGMP-dependent kinase (PKG) and protein tyrosine kinase (PTK). The first two objectives of the Project are to determine whether the induction of acrosomal loss by SAMMA is mediated by an effect on calcium transport and/or on one or more of the protein kinases (Aims 1 and 2). The third objective is to assess the structural requirements for SAMMA and its derivatives to induce acrosomal loss through these mechanisms (Aim 3). The final objective is to obtain and test highly active SAMMA derivatives, based on these structural requirements, and to select the most effective SAMMA derivatives based on their ability to induce acrosomal loss and their potency in the rabbit contraceptive assay (Aim 4). The isomers of the active SAMMA derivative will also be compared for their relative activity in the acrosomal loss assay and in the contraceptive test (Aim 4). As a result of these studies, the mechanism of SAMMA's acrosomal loss-inducing activity will be better understood, and can be compared to its mechanism of antiviral action (evaluated in the other projects). If similar, this would help explain the ability of SAMMA to be both antimicrobial and contraceptive, and can lead to the development of other non-cytotoxic entry inhibitors with dual activity. In addition, the most active SAMMA derivative/isomer will have been selected and can be developed further through the pre-IND stages into clinical trial. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: LIGAND BINDING AND FUNCTIONAL ASSAY-BASED HERG DATABASE Principal Investigator & Institution: Perschke, Scott E.; Novascreen Biosciences Corporation 7170 Standard Dr Hanover, Md 21076 Timing: Fiscal Year 2002; Project Start 25-SEP-2002; Project End 24-MAR-2003
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Summary: (provided by applicant): The HERG (human ether-a-go-go-related) gene encodes a membrane protein that functions as a K+ -channel. There is intense interest in the HERG protein because interactions between drugs and the HERG channel protein have become a major impediment in the development of new and safe pharmaceuticals. Interactions of drugs with the HERG channel alter the repolarization of the hearts' electrical system, causing tachycardia and occasionally heart failure. This has led to the removal of at least one drug from the market, and caused many others to fail in clinical trials. There is an increasing demand for methodologies that will allow prediction and identification of lead compounds with potential HERG channel activity early in the drug discovery process. The specific aims of this proposal are to develop multiple ligand binding assays and a functional assay for the HERG channel, as expressed in CHO cells. Once developed, approximately 20 known HERG inhibiting drugs will be screened for dose response in all assays developed and the data collected and assembled in a database. This database will then be used as the basis for a Phase 2 study that greatly expands the chemicals tested, to identify key molecular and chemical descriptors that are predictive of drug and protein interactions with the channel. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: LITHIUM STEREOSELECTIVITY
MIXED
AGGREGATES
&
ENOLIZATION
Principal Investigator & Institution: Pratt, Lawrence M.; Fisk University Nashville, Tn 372083051 Timing: Fiscal Year 2002 Summary: This proposed research will develop the use of lithium dialkylamide mixed aggregates as reagents for the stereoselective synthesis of enolates. Lithium enolates are important reagents in the synthesis of carbon-carbon bonds, and are used extensively in the pr3eparation of medicinal compounds. Synthesis of chiral drugs often depends on the availability of stereoselective aldol condensations and other reactions of enolates the stereoselectivity of these reactions is often limited by the availability of pure diastereomeric enolates. The stereoselectivity of these reactions is often limited by the availability of pure diastereomeric enolates. Enolates are generally prepared by deprotonation of aldehydes, ketones, and esters, and the stereoselectivity of enolates. Enolates are generally prepared by deprotonat8ion of aldehydes, ketones, and esters, and the stereoselectivity of enolate format8ion is dependent on the structure of the base that is used. Lithium dialkylamide mixed aggregates with alkyllithiums and lithium halides will be tested as inexpensive and easily prepared reagents for this purpose. The enolization reactions will be performed by addition of the carbonyl compound to a solution of the lithium dialkylamide or its mixed aggregates. The enolate will be trapped as the trimethylsilyl enol ether and the E/Z ratio determined by gas chromatography. The enolization reactions will be performed with several carbonyl substrates to determine the effects of stereoelectronic factors and to predict the stereoselectivity of enolization of carbonyl compounds that are actually used in drug synthesis. Ab initio calculations will be used to determine the activation energies leading to the E and Z 4enolates. Deprotonation activation energies will be calculated for lithium dialkylamides and their alkylithium and lithium halide mixed aggregates. The calculations will be performed on a variety of aldehyde, ketone, and ester substrate to capture the behavior of a range of stereoelectronic effects. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: LUNG DEVELOPMENT IN CONGENITAL DIAPHRAGMATIC HERNIA Principal Investigator & Institution: Larson, Janet E.; Ochsner Clinic Foundation New Orleans, La 70121 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2005 Summary: (provided by applicant): Congenital diaphragmatic hernia (CDH) is associated with the structural abnormality of pulmonary hypoplasia. These changes are mimicked in the rodent model of nitrofen-induced CDH. Nitrofen (2,4-dichlorophenylp-nitrophenyl ether) is an herbicide that when fed to a pregnant rodent at day 9 or 10 creates diaphragmatic hernia and/or lung hypoplasia in the fetuses. When treated with nitrofen the fetuses demonstrate epithelial cell immaturity as well as hypoplasia. In contrast, the investigators have found that in utero gene therapy with CFTR (the gene responsible for Cystic Fibrosis) results in epithelial cell hyperplasia and accelerated epithelial cell differentiation. The investigators hypothesize that in utero gene therapy with cftr will reduce the pulmonary hypoplasia and epithelial cell immaturity associated with CDH. This hypothesis can be tested in the fetal rat by treatment with nitrofen at 910 days gestation followed by in utero gene therapy at 16-17 days gestation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: LUNG REPLACEMENT
SURFACTANT
ACTIVITY,
INHIBITION
AND
Principal Investigator & Institution: Notter, Robert H.; Pediatrics; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2003; Project Start 01-JUL-1997; Project End 31-MAR-2007 Summary: (provided by applicant): This research studies the component-specific molecular biophysics and physiological activity of biological and synthetic pulmonary surfactants. A major goal is to develop new highly active phospholipase-resistant synthetic exogenous surfactants containing novel lipids and peptides for use in the neonatal and acute respiratory distress syndromes (RDS and ARDS). The research also seeks to improve fundamental understanding about surfactant activity and dysfunction. Aims 1 and 2 examine the surface activity, resistance to inhibition, and P-V mechanical effects in lavaged excised rat lungs of synthetic exogenous surfactants containing novel phospholipase-resistant phospholipid analogs plus synthetic peptides or purified apoproteins. Lavaged calf lung surfactant and current animal-derived clinical surfactants are comparative standards. Complementary biophysical methods are used to fully assess surface-active behavior (Wilhelmy balance, pulsating bubble, adsorption, Brewster-angle microscopy, differential scanning calorimetry, FTIR spectroscopy). Materials studied include synthetic di-ether and ether-thio-phosphonolipids and phospholipids, synthetic regional human-sequence SP-B, SP-C, and SP-A peptides, synthetic glycerophospholipids, and specific lipids and apoproteins purified chromatographically from natural surfactant. Biophysical and excised lung studies in Aims 1, 2 are extended in Aim 3, to define the efficacy of the most active exogenous surfactants in reversing surfactant dysfunction, improving gas exchange, and reducing lung injury in rats with ARDS-related gram negative pneumonitis in vivo. Also studied is the formulation of surfactant dispersions with low shear viscosity to enhance their pulmonary delivery and distribution following tracheal instillation. This integrated hierarchy of biophysical and physiological research will advance basic knowledge about surfactant activity and dysfunction, and define new exogenous surfactants with
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maximal activity, inhibition resistance, and pulmonary delivery for therapeutic applications. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MECHANISM & CHARGE CONTROL OF METAL CATALYZED RNA TRANSESTERIFICATION Principal Investigator & Institution: Bashkin, James K.; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002 Summary: We have begun to develop a detailed description of the metal-catalyzed cleavage (transesterification) of single-stranded RNA through the use of the embedded RNA (embRNA) assay.1-3 EmbRNA contains a single RNA residue in a DNA oligomer. The relative effectiveness of catalysts reported by different groups is often assessed by comparison of these kobs values. We have found that, in a number of cases, the kobs values for cleavage of RNA dimers do not correlate with kobs for cleavage of related RNA oligomers. This makes the dimeric assays potentially misleading in the choice of reagents to cleave high MW, biological RNA samples. We are investigating which factors account for this behavior. Possible contributors include the multitude of metal binding sites on high MW RNA (at phosphodiester, O-4'-ether, 2'-hydroxyl and nucleobase sites), the potential for more than one kinetically-important metal ion, the greater variety of conformations available to oligomeric RNA vs. di meric substrates, and polyelectrolyte effects. Furthermore, as part of our kinetic investigations of RNA cleavage, we have determined the effect of catalyst concentration on kobs for several catalysts, including Ce(III) and La(III) ions and Ce(III) macrocycles. We found that, for aqueous Ce(III), the order of the reaction with respect to Ce(III) varied dramatically. Thus, small changes in catalyst concentration can have huge effects on the observed rate constant. In contrast, the transesterification of embRNA by Ce(III) macrocycles was found to be first order with respect to catalyst.4 This difference is likely due to the suppression of polynuclear species by the macrocyclic ligand. We have determined pHrate profiles and reaction orders for both "free" Ln3+ ions and the macrocycles, and we are now able to compare these reagents in a meaningful way to Cu(II)- and Zn(II)-based RNA transesterification catalysts. The pH-rate profile helps determine which protonation state of the ca talyst is kinetically important. We have also begun to use multiply-chimeric embRNA substrates (i.e. DNA/RNA/methyl-phosphonate combinations) to determine the role of specific phosphate residues in catalyst binding. Mass spectrometry is required for the identification of cleavage products Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MECHANISM OF SAMMA AGAINST HSV: KEY COFACTOR FOR HIV Principal Investigator & Institution: Herold, Betsy C.; Chief, Division of Pediatric Infectious; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2002 Description (provided by applicant): The overall goal of this Program is to develop safe and effective topical microbicides for intravaginal or rectal use that will block sexual transmission of human immunodeficiency virus (HIV) and other sexually transmitted diseases. The program focuses on a novel family of candidate microbicides based on the parent compound, sodium dimandelic acid ether (SAMMA). The applicant has found
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that SAMMA has excellent anti-HIV and anti-herpes simplex virus (HSV) activity, while exhibiting no cytotoxicity in tissue culture. Preliminary studies suggest that SAMMA inhibits viral entry, but it is unique among other inhibitors of entry because it contains no sulfur. Project II focuses on defining the mechanism of activity of SAMMA and structural derivatives against HSV. There are several reasons to focus on HSV in the development of topical microbicides. HSV is a major co-factor in HIV transmission and recent epidemiological studies highlight the urgent need for HSV control if HIV is to be successfully combated. HSV ulcerative lesions enhance acquisition of HIV-1. At a molecular level, HSV infection may induce the expression of pro-inflammatory cytokines that are known to induce HIV-1 replication and may activate cellular pathways, which may enhance HIV-1 replication. In addition, mouse studies of genital herpes are an excellent surrogate small animal model for evaluating the anti-viral and local immunological effects of candidate agents. Also, recent studies from our laboratories clearly demonstrate parallels in the pathways of invasion of HSV and HIV and in the anti-viral activity of candidate agents. Thus, understanding the mechanism of anti-HSV activity of this family of drugs may shed light on mechanism of anti- HIV activity.The first aim of Project II is to evaluate the efficacy, cytotoxicity and mechanisms of activity of SAMMA and chemical derivatives against HSV using primary and permanent human cell culture systems. In Aim 2, the applicant will isolate viruses resistant to SAMMA or lead derivatives. Resistant variants will provide insight into the mechanism of anti-viral activity of the compound and the potential for generating resistant virus in humans. The third aim will focus on identifying the viral and cellular factors important in HSV-induced enhancement of HIV replication and the effects of SAMMA on this phenomenon. The knowledge gained from these studies will provide important data for advancing SAMMA or one of its lead derivatives to clinical trials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MODIFIERS OF POTASSIUM CHANNEL FUNCTION AND EXPRESSION Principal Investigator & Institution: Robertson, Gail A.; Associate Professor; Physiology; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2002; Project Start 15-AUG-2002; Project End 31-JUL-2006 Summary: (provided by applicant): The human ether-a-go-go-related gene (HERG) encodes an ion channel subunit underlying IKr, a potassium current required for the normal repolarization of ventricular cells in the human heart. More than 90 inherited mutations in HERG cause Long QT Syndrome (LQTS), a leading cause of sudden cardiac death. Some mutations alter gating, but more disrupt trafficking. Because the subunit composition of HERG is uncertain, and the mechanisms underlying HERG biogenesis, processing and targeting to the membrane are unknown, we carried out a yeast two-hybrid screen to identify proteins that interact with HERG. Using the carboxy terminus as bait to screen a human heart library, we isolated five genes encoding HERGinteracting proteins ("HIPs"). Two of these proteins have been previously identified: Tara, an actin-binding protein, and GM 130, a peripheral membrane protein of the Golgi apparatus. Little is known about the function of either. Tara co-localizes with HERG to a region in rat cardiac myocytes corresponding to the T-tubules, as determined by confocal immunocytochemistry. Consistent with a stabilizing role at the membrane, Tara enhances expression in HERG when co-expressed in Xenopus oocytes. GM 130 specifically localizes to the Golgi, where a prominent HERG signal is also observed. In contrast to Tara, GM130 suppresses HERG signal in oocytes. Deletion mapping in binary yeast two-hybrid assays reveals that the C terminus contains distinct domains
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with which the HIPs selectively interact. Certain LQT2 (HERG) mutations selectively disrupt interactions with only two of the proteins. Three of the proteins, Tara, H17 and H3, interact with each other, implying that they function as an interactive complex. Of the HIPs, Tara alone interacts with another cardiac ion channel protein, KvLQT1, in binary yeast two-hybrid assays, but none interacts with Shaker. Each HIP represents a potential target for LQTS to the extent that its expression is required for the normal expression or targeting of HERG channels. The long-range goal of this research is to elucidate the basic biological processes that are disrupted by the disease process. The specific aims of this proposal are: (1) to demonstrate that HERG and the HIPs interact in vivo: (2) to extend our immunocytochemical and electrophysiological analyses, tests for specificity and domain mapping; (3) to determine the necessity of HIP interactions for HERG channels by reciprocal analysis of HERG C terminal truncations and selective disruption of HIPs in native tissues and heterologous systems; and (4) to screen unmapped LQTS families for disease mutations in the genes encoding the HIPs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MODULATION OF POTASSIUM CHANNELS IN DROSOPHILA Principal Investigator & Institution: Wilson, Gisela F.; Assistant Professor; Biology; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002; Project Start 15-MAR-2001; Project End 29-FEB-2004 Summary: This proposal will examine whether signaling modules serve to co-localize intracellular messengers with potassium channels of the ether-a-go-go (EAG) family by determining the physiological importance of EAG-associated signaling modules in the physiology and behavior of Drosophila. The role of signaling modules in the regulation of EAG currents will be examined (a) by co-expressing individual components in heterologous expression systems and examining the resulting currents using voltage clamp and patch clamp techniques, and (b) by electrophysiological recordings of nerve and muscle activity at the larval neuromuscular junction. Recordings from normal flies will be compared to those obtained from mutants in which components of the signaling modules have been deleted or the normal associations disrupted. The consequences of observed electrophysiological defects for hyperexcitability and other behaviors, specifically learning as assayed using a courtship conditioning assay, will also be examined. In addition to linking mechanisms of channel modulation to changes in behavior, these studies will provide evidence for one possible mechanism by which the specificity of action of intracellular enzymes can be achieved. Once understood, this mechanism can be used as a target for therapeutic agents that will be more specific than those currently employed in the treatment of a number of psychological and neuromuscular disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MODULATORS OF HERG FUNCTION AND PHARMACOLOGY Principal Investigator & Institution: Balser, Jeffrey R.; Professor; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2007 Summary: (provided by applicant): The Human Ether-a-go-go Related Gene (HERG, KCNH2) encodes the major, pore-forming subunit of the cardiac K+ current IKr. Suppression of IKr, through inherited mutations or pharmacologic blockade, can provoke sudden death from a ventricular arrhythmia (Torsades de Pointes). Like IKr,
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HERG channels are sensitive to a wide array of therapeutic agents but in practice, the development of cardiac arrhythmias upon exposure to HERG-blocking compounds is unpredictable, suggesting modulating factors critically influence HERG pharmacology. The goal of this proposal is to identify molecular mechanisms that mediate drug interactions with the IKr complex. While HERG block by most pharmacologic agents develops as the membrane is depolarized and channels open, block still develops slowly (over minutes) suggesting that access of drug to its receptor site in the inner pore vestibule (S6) is limited. While the mechanisms that underlie drug interactions with HERG are incompletely understood, our recent studies have identified the HERG Cterminus and a HERGinteracting protein (KCR1) as inhibitors of block. We will test the hypothesis that HERG blockade by therapeutic compounds is modulated by functional interactions involving HERG subdomains and other proteins that compose the IKr complex. Using electrophysiologic and biochemical approaches, Cterminal deletion mutants, and C-terminal peptides, we will determine the mechanism whereby the HERG C-terminus limits drug access to the pore. Using the same approaches, we will elucidate the molecular mechanism whereby human KCR1 inhibits drug block. Finally, to expand our understanding of the IKr complex and the molecular substrates of proarrhythmic risk, we will utilize the enetically tractable organism C. elegans as a model system to identify new HERG-interacting protein candidates, taking advantage of the association among the C. elegans homologue of HERG (UNC-103), methanesulfonanilde drug action, and the rhythmic pattern of pharyngeal pumping in the worm. The improved understanding of drug-channel interactions arising from this research should enable improvements in predicting risk for drug-induced arrhythmias, and the development of improved antiarrhythmic therapies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MOLEC DYNAMIC SIMULATIONS OF INHALED ANESTHETIC INTERACTIONS W/PEPTIDES & LIPID Principal Investigator & Institution: Klein, Michael L.; Director; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 30-JUN-2003 Summary: (taken from the application). Computer simulation molecular dynamics (MD) techniques are proposed to complement experiments designed to elucidate the molecular mechanism of action of inhaled anesthetics (IAs). The goal is classification of molecular aspects of anesthetic pharmacokinetics. To this end, constant pressure and temperature MD simulations will be used to detail the interactions of IAs with model protein and lipid systems and thereby provide important complementary information to contemporary experiments. Specifically, this project will characterize the interactions of halothane and ether based IAs with structural motifs that are directly related to probable sites of action and binding. Detailed simulations will be performed on a-helical peptide bundles with demonstrated specific binding to halothane. The aim will be to examine the properties of the proposed binding cavity, its suitability to accommodate halothane molecules, other IAs, and binding selectivity using specific mutations. Potential energy functions will be developed for commonly used ether-based IAs, such as isoflurane and sevoflurane. These will be used in classical simulations of IAs interacting with peptide bundles. Ab initio calculations will be employed to probe the interactions between halothane/isoflurane and specific amino acids. Extensive simulations will be performed to elucidate the distribution and behavior of IAs in model membranes. The focus will be on possible differences between the distribution of halothane, ether-based IAs and non-anesthetics in model membranes of saturated and
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unsaturated lipids. These calculations will produce models to assist the design and analysis of neutron diffraction experiments. Simulation studies will be initiated on a membrane-bound synthetic (GCN4-based) peptide bundle, which binds IAs. The goal is to probe the interactions of IAs with a model trams-membrane a-helical bundle, which exhibits specific binding for IAs when inserted in a bilayer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MOLECULAR ANALYSIS OF THE GLYCOSOME. Principal Investigator & Institution: Parsons, Marilyn; Professor and Associate Director; Seattle Biomedical Research Institute 4 Nickerson St, Ste 200 Seattle, Wa 98109 Timing: Fiscal Year 2002; Project Start 01-DEC-1986; Project End 31-MAY-2005 Summary: (Adapted from the Applicant's Abstract): Members of the order kinetoplastida are the causative agents of African sleeping sickness (Trypanosoma brucei subspecies), leishmaniasis (Leishmania spp.) and Chagas' disease (Trypanosoma cruzi). There is no vaccine against any of these diseases and current treatments are toxic. The parasite possesses a unique subcellular organelle, the clycosome, which is a distant relative of the peroxisome found in higher eukaryotes. The glycosome houses many of the enzymes of the Embden-Meyerhof pathway of glycolysis, as well as enzymes involved in nucleotide biosynthesis, ether-lipid biosynthesis, Beta-oxidation of fatty acids, purine salvage and pyrimidine biosynthesis. Given the importance of these metabolic pathways to the parasite, the glycosome and its constitution's have been recognized as a possible target for the development of new chemotherapies. Their studies are aimed at understanding glycosomal biogenesis and protein input and the relationship of these processes and the molecules involved to peroxisome biogenesis in the human host. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MOLECULAR CHARACTERIZATION OF AQUIFER MICROBIAL COMMUNI* Principal Investigator & Institution: Scow, Kate M.; Land, Air and Water Resources; University of California Davis Sponsored Programs, 118 Everson Hall Davis, Ca 95616 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-JUL-2005 Summary: Numerous groundwater aquifers are contaminated with organic and inorganic pollutants. Directly monitoring biodegrading microbial communities could guide decisions about treatment and facilitate monitoring of remediation. A common, but not well-investigated, challenge at Superfund sites is managing remediation of mixtures of contaminants. Superfund chemicals, toluene, benzene and xylene, along with fuel oxygenates, comprise mixed contaminants associated with petroleum pollution. Our aim is to adapt and develop molecular tools to assess the behavior of microbial communities associated with mixtures of pollutants. The underlying hypothesis that will guide our technology development is that microbial community structure (diversity and numbers of total bacteria, certain anaerobic toluene/xylene degraders, and denitrifiers) and community functions (e.g. rates of utilization of pollutants as e donors, use of electron acceptors) when exposed to mixtures of contaminants will not behave as predicted from behavior on single contaminants. We will focus on toluene and xylene biodegradation under nitrate reducing conditions, but also consider interactions of these processes with other BTEX compounds and the fuel additives, methyl tertiary butyl ether (MTBE) and ethanol. Our study system will be groundwater aquifer microbial communities, in microcosm and controlled field studies.
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Questions to be addressed include: 1) Are differences in biodegradation rates of contaminants, alone versus mixed with other chemicals, associated with differences in diversity and numbers of total bacteria, toluene/xylene degraders, and denitrifiers? 2) Do the same microbial populations use multiple contaminants? 3) Do readily degradable (e.g., ethanol) and recalcitrant (e.g., MTBE) fuel additives alter the biodegradation of BTEX under anaerobic conditions? We will use DGGE analysis and real-time quantitative PCR, targeting primers for enzymes involved in contaminant degradation (bssA) and nitrate reduction (nirS and nirK) and total bacterial cells (universal bacterial 16S rDNA). We will measure the accumulation of carbon from 14C labeled compounds (toluene, MTBE) into cellular constituents (PLFA, determine signature lipids/markers) of microbial communities using GC-MS and AMS (at Lawrence Livermore National Lab) in artificial mixes of bacterial strains and in microcosms. We will conduct studies in microcosms and across pollutant gradients (of BTEX, BTEX + MTBE or ethanol) at a field site containing a petroleum spill (with BTEX and MTBE) at Vandenberg Air Force Base in CA. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NATURAL DIRECTED C-H
PRODUCT
SYNTHESIS
THROUGH
TEMPLATE
Principal Investigator & Institution: Wardrop, Duncan John.; Chemistry; University of Illinois at Chicago 1737 West Polk Street Chicago, Il 60612 Timing: Fiscal Year 2002; Project Start 01-JUN-1999; Project End 31-MAY-2004 Summary: The successful development of methods for catalytic asymmetric C-C bond formation is one of the most fundamentally important endeavors in synthetic organic chemistry. During the last two decades, the dirhodium(II)-catalyzed intramolecular insertion of alpha-diazocarbonyl compounds into unactivated C-H bonds has emerged as a particularly powerful method for the construction of both carbocyclic and heterocyclic systems. When this insertion process occurs at a C-H bond adjacent to an ether oxygen, beta- alkoxycarbonyl products are obtained and consequently this transformation can be considered to be a synthetic alternative to aldol-type reactions. Since 1,3-diols or derivatives thereof are found in a large number of biologically active natural products the development of this transformation is of considerable importance. The long-term objective of this project is therefore to successfully develop a unique C-H bond insertion strategy which can be applied to the synthesis of a range of pharmacologically active natural products. The specific aims of this project are: i) to investigate the use of a dirhodium(II)-catalyzed asymmetric intramolecular metal carbene C-H insertion reaction as an efficient method for the preparation of the synthetically useful 2,8-dioxabicyclo[3.2.1]octane ring system; ii) to develop this reaction as a novel method for the simultaneous functionalization and asymmetric desymmetrization of meso 1,3-diol systems; iii) to illustrate the potential of this chemistry through its application to the synthesis of a diverse range of biologically active target molecules, including the antihypercholesterolaemic agent zaragozic acid A/squalestatin S1 and the potent antifungal agent sphingofungin E; and iv) to develop a novel method for the synthesis of branched-chain carbohydrates by extending this chemistry to the direct functionalization of various pyranoside systems. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: NEUROCHEMISTRY AND GENETICS OF DROSOPHILA CAM KINASE II Principal Investigator & Institution: Griffith, Leslie C.; Associate Professor; Biology; Brandeis University 415 South Street Waltham, Ma 024549110 Timing: Fiscal Year 2002; Project Start 01-MAY-1996; Project End 30-APR-2003 Summary: (from abstract) Calcium/calmodulin-dependent protein kinase II (CaMKII) has been implicated in synaptic plasticity in both vertebrates and invertebrates and has properties which suggest that it may be a "molecular switch". The applicants will analyze the biochemistry of CaMKII in Drosophila and identify components of its biochemical pathways. 1) Analysis of the biochemical function of isoform diversity of the Drosophila CaMKII. This kinase consists of multiple subunits generated by alternative splicing. What are the biochemical consequences of isoform diversity? They will investigate the effects of variable region diversity on regulatory properties of the enzyme. 2) Analysis of the in vivo function of Drosophila CaMKII isoform diversity. Alternative splicing induces changes in the ability of CaM to regulate kinase activity and also regulates substrate specificity in vitro. What is the in vivo function of isoform diversity? They will examine the subcellular localization of the different isoforms and the ability of individual isoforms to phosphorylate unique sets of substrates in intact cells. 3) Regulation of CAMKII levels. They have identified a heterozygous mutation that, in combination with a CaMKII/+ genotype, leads to lethality. Mutations in this gene reduce the level of CaMKII mRNA and protein. They will investigate how this protein regulates CaMKII levels and splicing in the nervous system. 4) Regulation of Ether a go go (Eag) function by CaMKII. The Eag potassium channel has been shown to interact with CaMKII to regulate plasticity. How does CaMKII regulate Eag function? They will investigate the ability of CaMKII to modulate Eag complex formation and channel function. 5) Characterization of novel genes that interact with CaMKII. They will expand the number of identified targets and regulators of CaMKII using both enhancer and suppressor screens for additional interacting genes. Cognitive functions are impaired in many disease states. Understanding the biochemical basis of normal changes in neuronal properties is an important first step in understanding how pathological processes can disrupt brain function. CaMKII has been proposed to play a role in many plastic processes, from long-term potentiation to whole animal behavior. The ability to genetically manipulate CaMKII in Drosophila will allow us to understand not only its biochemical role, but its role in cellular and behavioral processes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: NM-404 A NOVEL IMAGING AGENT IN LUNG CANCER Principal Investigator & Institution: Schiller, Joan H.; Professor; Medicine; University of Wisconsin Madison 750 University Ave Madison, Wi 53706 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2004 Summary: (provided by applicant): Non-small cell lung cancer (NSCLC) is the leading cause of cancer death in the United States today. Accurate preoperative assessment of local, regional and distant metastatic spread is critical for optimal management. Positron emission tomography scanning is a more sensitive technique for identifying mediastinal nodal metastases, but has the disadvantage of expense and lack of availability. Our approach to the development of a sensitive, more readily available imaging test is to explore a more appropriate carrier molecule, which is key in achieving delivery of a radiopharmaceutical probe to the desired target issue. To do this, we have capitalized on radioiodinated phospholipid either analogs (PLE) as potential diagnostic imaging
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agents. These lipid analogues are selectively retained in tumor membranes due to their inability to become metabolized and cleared. In preclinical studies, we have shown these molecules have high levels of selective accumulation in a wide variety of murine and human tumors including a human NSCLC model (A549) in SCID mice. The objective of this proposal is to generate preliminary human data regarding the use of the secondgeneration PLE analog, NM-404 in imaging patients with NSCLC. The specific aims of this proposal are to: 1) Determine the optimal imaging characteristics of radiolabeled I131 NM-404 in ten patients with NSCLC. The pharmacokinetics, radiation dosimetry, biodistribution, and optimal imaging times will be determined. 2) Determine the specific tumor accumulation and metabolic fate of NM-404 in NSCLC tumors collected in five patients undergoing resection. 3) Collect preliminary data on imaging NSCLC tumors in ten patients with evaluable disease. Due to favorable efficacy, toxicity (two animal species at 200 times the anticipated imaging dose), and dosimetry results, an IND was recently filed to evaluate NM-404 in human prostate cancer patients. The results of this exploratory study will provide the preliminary data for a larger study designed to more accurately estimate the predictive power of NM-404 for staging and/or following response to therapy in NSCLC. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ONCOGENE DIRECTED SYNTHESIS OF CEPHALOSTATIN CANCER DRUG Principal Investigator & Institution: Fuchs, Philip L.; Professor of Chemistry; Chemistry; Purdue University West Lafayette West Lafayette, in 479072040 Timing: Fiscal Year 2002; Project Start 09-AUG-1996; Project End 31-MAY-2005 Summary: (Principal Investigator's Abstract) This proposal has seven medicinal/biological goals: (1) Synthesize up to seven North 1 and South 1 'slightly simplified' hexacyclic steroidal spiroketal subunits. Convert these materials to South-pyrazine--North trisdecacyclic (thirteen rings) pyrazines using our method for unsymmetrical pyrazine synthesis and compare their anticancer activity to cephalostain 1 (1.2nM avg. NCI panel). (2) Study the contribution of the central arene moiety to anticancer activity by testing pairs of unsymmetrical annulated pyridines derived from the best simplified hexacyclic steroidal subunits. (3) Construct and evaluate one member of a designed new class of inter-phylal agents termed the cephalofurthins to evaluate whether the geranyl geranyl moiety is a recognition element. (4) Prepare and test covalent conjugates of the new agent(s) with folic acid to assay for enhanced (targeted) activity for the treatment of the around 40 percent of cancers which over-express (ten to the 4th power) the folate receptor. (5) Use the biological data from testing of the proposed new materials to complete the mapping of the minimum pharmacophore for the cephalostatin class of antieoplastics. (6) Determine the biological mechanism of action of the trisdecacyclic pyrazines; and (7) Prepare 2-5g of the material which best combines high activity with expedient synthesis to provide a set of new biological tools as well as generating enough agent to initiate clinical trials. Synthesis of the seven hexacyclic spiroketals are projected to require 9-16 operations (compared with 29-31 operations in our 'first generation' synthesis). To accomplish the medicinal/biological goals, efficient new chemistry is required. (A) Utilize a vigorous interactive calculational approach to constantly evaluate synthetic approaches and biological testing data. (B) Test a new siloxysulfonium triflate reagent to effect stereospecific allylic oxidation of a vinyl ether. (C) Investigate the resulting ortho-methylthiophenyldimethylsilyl ether for chemospecific ion-pair self-immolative deprotection. (D) Develop a new annulation of unsymmetrical pyridine rings from 3-ketosteroids via an intramolecular aza-Horner
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reaction. (E) Generation of the Southern hemispheres requires hydroxylation of the unactivated angular methyl group at the steroidal CD ring junction. This will be accomplished by systematic exploration of the potential of a previously unknown stereospecific dyatropic rearrangement of beta-hydroxyketones and beta-hydroxy lactones to accomplish this transformation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: OPTIMIZATION OF PHOTODYNAMIC THERAPY USING MESOTETRA(HYDROXYPHENYL) CLORIN Principal Investigator & Institution: Shikowitz, Mark J.; Long Island Jewish Medical Center New Hyde Park, Ny 11040 Timing: Fiscal Year 2002 Summary: There is no cure for laryngeal papillomas. Conventional and experimental treatments can, at best, control the disease but many patients suffer frequent recurrences. We are currently testing photodynamic therapy (PDT), using dihematoporphyrin ether (DHE) (photofrin). The recurrence rate was reduced, and some patients are now free of disease. However, most patients still have recurrent disease, and not all responded. This project is a continued study of PDT efficacy, but with a new drug, meso- Tetra(hydroxyphenyl) Chlorin (mTHPC), which has potential for improved efficacy and lower photosensitivity. Patients with moderate to severe disease will be evaluated at fixed intervals for 6 months prior to PDT and 12 months post PDT, such that each patient will be used as his own control. The PDT group will also be compared to a concurrent control group with comparable disease severity receiving standard treatment. In addition to evaluating efficacy, we will ask why some patients respond while others do not. We will determine whether mTHPC levels in tissues correlate with response. We also will determine whether PDT with mTHPC induces changes in viral persistence or expression in clinically normal tissue. These studies should increase our understanding of PDT effectiveness. The specific aims address the following questions: l. Does mTHPC reduce the score reflecting recurrent growth of papilloma significantly? 2. Do age at disease onset or initiation of treatment, gender or disease severity correlate with change in score from pre- to post-treatment? 3. Do tissue and plasma levels of mTHPC at the time of treatment correlate with clinical outcome? 4. Does PDT with mTHPC eliminate persistence of HPV DNA? 5. If HPV infection remains, does PDT reduce or eliminate viral transcription and does this correlate with clinical outcome? Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ORGANIC SYNTHESIS REAGENTS ON TRANSITION METALS Principal Investigator & Institution: Grubbs, Robert H.; Victor & Elizabeth Atkins Professor of c; None; California Institute of Technology Mail Code 201-15 Pasadena, Ca 91125 Timing: Fiscal Year 2002; Project Start 01-MAR-1983; Project End 28-FEB-2005 Summary: (Applicant's Description) There has been a dramatic increase in the use of transition metal catalysts in organic synthesis. Most of these processes depend on the availability of catalysts to perform specific transformations that allow for a new array of bond constructions. One of the advantages of organometallic catalytic processes is the ability to tune the activity and selectivity by the modification of the ligands around a metal reaction center. Olefin methathesis has provided a new way of constructing carbon-carbon double bonds that has seen an explosion of new uses over the past few
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years. This new usage has resulted from the development of a family of easy to prepare catalysts that are robust and can be used under normal organic conditions. Key to the development of these catalysts has been the ability to design and control the ligand environment to regulate the reactivity and open new reaction modes. The present proposal builds on the past work in our group that has produced the work horse catalysts for majority of the applications in organic synthesis. By the appropriate modification of ligands, these catalysts have developed from ill-defined catalysts with low activity to a new generation of systems that open a wide variety of new applications. A part of this proposal will be directed toward the exploitation of a new family of catalysts that allow for the metathesis of olefins containing electronwithdrawing groups. The majority of the present proposal will focus on the development of new catalysts that allow for the stereoselective synthesis of olefins. The goal is to develop the catalysts and surrounding technology that allows high Z or E olefins to be prepared from simple starting materials by catalytic processes. The catalyst will control the stereochemistry of the resulting double bond, not the substrate. In a related way, catalysts that will allow the kinetic resolution of dienes to be performed to give products of high e.e. will be developed. Ligands that are easily prepared will be used in catalytic systems that can be used under normal organic conditions. This research is directed toward the development of strategies and catalysts that will make the olefin metathesis reaction the method of choice for the stereoselective synthesis of olefins and polyenes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PATHOGENESIS OF HERG MUTATIONS IN HUMAN LONG QT SYNDROME Principal Investigator & Institution: Zhou, Zhengfeng; Medicine; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2002; Project Start 05-DEC-2001; Project End 30-NOV-2005 Summary: (provided by applicant): Congenital long QT syndrome (LQTS) is a disease associated with delayed cardiac repolarization and prolonged QT intervals on the electrocardiogram, which can lead to ventricular arrhythmia with cardiac sudden death. One of the major forms of LQTS (LQT2) is caused by mutations in the human ether-ago-go-related gene (HERG) that encodes the rapidly activating delayed rectifier potassium channel. To date, more than 100 HERG mutations have been identified in patients with LQTS. Our previous work has shown that a major mechanism for loss of HERG channel function in LQT2 is defective protein trafficking which results in failure of mutant channels to reach the cell surface. We also showed that high affinity HERG channel blockers can correct defective protein trafficking of some LQT2 mutants. The goals of this proposal are (1) to study the mechanisms of defective protein trafficking of LQT2 mutant channels, and (2) to determine how HERO channel blockers rescue trafficking defective LQT2 mutant channels. Our hypotheses are (1) LQT2 mutations cause misfolding or improper assembly of HERO protein which is recognized by quality control system leading to ER retention and degradation by the proteasome, and (2) drugs that bind to HERO channels with high affinity act as pharmacological chaperones to promote proper folding or assembly in a conformation that permits trafficking to the plasma membrane. We will test these hypotheses by four specific aims: aim I to determine whether LQT2 mutations cause misfolding or improper assembly of mutant channels; aim 2 to study the role of molecular chaperones in the ER retention of LQT2 mutant channels; aim 3 to investigate the mechanisms by which LQT2 mutants are recognized and degraded by the proteasome; and aim 4 to elucidate the mechanisms by
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which high affinity HERG channel blockers correct defective protein trafficking of LQT2 mutant channels. We will use a combination of biochemical, immunohistochemical and patch clamp techniques to study wild type HERG and LQT2 mutant channels expressed in transfected tissue culture cells and in cell-free systems. These studies will strengthen our knowledge of how misfolded and improperly assembled LQT2 mutant channels are recognized, retained and degraded by the ER quality control system and how HERG channel blockers modify these processes and rescue LQT2 mutant channels. Elucidating these mechanisms is an important step towards the development of pharmacological strategies for therapies of congenital LQTS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: RECEPTORS
PHARMACOLOGY
OF
ENDOCANNABINOIDS
&
THEIR
Principal Investigator & Institution: Pertwee, Roger; University of Aberdeen Aberdeen Ab9 1Fx, Scotland Aberdeen, Timing: Fiscal Year 2002; Project Start 15-SEP-1995; Project End 31-MAR-2007 Summary: (provided by applicant): The cannabinoid receptors, CB1 and CB2, and endogenous ligands for these receptors, anandamide (AEA), 2-arachidonoyl glycerol (2AG) and 2-arachidonoyl glyceryl ether (noladin), together form the ?endocannabinoid system?. AEA interacts not only with CB1 and CB2 receptors but also with vanilloid VR1 receptors on sensory neurons. We propose to use analogs obtained from Drs. Martin and Razdan to look for differences in the structure-activity relationships of AEA analogs at CB1 and VR1 receptors and for evidence of ?cross-talk? between CB1 and VR1 receptors. The possibility that AEA or other endocannabinoids act on neuronal receptor types other than CB1, CB2 and VR1 will also be investigated. Some of these experiments will build on pilot data that we have recently obtained with an analog of ()-cannabidiol. These data point to the existence of an as yet uncharacterized SR141716Asensitive non-CB1, non-CB2 receptor in the mouse vas deferens. It is also proposed to characterize the pharmacology of the endocannabinoids, 2-AG and noladin, more fully by investigating their pharmacological actions in vitro. We also intend to investigate the presence of tonic activity of the endocannabinoid system in the peripheral nervous system and to establish the extent to which this arises from tonic endocannabinoid release or from the presence of constitutively active CB1 receptors. This will involve the development and/or characterization of inhibitors of processes responsible for terminating the actions of added or endogenously released endocannabinoids: (a) tissue uptake and (b) intracellular enzymic hydrolysis by fatty acid amide hydrolase. Both these processes are potential targets for drugs that by inhibiting endocannabinoid uptake or metabolism could be used to explore the physiological and pathophysiological role(s) of the endocannabinoid system. Such drugs might also come to be exploited clinically. Experiments in this part of the project will also be performed with a silent CB1 receptor antagonist if such a compound becomes available (from the projects of Drs. Razdan and Martin). Whilst some of our experiments will be carried out with isolated tissue preparations containing functional neuronal cannabinoid or vanilloid receptors (or other ?anandamide receptors?), we shall conduct other experiments (a) with brain membranes or CB1, CB2 or VR1-transfected cells that will be used for binding or functional assays or (b) with cells that express an AEA membrane transporter. Many of these experiments will be carried out with novel compounds provided by other members of this group. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PHOSPHATIDYLINOSITOL-3-KINASE AND AKT SIGNALING TARGETS Principal Investigator & Institution: Powis, Garth; Director of Basic Science; University of Arizona P O Box 3308 Tucson, Az 857223308 Timing: Fiscal Year 2002 Summary: Description (provided by applicant) The target area to be studied in this proposal are the molecular targets provided by survival (anti-apoptosis) signaling pathways in cancer cells. The objectives of the study are to develop specific, sensitive and robust assays for the molecular target, to validate them in cellular and animal models, and to use the assays to measure drug effects on their targets in patient clinical trials. The targets we will study in Project 1 are 1) phosphatidylinositol-3- kinase (Ptdlns-3-kinase), an enzyme that phosphorylates membrane Ptdlns at the D-3-OH position of myo-inositol ring to give 3-phospho-Ptdlns. Ptdins-3-kinase is over expressed in a number of human cancers and t leads to increased proliferation and inhibition of apoptosis. The tumor suppresser PTEN, which is lost in a number of human tumors, antagonizes Ptdins-3-kinase signaling by dephosphorylating Ptdlns-3phosphates. 2) A down stream target activated by Ptdlns-3-kinase is Akt (protein kinase B), itself an oncogene, that causes activation of a number of genes that inhibit apoptosis in cancer cells. Thus, Ptdins-3-kinase and Akt are important new anticancer drug targets on the same signaling pathway. We have identified the fungal metabolite wortmannin as a potent inhibitor of Ptdlns-3-kinase and an antitumor agent We have also identified 3-deoxy-phosphatidyl-myo-inositol ether lipid (DPIEL) as an inhibitor of the activation of Akt and an antitumor agent. Both drugs are currently undergoing preclinical development. The hypothesis, upon which our studies are based is that the inhibitors of Ptdins-3-kinase and Akt, wortmannin and DPIEL respectively, are promising new anticancer drugs that can be used to assess the usefulness of Ptdins-3-kinase and Akt as molecular cancer drug targets in animal models and in clinical trials in patients receiving these drugs. The goal of our studies is to provide a translational bridge between preclinical studies and clinical trials of molecularly targeted drugs and to develop more effective ways of preventing and treating cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PHOSPHOLIPID FLIP ACROSS THE YEAST PLASMA MEMBRANE Principal Investigator & Institution: Nichols, John W.; Associate Professor; Physiology; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2002; Project Start 01-FEB-2002; Project End 31-JAN-2006 Summary: (provided by applicant): A combination of selective synthesis, degradation and transport produces a non-random phospholipid distribution across the plasma membrane of most eukaryotic cells. The long-term objectives of our research program are to understand the mechanisms by which this asymmetric phospholipid distribution is established and its significance to cellular function. Preliminary experiments demonstrated that in the yeast, S. cerevisiae, inward-directed transport (flip) of phosphatidyicholine (PtdCho), as reported by a short chain, fluorescent-labeled PtdCho (NBD-PC), is coupled to the plasma membrane, proton-electrochemical gradient and is down-regulated by nutrient deprivation and by activated drug resistance transcription factors. A classical mutagenesis approach identified a loss of function mutation in a gene that reduces NBD-PC flip by >90% and dramatically increases resistance to the toxic lysophospholipid analogue, ET-18-O-CH3. This gene is predicted to encode a membrane protein with two transmembrane domains and has no identifiable functional motifs.
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Although no molecular function has been identified, two additional homologues exist in the S. cerevisiae genome as well as in a wide range of metazoans including humans. The specific aims of this proposal are to test the hypothesis that the three yeast genes encode plasma membrane-localized, inward-directed, phospholipid transporters (flippases) that are regulated in response to growth state and toxic stress. Specifically these genes will be characterized by classic molecular, genetic, and biochemical analyses to determine the relationship of their expression to in vivo function, their cellular location, specific domains essential to function, interactions with other proteins, response to nutrient deprivation and drug resistance factors, and their in vitro flippase activity. In addition to providing a better understanding of the role of phospholipid membrane dynamics to cell function, these studies will likely identify the mechanism of internalization of ET-18O-CH3, and other ether lipid drugs, that have anti-fungal. anti-protozoal, and antineoplastic activity. Understanding the mechanism by which these drugs are internalized may lead to the discovery of new drugs of this class that are internalized more efficiently and are less susceptible to the development of resistance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SECRETION
PHOSPHOLIPID-DERIVED
MEDIATORS
AND
INSULIN
Principal Investigator & Institution: Turk, John W.; Professor; Pathology and Immunology; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 01-JUL-1984; Project End 30-JUN-2006 Summary: (provided by applicant): Our hypothesis in the previous project period was that a pancreatic islet Ca2+ -independent phospholipase A2 (iPLA2B) is activated upon stimulation with secretagogues and that its products participate in B-cell signaling. We have now cloned iPLA2B from islet mRNA and determined the human iPLA2 gene structure and chromosomal location. Recombinant iPLA2B is inhibited by a bromoenol lactone (BEL) suicide substrate that also suppresses glucose-induced insulin secretion, and iPLA2B overexpression. amplifies insulinoma cell secretion and proliferation. We have also found that arachidonate-containing plasmalogens, which participate in membrane fusion and exocytosis, are abundant in B-cells, and these ether lipids are produced from peroxisome-derived intermediates. An iPLA2gamma isozyme targeted to peroxisomes is also expressed in islets and may participate in regulating complex lipid synthesis. Peroxisomal dysregulation could contribute to pathologic tissue lipid accumulation in diabetes. The recent success of human islet transplantation and the limited availability of donor organs highlights the need to identify genes and their products that affect B-cell secretion and survival to facilitate construction of engineered B-cell lines that might serve as an alternate source of transplantable B-cells. In the coming project period, we propose to further characterize roles of iPLA2 isozymes, complex lipids, and peroxisomes in B-cell function and to develop genetically modified mice with altered iPLA2B expression for in vivo studies. Aim 1 is to characterize secretion, proliferation, and other responses of insulinoma cells and islets in which iPLA2B expression is manipulated by molecular biologic means. Aim 2 is to characterize roles of complex lipids in B-cell function and of iPLA2 isozymes and peroxisomes in lipid formation. Aim 3 is to characterize regulatory post-translational modifications of the iPLA2B protein. Aim 4 is to conduct cell biologic studies of iPLA2B translocation among cellular compartments and interactions with other proteins. Aim 5 is to develop genetically modified mice with altered iPLA2B expression for in vivo studies. We have prepared mouse embryonic stem cells in which an iPLA2B allele has been disrupted by homologous recombination as a step to generate mice that do not express the enzyme.
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Project Title: PHOTOREACTIVE SELF-ASSEMBLED MONOLAYERS Principal Investigator & Institution: Guire, Patrick E.; Surmodics, Inc. 9924 W 74Th St Eden Prairie, Mn 55344 Timing: Fiscal Year 2002; Project Start 01-SEP-1998; Project End 31-AUG-2004 Summary: (provided by applicant): This project is designed to optimize and extend the ultrathin coating technology demonstrated in the Phase I project, which is aimed at facile, cost-effective, and broadly applicable thin-film coatings for the passivation of biosensor and medical device surfaces. Prevention of non-specific binding of proteins and other biomolecules is important for a large variety of biomaterial, optical, electrical and structural surfaces which suffer fouling (protein and cellular adhesion, microbial proliferation, and pore plugging) from functioning in contact with physiological fluids and pharmaceuticals. A new class of block copolymer reagents was prepared and demonstrated to provide self-assembled monolayers which can be photochemically fixed on the surface. After spontaneous formation from aqueous coating fluid, the monolayer film on the hydrophobic surface is stabilized through covalent attachment to the surface and in situ polymerization or crosslinking of diblock polymer molecules. The resulting "field of grass" from the hydrophilic block inhibits biomolecule adsorption and can provide attachment sites for desired biomolecules such as heparin. This Phase II effort will synthesize improved test models of this new class of multifunctional selfassembling monolayer molecules. "Living polymerization" will be used to prepare these photoreactive macromer surfactants, which will be use-tested on distal protection screens and hemodialysis membranes. PROPOSED COMMERCIAL APPLICATION: This effort is expected to provide new reagents and coating methodology for distal protection devices (thrombi collection screens) and hemodialysis membranes. Almost one million patients need hemodialysis three times per week. These coatings would provide reduced fouling and increased flux for microporous medical devices. The proposed work will also extend the block copolymer technology to alternate polymer backbones for increased lubricity and to biomolecule immobilization for increased hemocompatibility, providing better coatings for a variety of medical devices. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PHOTOSENSITIZER STRUCTURE/BIOLOGICAL RESPONSES-RATIONAL PHOTOSENSITIZER DESIGN Principal Investigator & Institution: Dougherty, Thomas J.; Chair; Roswell Park Cancer Institute Buffalo, Ny 14263 Timing: Fiscal Year 2002 Summary: The overall goal of this proposal is to further our understanding of how photosensitizer structure affects the biological response to photodynamic therapy (PDT) and to use this information to develop an approach for rational design of photosensitizers for PDT. This will be done by utilizing extensive information already developed in our laboratory and others and applying similar and expanded in vivo and in vitro studies to selected photosensitizer series. The specific aims are: (1) To expand an existing in vivo quantitative structure activity (QSAR) study of a congeneric series of pyropheophorbide ether photosensitizers for photodynamic therapy to address issues for both efficacy and selectivity. (2) To prepare additional congeneric series of compounds which differ in critical ways from the pyropheophorbide ethers, and to determine whether similar QSAPs exist. (3) To explore in vivo the possible importance
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of specific, optimal intracellular binding sites in both the pyropheophorbide ether series and the new series emerging from Aim 2. (4) To use the existing and new data as they are developed in Aims 1, 2, 3 and Project III to carry out molecular modeling using 3D QSAR as well as modeling specific binding to site II of albumin (benzodiazepine site), the peripheral benzodiazepine receptor and other important binding sites identified in Project III. (5) To introduce into clinical trials the optimal pyropheophorbide ether (hexyl) identified in the QSAR study of a congeneric series of pyropheophorbide ether. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ISCHEMIA
PLASMALOGEN
CATABOLISM
DURING
MYOCARDIAL
Principal Investigator & Institution: Ford, David A.; Biochem and Molecular Biology; St. Louis University St. Louis, Mo 63110 Timing: Fiscal Year 2002; Project Start 01-FEB-2000; Project End 31-JAN-2004 Summary: Ischemic heart disease is responsible for the sudden death of over 500,000 U.S. citizens per year and is a leading public health problem in the United States. The pathophysiological sequelae following an acute myocardial infarction normally include depressed myocardial function leading to congestive heart failure and death. Thus, understanding the biochemical mechanisms responsible for ischemia-induced myocardial dysfunction, as well as reperfusion injury, represents a major U.S. health concern. One biochemical mechanism that likely contributes to myocardial dysfunction in ischemic myocardium is accelerated phospholipid catabolism. Since plasmalogens are the predominant phospholipid of myocardium, we have directed our efforts toward identifying accelerated plasmalogen catabolism during myocardial ischemia as a biochemical mechanism that mediates myocardial dysfunction during ischemia. We have previously demonstrated that plasmalogen-selective, calcium-independent phospholipase A2 (iPLA2) is activated in the membranes of ischemic myocardium and our preliminary studies now show that ischemic injury is reduced in hearts that are pretreated with the specific iPLA2 inhibitor, HELSS. We have also recently found that the nuclear membranes isolated from myocardium are enriched with plasmalogen molecular species and that catalytically-active iPLA2 is translocated to the nucleus during myocardial ischemia. These data suggest that accelerated nuclear membrane plasmalogen catabolism may participate in nuclear signaling responses that mediate alterations in myocardial gene expression. Additionally, we have recently discovered that myeloperoxidase, released from activated neutrophils, generates reactive chlorinating species that attack the vinyl ether bond of plasmalogens. These data suggest that cardiac myocyte and endothelial cell plasmalogens are targets for reactive chlorinating species produced by activated neutrophils during ischemia/reperfusion injury. Accordingly, the overall hypothesis of this proposal is that accelerated plasmalogen catabolism during myocardial ischemia and reperfusion is a key mechanism in cardiac injury and in nuclear signaling responses. We have three specific aims: Specific Aim 1 is to test the hypothesis that nuclear membrane plasmalogen catabolism is accelerated during myocardial ischemia and reperfusion. Specific Aim 2 is to test the hypothesis that accelerated plasmalogen catabolism mediates both cardiac injury and nuclear signaling responses during ischemia and reperfusion. Specific Aim 3 is to test the hypothesis that myocardial ischemia/reperfusion injury is mediated, in part, by plasmalogen degradation by reactive chlorinating species released from activated neutrophils. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PRECONCENTRATORS BASED ON SELF-ASSEMBLED REAGENTS Principal Investigator & Institution: Cox, James A.; Professor; Chemistry and Biochemistry; Miami University Oxford 500 E High St Oxford, Oh 45056 Timing: Fiscal Year 2002; Project Start 01-FEB-2002; Project End 31-JAN-2005 Summary: (provided by applicant): The long-term objective of our program is to develop analytical methods on micromachined platforms for biomedical analytes. The present proposal deals with the separation and preconcentration of selected analytes onto reagents that are tethered to gold electrodes or nanoclusters. The tethering is via molecular self-assembly. Fluorogenic crown ethers will be modified with alkanethiol tags and attached to gold by spontaneous formation of the thiolate. Selective uptake of lithium or potassium ion by the crown will provide the separation step. Release of the entire assembly into a flowing carrier solution by oxidation of the thiolate will be one strategy that will allow quantifying the results at a downstream detector. Prior to the next measurement, the assembly will be re-made or a new electrode will be placed in the system. Alternatives of the basic experiment include other combinations of capture reagent and analyte, e.g. a cyclophane and phenylalanine or adrenaline; tethering reagents to gold nanoclusters embedded in a flow-through silica sol-gel electrode; and chemical release that retains the integrity of the self-assembled monolayer on gold. These systems are designed specifically to be integrated with microchip and micromachined platforms to yield Total Analytical Systems. Applications as disposal devices for selective determinations of analytes in blood are envisioned. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PROBING CATALYSIS BY HYDROGEN BONDS Principal Investigator & Institution: Anslyn, Eric V.; University Distinguished Teaching Profes; Chemistry and Biochemistry; University of Texas Austin 101 E. 27Th/Po Box 7726 Austin, Tx 78712 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2006 Summary: (provided by applicant): Enzymes often use hydrogen-bonding interactions and general-acid catalysis as part of their catalytic machinery. The two effects are similar, but distinctly different. In simple hydrogen-bonding catalysis, the proton is not transferred, while in general-acid catalysis the proton is transferred. Although proton transfer is one of the simplest reactions, how these two forms of catalysis function still has facets that are under debate. In this proposal we explore how these two forms of catalysis are influenced by hydrogen bond geometry, solvation, and differences in acidity of the donor. This is first done within the context of a D/H scrambling experiment where the hydrogen-bonding interaction is relevant to the debate about low barrier hydrogen bonds (LBHBs). Our interpretation of the theory of LBHB catalysis is that very steep Bronsted plots should be evident. Our second study is oriented at determining how hydrogen bonds and metal coordinations influence carbon acidity. We will use synthetic mimics of enolase and racemase enzymes to quantitate the stabilization imparted to enolates, and then measure their ability to increase the acidity of the enolate's conjugate acids. Our last study of hydrogen-bonding and general-acid catalysis involves quantitating the ability of imidazoliums, ammoniums, and guanidiniums to catalyze a phosphoryl transfer reaction. Enzymes commonly use these functional groups, but their role, as hydrogen-bonding or as general-acid catalysts have not been deciphered. In all these projects described herein, we will use physical organic and molecular recognition techniques to probe aspects of catalysis. We have carefully chosen problems where model studies such as those presented herein can answer the
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questions, while the literature studies on the enzymes themselves have only lead to further debate. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REACTIVITY AND SELECTIVITY OF REACTIONS IN POLAR MEDIA Principal Investigator & Institution: Grieco, Paul A.; Professor; Chemistry and Biochemistry; Montana State University (Bozeman) Bozeman, Mt 59717 Timing: Fiscal Year 2002; Project Start 01-JUL-1980; Project End 31-MAR-2004 Summary: The major focus of this grant renewal application is to further examine the reactivity and selectivity of a number of organic reactions in highly polar media such as 3.0-5.0 M lithium perchlorate-diethyl ether with applications to molecules of biological interest. During the course of this investigation we will continue to search for substitutes for lithium perchlorate in ether. In addition we remain focused on anions that are more weakly coordinating than perchlorate. This proposal is divided into three parts. The first section concentrates on studying the reaction of nucleophiles with oxabicyclo[2.2.1]heptanes and oxabicyclo [3.2.1]octanes i highly polar media. All the proposed studies will be of a fundamental nature in order to define the scope, limitations, and mechanism of this potentially very useful new reaction. Applications to the total synthesis of epothilone B, ulapualide A, aplyronine A, morphine, and the C(19)-C(27) aliphatic building block of rifamycin S are proposed. The second part of this grant application focuses on extending the ionic intramolecular Diels-Alder reaction in polar media for the construction of carbocyclic ring systems. Substrates will be examined wherein conformationally restricted tethered dienes are attached to the alpha, beta, and delta carbon atoms of the dienophiles. Application to syntheses of quadrone, magellaninone and pentalenene are proposed. In the third part of this grant application we will examine unique solvent systems (e.g. Li2B12H12-acetone, MgB12H12-acetone) in hopes of finding new opportunities for altering transition states while accelerating organic reactions. In addition we plan to examine lithium borates and lithium phosphates wherein the anions are chiral in hopes of catalyzing substitution reactions of allylic and benzylic acetates via single diastereomeric ion pairs which undergo facial discrimination in the attack by a nucleophile. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: RHOMOCYCSTEINASE FOR HOMOCYSTEINE ASSAY Principal Investigator & Institution: Tan, Yuying; Anticancer, Inc. 7917 Ostrow St San Diego, Ca 92111 Timing: Fiscal Year 2002; Project Start 01-APR-1999; Project End 31-AUG-2003 Summary: (applicant's abstract): There is an important need to develop accurate, simple and economic methods to determine total homocysteine (tHCY) levels in order to make such an assay a recognized part of standard medical practice available for the general population. HPLC methods for tHCY measurement have been developed and have been used as the standard assay for tHCY. HPLC is highly specialized and low throughput, however. A fluorescence polarization immunoassay for tHCY has also been developed. However, it appears that this method can only be practiced with specialized lowthroughput instrumentation. The currently used assays are therefore neither suitable for high-throughput tHCY measurement and nor for routine clinical laboratories. In Phase I, a simple high specificity and sensitivity tHCY enzymatic assay was developed using a homocysteine-speciflc recombinant homocysteinase (rHCYase) and H2Sspecific
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chromogenic agent N, N-dibutylphenylenediamine (DBPDA). The tHCY enzymatic assay highly correlates to the standard HPLC tHCY assay. The goal of Phase II is to apply the total homocysteine (tHCY) enzymatic assay developed in Phase I for broad base clinical use to enable tHCY to be a routine test as a risk factor for cardiovascular and other diseases. In order to achieve this specific goal, the specific aims of the Phase II application are to adapt the tHCY enzymatic assay on examples of widely-used instruments, a robotic microtiter plate reader and an automatic chemistry analyzer adapted for high throughput screening and routine testing. To adapt the tHCY enzymatic assay for robotic rnicrotiter plate readers, the Tecan Genesis (100/8) Robotic Sampler Processor will be used. To adapt the tHCY enzymatic assay for automatic chemistry analyzers, the Hitachi 912 automated chemistry analyzer will be used. Validation of the robotic microtiter plate reader and automatic chemistry analyzer tHCY enzymatic assays will be carried out by comparing their performance with the manual tHCY enzymatic assay thus far developed and the HPLC tHCY assay in a prospective clinical trial of the efficacy of high-dose folic acid to lower tHCY levels and improve outcome of patients having both end stage renal disease and cardiovascular disease. The tHCY enzymatic kits for these applications will be ready for commercial launch at this point. PROPOSED COMMERCIAL APPLICATION: Not Available Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: RIGID-THREAD ROTAXANES FOR ARTIFICIAL MOLECULAR MUSCLES Principal Investigator & Institution: Belitsky, Jason M.; Chemistry and Biochemistry; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 01-NOV-2002; Project End 31-AUG-2005 Summary: (provided by applicant): Artificial molecular muscles might someday be core components of artificial limbs. In the near term they will be useful to power mechanical movements in nanoscale devices. Switchable rotaxanes composed of polyether threads containing pi-donors encircled by a macrocyclic pi-acceptor have already been successfully incorporated in functional molecular electronic devices. To develop a rotaxane-based molecular muscle, it is intuitively desirable to replace the polyether threads with more rigid linkers. However, the ether oxygens are necessary for a successful template-directed synthesis, which relies on weak noncovalent interactions, particularly [CH-O] hydrogen bonds, in organic solvents. In an aqueous self-assembly process, the hydrophobic effect is expected to dominate, a feature which may allow for the efficient synthesis of rotaxanes with increased rigidity. For potential therapeutic and diagnostic applications of interlocked molecules, it is advantageous to study their switching behavior in aqueous solution. This proposal describes the self-assembly in aqueous solution of rigid-thread [2]pseudorotaxanes, [2]rotaxanes, and palindromic [3]rotaxanes which have been designed to promote contraction and extension, as a first step in the development of an artificial molecular muscle, and an examination of the molecular shuttling behavior of these rigid-thread rotaxanes in aqueous and organic solutions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ROLE OF HERG-LIKE K+ CHANNELS IN G.I. SMOOTH MUSCLE Principal Investigator & Institution: Akbarali, Hamid I.; Associate Professor; Physiology; University of Oklahoma Hlth Sciences Ctr Health Sciences Center Oklahoma City, Ok 73126
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Timing: Fiscal Year 2002; Project Start 15-SEP-2000; Project End 31-AUG-2004 Summary: The objective of this proposal is to pursue studies on the genesis of the resting membrane potential in visceral smooth muscle. The resting potential is one of the major determinants of smooth muscle excitability and is largely governed by the permeability to K+ ions. Preliminary studies demonstrate that the resting potential of several gastrointestinal smooth muscle is, in part, controlled by a unique human ether-ago-go (HERG)-like K+ channel. This K+ current demonstrates inward rectification and appears to be a potential target of the commonly used prokinetic agent, cisapride. The first specific aim is to characterize the detailed biophysical properties of the HERG-like K+ current in gastrointestinal smooth muscle cells. The voltage- dependent kinetics of this current in single cells will be determined using the patch clamp technique and its physiological role in resting potential and repolarization of the action potential will be characterized. The second specific aim is to identify the pharmacological regulation of the smooth muscle HERG-like K+ currents. in these studies, the effects of class III antiarrhythmic compounds which are known HERG channel blockers will be determined, and the mechanism of action of the prokinetic agent, cisapride on the HERG currents will be investigated. Preliminary data show that cisapride attenuates the HERG currents in single gastrointestinal smooth muscle cells and depolarizes muscle strips. The effects of the excitatory neurotransmitter, acetylcholine on these K currents will be determined and the involvement of the second messenger regulation by protein kinase C will be evaluated. In the third specific aim, the protein expression of HERG-like channels will be localized by immunofluorescence techniques and by Western blotting. The fourth specific aim is to define the relationship of the HERG-like conductance with those of the other inwardly rectifying currents in smooth muscle. In these studies the role of IKi, ATP- sensitive K+ channel and the hyperpolarization-activated cation currents will be examined. Inhibitory modulators of the HERG-ike K+ channels in smooth muscle may provide new approaches to treatment of disorders that involve smooth muscle hyperexcitability. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SELECTIVE ANESTHETIC ACTIONS ON NMDA RECEPTORS Principal Investigator & Institution: Criswell, Hugh E.; Research Associate Professor; Anesthesiology; University of North Carolina Chapel Hill Aob 104 Airport Drive Cb#1350 Chapel Hill, Nc 27599 Timing: Fiscal Year 2002; Project Start 01-AUG-1999; Project End 31-JUL-2004 Summary: Volatile anesthetics produce a balanced anesthesia by acting on a number of neural systems. While early studies attributed this array of actions to a nonspecific fluidization of phospholipid membranes, more recent work has pointed to specific actions of anesthetics on ion channels. Selective blockade of NMDA- sensitive glutamate receptors by volatile anesthetics has been linked to their amnesic, analgesic, hypnotic and neuroprotective action. Recent work by our laboratory and others has shown that both volatile anesthetics and n-alcohols have differing effects on NMDA-receptor function depending on the brain area studied. Further, we have preliminary data showing that the effects of volatile anesthetics on the NMDA receptor are influenced by the presence of the exon-5 splice in the NMDAR-1 subunit the receptor. The proposed studies will examine the effect of various volatile anesthetics on the electrophysiological properties of native NMDA receptors in rat brain and correlate those effects with the subunit composition of the receptors using single-cell RT-PCR. Specific Aim I will use whole-cell patch recording of NMDA- induced currents from acutely dissociated neurons and neurons maintained in primary culture to examine the effect of isoflurane
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on NMDA receptor function. Following recording of the NMDA- mediated currents, cytoplasm will be extracted from individual cells to analyze the mRNAs for NMDA receptor subunits present in each cell. This specific aim will extend our preliminary data linking the presence of the exon-5 splice to increased anesthetic potency and extend this work to other NMDAR-1 and NMDAR-2 isoforms. This aim will test the hypothesis that the effect of isoflurane on NMDA receptor function depends upon the subunit composition of that receptor. Specific Aim II will compare the effects of ethyl ether, isoflurane, enflurane, halothane and chloral hydrate on whole- cell currents elicited by NMDA and correlate those responses with the presence or absence of specific NMDA receptor subunit mRNAs. This specific aim will test the hypothesis that volatile anesthetics share a common dependence on subunit composition. Specific Aim III will examine the effect of volatile anesthetics on NMDA receptors expressed in HEK-293 cells transfected with combinations of NMDA receptor subunits found to influence anesthetic potency in native receptors. This Aim will verify experimentally, the correlational data from Specific Aims I and II. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SHAKER K+ CHANNELS-FUNCTION OF S4 AND BIOCHEMISTRY Principal Investigator & Institution: Papazian, Diane M.; Professor; Physiology; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 01-DEC-1989; Project End 30-JUN-2004 Summary: The long term goal of this research is to elucidate the physical mechanism of voltage-dependent activation in K+ channels by identifying structural interactions in the voltage sensor and characterizing their rearrangements during activation. Shaker and ether a go-go (eag) K+ channels will be expressed in Xenopus oocytes for electrophysiological, biochemical, and spectroscopic analysis. Unlike Shaker, eag activation is dramatically modulated by extracellular Mg2+. To obtain unique insights into voltage sensor, in voltage-dependent transitions during activation will be investigated. The specific aims of the proposal are: 1) To test the hypothesis that eagspecific acidic residues in S2 and S3 compose the Mg2+ binding site. 2) To test the hypothesis that the Mg2+ binding site in eag represents a general structural constraint in other K+ channels, including HERG and Shaker. 3) To identify structural constraints in the Shaker voltage sensor. This aim concludes work in the previous period. 4) To test the feasibility of site-directed fluorescent labeling in eag, and then use this approach to test the hypothesis that the S2 segment participates in rate-limiting, Mg2+-sensitive, conformational changes at hyperpolarized potentials during eag activation. Dr. F. Bezanilla of UCLA will collaborate in these experiments. This proposal describes basic research aimed at understanding the structure and function of voltage-dependent ion channels. The research is likely to have significant health relevance because ion channels play essential biological roles in the brain, heart, and skeletal muscle. The research may also contribute to our arrhythmias and neurological seizures. Among K+ channels, eag homologues, which are widely expressed in the brain and heart, are uniquely regulated by Mg2+, and thus may underlie some of these effects. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: STEREOSELECTIVE POLYMERIZATION OF VINYLETHERS Principal Investigator & Institution: Lavoie, Adrien R.; Chemistry; Stanford University Stanford, Ca 94305
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Timing: Fiscal Year 2002; Project Start 21-AUG-2002 Summary: (provided by applicant): A polymer's stereoregularity influences its rheology and thus, its potential as a useful material. As such, the next generation of biocompatible polymers is dependent upon the ability to precisely control stereoregularity. Potential uses for stereoregular polymers include: end surfaces for bones and joints, skin grafts, biodegradable materials, controlled drug delivery systems, and synthetic cornea replacements to name a few. In light of these uses, a method for the stereoregulation of vinyl ether polymerization could lead to fantastic new opportunities in the fields of tissue engineering and the development of biocompatible materials. This proposal outlines three general novel strategies aimed toward the stereospecific polymerization of vinylethers. The first, asymmetric Lewis acid catalysis, will employ asymmetric Cu and Ti complexes to be screened for the ability to initiate and provide stereocontrol and molecular weight control in polymerization. In the second method, carbenes and thiazol-2-ylidenes will be modified in order to generate electrophilic zwitterions. The third method that we propose integrates both Lewis-acid and organocatalytic polymerization methods with chiral counter-anions in order to probe the effects on polymer stereoregulation, catalyst stability, catalyst activity, and chain-transfer characteristics. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: STEREOSELECTIVE SYNTHESIS OF CYCLIC ETHERS Principal Investigator & Institution: Evans, P Andrew.; Professor; Chemistry; Indiana University Bloomington P.O. Box 1847 Bloomington, in 47402 Timing: Fiscal Year 2004; Project Start 01-MAY-1997; Project End 31-DEC-2007 Summary: (provided by applicant): The aim of this proposal is the development of new tandem bismuth-catalyzed inter- and intramolecular etherification reactions for the construction of non-adjacent and fused polycyclic ethers. The bismuth-catalyzed etherification reactions exhibit remarkable catalytic activity and unusual chemoselectivity, in which the direct addition to the carbonyl does not compete with the formation of the oxocarbenium ion. The bismuth catalysts are commercially availabile, inexpensive and non-toxic, making them ideal for many synthetic applications. The development of metal-catalyzed multi-component reactions for the rapid construction of complex polycyclic skeletons provides new and exciting opportunities for the synthesis of pharmacologically active agents. The specific areas of interest are summarized as follows: Tandem Stereoselective Intra- and Intermolecular Etherifications: The first section of the proposal will involve the development of tandem diastereoselective bismuth-catalyzed etherification reactions, through the sequencing of oxocarbenium ions, for the construction of non-adjacent tetrahydropyran rings. This methodology will then be applied to a convergent total synthesis of the potent antitumor agent leucascandrolide A. Annulation and Reductive Etherifications for Fused Polycyclic Ethers: The second aspect of the proposal details the development of new bismuthcatalyzed one-step annulation reactions in combination with ring-closing metathesis for the construction of polycyclic ethers. We will also examine the merit of temporary silicon-tethered ring-closing metathesis followed by the stereoselective bismuthcatalyzed reductive etherification, and its subsequent application to the DEFGH portion of the gambieric acids A-D. Finally, we will examine a series bismuth-catalyzed bisreductive etherification reactions for the construction of linear fused polycyclic ethers. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: STRUCTURE AND FUNCTION OF ENTF Principal Investigator & Institution: Walsh, Christopher T.; Assistant Professor; Harvard University (Medical School) Medical School Campus Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-MAY-2002; Project End 30-APR-2007 Summary: The E. coli non-ribosomal peptide synthetase (NRPS), a four-protein (EntE, B, D, F) six-module system is a paradigm for a bacterial "assembly-line" enzymes that produce molecules, such as antibiotics and metal-chelating siderophores. Our goal is to study the 142 kDa EntF component consisting of a condensation domain (C,49 kDa), an adenylase (A, 59 kDa) a peptidyl carrier or thiolation module (T, 9 kDa), and a thioesterase (TE, 27 kDa). EntF cooperates with EntB which consists of an A and a T domain. We plan to solve structures of individual domains and several di-domain constructs or even larger portions using modern NMR methods. Of particular interest will be to elucidate the orientation of the individual domains relative to each other, which will be pursued by measuring residual dipolar couplings and utilizing paramagnetic broadening of NMR signals by strategically induced spin labels. The relative orientation of the domains is of crucial importance for understanding the mechanism of how the fragments of the growing peptide chain are brought together. The research will be pursued with four specific aims. Aim 1 is to establish expression and isotope labeling of individual domains of EntF and EntB, as well as di- tri- and tetra-domain constructs and to explore the feasibility of NMR spectroscopy of the constructs. In this aim we will include segmental labeling using inteins or related technologies. Aim 2 is to perform resonance assignments starting with the single domains and proceeding to multi-domain constructs of increasing complexity. Aim 3 is to solve structures of individual domains an larger fragments. Aim 4 is to elucidate the orientations of the domains to each other and relative to the individual active sites. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: SYNTHESIS & PROPERTIES OF NOVEL POLYMERS W/ ROTAXANE ARCHITECTURES Principal Investigator & Institution: Gibson, Henry W.; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002 Summary: This effort is concerned with the synthesis and characterization of a new type of polymer architecture, polyrotaxanes. These structures consist of linear polymers which have been threaded through the cavities of a large number of cyclic molecules. The polyrotaxanes consist then of a physically bonded set of molecules; there is no covalent bond between the linear and cyclic species. We have utilized aliphatic crown ethers nearly exclusively as the cyclic molecules. The linear polymers have included polyesters, polyurethanes, polyamides, polystyrene, poly(phenylene vinylene), poly(ether ketone)s and poly(ether sulfone)s. Significant changes in properties result from the physical linkage of the cyclic species into the polymer; these include enhanced solubility, solvent induced changes in hydrodynamic volume, alteration of the glass transition temperature and introduction of crystalline domains of the macro-cyclic component. These polymeric systems, accessible by step growth (condensation), free radical, anionic, or cationic techniques, possess unique physical and chemical properties. Molecular engineering should provide materials useful in a number of application, such as adhesives, composite matrices, polymer blending and toughening, energy and electron transfer, controlled-release membranes, and perhaps further into the future, molecular-level electronic devices.
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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SYNTHESIS CYCLIZATIONS
OF
ANTICANCER
AGENTS
USING
PRINS
Principal Investigator & Institution: Rychnovsky, Scott D.; Professor; Chemistry; University of California Irvine Irvine, Ca 926977600 Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-JUL-2004 Summary: The principle synthetic target in this proposal is phorboxazole B, a remarkably potent anticancer agent. Phorboxazole B was tested against the NCI's panel tumor cell lines and was found, for example, to inhibit the growth of colon tumor cells HCT-116 (GI50 4.36 X 10(-10) M). Two of the key segments of phorboxazole were prepared in the previous grant period using our segment-coupling Prins cyclization. Completion of the synthesis will be accomplished by assembly of the macrolide A and attaching the side chain B. Synthetic phorboxazole will be made available to collaborators to evaluate its mode of action, and to evaluate its potential as an anticancer agent. We are developing Prins cyclizations for the synthesis of complex tetrahydropyran rings found in many natural products. In this new grant period we will investigate the stereoselectivity and regioselectivity of the segment-coupling Prins cyclization. A regioselective version of this reaction is the key step in a proposed synthesis of the natural product ratjadone. We will also develop two new oxacarbenium ion cyclizations: the Mukaiyama aldol-Prins (MAP) cyclization and the carbon-trapping Prins cyclizations. Simple versions of both of these new reactions have been demonstrated and presented in the progress report. The MAP reaction combines a Mukaiyama aldol reaction of alkyl enol ether with a Prins cyclization to produce two new carbon-carbon bonds, one new ring and several stereogenic centers. It is the basis for a proposed highly convergent synthesis of leucascandrolide A. The carbon-trapping Prins cyclization produces two new carbon-carbon bonds, one ring and several stereogenic centers. It is the basis of a proposed synthesis of epicalyxin F, an anticancer compound isolated from a traditional Chinese medicinal plant. These new methods will be powerful tools for the assembly of tetrahydropyran natural products. Each of the synthetic targets selected for investigation has antitumor activity. Phorboxazole B is clearly the most important because of its extreme potency and because of the dearth of naturally available material. However, the other synthetic targets, leucascandrolide A, epicalyxin F and ratjadone also have interesting antitumor activity, and these synthetic products will be made available to collaborators for evaluation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SYNTHESIS OF NEW NNRTLS FOR THE TREATMENT OF AIDS Principal Investigator & Institution: Cushman, Mark S.; Medicinal Chem/Molecular Pharm; Purdue University West Lafayette West Lafayette, in 479072040 Timing: Fiscal Year 2003; Project Start 01-JAN-1999; Project End 31-MAR-2006 Summary: (provided by applicant): A current need exists for novel non-nucleoside HIV1 reverse transcriptase inhibitors (NNRTIs) that: 1) have lower toxicities than the existing NNRTIs, 2) have unique resistance mutation profiles and remain active against mutant reverse transcriptases that are resistant to the existing NNRTIs, 3) have the ability to suppress the emergence of resistant viral strains when used in combination with other anti-HIV agents, 4) have synergistic anti-HIV activity in combination with other anti-HIV agents, 5) are metabolically more stable than the existing ADAMs and therefore have enhanced bioavailabilities, 6) have a wide range of activity vs. various
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HIV-1 strains, and 7) have high affinities for RT, and therefore have the potential for high anti-HIV potency. Our research group has recently reported the design and synthesis of a novel series of alkenyldiarylmethane (ADAM) NNRTIs that are potent inhibitors of the cytopathic effect of HIV-1. Although some of the ADAMs inhibit the cytopathic effect of HIV-1RF in CEM-SS cell culture at low nanomolar concentrations, the potential therapeutic utility of the ADAMs is compromised by the presence of three methyl ester moieties that are readily hydrolyzed by plasma esterases. Consequently, the main goal of the present project is to find suitable replacements for these three labile esters that will be metabolically stable and will also retain the potent anti-HIV activity of the parent compound. Preliminary studies have shown promising activity resulting from oxazolidinone and methyl ether replacements of the methyl esters, and a variety of additional metabolically stable moieties are proposed. These include ethyl ketone, isobutylene, enol ether, ether, vinyl ketone, n-propyl, alpha, alpha -difluoroketone, difluoroenol ether, tetrafluoroisobutylene, difluoroisobutylene, imidoyl fluoride, amide, thioester, thionoester, and dithioester replacements. Syntheses are proposed for ADAMs containing each of these structurally simple methyl ester replacements. The hydrolytic stabilities of the new ADAMs will be investigated in human plasma. In addition, the anti-HIV activities of the new ADAMs will be determined in a variety of biological systems. The potencies of the compounds as inhibitors of the cytopathic effect of a variety of HIV-1 strains will be determined in cell culture. The cytotoxicities of the compounds in uninfected lymphocytes will also be investigated. The enzyme inhibitory activities of the ADAMs will be established in cell-free systems using both wild type and mutant proteins. Mechanism of action studies will include both time-of-addition (time course) studies as well as the examination of the compounds in a number of assays employing targets that represent various stages in the replication cycle of the virus. The synergistic activities of the compounds with existing anti-HIV agents will be established. The activities of the ADAMs vs. NNRTI resistant viruses will be investigated. The aqueous solubilities of the new ADAMs will be measured accurately. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SYNTHESIS OF NOVEL BIOLOGICALLY ACTIVE NATURAL PRODUCTS Principal Investigator & Institution: Boeckman, Robert K.; Professor of Chemistry; Chemistry; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2002; Project Start 15-SEP-1982; Project End 31-DEC-2002 Summary: The studies to be conducted under this grant fall in three major areas: 1) complete work on the total synthesis of the hypoglycemic agent Saudin (1); test 1 and its precursors to identify the pharmacophore, and determine if possible the mechanism by which the hypoglycemic effects are elicited (in collaboration with Sandoz Research Institute); prepare appropriate analogues as warranted by the preceding studies; 2) continue work directed at the application of Lewis acid catalyzed asymmetric [2+2] cycloaddition reactions and asymmetric SN2' substitutions as general methods to access the chiral vinylcyclobutane precursors for (+)-Laurencin (2) and (+)-Laurenyne (3). To employ the novel retro-Claisen rearrangement to create the required oxocene ring system in enantiomerically pure form. 3) investigate the mechanism, scope, and limitations of the novel TiC14 catalyzed Claisen rearrangement of endocyclic vinyl allyl ethers. This process permits modification of the stereochemical outcome of the process relative to the thermal rearrangement. The hypothesis that an internal chelate of suitably disposed oxygen functions permits the modification of the ring conformation from halfchair to half-boat will be tested.
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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SYNTHESIS AMPHIDINOLIDE C
OF
THE
ANTI-TUMOR
MARCROLIDE
Principal Investigator & Institution: Shotwell, John B.; Chemistry; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2003; Project Start 15-SEP-2003; Project End 14-SEP-2006 Summary: (provided by applicant): This proposal details studies directed toward the total synthesis of amphidinolide C. The amphidinolides, a structurally diverse group of over 30 macrolides, exhibit potent and selective anti-tumor profiles. The unparalleled structural heterogeneity in this class is indicative either of a host of mechanistically unique inroads to the treatment of cancers or a single unidentified intracellular effector which exhibits tremendous promiscuity in ligand binding. The mechanisms of action of the amphidinolides have gone unstudied, primarily due to a lack of available natural products, analogs, and biochemical reagents (e.g., amphidinolide-based affinity probes and/or columns, etc.). The proposed synthesis involves the development of a tandem asymmetric Heck/enol-ether oxidation strategy for the preparation of chiral allylic 1,2anti diols and describes its application toward the preparation of the highly oxygenated C3-C9 region of amphidinolide C. The route is highly convergent, will expand the scope of enantioselective and doubly-diastereoselective [3+2] annulation strategies for the efficient construction of tetrahydrofurans, and will represent the first total synthesis of amphidinolide C. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SYNTHETIC APPLICATIONS OF CARBENE COMPLEXES Principal Investigator & Institution: Wulff, William D.; Professor; Chemistry; Michigan State University 301 Administration Bldg East Lansing, Mi 48824 Timing: Fiscal Year 2002; Project Start 01-DEC-1983; Project End 30-NOV-2003 Summary: The broad scope of the work proposed involves the development of the chemistry of Fischer carbene complexes to the field of organic synthesis and to the synthesis of organic compounds of importance in human health. The reactions of Fischer carbene complexes with alkynes will be examined for the synthesis of the platelet activating factor antagonist phomactin D and for the synthesis of colchicine and allocolchicinoids that have been investigated for the treatment of gout, familial Mediterranean fever and liver cirrhosis. Asymmetric versions of this reaction will also be used to prepare aS,7S and aR,7S isomers of 1 2 - methylcolchinyl methyl ether to test an unresolved issue regarding the stereochemical requirements for binding of colchicine and allocolchicinoids to tubulin. A new strategy for the synthesis of the new anticancer agent eluetherobin will be explored which involves an intramolecular exo-selective Diels-Alder reaction as a key step. The aldol reaction of Fischer carbene complexes will be utilized in the first synthesis of the anticancer agent fostriecin and analogs of fostriecin which are more stable and thus more useful in the clinic. The reaction of Fischer carbene complexes with 1,6-enynes will be explored as a method for rapid access to the taxol family of antitumor agents. The the cyclopropanation reactions of chiral carbene complexes will be examined for the synthesis of aminocyclopropanes and for a synthesis of the antitumor agent helenalin which involves a tandem cyclopropanation/Cope rearrangement sequence. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: SYNTHETIC EXPLORATION OF CENTRAL NICOTINIC RECEPTORS Principal Investigator & Institution: Glassco, Williams S.; Pharmacology and Toxicology; Virginia Commonwealth University Richmond, Va 232980568 Timing: Fiscal Year 2002; Project Start 01-MAR-1999; Project End 28-FEB-2003 Summary: A combination of pharmacological, molecular and physiological data suggest the presence of multiple subpopulations of nicotinic acetylcholine receptors (nAChR) in the central nervous system. To date, molecular biologists have identified eleven distinct nAChR subunits in neuronal tissue (five such subunits are believed to combine to form the functional nAChR), and over half a dozen different combinations of these subunits, when expressed together in various cell lines, produce functional, ligand-gated ion channels. However, only three distinct nAChRs can be identified using chemical ligands, and two of these are distinguished by polypeptide toxins. We have found differences between the structure-activity relationships (SARs) for various nicotinemediated in vivo effects and in vitro affinity. We propose to continue these studies by synthesizing and testing a series of 5- and 6- substituted isonicotines, and to compare these with the SARs of previously reported 5- and 6-substituted nicotines. We additionally propose to synthesize some isonicotine analogs with an ether link between the 3-positions of the pyridine and pyrrolidine rings. We also propose to study the SAR of substituents attached at the 2'- and 4- positions of nicotine, as well as to the comparable positions on a series of pyrrolidine ring-opened analogs of nicotine. Susceptibility to mecamylamine antagonism is a hallmark of agonists to the central nicotine high affinity site, but this may not be the case for some of the 2'- and 4substituted derivatives we are proposing. Additionally, we propose to synthesize analogs of trans-metanicotine, a central nicotine agonist with in vitro and in vivo selectivity, in which the carbon-carbon double bond off the 3-position of the pyridine ring is replaced by a bioisosteric sulfur atom. This modification will allow introduction of oxygen atoms (sulfoxide and/or sulfone) to mimic the structurally and pharmacologically similar pseudooxynicotine. We further propose to synthesize a series of N6-substituted 6- aminonicotines and 6-substituted nicotines as potential competitive nAChR antagonists. Key to these studies is a comprehensive approach to pharmacological evaluation of the various series of compounds. In vitro and in vivo evaluation will be needed for most of these compounds, as we have previously found instances where affinity and activity can vary independently of each other. We have a standard series of tests for evaluation of nicotine-like activity, including displacement of [3H]nicotine from rat brain, two functional assay using mice (inhibition of spontaneous activity and tail-flick antinociception) and drug discrimination using rats trained on nicotine. We additionally propose to utilize the newer in vitro expression systems to correlate selectivity with affinity for specific subunit combination using an oocyte expression systems (alpha4beta2, alpha3beta2). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: TARGETED RETROVIRAL VECTORS FOR GENE THERAPY OF DIABETES Principal Investigator & Institution: Roth, Monica J.; Professor; Biochemistry; Univ of Med/Dent Nj-R W Johnson Med Sch Robert Wood Johnson Medical Sch Piscataway, Nj 08854 Timing: Fiscal Year 2002; Project Start 01-SEP-2001; Project End 31-AUG-2004 Summary: (provided by applicant) The long-term objective of this proposed research is to develop retroviral vectors which deliver therapeutic genes for diabetes specifically to
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liver and pancreatic beta-cells. The short-term aim of this project is to alter the cellbinding site of the retroviral surface Envelope protein (Env) such that it only mediates binding and entry of the retrovirus specifically into liver or beta-cells. This research develops the use of the feline leukemia virus (FeLV) Env as the backbone for modification. The FeLV Env is more amenable for this modification than previously studied Env proteins, such as those of the marine leukemia viruses, because the FeLV Env encodes a short stretch of amino acids within its amino terminus that determines receptor specificity. One targeting strategy employs a library of 106-107 env genes with random amino acids substituted into this receptor-determining region. The library will be screened for the ability of am of the random sequences to enable entry specifically into liver or beta-cells. Preliminary results indicate that Env proteins with novel targeting specificities can be derived from such a selection screen. A second strategy is to use a library with a liver-specific peptide substituted into the receptor-determining region. In this approach, the liver-targeting peptide is flanked by random amino acids in order to optimize the conformation of the peptide. This library will be screened for the specific targeting of liver cells. These strategies differ from earlier approaches to alter retroviral targeting by the use of bulky antibody fragments or other large cell-binding ligands. The short peptide sequences being introduced into the FeLV Env in the project described here should only minimally perturb the Env protein. These specifically targeted Env proteins will eventually be used to deliver genes that can ether protect beta cells from immune destruction or induce insulin expression in liver cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TARGETING HERG: A MOUSE MODEL OF THE LONG QT SYNDROME Principal Investigator & Institution: London, Barry; Associate Professor of Medicine; Medicine; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 30-SEP-1999; Project End 31-AUG-2004 Summary: Arrhythmias and sudden death remain a major public health problem. Mutations of the K+ channel HERG, the human ether-a-gogo related gene, cause the long QT syndrome (LQTS), a genetic disorder characterized by lethal ventricular arrhythmias. HERG subunits are expressed in the heart and are responsible for IKr, a K+ current important in the repolarization phase of the cardiac action potential. HERG subunits interact in-vitro with IsK (minK), a K+ channel beta-subunit that coassembles with KvLQT1 to form the cardiac current IKs. It is not known whether HERG mutations affect currents other than IKr. Patients with HERG mutations and arrhythmias can have normal QT intervals. The role of HERG in other tissues and in development is unknown. Limited access to tissue and myocytes from LQTS patients presents a major obstacle towards a full understanding of the role of HERG in the heart. We have characterized Merg1 (the mouse homolog of HERG) and engineered mice with a targeted truncation of Merg1 similar to the HERG mutations that cause LQTS. Homozygous embryos are abnormal and die between embryonic days Ell and E14. Heterozygous mice (Merg1+/-) have decreased transcript levels of Merg1; levels of minK are decreased in neonates but markedly increased in adults. Heterozygotes have prolonged QT intervals as neonates, and although the QT interval normalizes with age, the adults remain susceptible to arrhythmias when treated with the alpha1-agonist methoxamine. We will test the hypotheses that Merg1 mutations cause LQTS and arrhythmias by affecting both IKr and IKs, that the cellular mechanisms that control QT interval are in part distinct from those that lead to arrhythmias, and that Merg1 is essential for cardiovascular
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development. Specifically, we will 1) Correlate changes in channel expression in Merg1+/- mice of several ages to changes in cardiac K+ currents; 2) Determine whether pharmacological agents that cause arrhythmias in the mice prolong the QT interval; 3) Mate the Merg1+/-mouse to a minK-/-/lacZ mouse to identify areas of altered minK expression and the significance of the Merg1/minK interaction in-vivo; and 4) Study the effects of the loss of Merg1 on embryonic development. A better understanding of the molecular basis of cardiac electrophysiology is an essential first step towards the goal of ameliorating the diverse group of diseases known as cardiac arrhythmias. The studies proposed here will extend our knowledge of the role of the HERG gene family in normal cardiac function and help to define the mechanisms by which mutations lead to arrhythmias. Information gained from these studies may help to clarify the mechanisms of the more common arrhythmias that cause sudden death. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: THE ASYMMETRIC SYNTHESIS OF GUAIANOLIDES AND ARTEMINOLID Principal Investigator & Institution: Bur, Scott K.; Chemistry; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2002; Project Start 01-SEP-2001 Summary: This proposal describes a general asymmetric synthetic route to guaianolide sesquiterpenes and the sesquiterpene dimer arteminolide. Guaianolide sesquiterpenes have a wide array of biological activity, yet very few syntheses have been described. The construction the guaianolide skeleton relies on a stereoselective tandem conjugate addition-enolate trapping strategy to build a highly functionalized cyclopentanone. The synthesis features a ring-closing olefin metathesis reaction, involving a silyl enol ether and a terminal alkene, to form the seven-membered ring. Development of Diels-Alder cycloaddition methods are described for the reaction of silyloxycyclopentadienes with alpha-methylene lactones. These results will produce a convergent strategy for the formation of sesquiterpene dimers such as arteminolide, a novel farnesyl: protein transferase (FPTase) inhibitor. As FPTase inhibitors are believed to help potential as therapeutic agents for the treatment of some kinds of cancer, compounds such as arteminolide are valuable lead compounds. These methods will allow for the total synthesis of either enantiomer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: THE STUDY OF HERG-INTERACTING PROTEINS IN C. ELGANS Principal Investigator & Institution: Petersen, Christina I.; Anesthesiology; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2003; Project Start 01-DEC-2001; Project End 30-NOV-2003 Summary: (the applicant?s description verbatim): Mutations in the human ether-a-go-go related gene (HERG) are linked to acquired and inherited forms of the long QT syndrome (LQTS), which can provoke the life-threatening arrythmia, Torsades de Pointes. Acquired LQTS is induced by a variety of drugs, many of which block HERG, underscoring the importance of this voltage-gated K+ channel in the maintenance of normal cardiac rhythm. Accessory proteins (beta subunits) are known to modify the current and drug sensitivity of various voltage-gated K+ channels, including HERG. We will study HERG function and accessory protein interactions in vivo using the model organism, C. elegans. An orthologue of HERG, unc-103, has been identified in C. elegans. We will test the hypothesis that unc-103 possesses biophysical and
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pharmacologic features characteristic of HERG, and that C. elegans can be used as a model organism for identifying and isolating HERG-interacting proteins. To accomplish this goal we will: 1. Determine if HERG and UNC-l03 have analogous function, using complemenatary approaches of a) electrophysiological characterization of unc-103 biophysics and drug sensitivity, in a heterologous expression system and b) in vivo pharmacologic characterization of worms that carry an unc-103 gain-of-function (gf mutation. 2. Characterize candidate UNC-103-interacting proteins, using similar heterologous electrophysiologic and in vivo assays, and 3. Isolate novel UNC-103 interacting proteins using a genetic mutagenesis screen in the C. elegans unc-103 gf background. These studies will improve our understanding of HERG and HERG/accessory protein interactions, and will facilitate drug design and aid in the prevention of life-threatening arrythmias. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: THE TOTAL SYNTHESIS OF ASBESTININ-6 Principal Investigator & Institution: Papa, Patrick W.; Chemistry; University of California Irvine Irvine, Ca 926977600 Timing: Fiscal Year 2002; Project Start 08-JUL-2002 Summary: (provided by applicant): Asbestinin-6 was isolated from Briareum asbestinum of the order (Gorgonacea. Although the absolute stereochemistry has not been established for any member of the asbestinin family of natural products, it is thought to be related biosynthetically to the cladiellins, which have established structures. The asbestinins have been shown to have strong antitumor, antimicrobial activity, and exhibit histamine and acetylcholine antagonism. The asbestinins have similar cyclic skeletons which contain a stereochemically complex hexahydroisobenzofuran ring. The key step of this proposed synthesis of asbestinin-6 will focus on the formation of this ring in a stereoselective fashion by further optimization of the Prins-pinacol methodology previously reported by the Overman group. Other key steps will include the formation of a nine member ring system through olefin metathesis, and the formation of a seven member cyclic ether. Upon completion of the first total synthesis of asbestinin-6 it is anticipated that several objectives will be achieved. These objectives include: 1) development of a general method to access structurally similar biologically active compounds; 2) further investigation into biological activity; and 3) determination of the absolute stereochemistry of asbestinin-6. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: TI(IV) PROMOTED MUKAIYAM ALDOL-PRINS CYCLIZATION Principal Investigator & Institution: Patterson, Brian D.; Chemistry; University of California Irvine Irvine, Ca 926977600 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2006 Summary: (provided by applicant): Facile syntheses of biologically active natural products have often been the motive for development of new methodologies in organic chemistry. The recent development of the Ti(IV) promoted Mukaiyama aldol-Prins cyclization by the Rychnovsky group has allowed entry to complex tetrahydropyran ring systems with concomitant formation of a secondary alcohol. Prins cyclization proceeds stereoselectively to give the 2,4,6-syn-trisubstituted tetrahydropyran in >95:5 diastereoselectivity. The initial aldol adduct proceeds with low diastereoselectivity, which allows for possible asymmetric induction either by introduction of a chiral aldehyde or a chiral Lewis acid. Investigation into the improvement of
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diastereoselectivity at the exocyclic alcohol center in conjunction with the use of an enantiopure enol ether would provide a methodology that forms two carbon-carbon bonds as well as setting three stereocenters. Application of this methodology to the synthesis of leucascandrolide A would provide a highly efficient synthetic route to a natural product that has shown high activity against cancer cell lines. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TRANSITION METAL-CATALYZED SYNTHESIS OF AMINES AND ETHER Principal Investigator & Institution: Hartwig, John F.; Professor; Chemistry; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2002; Project Start 01-DEC-1996; Project End 31-JAN-2005 Summary: Several efficient, transition metal-catalyzed routes to amines and ethers are presented in this proposal. Many amines and ethers are biologically active, and most of the best-selling drugs contain this type of functionality. During the past funding period, we uncovered several transition metal-catalyzed routes to amines and ethers. We developed palladium-catalyzed C-N and C-O coupling of aryl halides and we recently uncovered new metal-catalyzed hydroaminations. The amination of aryl halides and accompanying mechanistic information has already affected dramatically how drug discovery and process groups prepare arylamines. Our hydroaminations should influence the way they prepare alkylamines. In the next funding period, we will gain an understanding of how our new, most active catalysts work and we will determine the extent to which these catalysts improve the scope of C-N bond formation. In addition, we will seek an understanding of the mechanism of related C-O bond forming crosscouplings that use recently discovered catalysts. We will also outline rules that govern the scope and rates for palladium- catalyzed aromatic aminations with medicinally important heterocyclic substrates. In addition to aromatic C-N and C-O bond-forming processes, we will investigate our new hydroaminations of dienes and vinylarenes. Diene hydroaminations produce allylic amines, which are common synthetic intermediates. Vinylarene hydroaminations produce phenethylamines, which are part of drugs such as Sertraline. We will define the scope of these new processes, will investigate enantioselective hydroaminations and will obtain a detailed understanding of how the reactions occur. This information should enable us to design efficient hydroamination catalysts with broad substrate scope and to use mild reaction conditions for highly enantioselective hydroaminations. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ULTRALOW BIOMATERIALS
PROTEIN
ADSORPTION
HEMOCOMPATIBLE
Principal Investigator & Institution: Horbett, Thomas A.; Professor; Chemical Engineering; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 23-JUL-2001; Project End 30-JUN-2005 Summary: Blood clotting on foreign surfaces remains a major limitation in the clinical application of many devices, including cardiovascular bypass, stents, catheters, and glucose sensors. In many situations, platelets are the initiator of blood clotting on the biomaterial surface. Recent studies in our lab have identified a quantitative design criterion to eliminate platelet adhesion, namely the need to reduce fibrinogen adsorption to very low levels (less than 5 ng/cm2), far below that which occurs on most materials. Radio frequency plasma deposited tetraglyme materials we have made can often meet
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this criteria, but it remains to be shown whether this results in the perfectly blood compatible biomaterial that we seek. We also must establish that ultra-low fibrinogen uptake can be achieved consistently and that the materials are stable in this regard. Therefore, a series of studies to perfect the glyme technology and evaluate its blood compatibility is proposed. The specific aims of the proposal are as follows: 1. Tetraglyme plasma treatment conditions will be optimized to achieve coating uniformity, durability and ultra low protein uptake and a new reactor to treat the inside surfaces of longer tubes will be made. A hypothesis about the role of tightly bound water in causing non-fouling of glyme coatings will be tested. Two new monomers for producing plasma deposited PEG- like surfaces will be evaluated. 2. Fibrinogen adsorption from plasma will be compared to ESCA and TOF-SIMS surface chemical data for a series of tetraglymes to establish the conditions that result in ultra-low fibrinogen uptake. The tetraglyme series will be made under varying reactor conditions which will cause variations in surface chemistry, and thus allow us to test the hypothesis that the criteria that must be met to achieve ultra- low fouling are high, optimized ether carbon content relative to non-ether carbon and prevention of delamination. Resistance to fouling by fibronectin, vitronectin, von Willebrand factor, and IgG will also be measured. Resistance to uptake of all proteins from plasma will be characterized with surface plasmon resonance and by two dimensional gel electrophoresis. 3. Blood interactions will be characterized using both in vitro and in vivo methodology. In vitro platelet adhesion and procoagulant activation on a series of glyme coated materials will be measured after their pre-exposure to blood plasma or fibrinogen. The role of non-platelet mediated clotting events will be assessed by measuring clotting times and clotting enzyme activity in recalcified plasma in contact with the tetraglymes. The effect of non-adhesive encounters on platelet activation and aggregation will be characterized using laser emboli detection. In vivo blood compatibility of materials exhibiting ultralow fibrinogen and platelet uptake will be assessed in dogs with tubular tetraglyme ex vivo shunts by measuring both acute phase and steady state indicators of clotting. 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 “ether” (or synonyms) into the search box. This search gives you access to full-text articles. The following is a sample of items found for ether in the PubMed Central database:
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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2-Arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB1 receptor. by Hanus L, Abu-Lafi S, Fride E, Breuer A, Vogel Z, Shalev DE, Kustanovich I, Mechoulam R.; 2001 Mar 27; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=31108
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Acylation stabilizes a protease-resistant conformation of protoporphyrinogen oxidase, the molecular target of diphenyl ether-type herbicides. by Arnould S, Takahashi M, Camadro JM.; 1999 Dec 21; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=24732
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Aerobic Biodegradation of Methyl tert-Butyl Ether by Aquifer Bacteria from Leaking Underground Storage Tank Sites. by Kane SR, Beller HR, Legler TC, Koester CJ, Pinkart HC, Halden RU, Happel AM.; 2001 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=93377
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An [alpha]-Proteobacterium Converts Linear Alkylbenzenesulfonate Surfactants into Sulfophenylcarboxylates and Linear Alkyldiphenyletherdisulfonate Surfactants into Sulfodiphenylethercarboxylates. by Schleheck D, Dong W, Denger K, Heinzle E, Cook AM.; 2000 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=101432
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Anaerobic degradation of veratrylglycerol-beta-guaiacyl ether and guaiacoxyacetic acid by mixed rumen bacteria. by Chen W, Supanwong K, Ohmiya K, Shimizu S, Kawakami H.; 1985 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=238779
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Biodegradation and transformation of 4,4'- and 2,4-dihalodiphenyl ethers by Sphingomonas sp. strain SS33. by Schmidt S, Fortnagel P, Wittich RM.; 1993 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=182552
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Biodegradation of diphenyl ether and its monohalogenated derivatives by Sphingomonas sp. strain SS3. by Schmidt S, Wittich RM, Erdmann D, Wilkes H, Francke W, Fortnagel P.; 1992 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=183002
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Biodegradation of Methyl tert-Butyl Ether and Other Fuel Oxygenates by a New Strain, Mycobacterium austroafricanum IFP 2012. by Francois A, Mathis H, Godefroy D, Piveteau P, Fayolle F, Monot F.; 2002 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=123982
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Biodegradation of Methyl tert-Butyl Ether by a Bacterial Pure Culture. by Hanson JR, Ackerman CE, Scow KM.; 1999 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=91645
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Biodegradation of Methyl tert-Butyl Ether by a Pure Bacterial Culture. by Hatzinger PB, McClay K, Vainberg S, Tugusheva M, Condee CW, Steffan RJ.; 2001 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=93349
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Biodegradation of the gasoline oxygenates methyl tert-butyl ether, ethyl tert-butyl ether, and tert-amyl methyl ether by propane-oxidizing bacteria. by Steffan RJ, McClay K, Vainberg S, Condee CW, Zhang D.; 1997 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=168740
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Characterization of the Initial Reactions during the Cometabolic Oxidation of Methyl tert-Butyl Ether by Propane-Grown Mycobacterium vaccae JOB5. by Smith CA, O'Reilly KT, Hyman MR.; 2003 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=143618
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Clinical comparison of ethyl acetate and diethyl ether in the formalin-ether sedimentation technique. by Erdman DD.; 1981 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=273973
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Cloning and sequencing of the gene for a Pseudomonas paucimobilis enzyme that cleaves beta-aryl ether. by Masai E, Katayama Y, Kawai S, Nishikawa S, Yamasaki M, Morohoshi N.; 1991 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=212589
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Cloning of a Genetically Unstable Cytochrome P-450 Gene Cluster Involved in Degradation of the Pollutant Ethyl tert-Butyl Ether by Rhodococcus ruber. by Chauvaux S, Chevalier F, Le Dantec C, Fayolle F, Miras I, Kunst F, Beguin P.; 2001 Nov 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=95485
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Comparison of clinical results for the use of ethyl acetate and diethyl ether in the formalin-ether sedimentation technique performed on polyvinyl alcohol-preserved specimens. by Garcia LS, Shimizu R.; 1981 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=273864
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Comparison of formalin-ethyl ether sedimentation, formalin-ethyl acetate sedimentation, and zinc sulfate flotation techniques for detection of intestinal parasites. by Truant AL, Elliott SH, Kelly MT, Smith JH.; 1981 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=273909
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Comparison of new triton X-100- and tween-ether-treated split-treated vaccines in children. by Gross PA, Ennis FA, Gaerlan PF, Denning CR, Setia U, Davis WJ, Bisberg DS.; 1981 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=273983
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Comparison of polyvinyl alcohol- and formalin-preserved fecal specimens in the formalin-ether sedimentation technique for parasitological examination. by Carroll MJ, Cook J, Turner JA.; 1983 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=272843
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CP-72,588, a semisynthetic analog of the polyether ionophore UK-58,582 with increased anticoccidial potency. by Ricketts AP, Chappel LR, Frame GM, Glazer EA, Migaki TT, Olson JA.; 1992 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=245459
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Degradation of 2-Chloroethylvinylether by Ancylobacter aquaticus AD25 and AD27. by van den Wijngaard AJ, Prins J, Smal AJ, Janssen DB.; 1993 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=182365
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Deoxyribonucleic Acid Synthesis in Saccharomyces cerevisiae Cells Permeabilized with Ether. by Oertel W, Goulian M.; 1979 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=216654
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Desulfonation and Degradation of the Disulfodiphenylethercarboxylates from Linear Alkyldiphenyletherdisulfonate Surfactants. by Schleheck D, Lechner M, Schonenberger R, Suter MJ, Cook AM.; 2003 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=143680
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Detection and Quantification of Methyl tert-Butyl Ether-Degrading Strain PM1 by Real-Time TaqMan PCR. by Hristova KR, Lutenegger CM, Scow KM.; 2001 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=93284
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Dibiphytanyl Ether Lipids in Nonthermophilic Crenarchaeotes. by DeLong EF, King LL, Massana R, Cittone H, Murray A, Schleper C, Wakeham SG.; 1998 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=106379
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Divinyl ether fatty acid synthesis in late blight-diseased potato leaves. by Weber H, Chetelat A, Caldelari D, Farmer EE.; 1999 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=144186
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DNA adducts of antitumor trans-[PtCl2 (E-imino ether)2]. by Brabec V, Vrana O, Novakova O, Kleinwachter V, Intini FP, Coluccia M, Natile G.; 1996 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=145631
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Effects of a Squalene Epoxidase Inhibitor, Terbinafine, on Ether Lipid Biosyntheses in a Thermoacidophilic Archaeon, Thermoplasma acidophilum. by Kon T, Nemoto N, Oshima T, Yamagishi A.; 2002 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=134840
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Enhancing Transport of Hydrogenophaga flava ENV735 for Bioaugmentation of Aquifers Contaminated with Methyl tert-Butyl Ether. by Streger SH, Vainberg S, Dong H, Hatzinger PB.; 2002 Nov; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=129923
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Enzymatic bromination of 16-dehydroestradiol 3-methyl ether 17-acetate to 16-alphabromoestrone 3-methyl ether. by Neidleman SL, Oberc MA.; 1968 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=315184
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Ether treatment of type B influenza virus antigen for the hemagglutination inhibition test. by Monto AS, Maassab HF.; 1981 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=273720
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Ethyl acetate as a substitute for diethyl ether in the formalin-ether sedimentation technique. by Young KH, Bullock SL, Melvin DM, Spruill CL.; 1979 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=273283
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Flavin-Linked Dehydrogenation of Ether Glycols by Cell-Free Extracts of a Soil Bacterium. by Payne WJ, Todd RL.; 1966 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=316073
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Freeze-fracture planes of methanogen membranes correlate with the content of tetraether lipids. by Beveridge TJ, Choquet CG, Patel GB, Sprott GD.; 1993 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=193038
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Importance of tetrahydrofolate and ATP in the anaerobic O-demethylation reaction for phenylmethylethers. by Berman MH, Frazer AC.; 1992 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=195357
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In vivo stability of ester- and ether-linked phospholipid-containing liposomes as measured by perturbed angular correlation spectroscopy. by Derksen JT, Baldeschwieler JD, Scherphof GL.; 1988 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=282862
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Increased sensitivity and reduced specificity of hemagglutination inhibition tests with ether-treated influenza B/Singapore/222/79. by Kendal AP, Cate TR.; 1983 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=270933
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Inhibition of Cryptosporidium parvum in neonatal Hsd:(ICR)BR Swiss miceby polyether ionophores and aromatic amidines. by Blagburn BL, Sundermann CA, Lindsay DS, Hall JE, Tidwell RR.; 1991 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=245207
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Inhibition of dimethyl ether and methane oxidation in Methylococcus capsulatus and Methylosinus trichosporium. by Patel R, Hou CT, Felix A.; 1976 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=233246
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Inhibition of peptidoglycan synthesis in ether-permeabilized Escherichia coli cells by structural analogs of D-alanyl-D-alanine. by Pelzer H, Reuter W.; 1980 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=352984
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Inhibitory effects of polyethers on human immunodeficiency virus replication. by Nakamura M, Kunimoto S, Takahashi Y, Naganawa H, Sakaue M, Inoue S, Ohno T, Takeuchi T.; 1992 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=188467
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Isolation of a Bacterial Culture That Degrades Methyl t-Butyl Ether. by Salanitro JP, Diaz LA, Williams MP, Wisniewski HL.; 1994 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=201688
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Kinetics of Methyl t-Butyl Ether Cometabolism at Low Concentrations by Pure Cultures of Butane-Degrading Bacteria. by Liu CY, Speitel GE Jr, Georgiou G.; 2001 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=92855
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Light inhibits the production of alternariol and alternariol monomethyl ether in Alternaria alternata. by Soderhall K, Svensson E, Unestam T.; 1978 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=243116
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Long-Chain Glycerol Diether and Polyol Dialkyl Glycerol Triether Lipids of Sulfolobus acidocaldarius. by Langworthy TA, Mayberry WR, Smith PF.; 1974 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=245579
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Metabolism of Lignin Model Compounds of the Arylglycerol-[beta]-Aryl Ether Type by Pseudomonas acidovorans D3. by Vicuna R, Gonzalez B, Mozuch MD, Kirk TK.; 1987 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=204160
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Metabolism of Radiolabeled [beta]-Guaiacyl Ether-Linked Lignin Dimeric Compounds by Phanerochaete chrysosporium. by Weinstein DA, Krisnangkura K, Mayfield MB, Gold MH.; 1980 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=291373
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Metabolism of the alkane analogue n-dioctyl ether by Acinetobacter species. by Modrzakowski MC, Makula RA, Finnerty WR.; 1977 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=235395
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Metal ion recognition and molecular templating in self-assembled monolayers of cyclic and acyclic polyethers. by Herranz MA, Colonna B, Echegoyen L.; 2002 Apr 16; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122718
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Methyl t-Butyl Ether Mineralization in Surface-Water Sediment Microcosms under Denitrifying Conditions. by Bradley PM, Chapelle FH, Landmeyer JE.; 2001 Apr; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=92824
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Molecular cloning and expression of an Erwinia sp. gene encoding diphenyl ether cleavage in Escherichia coli. by Liaw HJ, Srinivasan VR.; 1989 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=203059
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Naturally Occurring Bacteria Similar to the Methyl tert-Butyl Ether (MTBE)Degrading Strain PM1 Are Present in MTBE-Contaminated Groundwater. by Hristova K, Gebreyesus B, Mackay D, Scow KM.; 2003 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=154499
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Obligate methylotrophy: evaluation of dimethyl ether as a C1 compound. by Meyers AJ Jr.; 1982 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=216452
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Occurrence of dialkyl ether phospholipids in Stigmatella aurantiaca DW4. by Caillon E, Lubochinsky B, Rigomier D.; 1983 Mar; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=221784
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Overexpression of Plastidic Protoporphyrinogen IX Oxidase Leads to Resistance to the Diphenyl-Ether Herbicide Acifluorfen. by Lermontova I, Grimm B.; 2000 Jan 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=58846
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Oxidation of methyl fluoride and dimethyl ether by ammonia monooxygenase in Nitrosomonas europaea. by Hyman MR, Page CL, Arp DJ.; 1994 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=201762
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Proportions of diether, macrocyclic diether, and tetraether lipids in Methanococcus jannaschii grown at different temperatures. by Sprott GD, Meloche M, Richards JC.; 1991 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=208025
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Reactivation of peptidoglycan synthesis in ether-permeabilized Escherichia coli after inhibition by beta-lactam antibiotics. by Talbot MK, Schaefer F, Brocks V, Christenson JG.; 1989 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=172829
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Ribonucleotide reductase activity in ether-treated cells of Agmenellum quadruplicatum. by Gleason FK, Wood JM.; 1976 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=232809
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Roles of the Enantioselective Glutathione S-Transferases in Cleavage of [beta]-Aryl Ether. by Masai E, Ichimura A, Sato Y, Miyauchi K, Katayama Y, Fukuda M.; 2003 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=150126
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Sensitivity of infectious bovine rhinotracheitis virus to ether. by Crandell RA, Melloh AJ, Sorlie P.; 1975 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=275200
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Synergism between the antifungal agents amphotericin B and alkyl glycerol ethers. by Haynes MP, Buckley HR, Higgins ML, Pieringer RA.; 1994 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=284587
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Synthesis of active nitroguaiacol ether derivatives of streptomycin. by Abad JP, Amils R.; 1990 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=171963
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UDP-N-acetylmuramylpentapeptide as acceptor in murein biosynthesis in Escherichia coli membranes and ether-permeabilized cells. by Kraus W, Glauner B, Holtje JV.; 1985 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=215874
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Widespread occurrence of structurally diverse tetraether membrane lipids: Evidence for the ubiquitous presence of low-temperature relatives of hyperthermophiles. by Schouten S, Hopmans EC, Pancost RD, Damste JS.; 2000 Dec 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=18934
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 6 PubMed was developed by the National Center for Biotechnology Information (NCBI) at the National Library of Medicine (NLM) at the National Institutes of Health (NIH). The PubMed database was developed in conjunction with publishers of biomedical literature as a search tool for accessing literature citations and linking to full-text
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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 ether, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “ether” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for ether (hyperlinks lead to article summaries): •
2-(anilinomethyl)imidazolines as alpha1A adrenergic receptor agonists: 2'-heteroaryl and 2'-oxime ether series. Author(s): Navas F 3rd, Bishop MJ, Garrison DT, Hodson SJ, Speake JD, Bigham EC, Drewry DH, Saussy DL, Liacos JH, Irving PE, Gobel MJ. Source: Bioorganic & Medicinal Chemistry Letters. 2002 February 25; 12(4): 575-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11844675&dopt=Abstract
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A new dicoumarinyl ether and two rare furocoumarins from Ruta montana. Author(s): Kabouche Z, Benkiki N, Seguin E, Bruneau C. Source: Fitoterapia. 2003 February; 74(1-2): 194-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12628424&dopt=Abstract
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A review on human exposure to brominated flame retardants--particularly polybrominated diphenyl ethers. Author(s): Sjodin A, Patterson DG Jr, Bergman A. Source: Environment International. 2003 September; 29(6): 829-39. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12850099&dopt=Abstract
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Actual commuter exposure to methyl-tertiary butyl ether, benzene and toluene while traveling in Korean urban areas. Author(s): Lee JW, Jo WK. Source: The Science of the Total Environment. 2002 May 27; 291(1-3): 219-28. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12150439&dopt=Abstract
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Aglacins A-D, first representatives of a new class of aryltetralin cyclic ether lignans from Aglaia cordata. Author(s): Wang BG, Ebel R, Nugroho BW, Prijono D, Frank W, Steube KG, Hao XJ, Proksch P. Source: Journal of Natural Products. 2001 December; 64(12): 1521-6. Erratum In: J Nat Prod. 2003 January; 66(1): 155. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11754603&dopt=Abstract
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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Amended final report on the safety assessment of PPG-40 butyl ether with an addendum to include PPG-2, -4, -5, -9, -12, -14, -15, -16, -17, -18, -20, -22, -24, -26, -30, -33, -52, and -53 butyl ethers. Author(s): Lanigan RS; Cosmetic Ingredient Review Expert Panel. Source: International Journal of Toxicology. 2001; 20 Suppl 4: 39-52. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11800051&dopt=Abstract
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An ion channel 'addicted' to ether, alcohol and cocaine: the HERG potassium channel. Author(s): Karle CA, Kiehn J. Source: Cardiovascular Research. 2002 January; 53(1): 6-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11744008&dopt=Abstract
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An orally bioavailable oxime ether capsid binder with potent activity against human rhinovirus. Author(s): Watson KG, Brown RN, Cameron R, Chalmers DK, Hamilton S, Jin B, Krippner GY, Luttick A, McConnell DB, Reece PA, Ryan J, Stanislawski PC, Tucker SP, Wu WY, Barnard DL, Sidwell RW. Source: Journal of Medicinal Chemistry. 2003 July 17; 46(15): 3181-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12852746&dopt=Abstract
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Anandamide and noladin ether prevent neurotoxicity of the human amyloid-beta peptide. Author(s): Milton NG. Source: Neuroscience Letters. 2002 October 31; 332(2): 127-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12384227&dopt=Abstract
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APETx1, a new toxin from the sea anemone Anthopleura elegantissima, blocks voltage-gated human ether-a-go-go-related gene potassium channels. Author(s): Diochot S, Loret E, Bruhn T, Beress L, Lazdunski M. Source: Molecular Pharmacology. 2003 July; 64(1): 59-69. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12815161&dopt=Abstract
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Asphyxial death by ether inhalation and plastic-bag suffocation instructed by the press and the Internet. Author(s): Athanaselis S, Stefanidou M, Karakoukis N, Koutselinis A. Source: Journal of Medical Internet Research [electronic Resource]. 2002 December; 4(3): E18. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12554549&dopt=Abstract
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Biological activities, mechanisms of action and biomedical prospect of the antitumor ether phospholipid ET-18-OCH(3) (edelfosine), a proapoptotic agent in tumor cells. Author(s): Gajate C, Mollinedo F. Source: Current Drug Metabolism. 2002 October; 3(5): 491-525. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12369895&dopt=Abstract
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Biotransformation of L-cysteine S-conjugates and N-acetyl-L-cysteine S-conjugates of the sevoflurane degradation product fluoromethyl-2,2-difluoro-1(trifluoromethyl)vinyl ether (compound A) in human kidney in vitro: interindividual variability in N-acetylation, N-deacetylation, and beta-lyase-catalyzed metabolism. Author(s): Gul Altuntas T, Kharasch ED. Source: Drug Metabolism and Disposition: the Biological Fate of Chemicals. 2002 February; 30(2): 148-54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11792683&dopt=Abstract
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Bisphenol A diglycidyl ether induces apoptosis in tumour cells independently of peroxisome proliferator-activated receptor-gamma, in caspase-dependent and independent manners. Author(s): Fehlberg S, Trautwein S, Goke A, Goke R. Source: The Biochemical Journal. 2002 March 15; 362(Pt 3): 573-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11879183&dopt=Abstract
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Bisphenol A diglycidyl ether-induced apoptosis involves Bax/Bid-dependent mitochondrial release of apoptosis-inducing factor (AIF), cytochrome c and Smac/DIABLO. Author(s): Fehlberg S, Gregel CM, Goke A, Goke R. Source: British Journal of Pharmacology. 2003 June; 139(3): 495-500. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12788809&dopt=Abstract
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Blockade of human cardiac potassium channel human ether-a-go-go-related gene (HERG) by macrolide antibiotics. Author(s): Volberg WA, Koci BJ, Su W, Lin J, Zhou J. Source: The Journal of Pharmacology and Experimental Therapeutics. 2002 July; 302(1): 320-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12065733&dopt=Abstract
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Carcinogenicity of methyl-tertiary butyl ether in gasoline. Author(s): Mehlman MA. Source: Annals of the New York Academy of Sciences. 2002 December; 982: 149-59. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12562634&dopt=Abstract
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Chemical synthesis and calcium release activity of N(1)-ether strand substituted cADPR mimic. Author(s): Huang LJ, Zhao YY, Yuan L, Min JM, Zhang LH. Source: Bioorganic & Medicinal Chemistry Letters. 2002 March 25; 12(6): 887-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11958986&dopt=Abstract
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Chiral separation of gemifloxacin in sodium-containing media using chiral crown ether as a chiral selector by capillary and microchip electrophoresis. Author(s): Cho SI, Lee KN, Kim YK, Jang J, Chung DS. Source: Electrophoresis. 2002 March; 23(6): 972-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11920885&dopt=Abstract
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Cloning and functional characterization of the smooth muscle ether-a-go-go-related gene K+ channel. Potential role of a conserved amino acid substitution in the S4 region. Author(s): Shoeb F, Malykhina AP, Akbarali HI. Source: The Journal of Biological Chemistry. 2003 January 24; 278(4): 2503-14. Epub 2002 November 09. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12427763&dopt=Abstract
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Comparing electron ionization high-resolution and electron capture low-resolution mass spectrometric determination of polybrominated diphenyl ethers in plasma, serum and milk. Author(s): Thomsen C, Haug LS, Leknes H, Lundanes E, Becher G, Lindstrom G. Source: Chemosphere. 2002 February; 46(5): 641-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11999787&dopt=Abstract
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Comparison of different fluorimetric HPLC methods for analysis of acidic polyether toxins in marine phytoplankton. Author(s): Nogueiras MJ, Gago-Martinez A, Paniello AI, Twohig M, James KJ, Lawrence JF. Source: Analytical and Bioanalytical Chemistry. 2003 December; 377(7-8): 1202-6. Epub 2003 October 09. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14551661&dopt=Abstract
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Comparison of polybrominated diphenyl ethers in fish, vegetables, and meats and levels in human milk of nursing women in Japan. Author(s): Ohta S, Ishizuka D, Nishimura H, Nakao T, Aozasa O, Shimidzu Y, Ochiai F, Kida T, Nishi M, Miyata H. Source: Chemosphere. 2002 February; 46(5): 689-96. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11999792&dopt=Abstract
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Correlation of bispectral index and Guedel's stages of ether anesthesia. Author(s): Bhargava AK, Setlur R, Sreevastava D. Source: Anesthesia and Analgesia. 2004 January; 98(1): 132-4, Table of Contents. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14693605&dopt=Abstract
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Current progress in the development and use of artemether for chemoprophylaxis of major human schistosome parasites. Author(s): Utzinger J, Xiao S, Keiser J, Chen M, Zheng J, Tanner M. Source: Current Medicinal Chemistry. 2001 December; 8(15): 1841-60. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11772354&dopt=Abstract
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Cytotoxicity of S-conjugates of the sevoflurane degradation product fluoromethyl-2,2difluoro-1-(trifluoromethyl) vinyl ether (Compound A) in a human proximal tubular cell line. Author(s): Altuntas TG, Zager RA, Kharasch ED. Source: Toxicology and Applied Pharmacology. 2003 November 15; 193(1): 55-65. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14613716&dopt=Abstract
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Defective human Ether-a-go-go-related gene trafficking linked to an endoplasmic reticulum retention signal in the C terminus. Author(s): Kupershmidt S, Yang T, Chanthaphaychith S, Wang Z, Towbin JA, Roden DM. Source: The Journal of Biological Chemistry. 2002 July 26; 277(30): 27442-8. Epub 2002 May 20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12021266&dopt=Abstract
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Depletion of GIM5 causes cellular fragility, a decreased glycosome number, and reduced levels of ether-linked phospholipids in trypanosomes. Author(s): Voncken F, van Hellemond JJ, Pfisterer I, Maier A, Hillmer S, Clayton C. Source: The Journal of Biological Chemistry. 2003 September 12; 278(37): 35299-310. Epub 2003 June 26. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12829709&dopt=Abstract
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Determination of polybrominated diphenyl ethers and polychlorinated biphenyls in human adipose tissue by large-volume injection-narrow-bore capillary gas chromatography/electron impact low-resolution mass spectrometry. Author(s): Covaci A, de BJ, Ryan JJ, Voorspoels S, Schepens P. Source: Analytical Chemistry. 2002 February 15; 74(4): 790-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11866059&dopt=Abstract
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Diversity of selective environmental substrates for human cytochrome P450 2A6: alkoxyethers, nicotine, coumarin, N-nitrosodiethylamine, and Nnitrosobenzylmethylamine. Author(s): Le Gal A, Dreano Y, Lucas D, Berthou F. Source: Toxicology Letters. 2003 September 15; 144(1): 77-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12919726&dopt=Abstract
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Effects of a diphenyl ether-type herbicide, chlornitrofen, and its amino derivative on androgen and estrogen receptor activities. Author(s): Kojima H, Iida M, Katsura E, Kanetoshi A, Hori Y, Kobayashi K. Source: Environmental Health Perspectives. 2003 April; 111(4): 497-502. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12676605&dopt=Abstract
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Effects of experimental conditions on absorption of glycol ethers through human skin in vitro. Author(s): Wilkinson SC, Williams FM. Source: International Archives of Occupational and Environmental Health. 2002 October; 75(8): 519-27. Epub 2002 August 27. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12373313&dopt=Abstract
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Efficient synthesis of 'redox-switched' naphthoquinone thiol-crown ethers and their biological activity evaluation. Author(s): Huang ST, Kuo HS, Hsiao CL, Lin YL. Source: Bioorganic & Medicinal Chemistry. 2002 June; 10(6): 1947-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11937353&dopt=Abstract
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Estrogenic effects of ethanol and ether extracts of propolis. Author(s): Song YS, Jin C, Jung KJ, Park EH. Source: Journal of Ethnopharmacology. 2002 October; 82(2-3): 89-95. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12241982&dopt=Abstract
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Ether fraction of methanol extracts of Gastrodia elata, medicinal herb protects against neuronal cell damage after transient global ischemia in gerbils. Author(s): Kim HJ, Lee SR, Moon KD. Source: Phytotherapy Research : Ptr. 2003 September; 17(8): 909-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=13680822&dopt=Abstract
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Ether: a forgotten addiction. Author(s): Krenz S, Zimmermann G, Kolly S, Zullino DF. Source: Addiction (Abingdon, England). 2003 August; 98(8): 1167-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12873252&dopt=Abstract
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Ethyl ether fraction of Gastrodia elata Blume protects amyloid beta peptide-induced cell death. Author(s): Kim HJ, Moon KD, Lee DS, Lee SH. Source: Journal of Ethnopharmacology. 2003 January; 84(1): 95-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12499082&dopt=Abstract
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Exposure to ethylene glycol monomethyl ether: clinical and cytogenetic findings. Author(s): El-Zein RA, Abdel-Rahman SZ, Morris DL, Legator MS. Source: Archives of Environmental Health. 2002 July-August; 57(4): 371-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12530607&dopt=Abstract
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Exposure to polybrominated diphenyl ethers and tetrabromobisphenol A among computer technicians. Author(s): Jakobsson K, Thuresson K, Rylander L, Sjodin A, Hagmar L, Bergman A. Source: Chemosphere. 2002 February; 46(5): 709-16. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11999794&dopt=Abstract
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Final report on the safety assessment of PPG-11 and PPG-15 stearyl ethers. Author(s): Lanigan RS; Cosmetic Ingredient Review Expert Panel. Source: International Journal of Toxicology. 2001; 20 Suppl 4: 53-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11800052&dopt=Abstract
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Glutathione S-conjugation of the sevoflurane degradation product, fluoromethyl-2,2difluoro-1-(trifluoromethyl)vinyl ether (compound A) in human liver, kidney, and blood in vitro. Author(s): Altuntas TG, Kharasch ED. Source: Toxicology and Applied Pharmacology. 2001 December 1; 177(2): 85-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11740907&dopt=Abstract
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Goniodomin A, an antifungal polyether macrolide, exhibits antiangiogenic activities via inhibition of actin reorganization in endothelial cells. Author(s): Abe M, Inoue D, Matsunaga K, Ohizumi Y, Ueda H, Asano T, Murakami M, Sato Y. Source: Journal of Cellular Physiology. 2002 January; 190(1): 109-16. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11807817&dopt=Abstract
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Grafting sulfobetaine monomer onto the segmented poly(ether-urethane) surface to improve hemocompatibility. Author(s): Yuan YL, Ai F, Zhang J, Zang XB, Shen J, Lin SC. Source: Journal of Biomaterials Science. Polymer Edition. 2002; 13(10): 1081-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12484485&dopt=Abstract
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High body burdens of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) in California women. Author(s): Petreas M, She J, Brown FR, Winkler J, Windham G, Rogers E, Zhao G, Bhatia R, Charles MJ. Source: Environmental Health Perspectives. 2003 July; 111(9): 1175-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12842770&dopt=Abstract
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Histidines 578 and 587 in the S5-S6 linker of the human Ether-a-gogo Related Gene-1 K+ channels confer sensitivity to reactive oxygen species. Author(s): Pannaccione A, Castaldo P, Ficker E, Annunziato L, Taglialatela M. Source: The Journal of Biological Chemistry. 2002 March 15; 277(11): 8912-9. Epub 2001 December 26. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11756457&dopt=Abstract
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Human platelets respond differentially to lysophosphatidic acids having a highly unsaturated fatty acyl group and alkyl ether-linked lysophosphatidic acids. Author(s): Tokumura A, Sinomiya J, Kishimoto S, Tanaka T, Kogure K, Sugiura T, Satouchi K, Waku K, Fukuzawa K. Source: The Biochemical Journal. 2002 August 1; 365(Pt 3): 617-28. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11982483&dopt=Abstract
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Identification of a COOH-terminal segment involved in maturation and stability of human ether-a-go-go-related gene potassium channels. Author(s): Akhavan A, Atanasiu R, Shrier A. Source: The Journal of Biological Chemistry. 2003 October 10; 278(41): 40105-12. Epub 2003 July 28. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12885765&dopt=Abstract
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Impairment of human ether-a-go-go-related gene (HERG) K+ channel function by hypoglycemia and hyperglycemia. Similar phenotypes but different mechanisms. Author(s): Zhang Y, Han H, Wang J, Wang H, Yang B, Wang Z. Source: The Journal of Biological Chemistry. 2003 March 21; 278(12): 10417-26. Epub 2003 January 16. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12531891&dopt=Abstract
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Impression materials: a new look at the polyether system. Author(s): Leinfelder KF, Ritter AV. Source: Dent Today. 2001 April; 20(4): 72-9. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12528208&dopt=Abstract
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In vitro and in vivo antimalarial activities of the monoglycoside polyether antibiotic, K-41 against drug resistant strains of Plasmodia. Author(s): Otoguro K, Ishiyama A, Ui H, Kobayashi M, Manabe C, Yan G, Takahashi Y, Tanaka H, Yamada H, Omura S. Source: J Antibiot (Tokyo). 2002 September; 55(9): 832-4. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12458776&dopt=Abstract
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In vitro assay of hydrolysis and chlorohydroxy derivatives of bisphenol A diglycidyl ether for estrogenic activity. Author(s): Nakazawa H, Yamaguchi A, Inoue K, Yamazaki T, Kato K, Yoshimura Y, Makino T. Source: Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association. 2002 December; 40(12): 1827-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12419697&dopt=Abstract
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In vitro assessment of potential mechanism-specific effects of polybrominated diphenyl ethers. Author(s): Villeneuve DL, Kannan K, Priest BT, Giesy JP. Source: Environmental Toxicology and Chemistry / Setac. 2002 November; 21(11): 24313. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12389923&dopt=Abstract
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Increased risk of arrhythmic events in long-QT syndrome with mutations in the pore region of the human ether-a-go-go-related gene potassium channel. Author(s): Moss AJ, Zareba W, Kaufman ES, Gartman E, Peterson DR, Benhorin J, Towbin JA, Keating MT, Priori SG, Schwartz PJ, Vincent GM, Robinson JL, Andrews ML, Feng C, Hall WJ, Medina A, Zhang L, Wang Z. Source: Circulation. 2002 February 19; 105(7): 794-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11854117&dopt=Abstract
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Influence of ethyl acetate extract and quercetin-3-methyl ether from Polygonum amphibium on activation lymphocytes from peripheral blood of healthy donor in vitro. Author(s): Smolarz HD, Surdacka A, Rolinski J. Source: Phytotherapy Research : Ptr. 2003 August; 17(7): 744-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12916071&dopt=Abstract
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Influence of opioid agonists on cardiac human ether-a-go-go-related gene K(+) currents. Author(s): Katchman AN, McGroary KA, Kilborn MJ, Kornick CA, Manfredi PL, Woosley RL, Ebert SN. Source: The Journal of Pharmacology and Experimental Therapeutics. 2002 November; 303(2): 688-94. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12388652&dopt=Abstract
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Inhibition of monocyte adhesion and fibrinogen adsorption on glow discharge plasma deposited tetraethylene glycol dimethyl ether. Author(s): Shen M, Pan YV, Wagner MS, Hauch KD, Castner DG, Ratner BD, Horbett TA. Source: Journal of Biomaterials Science. Polymer Edition. 2001; 12(9): 961-78. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11787523&dopt=Abstract
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Interaction with GM130 during HERG ion channel trafficking. Disruption by type 2 congenital long QT syndrome mutations. Human Ether-a-go-go-Related Gene. Author(s): Roti EC, Myers CD, Ayers RA, Boatman DE, Delfosse SA, Chan EK, Ackerman MJ, January CT, Robertson GA. Source: The Journal of Biological Chemistry. 2002 December 6; 277(49): 47779-85. Epub 2002 September 20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12270925&dopt=Abstract
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Internalization of aggregated photosensitizers by tumor cells: subcellular timeresolved fluorescence spectroscopy on derivatives of pyropheophorbide-a ethers and chlorin e6 under femtosecond one- and two-photon excitations. Author(s): Kelbauskas L, Dietel W. Source: Photochemistry and Photobiology. 2002 December; 76(6): 686-94. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12511052&dopt=Abstract
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Investigation of endotoxin adsorption with polyether polymer alloy dialysis membranes. Author(s): Nakatani T, Tsuchida K, Sugimura K, Yoshimura R, Takemoto Y. Source: International Journal of Molecular Medicine. 2003 February; 11(2): 195-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12525877&dopt=Abstract
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Involvement of caspase 3 mediated apoptosis in hematopoietic cytotoxicity of metabolites of ethylene glycol monomethyl ether. Author(s): Takagi A, Yamada T, Hayashi K, Nakade Y, Kojima T, Takamatsu J, Shibata E, Ichihara G, Takeuchi Y, Murate T. Source: Ind Health. 2002 October; 40(4): 371-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12502240&dopt=Abstract
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Isolation of a new organochlorine pollutant 2,3,3,3,2',3',3',3'-octachlorodipropyl ether from fish. Author(s): Yoshida S, Taguchi S, Kitagawa M. Source: Bulletin of Environmental Contamination and Toxicology. 2001 October; 67(4): 568-73. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11779073&dopt=Abstract
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Lessons from the polybrominated diphenyl ethers (PBDEs): precautionary principle, primary prevention, and the value of community-based body-burden monitoring using breast milk. Author(s): Hooper K, She J. Source: Environmental Health Perspectives. 2003 January; 111(1): 109-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12515688&dopt=Abstract
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Mapping the binding site of a human ether-a-go-go-related gene-specific peptide toxin (ErgTx) to the channel's outer vestibule. Author(s): Pardo-Lopez L, Zhang M, Liu J, Jiang M, Possani LD, Tseng GN. Source: The Journal of Biological Chemistry. 2002 May 10; 277(19): 16403-11. Epub 2002 February 25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11864985&dopt=Abstract
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Maternal exposure to diethylene glycol monomethyl ether: a possible role in the etiology of retrocaval ureter. Author(s): Karaman MI, Gurdal M, Ozturk M, Kanberoglu H. Source: Journal of Pediatric Surgery. 2002 August; 37(8): E23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12149723&dopt=Abstract
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Metabolic markers of breast cancer: enhanced choline metabolism and reduced choline-ether-phospholipid synthesis. Author(s): Katz-Brull R, Seger D, Rivenson-Segal D, Rushkin E, Degani H. Source: Cancer Research. 2002 April 1; 62(7): 1966-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11929812&dopt=Abstract
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Molecular determinants of voltage-dependent human ether-a-go-go related gene (HERG) K+ channel block. Author(s): Sanchez-Chapula JA, Navarro-Polanco RA, Culberson C, Chen J, Sanguinetti MC. Source: The Journal of Biological Chemistry. 2002 June 28; 277(26): 23587-95. Epub 2002 April 17. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11960982&dopt=Abstract
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Morton's design of the early ether vaporisers. Author(s): Desbarax P. Source: Anaesthesia. 2002 May; 57(5): 463-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11966556&dopt=Abstract
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Mutagenic and genotoxic evaluation of bisphenol F diglycidyl ether (BFDGE) in prokaryotic and eukaryotic systems. Author(s): Sueiro RA, Suarez S, Araujo M, Garrido MJ. Source: Mutation Research. 2003 April 20; 536(1-2): 39-48. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12694744&dopt=Abstract
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Occupational contact urticaria from diglycidyl ether of bisphenol A epoxy resin. Author(s): Kanerva L, Pelttari M, Jolanki R, Alanko K, Estlander T, Suhonen R. Source: Allergy. 2002 December; 57(12): 1205-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12464052&dopt=Abstract
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Occupational exposure to methyl tertiary butyl ether: a risk to be assessed. Author(s): Iavicoli I, Carelli G. Source: Occupational Medicine (Oxford, England). 2003 September; 53(6): 408-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14514910&dopt=Abstract
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Octachlorodipropyl ether (s-2) mosquito coils are inadequately studied for residential use in Asia and illegal in the United States. Author(s): Krieger RI, Dinoff TM, Zhang X. Source: Environmental Health Perspectives. 2003 September; 111(12): 1439-42. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12948880&dopt=Abstract
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Optimization of a tertiary alcohol series of phosphodiesterase-4 (PDE4) inhibitors: structure-activity relationship related to PDE4 inhibition and human ether-a-go-go related gene potassium channel binding affinity. Author(s): Friesen RW, Ducharme Y, Ball RG, Blouin M, Boulet L, Cote B, Frenette R, Girard M, Guay D, Huang Z, Jones TR, Laliberte F, Lynch JJ, Mancini J, Martins E, Masson P, Muise E, Pon DJ, Siegl PK, Styhler A, Tsou NN, Turner MJ, Young RN, Girard Y. Source: Journal of Medicinal Chemistry. 2003 June 5; 46(12): 2413-26. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12773045&dopt=Abstract
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Parallel fragment assembly strategy towards multiple-ether mimicry of anticancer annonaceous acetogenins. Author(s): Jiang S, Li Y, Chen XG, Hu TS, Wu YL, Yao ZJ. Source: Angewandte Chemie (International Ed. in English). 2004 January 3; 43(3): 329-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14705089&dopt=Abstract
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Pharmacological rescue of human K(+) channel long-QT2 mutations: human ether-ago-go-related gene rescue without block. Author(s): Rajamani S, Anderson CL, Anson BD, January CT. Source: Circulation. 2002 June 18; 105(24): 2830-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12070109&dopt=Abstract
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Phase separation and physical properties of PEO-containing poly(ether ester amide)s. Author(s): Deschamps AA, Grijpma DW, Feijen J. Source: Journal of Biomaterials Science. Polymer Edition. 2002; 13(12): 1337-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12555900&dopt=Abstract
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Polybrominated dibenzo-p-dioxins, dibenzofurans, and diphenyl ethers in Japanese human adipose tissue. Author(s): Choi JW, Fujimaki TS, Kitamura K, Hashimoto S, Ito H, Suzuki N, Sakai S, Morita M. Source: Environmental Science & Technology. 2003 March 1; 37(5): 817-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12666907&dopt=Abstract
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Polybrominated diphenyl ethers (PBDEs) in foodstuffs: human exposure through the diet. Author(s): Bocio A, Llobet JM, Domingo JL, Corbella J, Teixido A, Casas C. Source: Journal of Agricultural and Food Chemistry. 2003 May 7; 51(10): 3191-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12720414&dopt=Abstract
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Polybrominated diphenyl ethers (PBDEs) in U.S. mothers' milk. Author(s): Schecter A, Pavuk M, Papke O, Ryan JJ, Birnbaum L, Rosen R. Source: Environmental Health Perspectives. 2003 November; 111(14): 1723-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14594622&dopt=Abstract
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Polybrominated diphenyl ethers in breast milk from Uppsala County, Sweden. Author(s): Lind Y, Darnerud PO, Atuma S, Aune M, Becker W, Bjerselius R, Cnattingius S, Glynn A. Source: Environmental Research. 2003 October; 93(2): 186-94. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12963403&dopt=Abstract
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Polybrominated diphenyl ethers in whitefish from Swiss lakes and farmed rainbow trout. Author(s): Zennegg M, Kohler M, Gerecke AC, Schmid P. Source: Chemosphere. 2003 May; 51(7): 545-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12615108&dopt=Abstract
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Polybrominated diphenyl ethers: neurobehavioral effects following developmental exposure. Author(s): Branchi I, Capone F, Alleva E, Costa LG. Source: Neurotoxicology. 2003 June; 24(3): 449-62. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12782110&dopt=Abstract
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Polybromo diphenyl ethers. Author(s): Czap A. Source: Alternative Medicine Review : a Journal of Clinical Therapeutic. 2001 December; 6(6): 539. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11804545&dopt=Abstract
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Prolonged time to pregnancy in female workers exposed to ethylene glycol ethers in semiconductor manufacturing. Author(s): Chen PC, Hsieh GY, Wang JD, Cheng TJ. Source: Epidemiology (Cambridge, Mass.). 2002 March; 13(2): 191-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11880760&dopt=Abstract
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Propylene glycol monomethyl ether occupational exposure (PGME). 4. Analysis of 2methoxypropionic acid in urine. Author(s): Devanthery A, Berode M, Droz PO, Pulkkinen J. Source: International Archives of Occupational and Environmental Health. 2003 March; 76(2): 151-5. Epub 2002 December 10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12733088&dopt=Abstract
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Propylene glycol monomethyl ether occupational exposure. 3. Exposure of human volunteers. Author(s): Devanthery A, Berode M, Droz PO. Source: International Archives of Occupational and Environmental Health. 2002 April; 75(4): 203-8. Epub 2002 February 05. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11981652&dopt=Abstract
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Protease-mediated fragmentation of p-amidobenzyl ethers: a new strategy for the activation of anticancer prodrugs. Author(s): Toki BE, Cerveny CG, Wahl AF, Senter PD. Source: The Journal of Organic Chemistry. 2002 March 22; 67(6): 1866-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11895404&dopt=Abstract
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Quantitative detection of bisphenol A and bisphenol A diglycidyl ether metabolites in human plasma by liquid chromatography-electrospray mass spectrometry. Author(s): Inoue K, Yamaguchi A, Wada M, Yoshimura Y, Makino T, Nakazaw H. Source: J Chromatogr B Biomed Sci Appl. 2001 December 25; 765(2): 121-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11767304&dopt=Abstract
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Radical scavenging activity and cytotoxicity of phenethyl ether and cinnamic amide derivatives. Author(s): Imai K, Inagaki M, Saitoh Y, Yura A, Sakagami H, Suzuki M, Oguchi K. Source: Anticancer Res. 2002 May-June; 22(3): 1661-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12168851&dopt=Abstract
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Reactive brominating species produced by myeloperoxidase target the vinyl ether bond of plasmalogens: disparate utilization of sodium halides in the production of alpha-halo fatty aldehydes. Author(s): Albert CJ, Crowley JR, Hsu FF, Thukkani AK, Ford DA. Source: The Journal of Biological Chemistry. 2002 February 15; 277(7): 4694-703. Epub 2001 December 07. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11836259&dopt=Abstract
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Recent developments in the construction of trans-fused polycyclic ethers. Author(s): Evans PA, Delouvrie B. Source: Curr Opin Drug Discov Devel. 2002 November; 5(6): 986-99. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12478729&dopt=Abstract
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Role of ether-linked lysophosphatidic acids in ovarian cancer cells. Author(s): Lu J, Xiao Yj YJ, Baudhuin LM, Hong G, Xu Y. Source: Journal of Lipid Research. 2002 March; 43(3): 463-76. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11893783&dopt=Abstract
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Selective binding of albumin on stearyl poly(ethylene oxide) coupling polymermodified poly(ether urethane) surfaces. Author(s): Wang DA, Ji J, Feng LX. Source: Journal of Biomaterials Science. Polymer Edition. 2001; 12(10): 1123-46. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11853382&dopt=Abstract
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Solubilization of human erythrocyte membranes by non-ionic surfactants of the polyoxyethylene alkyl ethers series. Author(s): Prete PS, Gomes K, Malheiros SV, Meirelles NC, de Paula E. Source: Biophysical Chemistry. 2002 May 23; 97(1): 45-54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12052494&dopt=Abstract
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Spironolactone and its main metabolite, canrenoic acid, block human ether-a-go-gorelated gene channels. Author(s): Caballero R, Moreno I, Gonzalez T, Arias C, Valenzuela C, Delpon E, Tamargo J. Source: Circulation. 2003 February 18; 107(6): 889-95. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12591761&dopt=Abstract
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Synthesis and antitumor activity of novel C-7 paclitaxel ethers: discovery of BMS184476. Author(s): Altstadt TJ, Fairchild CR, Golik J, Johnston KA, Kadow JF, Lee FY, Long BH, Rose WC, Vyas DM, Wong H, Wu MJ, Wittman MD. Source: Journal of Medicinal Chemistry. 2001 December 20; 44(26): 4577-83. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11741476&dopt=Abstract
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Synthesis and cytotoxicity of dihydroartemisinin ethers containing cyanoarylmethyl group. Author(s): Li Y, Wu JM, Shan F, Wu GS, Ding J, Xiao D, Han JX, Atassi G, Leonce S, Caignard DH, Renard P. Source: Bioorganic & Medicinal Chemistry. 2003 March 20; 11(6): 977-84. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12614882&dopt=Abstract
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Synthesis and evaluation of a novel E-ring modified alpha-hydroxy keto ether analogue of camptothecin. Author(s): Du W, Curran DP, Bevins RL, Zimmer SG, Zhang J, Burke TG. Source: Bioorganic & Medicinal Chemistry. 2002 January; 10(1): 103-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11738612&dopt=Abstract
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Synthesis of lipid A type carboxymethyl derivatives with ether chains instead of ester chains and their LPS-antagonistic activities. Author(s): Watanabe Y, Miura K, Shiozaki M, Kanai S, Kurakata S, Nishijima M. Source: Carbohydrate Research. 2003 January 2; 338(1): 47-54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12504380&dopt=Abstract
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Temperature effects on the rheological properties of current polyether and polysiloxane impression materials during setting. Author(s): Berg JC, Johnson GH, Lepe X, Adan-Plaza S. Source: The Journal of Prosthetic Dentistry. 2003 August; 90(2): 150-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12886208&dopt=Abstract
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The antidepressant drug fluoxetine is an inhibitor of human ether-a-go-go-related gene (HERG) potassium channels. Author(s): Thomas D, Gut B, Wendt-Nordahl G, Kiehn J. Source: The Journal of Pharmacology and Experimental Therapeutics. 2002 February; 300(2): 543-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11805215&dopt=Abstract
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The antitumor ether lipid 1-Q-octadecyl-2-O-methyl-rac-glycerophosphocholine (ET18-OCH3) inhibits the association between Ras and Raf-1. Author(s): Samadder P, Richards C, Bittman R, Bhullar RP, Arthur G. Source: Anticancer Res. 2003 May-June; 23(3B): 2291-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12894505&dopt=Abstract
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The antitumor ether lipid ET-18-OCH(3) induces apoptosis through translocation and capping of Fas/CD95 into membrane rafts in human leukemic cells. Author(s): Gajate C, Mollinedo F. Source: Blood. 2001 December 15; 98(13): 3860-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11739199&dopt=Abstract
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The binding site for channel blockers that rescue misprocessed human long QT syndrome type 2 ether-a-gogo-related gene (HERG) mutations. Author(s): Ficker E, Obejero-Paz CA, Zhao S, Brown AM. Source: The Journal of Biological Chemistry. 2002 February 15; 277(7): 4989-98. Epub 2001 December 10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11741928&dopt=Abstract
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The functional properties of the human ether-a-go-go-like (HELK2) K+ channel. Author(s): Becchetti A, De Fusco M, Crociani O, Cherubini A, Restano-Cassulini R, Lecchi M, Masi A, Arcangeli A, Casari G, Wanke E. Source: The European Journal of Neuroscience. 2002 August; 16(3): 415-28. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12193184&dopt=Abstract
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The influence of protein adsorption and surface modifying macromolecules on the hydrolytic degradation of a poly(ether-urethane) by cholesterol esterase. Author(s): Jahangir R, McCloskey CB, Mc Clung WG, Labow RS, Brash JL, Santerre JP. Source: Biomaterials. 2003 January; 24(1): 121-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12417185&dopt=Abstract
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The role of the peripheral benzodiazepine receptor in photodynamic activity of certain pyropheophorbide ether photosensitizers: albumin site II as a surrogate marker for activity. Author(s): Dougherty TJ, Sumlin AB, Greco WR, Weishaupt KR, Vaughan LA, Pandey RK. Source: Photochemistry and Photobiology. 2002 July; 76(1): 91-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12126312&dopt=Abstract
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Three-dimensional quantitative structure-activity relationship for inhibition of human ether-a-go-go-related gene potassium channel. Author(s): Ekins S, Crumb WJ, Sarazan RD, Wikel JH, Wrighton SA. Source: The Journal of Pharmacology and Experimental Therapeutics. 2002 May; 301(2): 427-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11961040&dopt=Abstract
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Time-temperature study of the kinetics of migration of BADGE (bisphenol-Adiglycidyl-ether) into a fatty medium. Author(s): Simoneau C, Theobald A, Roncari P, Hannaert P, Anklam E. Source: Food Additives and Contaminants. 2002; 19 Suppl: 73-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11962717&dopt=Abstract
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Time-trend (1973-2000) of polybrominated diphenyl ethers in Japanese mother's milk. Author(s): Akutsu K, Kitagawa M, Nakazawa H, Makino T, Iwazaki K, Oda H, Hori S. Source: Chemosphere. 2003 November; 53(6): 645-54. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12962714&dopt=Abstract
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Uncertainties and data needs in risk assessment of three commercial polybrominated diphenyl ethers: probabilistic exposure analysis and comparison with European Commission results. Author(s): Wenning RJ. Source: Chemosphere. 2002 February; 46(5): 779-96. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11999800&dopt=Abstract
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Understanding the structure-activity relationship of the human ether-a-go-go-related gene cardiac K+ channel. A model for bad behavior. Author(s): Pearlstein R, Vaz R, Rampe D. Source: Journal of Medicinal Chemistry. 2003 May 22; 46(11): 2017-22. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12747773&dopt=Abstract
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Urinary bisphenol A and plasma hormone concentrations in male workers exposed to bisphenol A diglycidyl ether and mixed organic solvents. Author(s): Hanaoka T, Kawamura N, Hara K, Tsugane S. Source: Occupational and Environmental Medicine. 2002 September; 59(9): 625-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12205237&dopt=Abstract
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Uses of thermoresponsive and RGD/insulin-modified poly(vinyl ether)-based hydrogels in cell cultures. Author(s): Gumusderelioglu M, Karakecili AG. Source: Journal of Biomaterials Science. Polymer Edition. 2003; 14(3): 199-211. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12713094&dopt=Abstract
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Voltage-dependent profile of human ether-a-go-go-related gene channel block is influenced by a single residue in the S6 transmembrane domain. Author(s): Sanchez-Chapula JA, Ferrer T, Navarro-Polanco RA, Sanguinetti MC. Source: Molecular Pharmacology. 2003 May; 63(5): 1051-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12695533&dopt=Abstract
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CHAPTER 2. ALTERNATIVE MEDICINE AND ETHER Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to ether. 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 ether 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 “ether” (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 ether: •
A new dicoumarinyl ether and two rare furocoumarins from Ruta montana. Author(s): Kabouche Z, Benkiki N, Seguin E, Bruneau C. Source: Fitoterapia. 2003 February; 74(1-2): 194-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12628424&dopt=Abstract
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Aglacins A-D, first representatives of a new class of aryltetralin cyclic ether lignans from Aglaia cordata. Author(s): Wang BG, Ebel R, Nugroho BW, Prijono D, Frank W, Steube KG, Hao XJ, Proksch P. Source: Journal of Natural Products. 2001 December; 64(12): 1521-6. Erratum In: J Nat Prod. 2003 January; 66(1): 155. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11754603&dopt=Abstract
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Analgesic, antipyretic, anti-inflammatory effects of methanol, chloroform and ether extracts of Vernonia cinerea less leaf. Author(s): Iwalewa EO, Iwalewa OJ, Adeboye JO. Source: Journal of Ethnopharmacology. 2003 June; 86(2-3): 229-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12738092&dopt=Abstract
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Anandamide and noladin ether prevent neurotoxicity of the human amyloid-beta peptide. Author(s): Milton NG. Source: Neuroscience Letters. 2002 October 31; 332(2): 127-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12384227&dopt=Abstract
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Biosynthesis of new divinyl ether oxylipins in Ranunculus plants. Author(s): Hamberg M. Source: Lipids. 2002 April; 37(4): 427-33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12030324&dopt=Abstract
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Chiral separation of gemifloxacin in sodium-containing media using chiral crown ether as a chiral selector by capillary and microchip electrophoresis. Author(s): Cho SI, Lee KN, Kim YK, Jang J, Chung DS. Source: Electrophoresis. 2002 March; 23(6): 972-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11920885&dopt=Abstract
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Correlation of bispectral index and Guedel's stages of ether anesthesia. Author(s): Bhargava AK, Setlur R, Sreevastava D. Source: Anesthesia and Analgesia. 2004 January; 98(1): 132-4, Table of Contents. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14693605&dopt=Abstract
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Crystal structures of pinoresinol-lariciresinol and phenylcoumaran benzylic ether reductases and their relationship to isoflavone reductases. Author(s): Min T, Kasahara H, Bedgar DL, Youn B, Lawrence PK, Gang DR, Halls SC, Park H, Hilsenbeck JL, Davin LB, Lewis NG, Kang C. Source: The Journal of Biological Chemistry. 2003 December 12; 278(50): 50714-23. Epub 2003 September 16. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=13129921&dopt=Abstract
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Estrogenic effects of ethanol and ether extracts of propolis. Author(s): Song YS, Jin C, Jung KJ, Park EH. Source: Journal of Ethnopharmacology. 2002 October; 82(2-3): 89-95. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12241982&dopt=Abstract
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Ether fraction of methanol extracts of Gastrodia elata, a traditional medicinal herb, protects against kainic acid-induced neuronal damage in the mouse hippocampus. Author(s): Kim HJ, Moon KD, Oh SY, Kim SP, Lee SR. Source: Neuroscience Letters. 2001 November 13; 314(1-2): 65-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11698148&dopt=Abstract
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Ether fraction of methanol extracts of Gastrodia elata, medicinal herb protects against neuronal cell damage after transient global ischemia in gerbils. Author(s): Kim HJ, Lee SR, Moon KD. Source: Phytotherapy Research : Ptr. 2003 September; 17(8): 909-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=13680822&dopt=Abstract
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Ethereal epidemic: mesmerism and the introduction of inhalation anaesthesia to early Victorian London. Author(s): Winter A. Source: Social History of Medicine : the Journal of the Society for the Social History of Medicine / Sshm. 1991 April; 4(1): 1-27. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11622851&dopt=Abstract
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Ethyl ether fraction of Gastrodia elata Blume protects amyloid beta peptide-induced cell death. Author(s): Kim HJ, Moon KD, Lee DS, Lee SH. Source: Journal of Ethnopharmacology. 2003 January; 84(1): 95-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12499082&dopt=Abstract
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Evaluation of the antinociceptive action caused by ether fraction and a triterpene isolated from resin of Protium kleinii. Author(s): Otuki MF, Lima FV, Malheiros A, Cechinel-Filho V, Delle Monache F, Yunes RA, Calixto JB. Source: Life Sciences. 2001 September 28; 69(19): 2225-36. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11669465&dopt=Abstract
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Extraction of chili, black pepper, and ginger with near-critical CO2, propane, and dimethyl ether: analysis of the extracts by quantitative nuclear magnetic resonance. Author(s): Catchpole OJ, Grey JB, Perry NB, Burgess EJ, Redmond WA, Porter NG. Source: Journal of Agricultural and Food Chemistry. 2003 August 13; 51(17): 4853-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12903935&dopt=Abstract
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Feedback regulation of beta-thujaplicin production and formation of its methyl ether in a suspension culture of Cupressus lusitanica. Author(s): Yamada J, Fujita K, Sakai K.
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Source: Phytochemistry. 2002 July; 60(5): 447-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12052509&dopt=Abstract •
In vitro anti-inflammatory effects of quercetin 3-O-methyl ether and other constituents from Rhamnus species. Author(s): Wei BL, Lu CM, Tsao LT, Wang JP, Lin CN. Source: Planta Medica. 2001 November; 67(8): 745-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11731918&dopt=Abstract
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Influence of ethyl acetate extract and quercetin-3-methyl ether from Polygonum amphibium on activation lymphocytes from peripheral blood of healthy donor in vitro. Author(s): Smolarz HD, Surdacka A, Rolinski J. Source: Phytotherapy Research : Ptr. 2003 August; 17(7): 744-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12916071&dopt=Abstract
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Neuroprotective effects of antioxidative flavonoids, quercetin, (+)-dihydroquercetin and quercetin 3-methyl ether, isolated from Opuntia ficus-indica var. saboten. Author(s): Dok-Go H, Lee KH, Kim HJ, Lee EH, Lee J, Song YS, Lee YH, Jin C, Lee YS, Cho J. Source: Brain Research. 2003 March 7; 965(1-2): 130-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12591129&dopt=Abstract
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New clerodane diterpenoid and flavonol-3-methyl ethers from Dodonaea viscosa. Author(s): Abdel-Mogib M, Basaif SA, Asiri AM, Sobahi TR, Batterjee SM. Source: Pharmazie. 2001 October; 56(10): 830-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11683136&dopt=Abstract
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Pharmacological studies of geissoschizine methyl ether, isolated from Uncaria sinensis Oliv., in the central nervous system. Author(s): Pengsuparp T, Indra B, Nakagawasai O, Tadano T, Mimaki Y, Sashida Y, Ohizumi Y, Kisara K. Source: European Journal of Pharmacology. 2001 August 17; 425(3): 211-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11513840&dopt=Abstract
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Polybromo diphenyl ethers. Author(s): Czap A. Source: Alternative Medicine Review : a Journal of Clinical Therapeutic. 2001 December; 6(6): 539. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11804545&dopt=Abstract
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Radical scavenging activity and cytotoxicity of phenethyl ether and cinnamic amide derivatives. Author(s): Imai K, Inagaki M, Saitoh Y, Yura A, Sakagami H, Suzuki M, Oguchi K. Source: Anticancer Res. 2002 May-June; 22(3): 1661-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12168851&dopt=Abstract
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Short and stereoselective total synthesis of furano lignans (+/-)-dihydrosesamin, (+/-)lariciresinol dimethyl ether, (+/-)-acuminatin methyl ether, (+/-)-sanshodiol methyl ether, (+/-)-lariciresinol, (+/-)-acuminatin, and (+/-)-lariciresinol monomethyl ether and furofuran lignans (+/-)-sesamin, (+/-)-eudesmin, (+/-)-piperitol methyl ether, (+/-)pinoresinol, (+/-)-piperitol, and (+/-)-pinoresinol monomethyl ether by radical cyclization of epoxides using a transition-metal radical source. Author(s): Roy SC, Rana KK, Guin C. Source: The Journal of Organic Chemistry. 2002 May 17; 67(10): 3242-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12003531&dopt=Abstract
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Synthesis and antitumor activity of novel C-7 paclitaxel ethers: discovery of BMS184476. Author(s): Altstadt TJ, Fairchild CR, Golik J, Johnston KA, Kadow JF, Lee FY, Long BH, Rose WC, Vyas DM, Wong H, Wu MJ, Wittman MD. Source: Journal of Medicinal Chemistry. 2001 December 20; 44(26): 4577-83. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11741476&dopt=Abstract
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Synthesis and cytotoxicity of dihydroartemisinin ethers containing cyanoarylmethyl group. Author(s): Li Y, Wu JM, Shan F, Wu GS, Ding J, Xiao D, Han JX, Atassi G, Leonce S, Caignard DH, Renard P. Source: Bioorganic & Medicinal Chemistry. 2003 March 20; 11(6): 977-84. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12614882&dopt=Abstract
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Synthesis and evaluation of a novel E-ring modified alpha-hydroxy keto ether analogue of camptothecin. Author(s): Du W, Curran DP, Bevins RL, Zimmer SG, Zhang J, Burke TG. Source: Bioorganic & Medicinal Chemistry. 2002 January; 10(1): 103-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11738612&dopt=Abstract
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The potential of artemether for the control of schistosomiasis. Author(s): Utzinger J, Xiao S, N'Goran EK, Bergquist R, Tanner M. Source: International Journal for Parasitology. 2001 December; 31(14): 1549-62. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11730781&dopt=Abstract
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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 ether; 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 Abdominal Wall Inflammation Source: Integrative Medicine Communications; www.drkoop.com Acne Source: Prima Communications, Inc.www.personalhealthzone.com Age-Related Cognitive Decline Source: Healthnotes, Inc.; www.healthnotes.com AIDS and HIV Source: Integrative Medicine Communications; www.drkoop.com Alcohol Withdrawal Source: Healthnotes, Inc.; www.healthnotes.com Allergies Alternative names: Hay Fever Source: Prima Communications, Inc.www.personalhealthzone.com
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Allergies and Sensitivities Source: Healthnotes, Inc.; www.healthnotes.com Alzheimer's Disease Source: Healthnotes, Inc.; www.healthnotes.com Alzheimer's Disease Source: Integrative Medicine Communications; www.drkoop.com Amenorrhea Source: Healthnotes, Inc.; www.healthnotes.com Amyloidosis Source: Integrative Medicine Communications; www.drkoop.com Angina Source: Healthnotes, Inc.; www.healthnotes.com Anorexia Nervosa Source: Integrative Medicine Communications; www.drkoop.com Anxiety and Panic Attacks Source: Prima Communications, Inc.www.personalhealthzone.com Appendicitis Source: Integrative Medicine Communications; www.drkoop.com Arteriosclerosis Source: Integrative Medicine Communications; www.drkoop.com Ascariasis Source: Integrative Medicine Communications; www.drkoop.com Asthma Source: Healthnotes, Inc.; www.healthnotes.com Asthma Source: Prima Communications, Inc.www.personalhealthzone.com Atherosclerosis Source: Healthnotes, Inc.; www.healthnotes.com Atherosclerosis Source: Integrative Medicine Communications; www.drkoop.com Atherosclerosis and Heart Disease Prevention Source: Prima Communications, Inc.www.personalhealthzone.com Autism Source: Healthnotes, Inc.; www.healthnotes.com
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Bell's Palsy Source: Healthnotes, Inc.; www.healthnotes.com Benign Prostatic Hyperplasia Source: Healthnotes, Inc.; www.healthnotes.com Benign Prostatic Hyperplasia Alternative names: Prostate Enlargement Source: Prima Communications, Inc.www.personalhealthzone.com Bladder Infection Alternative names: Urinary Tract Infection [UTI] Source: Prima Communications, Inc.www.personalhealthzone.com Bone Cancer Source: Integrative Medicine Communications; www.drkoop.com Bone Loss Source: Integrative Medicine Communications; www.drkoop.com Breast Cancer Source: Healthnotes, Inc.; www.healthnotes.com Bronchitis Source: Healthnotes, Inc.; www.healthnotes.com Burns Source: Integrative Medicine Communications; www.drkoop.com Cancer Prevention (Reducing the Risk) Source: Prima Communications, Inc.www.personalhealthzone.com Canker Sores Source: Healthnotes, Inc.; www.healthnotes.com Canker Sores Source: Prima Communications, Inc.www.personalhealthzone.com Capillary Fragility Source: Healthnotes, Inc.; www.healthnotes.com Cardiac Arrhythmia Source: Healthnotes, Inc.; www.healthnotes.com Cardiomyopathy Source: Healthnotes, Inc.; www.healthnotes.com Cardiovascular Disease Overview Source: Healthnotes, Inc.; www.healthnotes.com Cataracts Source: Healthnotes, Inc.; www.healthnotes.com
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Cervical Dysplasia Source: Integrative Medicine Communications; www.drkoop.com Chronic Candidiasis Source: Healthnotes, Inc.; www.healthnotes.com Chronic Fatigue Syndrome Source: Healthnotes, Inc.; www.healthnotes.com Chronic Obstructive Pulmonary Disease Source: Healthnotes, Inc.; www.healthnotes.com Chronic Venous Insufficiency Source: Healthnotes, Inc.; www.healthnotes.com Colds and Flus Source: Prima Communications, Inc.www.personalhealthzone.com Colon Cancer Source: Healthnotes, Inc.; www.healthnotes.com Colorectal Cancer Source: Integrative Medicine Communications; www.drkoop.com Common Cold Source: Integrative Medicine Communications; www.drkoop.com Common Cold/Sore Throat Source: Healthnotes, Inc.; www.healthnotes.com Congestive Heart Failure Source: Healthnotes, Inc.; www.healthnotes.com Conjunctivitis Source: Integrative Medicine Communications; www.drkoop.com Conjunctivitis and Blepharitis Source: Healthnotes, Inc.; www.healthnotes.com Constipation Source: Healthnotes, Inc.; www.healthnotes.com Coronary Artery Disease Source: Integrative Medicine Communications; www.drkoop.com Cutaneous Drug Reactions Source: Integrative Medicine Communications; www.drkoop.com Depression Source: Healthnotes, Inc.; www.healthnotes.com
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Depression Source: Integrative Medicine Communications; www.drkoop.com Depression (Mild to Moderate) Source: Prima Communications, Inc.www.personalhealthzone.com Diabetes Source: Prima Communications, Inc.www.personalhealthzone.com Diabetes Mellitus Source: Integrative Medicine Communications; www.drkoop.com Diarrhea Source: Healthnotes, Inc.; www.healthnotes.com Dysmenorrhea Source: Healthnotes, Inc.; www.healthnotes.com Dysmenorrhea Source: Integrative Medicine Communications; www.drkoop.com Eczema Source: Healthnotes, Inc.; www.healthnotes.com Eczema Source: Prima Communications, Inc.www.personalhealthzone.com Edema Source: Healthnotes, Inc.; www.healthnotes.com Endocarditis Source: Integrative Medicine Communications; www.drkoop.com Endometriosis Source: Healthnotes, Inc.; www.healthnotes.com Epilepsy Source: Healthnotes, Inc.; www.healthnotes.com Fainting Source: Integrative Medicine Communications; www.drkoop.com Female Infertility Source: Healthnotes, Inc.; www.healthnotes.com Fibromyalgia Source: Healthnotes, Inc.; www.healthnotes.com Food Poisoning Source: Integrative Medicine Communications; www.drkoop.com
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Frostbite Source: Integrative Medicine Communications; www.drkoop.com Gallbladder Disease Source: Integrative Medicine Communications; www.drkoop.com Gallstones Source: Healthnotes, Inc.; www.healthnotes.com Gastritis Source: Healthnotes, Inc.; www.healthnotes.com Gastritis Source: Integrative Medicine Communications; www.drkoop.com Gastroesophageal Reflux Disease Source: Healthnotes, Inc.; www.healthnotes.com Genital Herpes Source: Healthnotes, Inc.; www.healthnotes.com Gestational Hypertension Source: Healthnotes, Inc.; www.healthnotes.com Glaucoma Source: Healthnotes, Inc.; www.healthnotes.com Glaucoma Source: Integrative Medicine Communications; www.drkoop.com Gout Source: Healthnotes, Inc.; www.healthnotes.com Guinea Worm Disease Source: Integrative Medicine Communications; www.drkoop.com Heart Attack Source: Healthnotes, Inc.; www.healthnotes.com Hemophilia Source: Integrative Medicine Communications; www.drkoop.com Hepatitis Source: Healthnotes, Inc.; www.healthnotes.com High Blood Pressure Source: Integrative Medicine Communications; www.drkoop.com High Cholesterol Source: Healthnotes, Inc.; www.healthnotes.com
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High Cholesterol Source: Integrative Medicine Communications; www.drkoop.com High Cholesterol Source: Prima Communications, Inc.www.personalhealthzone.com High Homocysteine Source: Healthnotes, Inc.; www.healthnotes.com High Triglycerides Source: Healthnotes, Inc.; www.healthnotes.com Hirsuitism Source: Integrative Medicine Communications; www.drkoop.com HIV and AIDS Source: Integrative Medicine Communications; www.drkoop.com HIV and AIDS Support Source: Healthnotes, Inc.; www.healthnotes.com Hives Source: Healthnotes, Inc.; www.healthnotes.com Hookworm Source: Integrative Medicine Communications; www.drkoop.com Hypercholesterolemia Source: Integrative Medicine Communications; www.drkoop.com Hypertension Source: Integrative Medicine Communications; www.drkoop.com Hypochondriasis Source: Integrative Medicine Communications; www.drkoop.com Hypothermia Source: Integrative Medicine Communications; www.drkoop.com Hypothyroidism Source: Healthnotes, Inc.; www.healthnotes.com Hypothyroidism Source: Integrative Medicine Communications; www.drkoop.com Immune Function Source: Healthnotes, Inc.; www.healthnotes.com Infantile Colic Source: Integrative Medicine Communications; www.drkoop.com
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Infection Source: Healthnotes, Inc.; www.healthnotes.com Inflammatory Bowel Disease Source: Integrative Medicine Communications; www.drkoop.com Insomnia Source: Healthnotes, Inc.; www.healthnotes.com Insomnia Source: Integrative Medicine Communications; www.drkoop.com Insulin Resistance Syndrome Source: Healthnotes, Inc.; www.healthnotes.com Intermittent Claudication Alternative names: Peripheral Vascular Disease Source: Prima Communications, Inc.www.personalhealthzone.com Intestinal Parasites Source: Integrative Medicine Communications; www.drkoop.com Iron-Deficiency Anemia Source: Healthnotes, Inc.; www.healthnotes.com Irritable Bowel Syndrome Alternative names: Spastic Colon Source: Prima Communications, Inc.www.personalhealthzone.com Kidney Stones Source: Healthnotes, Inc.; www.healthnotes.com Lactose Intolerance Source: Healthnotes, Inc.; www.healthnotes.com Leukemia Source: Integrative Medicine Communications; www.drkoop.com Liver Cirrhosis Source: Healthnotes, Inc.; www.healthnotes.com Loiasis Source: Integrative Medicine Communications; www.drkoop.com Lung Cancer Source: Healthnotes, Inc.; www.healthnotes.com Lung Cancer Source: Integrative Medicine Communications; www.drkoop.com Lupus Source: Integrative Medicine Communications; www.drkoop.com
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Lymphatic Filariasis Source: Integrative Medicine Communications; www.drkoop.com Ménière's Disease Source: Healthnotes, Inc.; www.healthnotes.com Macular Degeneration Source: Integrative Medicine Communications; www.drkoop.com Male Infertility Source: Healthnotes, Inc.; www.healthnotes.com Meningitis Source: Integrative Medicine Communications; www.drkoop.com Menkes' Disease Source: Healthnotes, Inc.; www.healthnotes.com Menopausal Symptoms (Other Than Osteoporosis) Source: Prima Communications, Inc.www.personalhealthzone.com Menopause Source: Integrative Medicine Communications; www.drkoop.com Menstrual Pain Source: Integrative Medicine Communications; www.drkoop.com Migraine Headaches Source: Healthnotes, Inc.; www.healthnotes.com Migraine Headaches Source: Prima Communications, Inc.www.personalhealthzone.com Miscarriage Source: Integrative Medicine Communications; www.drkoop.com Morning Sickness Source: Healthnotes, Inc.; www.healthnotes.com Motion Sickness Source: Integrative Medicine Communications; www.drkoop.com Multiple Sclerosis Source: Healthnotes, Inc.; www.healthnotes.com Mumps Source: Integrative Medicine Communications; www.drkoop.com Nausea Source: Prima Communications, Inc.www.personalhealthzone.com
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Obesity Source: Integrative Medicine Communications; www.drkoop.com Osteoarthritis Source: Integrative Medicine Communications; www.drkoop.com Osteoarthritis Source: Prima Communications, Inc.www.personalhealthzone.com Osteoporosis Source: Healthnotes, Inc.; www.healthnotes.com Osteoporosis Source: Integrative Medicine Communications; www.drkoop.com Osteoporosis Source: Prima Communications, Inc.www.personalhealthzone.com Pancreatic Insufficiency Source: Healthnotes, Inc.; www.healthnotes.com Parasites Source: Healthnotes, Inc.; www.healthnotes.com Parkinson's Disease Source: Healthnotes, Inc.; www.healthnotes.com Peptic Ulcer Source: Healthnotes, Inc.; www.healthnotes.com Peptic Ulcer Source: Integrative Medicine Communications; www.drkoop.com Pericarditis Source: Integrative Medicine Communications; www.drkoop.com Peripheral Vascular Disease Source: Healthnotes, Inc.; www.healthnotes.com Peritonitis Source: Integrative Medicine Communications; www.drkoop.com Pharyngitis Source: Integrative Medicine Communications; www.drkoop.com Phenylketonuria Source: Healthnotes, Inc.; www.healthnotes.com Photodermatitis Source: Integrative Medicine Communications; www.drkoop.com
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Pink Eye Source: Integrative Medicine Communications; www.drkoop.com Pinworm Source: Integrative Medicine Communications; www.drkoop.com Post Traumatic Stress Disorder Source: Integrative Medicine Communications; www.drkoop.com Preeclampsia Source: Healthnotes, Inc.; www.healthnotes.com Pregnancy and Postpartum Support Source: Healthnotes, Inc.; www.healthnotes.com Premenstrual Syndrome Source: Healthnotes, Inc.; www.healthnotes.com Proctitis Source: Integrative Medicine Communications; www.drkoop.com Prostate Cancer Source: Healthnotes, Inc.; www.healthnotes.com Prostate Cancer Source: Integrative Medicine Communications; www.drkoop.com Prostatitis Source: Healthnotes, Inc.; www.healthnotes.com Psoriasis Source: Healthnotes, Inc.; www.healthnotes.com PTSD Source: Integrative Medicine Communications; www.drkoop.com Pyloric Stenosis Source: Integrative Medicine Communications; www.drkoop.com Raynaud's Phenomenon Source: Integrative Medicine Communications; www.drkoop.com Rectal Inflammation Source: Integrative Medicine Communications; www.drkoop.com Recurrent Ear Infections Source: Healthnotes, Inc.; www.healthnotes.com Retinopathy Source: Healthnotes, Inc.; www.healthnotes.com
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Rheumatoid Arthritis Source: Healthnotes, Inc.; www.healthnotes.com Rheumatoid Arthritis Source: Integrative Medicine Communications; www.drkoop.com Rheumatoid Arthritis Source: Prima Communications, Inc.www.personalhealthzone.com River Blindness Source: Integrative Medicine Communications; www.drkoop.com Roundworms Source: Integrative Medicine Communications; www.drkoop.com Rubella Source: Integrative Medicine Communications; www.drkoop.com Schizophrenia Source: Healthnotes, Inc.; www.healthnotes.com Scleroderma Source: Integrative Medicine Communications; www.drkoop.com Serum Sickness Source: Integrative Medicine Communications; www.drkoop.com Sexual Dysfunction Source: Integrative Medicine Communications; www.drkoop.com Shock Source: Integrative Medicine Communications; www.drkoop.com Sickle Cell Anemia Source: Healthnotes, Inc.; www.healthnotes.com Sinusitis Source: Healthnotes, Inc.; www.healthnotes.com Skin Cancer Source: Integrative Medicine Communications; www.drkoop.com Sleeplessness Source: Integrative Medicine Communications; www.drkoop.com Sore Throat Source: Integrative Medicine Communications; www.drkoop.com Spontaneous Abortion Source: Integrative Medicine Communications; www.drkoop.com
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Sprains and Strains Source: Healthnotes, Inc.; www.healthnotes.com Sprains and Strains Source: Integrative Medicine Communications; www.drkoop.com Stomach Inflammation Source: Integrative Medicine Communications; www.drkoop.com Stroke Source: Healthnotes, Inc.; www.healthnotes.com Sunburn Source: Integrative Medicine Communications; www.drkoop.com Syncope Source: Integrative Medicine Communications; www.drkoop.com Systemic Lupus Erythematosus Source: Healthnotes, Inc.; www.healthnotes.com Systemic Lupus Erythematosus Source: Integrative Medicine Communications; www.drkoop.com Temporomandibular Joint Dysfunction Source: Integrative Medicine Communications; www.drkoop.com Threadworm Source: Integrative Medicine Communications; www.drkoop.com TIAs Source: Integrative Medicine Communications; www.drkoop.com TMJ Source: Integrative Medicine Communications; www.drkoop.com Transient Ischemic Attacks Source: Integrative Medicine Communications; www.drkoop.com Trichinosis Source: Integrative Medicine Communications; www.drkoop.com Ulcerative Colitis Source: Healthnotes, Inc.; www.healthnotes.com Ulcerative Colitis Source: Integrative Medicine Communications; www.drkoop.com Ulcers Source: Prima Communications, Inc.www.personalhealthzone.com
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Urinary Incontinence Source: Integrative Medicine Communications; www.drkoop.com Urinary Tract Infection Source: Healthnotes, Inc.; www.healthnotes.com Uveitis Source: Integrative Medicine Communications; www.drkoop.com Varicose Veins Source: Healthnotes, Inc.; www.healthnotes.com Varicose Veins Source: Prima Communications, Inc.www.personalhealthzone.com Viral Hepatitis Source: Prima Communications, Inc.www.personalhealthzone.com Visceral Larva Migrans Source: Integrative Medicine Communications; www.drkoop.com Vitiligo Source: Healthnotes, Inc.; www.healthnotes.com Whipworm Source: Integrative Medicine Communications; www.drkoop.com Wound Healing Source: Healthnotes, Inc.; www.healthnotes.com Wounds Source: Integrative Medicine Communications; www.drkoop.com •
Alternative Therapy Access Alternative names: Access Energy Transformation Source: The Canoe version of A Dictionary of Alternative-Medicine Methods, by Priorities for Health editor Jack Raso, M.S., R.D. Hyperlink: http://www.canoe.ca/AltmedDictionary/a.html Acupressure Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,662,00.html Acupuncture Source: Integrative Medicine Communications; www.drkoop.com
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Alchemical Hypnotherapy Alternative names: Alchemical work Source: The Canoe version of A Dictionary of Alternative-Medicine Methods, by Priorities for Health editor Jack Raso, M.S., R.D. Hyperlink: http://www.canoe.ca/AltmedDictionary/a.html Anthroposophical Medicine Alternative names: anthroposophically-extended medicine anthroposophical therapeutics Source: The Canoe version of A Dictionary of Alternative-Medicine Methods, by Priorities for Health editor Jack Raso, M.S., R.D. Hyperlink: http://www.canoe.ca/AltmedDictionary/a.html Apitherapy Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,669,00.html Aromatherapy Source: Integrative Medicine Communications; www.drkoop.com Aromatherapy Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,664,00.html Astara's Healing Science Source: The Canoe version of A Dictionary of Alternative-Medicine Methods, by Priorities for Health editor Jack Raso, M.S., R.D. Hyperlink: http://www.canoe.ca/AltmedDictionary/a.html Aston-Patterning Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10118,00.html Ayurveda Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,672,00.html Bach Flower Remedies Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,673,00.html Clear Certainty Rundown Source: The Canoe version of A Dictionary of Alternative-Medicine Methods, by Priorities for Health editor Jack Raso, M.S., R.D. Hyperlink: http://www.canoe.ca/AltmedDictionary/c.html
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Color Meditation Alternative names: CM Color Magick Source: The Canoe version of A Dictionary of Alternative-Medicine Methods, by Priorities for Health editor Jack Raso, M.S., R.D. Hyperlink: http://www.canoe.ca/AltmedDictionary/c.html Creative Kinesiology Source: The Canoe version of A Dictionary of Alternative-Medicine Methods, by Priorities for Health editor Jack Raso, M.S., R.D. Hyperlink: http://www.canoe.ca/AltmedDictionary/c.html Curative Eurhythmy Alternative names: curative eurythmy therapeutic eurhythmy Source: The Canoe version of A Dictionary of Alternative-Medicine Methods, by Priorities for Health editor Jack Raso, M.S., R.D. Hyperlink: http://www.canoe.ca/AltmedDictionary/c.html Dance Therapy Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,687,00.html Detoxification Therapy Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10119,00.html Drisana Alternative names: Tibetan Energy System Source: The Canoe version of A Dictionary of Alternative-Medicine Methods, by Priorities for Health editor Jack Raso, M.S., R.D. Hyperlink: http://www.canoe.ca/AltmedDictionary/d.html Emotional Clearing Source: The Canoe version of A Dictionary of Alternative-Medicine Methods, by Priorities for Health editor Jack Raso, M.S., R.D. Hyperlink: http://www.canoe.ca/AltmedDictionary/e.html Etheric Release Source: The Canoe version of A Dictionary of Alternative-Medicine Methods, by Priorities for Health editor Jack Raso, M.S., R.D. Hyperlink: http://www.canoe.ca/AltmedDictionary/e.html Etheric Touch Source: The Canoe version of A Dictionary of Alternative-Medicine Methods, by Priorities for Health editor Jack Raso, M.S., R.D. Hyperlink: http://www.canoe.ca/AltmedDictionary/e.html Face Modelling Source: The Canoe version of A Dictionary of Alternative-Medicine Methods, by Priorities for Health editor Jack Raso, M.S., R.D. Hyperlink: http://www.canoe.ca/AltmedDictionary/f.html
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Gerson Therapy Alternative names: Gerson dietary regime GDR Gerson method Gerson treatment Source: The Canoe version of A Dictionary of Alternative-Medicine Methods, by Priorities for Health editor Jack Raso, M.S., R.D. Hyperlink: http://www.canoe.ca/AltmedDictionary/g.html Guided Imagery Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,699,00.html Human Ecology Balancing Sciences Source: The Canoe version of A Dictionary of Alternative-Medicine Methods, by Priorities for Health editor Jack Raso, M.S., R.D. Hyperlink: http://www.canoe.ca/AltmedDictionary/h.html Human Energetic Assessment and Restorative Technic Alternative names: HEART Source: The Canoe version of A Dictionary of Alternative-Medicine Methods, by Priorities for Health editor Jack Raso, M.S., R.D. Hyperlink: http://www.canoe.ca/AltmedDictionary/h.html Hydrotherapy Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,705,00.html Hypnotherapy Source: Integrative Medicine Communications; www.drkoop.com Iridology Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,709,00.html Kahuna Healing Source: The Canoe version of A Dictionary of Alternative-Medicine Methods, by Priorities for Health editor Jack Raso, M.S., R.D. Hyperlink: http://www.canoe.ca/AltmedDictionary/k.html Lama Yoga Source: The Canoe version of A Dictionary of Alternative-Medicine Methods, by Priorities for Health editor Jack Raso, M.S., R.D. Hyperlink: http://www.canoe.ca/AltmedDictionary/l.html Life Care Kinesiology Alternative names: Life Care Source: The Canoe version of A Dictionary of Alternative-Medicine Methods, by Priorities for Health editor Jack Raso, M.S., R.D. Hyperlink: http://www.canoe.ca/AltmedDictionary/l.html
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Massage Therapy Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,716,00.html Meditation Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,717,00.html Meridian Energy Diagnosis Source: The Canoe version of A Dictionary of Alternative-Medicine Methods, by Priorities for Health editor Jack Raso, M.S., R.D. Hyperlink: http://www.canoe.ca/AltmedDictionary/m.html Meridian Therapy Source: The Canoe version of A Dictionary of Alternative-Medicine Methods, by Priorities for Health editor Jack Raso, M.S., R.D. Hyperlink: http://www.canoe.ca/AltmedDictionary/m.html Native American Medicine Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,721,00.html Naturopathy Source: Integrative Medicine Communications; www.drkoop.com Naturopathy Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,722,00.html Nutripathy Source: The Canoe version of A Dictionary of Alternative-Medicine Methods, by Priorities for Health editor Jack Raso, M.S., R.D. Hyperlink: http://www.canoe.ca/AltmedDictionary/n.html Nutrition Source: Integrative Medicine Communications; www.drkoop.com Osteopathy Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,724,00.html Pealeism Alternative names: Norman Vincent Pealeism Source: The Canoe version of A Dictionary of Alternative-Medicine Methods, by Priorities for Health editor Jack Raso, M.S., R.D. Hyperlink: http://www.canoe.ca/AltmedDictionary/p.html
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Physio-Spiritual Etheric Body Healing Alternative names: PSEB Source: The Canoe version of A Dictionary of Alternative-Medicine Methods, by Priorities for Health editor Jack Raso, M.S., R.D. Hyperlink: http://www.canoe.ca/AltmedDictionary/p.html Polarity Therapy Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,727,00.html Prakrtika Cikitsa Alternative names: naturopathy Source: The Canoe version of A Dictionary of Alternative-Medicine Methods, by Priorities for Health editor Jack Raso, M.S., R.D. Hyperlink: http://www.canoe.ca/AltmedDictionary/p.html Pranic Psychotherapy Source: The Canoe version of A Dictionary of Alternative-Medicine Methods, by Priorities for Health editor Jack Raso, M.S., R.D. Hyperlink: http://www.canoe.ca/AltmedDictionary/p.html Prayer Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,728,00.html Psionic Medicine Alternative names: psionics Source: The Canoe version of A Dictionary of Alternative-Medicine Methods, by Priorities for Health editor Jack Raso, M.S., R.D. Hyperlink: http://www.canoe.ca/AltmedDictionary/p.html Psychic Surgery Alternative names: etheric surgery Source: The Canoe version of A Dictionary of Alternative-Medicine Methods, by Priorities for Health editor Jack Raso, M.S., R.D. Hyperlink: http://www.canoe.ca/AltmedDictionary/p.html Psychometry Alternative names: object reading psychoscopy Source: The Canoe version of A Dictionary of Alternative-Medicine Methods, by Priorities for Health editor Jack Raso, M.S., R.D. Hyperlink: http://www.canoe.ca/AltmedDictionary/p.html Qigong Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,729,00.html Reiki Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com
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Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,731,00.html Reiki Plus Alternative names: Reiki Plus Natural Healing Reiki Plus System of Natural Healing Source: The Canoe version of A Dictionary of Alternative-Medicine Methods, by Priorities for Health editor Jack Raso, M.S., R.D. Hyperlink: http://www.canoe.ca/AltmedDictionary/r.html Rhythmical Massage Source: The Canoe version of A Dictionary of Alternative-Medicine Methods, by Priorities for Health editor Jack Raso, M.S., R.D. Hyperlink: http://www.canoe.ca/AltmedDictionary/r.html Shadow Sound Therapy Alternative names: SST shadow therapy Source: The Canoe version of A Dictionary of Alternative-Medicine Methods, by Priorities for Health editor Jack Raso, M.S., R.D. Hyperlink: http://www.canoe.ca/AltmedDictionary/s.html Shiatsu Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,733,00.html Spirituality Source: Integrative Medicine Communications; www.drkoop.com Suggestive Therapy Zone Procedure Alternative names: Concept-Therapy Adjusting Technique Health Zone Analysis zone testing Zone Therapy Diagnosis Source: The Canoe version of A Dictionary of Alternative-Medicine Methods, by Priorities for Health editor Jack Raso, M.S., R.D. Hyperlink: http://www.canoe.ca/AltmedDictionary/s.html Synergy Dance Source: The Canoe version of A Dictionary of Alternative-Medicine Methods, by Priorities for Health editor Jack Raso, M.S., R.D. Hyperlink: http://www.canoe.ca/AltmedDictionary/s.html Tai Chi Source: Integrative Medicine Communications; www.drkoop.com Tai Chi Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,737,00.html Tattva Shuddhi Alternative names: tattva shuddhi meditation Source: The Canoe version of A Dictionary of Alternative-Medicine Methods, by Priorities for Health editor Jack Raso, M.S., R.D.
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Hyperlink: http://www.canoe.ca/AltmedDictionary/t.html Testing for Stomach Acidity Source: Healthnotes, Inc.; www.healthnotes.com Therapeutic Touch Source: Integrative Medicine Communications; www.drkoop.com Therapeutic Touch Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,739,00.html Traditional Chinese Medicine Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10085,00.html Traditional Chinese Medicine Herbs Source: Healthnotes, Inc.; www.healthnotes.com Transformational Counseling Alternative names: ASAT Transformational Counseling Source: The Canoe version of A Dictionary of Alternative-Medicine Methods, by Priorities for Health editor Jack Raso, M.S., R.D. Hyperlink: http://www.canoe.ca/AltmedDictionary/t.html Vibrational Medicine Alternative names: energetic medicine energetics medicine energy medicine subtleenergy medicine vibrational healing vibrational therapies Source: The Canoe version of A Dictionary of Alternative-Medicine Methods, by Priorities for Health editor Jack Raso, M.S., R.D. Hyperlink: http://www.canoe.ca/AltmedDictionary/v.html Yoga Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,746,00.html •
Chinese Medicine Bimayou Alternative names: Castor Oil; Oleum Ricini Source: Chinese Materia Medica Bingpian Alternative names: Borneol; Bingpian (Bing Pi An); Borneolum Syntheticum Source: Chinese Materia Medica
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Bohe Alternative names: Peppermint; Herba Menthae Source: Chinese Materia Medica Chayou Alternative names: Tea-seed Oil; Oleum Camelliae Source: Chinese Materia Medica Chonglou Alternative names: Paris Root; Rhizoma Paridis Source: Chinese Materia Medica Dahuang Alternative names: Rhubarb; Radix et Rhizoma Rhei Source: Chinese Materia Medica Dingxiang Alternative names: Clove; Flos Caryophylli Source: Chinese Materia Medica Dingxiang Luoleyou Alternative names: Ocimum Oil; Oleum Ocimi Gratissimi Source: Chinese Materia Medica Fuzi Alternative names: Beivedere Fruit; Difuzi; Fructus Kochiae Source: Chinese Materia Medica Jinguolan Alternative names: Tinospora Root; Radix Tinosporae Source: Chinese Materia Medica Liuhe Dingzhong Wan Alternative names: Liuhe Dingzhong Pills Source: Pharmacopoeia Commission of the Ministry of Health, People's Republic of China Manshanhong Alternative names: Dahurian Rhododendron Leaf; Folium Rhododendri Daurici Source: Chinese Materia Medica Manshanhongyou Alternative names: Daurian Rhododendron Oil; Oleum Rhododendri Daurici Source: Chinese Materia Medica Maqianzi San Alternative names: Maqianzi Powder Source: Pharmacopoeia Commission of the Ministry of Health, People's Republic of China
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Mayou Alternative names: Castor Oil; Bimayou; Oleum Ricini Source: Chinese Materia Medica Mujingyou Alternative names: Negundo Chastetree Oil; Oleum Viticis Negundo Source: Chinese Materia Medica Oleum Menthae Alternative names: Peppermint Oil Source: Pharmacopoeia Commission of the Ministry of Health, People's Republic of China Qingyan Wan Alternative names: Qingyan Pills Source: Pharmacopoeia Commission of the Ministry of Health, People's Republic of China Shaii Alternative names: Seabuckthorn Fruit; Fructus Hippophae Source: Chinese Materia Medica Shaofu Zhuyu Wan Alternative names: Shaofu Zhuyu Pills; Shaofu Zhuyu Wan (Shao Fu Zhu Yu Wan) Source: Pharmacopoeia Commission of the Ministry of Health, People's Republic of China Songjieyou Alternative names: Turpentine Oil; Oleum Terebinthinae Source: Chinese Materia Medica Suhexiang Alternative names: Storax; Styrax Source: Chinese Materia Medica Xiangguozhi Alternative names: Spiceleaf Kernel Oil; Oleum Linderae Source: Chinese Materia Medica Yibeimu Alternative names: Sinkiang Fritillary Bulb; Yibeimu (Yi Bei Mu); Buibus Fritillariae Pallidiflorae Source: Chinese Materia Medica •
Herbs and Supplements 5-HTP (5-Hydroxytryptophan) Source: Prima Communications, Inc.www.personalhealthzone.com 5-Hydroxytryptophan Source: Healthnotes, Inc.; www.healthnotes.com
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Acanthopanax Senticosus Source: Integrative Medicine Communications; www.drkoop.com Achillea Alternative names: Yarrow; Achillea millefolium L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Acorus Alternative names: Sweet Flag; Acorus calamus L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Acyclovir Oral Source: Healthnotes, Inc.; www.healthnotes.com Adenosine Monophosphate Source: Healthnotes, Inc.; www.healthnotes.com Albuterol Source: Healthnotes, Inc.; www.healthnotes.com Allopurinol Source: Healthnotes, Inc.; www.healthnotes.com Aloe Source: Prima Communications, Inc.www.personalhealthzone.com Alpha Lipoic Acid Source: Healthnotes, Inc.; www.healthnotes.com Alpha-Lipoic Acid Source: Integrative Medicine Communications; www.drkoop.com Alpha-Lipoic Acid Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10002,00.html Aluminum Hydroxide Source: Healthnotes, Inc.; www.healthnotes.com American Ginseng Alternative names: Panax quinquefolius Source: Healthnotes, Inc.; www.healthnotes.com Aminoglycoside Antibiotics Source: Healthnotes, Inc.; www.healthnotes.com Amoxicillin Source: Healthnotes, Inc.; www.healthnotes.com Amphotericin B Source: Healthnotes, Inc.; www.healthnotes.com
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Ampicillin Source: Healthnotes, Inc.; www.healthnotes.com Ananas Comosus Alternative names: Bromelain Source: Integrative Medicine Communications; www.drkoop.com Andrographis Alternative names: Andrographis paniculata Source: Healthnotes, Inc.; www.healthnotes.com Androstenedione Source: Healthnotes, Inc.; www.healthnotes.com Androstenedione Source: Prima Communications, Inc.www.personalhealthzone.com Angelica sinensis Alternative names: Dong Quai Source: Integrative Medicine Communications; www.drkoop.com Angkak Source: Integrative Medicine Communications; www.drkoop.com Antibiotics Source: Healthnotes, Inc.; www.healthnotes.com Anticonvulsants Source: Healthnotes, Inc.; www.healthnotes.com Antioxidants Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10004,00.html Arctostaphylos Alternative names: Bearberry; Arctostaphylos uva-ursi (L.) Spreng. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Arctostaphylos Uva Ursi Alternative names: Uva Ursi Source: Integrative Medicine Communications; www.drkoop.com Arginine Source: Healthnotes, Inc.; www.healthnotes.com Aristolochia Alternative names: Snakeroot, Guaco; Aristolochia sp Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org
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Arnica Alternative names: Arnica montana L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Ashwagandha Alternative names: Withania somniferum Source: Healthnotes, Inc.; www.healthnotes.com Asian Ginseng Alternative names: Panax ginseng Source: Integrative Medicine Communications; www.drkoop.com Aspirin Source: Healthnotes, Inc.; www.healthnotes.com Astragalus Alternative names: Astragalus membranaceus Source: Healthnotes, Inc.; www.healthnotes.com Azithromycin Source: Healthnotes, Inc.; www.healthnotes.com AZT Source: Healthnotes, Inc.; www.healthnotes.com Baking Soda Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,835,00.html Bcaas Source: Prima Communications, Inc.www.personalhealthzone.com B-carotene Alternative names: Beta-Carotene Source: Integrative Medicine Communications; www.drkoop.com Bearberry Alternative names: Uva Ursi Source: Integrative Medicine Communications; www.drkoop.com Beargrape Alternative names: Uva Ursi Source: Integrative Medicine Communications; www.drkoop.com Beni-koji Source: Integrative Medicine Communications; www.drkoop.com Benzamycin Source: Healthnotes, Inc.; www.healthnotes.com
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Benztropine Source: Healthnotes, Inc.; www.healthnotes.com Beta-carotene Source: Healthnotes, Inc.; www.healthnotes.com Beta-carotene Alternative names: Betacarotenum Source: Integrative Medicine Communications; www.drkoop.com Beta-carotene Source: Prima Communications, Inc.www.personalhealthzone.com Betacarotenum Alternative names: Beta-Carotene Source: Integrative Medicine Communications; www.drkoop.com Beta-sitosterol Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,972,00.html Bilberry Alternative names: Vaccinium myrtillus Source: Healthnotes, Inc.; www.healthnotes.com Bilberry Source: Prima Communications, Inc.www.personalhealthzone.com Bilberry Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10007,00.html Bismuth Subsalicylate Source: Healthnotes, Inc.; www.healthnotes.com Bitter Melon Alternative names: Momordica charantia Source: Healthnotes, Inc.; www.healthnotes.com Black Cohosh Alternative names: Cimicifuga racemosa Source: Healthnotes, Inc.; www.healthnotes.com Black Cohosh Source: Prima Communications, Inc.www.personalhealthzone.com Black Cohosh Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10009,00.html
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Blue Cohosh Alternative names: Caulophyllum thalictroides Source: Healthnotes, Inc.; www.healthnotes.com Boswellia Source: Prima Communications, Inc.www.personalhealthzone.com Bovine Colostrum Source: Healthnotes, Inc.; www.healthnotes.com Brahmi Alternative names: Centella asiatica , Centella, March Pennywort, Indian Pennywort, Hydrocotyle, Brahmi (Sanskrit), Luei Gong Gen (Chinese)(Note: Gotu kola should not be confused with kola nut.) Source: Integrative Medicine Communications; www.drkoop.com Bromelain Source: Healthnotes, Inc.; www.healthnotes.com Bromelain Alternative names: Ananas comosus Source: Integrative Medicine Communications; www.drkoop.com Bromelain Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,760,00.html Bromelainum Alternative names: Bromelain Source: Integrative Medicine Communications; www.drkoop.com Calendula Source: The Canadian Internet Directory for Holistic Help, WellNet, Health and Wellness Network; www.wellnet.ca Calophyllum Alternative names: Punna, Kamani; Calophyllum sp. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Carbidopa Source: Healthnotes, Inc.; www.healthnotes.com Carbidopa/Levodopa Source: Healthnotes, Inc.; www.healthnotes.com Carotenoids Source: Healthnotes, Inc.; www.healthnotes.com Cascara Sagrada Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com
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Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10013,00.html Cat's Claw Source: Prima Communications, Inc.www.personalhealthzone.com Celecoxib Source: Healthnotes, Inc.; www.healthnotes.com Celery Extract Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10014,00.html Centella Source: Integrative Medicine Communications; www.drkoop.com Centella asiatica Alternative names: Centella asiatica , Centella, March Pennywort, Indian Pennywort, Hydrocotyle, Brahmi (Sanskrit), Luei Gong Gen (Chinese)(Note: Gotu kola should not be confused with kola nut.) Source: Integrative Medicine Communications; www.drkoop.com Cephalosporins Source: Healthnotes, Inc.; www.healthnotes.com Chamaemelum Nobile Source: Integrative Medicine Communications; www.drkoop.com Chaparral Alternative names: Larrea tridentata Source: Healthnotes, Inc.; www.healthnotes.com Chasteberry Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,767,00.html Chemotherapy Source: Healthnotes, Inc.; www.healthnotes.com Chinese Angelica Alternative names: Dong Quai Source: Integrative Medicine Communications; www.drkoop.com Chitosan Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10016,00.html Chlorhexidine Source: Healthnotes, Inc.; www.healthnotes.com
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Ciprofloxacin Source: Healthnotes, Inc.; www.healthnotes.com Citalopram Source: Healthnotes, Inc.; www.healthnotes.com Clarithromycin Source: Healthnotes, Inc.; www.healthnotes.com Clindamycin Oral Source: Healthnotes, Inc.; www.healthnotes.com Clindamycin Topical Source: Healthnotes, Inc.; www.healthnotes.com Clozapine Source: Healthnotes, Inc.; www.healthnotes.com Codeine Source: Healthnotes, Inc.; www.healthnotes.com Coenzyme Q Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,768,00.html Coenzyme Q10 Alternative names: CoQ10 Source: Integrative Medicine Communications; www.drkoop.com Colchicine Source: Healthnotes, Inc.; www.healthnotes.com Colestipol Source: Healthnotes, Inc.; www.healthnotes.com Colloidal Oatmeal Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10107,00.html Colostrum Source: Prima Communications, Inc.www.personalhealthzone.com Comfrey Alternative names: Symphytum officinale Source: Healthnotes, Inc.; www.healthnotes.com Comfrey Alternative names: Symphytum officinale, Knitbone Source: Integrative Medicine Communications; www.drkoop.com
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Conjugated Linoleic Acid Source: Healthnotes, Inc.; www.healthnotes.com Conjugated Linoleic Acid Source: Prima Communications, Inc.www.personalhealthzone.com Conjugated Linoleic Acid Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10102,00.html Coq10 Alternative names: Coenzyme Q10 Source: Integrative Medicine Communications; www.drkoop.com Cranberry Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10019,00.html Curcuma Alternative names: Turmeric; Curcuma longa L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Cyclosporine Source: Healthnotes, Inc.; www.healthnotes.com Cysteine Source: Integrative Medicine Communications; www.drkoop.com Dandelion Alternative names: Taraxacum officinale Source: Integrative Medicine Communications; www.drkoop.com Danggui Alternative names: Dong Quai Source: Integrative Medicine Communications; www.drkoop.com Dapsone Source: Healthnotes, Inc.; www.healthnotes.com Dehydroepiandrosterone (DHEA) Source: Healthnotes, Inc.; www.healthnotes.com Devil's Claw Alternative names: Harpagophytum procumbens, Harpagophytum zeyheri Source: Integrative Medicine Communications; www.drkoop.com Devil's Claw Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,970,00.html
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DHA Alternative names: Docosahexaenoic Acid (DHA) Source: Integrative Medicine Communications; www.drkoop.com DHEA Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10022,00.html DHEA (Dehydroepiandrosterone) Source: Prima Communications, Inc.www.personalhealthzone.com Diclofenac Source: Healthnotes, Inc.; www.healthnotes.com Dicloxacillin Source: Healthnotes, Inc.; www.healthnotes.com Digestive Enzymes Source: Healthnotes, Inc.; www.healthnotes.com Digoxin Source: Healthnotes, Inc.; www.healthnotes.com Dipyridamole Source: Healthnotes, Inc.; www.healthnotes.com Docetaxel Source: Healthnotes, Inc.; www.healthnotes.com Docosahexaenoic Acid (DHA) Alternative names: DHA Source: Integrative Medicine Communications; www.drkoop.com Docusate Source: Healthnotes, Inc.; www.healthnotes.com Donepezil Source: Healthnotes, Inc.; www.healthnotes.com Dong Quai Alternative names: Angelica sinensis Source: Integrative Medicine Communications; www.drkoop.com Dong Quai (Angelica) Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,774,00.html Doxycycline Source: Healthnotes, Inc.; www.healthnotes.com
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Dryopteris Alternative names: Male Fern; Dryopteris sp. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Echinacea Alternative names: Echinacea purpurea, Echinacea angustifolia, Echinacea pallida Source: Healthnotes, Inc.; www.healthnotes.com Echinacea Source: Prima Communications, Inc.www.personalhealthzone.com Eicosapentaenoic Acid (EPA) Alternative names: EPA Source: Integrative Medicine Communications; www.drkoop.com Elecampane Source: Prima Communications, Inc.www.personalhealthzone.com Eleuthero Source: Integrative Medicine Communications; www.drkoop.com Eleutherococcus Senticosus Source: Integrative Medicine Communications; www.drkoop.com EPA Alternative names: Eicosapentaenoic Acid (EPA) Source: Integrative Medicine Communications; www.drkoop.com Ephedra Alternative names: Ephedra sinica, Ephedra intermedia, Ephedra equisetina Source: Healthnotes, Inc.; www.healthnotes.com Ephedra Source: Prima Communications, Inc.www.personalhealthzone.com Erythromycin Source: Healthnotes, Inc.; www.healthnotes.com Estrogen Source: Prima Communications, Inc.www.personalhealthzone.com Estrogens (Combined) Source: Healthnotes, Inc.; www.healthnotes.com Etodolac Source: Healthnotes, Inc.; www.healthnotes.com Eucalyptus Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,778,00.html
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Evening Primrose Alternative names: Oenothera biennis Source: Integrative Medicine Communications; www.drkoop.com False Unicorn Root Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10075,00.html Felodipine Source: Healthnotes, Inc.; www.healthnotes.com Fennel Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,20,00.html Fenofibrate Source: Healthnotes, Inc.; www.healthnotes.com Fentanyl Source: Healthnotes, Inc.; www.healthnotes.com Feverfew Source: Prima Communications, Inc.www.personalhealthzone.com Feverfew Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,780,00.html Fiber Source: Healthnotes, Inc.; www.healthnotes.com Fiber Source: Integrative Medicine Communications; www.drkoop.com Fluorouracil Source: Healthnotes, Inc.; www.healthnotes.com Flurbiprofen Source: Healthnotes, Inc.; www.healthnotes.com GABA Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10027,00.html Gamma Oryzanol Source: Prima Communications, Inc.www.personalhealthzone.com
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Gamma-Linolenic Acid (GLA) Alternative names: GLA Source: Integrative Medicine Communications; www.drkoop.com Garcinia Man Alternative names: Mangosteen; Garcinia mangostana Linn. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org General Anesthetics Source: Healthnotes, Inc.; www.healthnotes.com Gentamicin Source: Healthnotes, Inc.; www.healthnotes.com German Chamomile Alternative names: Matricaria recutita Source: Integrative Medicine Communications; www.drkoop.com Ginkgo Alternative names: Ginkgo biloba Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Ginkgo Source: Prima Communications, Inc.www.personalhealthzone.com Ginkgo Biloba Alternative names: Maidenhair Tree Source: Integrative Medicine Communications; www.drkoop.com Ginseng Source: Prima Communications, Inc.www.personalhealthzone.com Ginseng (Panax) Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10029,00.html GLA Alternative names: Gamma-Linolenic Acid (GLA) Source: Integrative Medicine Communications; www.drkoop.com GLA (Gamma-Linolenic Acid) Source: Prima Communications, Inc.www.personalhealthzone.com Glimepiride Source: Healthnotes, Inc.; www.healthnotes.com Glucomannan Source: Healthnotes, Inc.; www.healthnotes.com Glucosamine Source: Integrative Medicine Communications; www.drkoop.com
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Glucosamine Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,790,00.html Glutamine Source: Prima Communications, Inc.www.personalhealthzone.com Glutamine Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10030,00.html Glutathione Source: Healthnotes, Inc.; www.healthnotes.com Glycyrrhiza glabra Source: Integrative Medicine Communications; www.drkoop.com Glycyrrhiza Alternative names: Licorice; Glycyrrhiza glabra L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Golden Rod Source: The Canadian Internet Directory for Holistic Help, WellNet, Health and Wellness Network; www.wellnet.ca Gotu Kola Alternative names: Centella asiatica , Centella, March Pennywort, Indian Pennywort, Hydrocotyle, Brahmi (Sanskrit), Luei Gong Gen (Chinese)(Note: Gotu kola should not be confused with kola nut.) Source: Integrative Medicine Communications; www.drkoop.com Gotu Kola Source: Prima Communications, Inc.www.personalhealthzone.com Gotu Kola Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10031,00.html Grape Seed Extract Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,793,00.html Grapefruit Seed Extract Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,985,00.html
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Green Tea Source: Prima Communications, Inc.www.personalhealthzone.com H2 Blockers Source: Prima Communications, Inc.www.personalhealthzone.com Harpagophytum Procumbens Source: Integrative Medicine Communications; www.drkoop.com Harpagophytum Zeyheri Source: Integrative Medicine Communications; www.drkoop.com Hawthorn Source: Prima Communications, Inc.www.personalhealthzone.com Heparin Source: Healthnotes, Inc.; www.healthnotes.com Heparin Alternative names: Hep-Lock Source: Prima Communications, Inc.www.personalhealthzone.com HMB (Hydroxymethyl Butyrate) Source: Prima Communications, Inc.www.personalhealthzone.com Hong Qu Source: Integrative Medicine Communications; www.drkoop.com Horse Chestnut Source: Healthnotes, Inc.; www.healthnotes.com Horse Chestnut Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10037,00.html Horseradish Alternative names: Cochlearia armoracia Source: Healthnotes, Inc.; www.healthnotes.com Hung-chu Source: Integrative Medicine Communications; www.drkoop.com Huperzine A Source: Prima Communications, Inc.www.personalhealthzone.com Huperzine A Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10038,00.html
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Hydrocotyle Source: Integrative Medicine Communications; www.drkoop.com Hydroxychloroquine Source: Healthnotes, Inc.; www.healthnotes.com Hydroxycitric Acid Source: Healthnotes, Inc.; www.healthnotes.com Hypericum Perforatum Alternative names: St. John's Wort Source: Integrative Medicine Communications; www.drkoop.com Hyssop Alternative names: Hyssopus officinalis Source: Healthnotes, Inc.; www.healthnotes.com Ibuprofen Source: Healthnotes, Inc.; www.healthnotes.com Indapamide Source: Healthnotes, Inc.; www.healthnotes.com Indian Pennywort Source: Integrative Medicine Communications; www.drkoop.com Indinavir Source: Healthnotes, Inc.; www.healthnotes.com Indomethacin Source: Healthnotes, Inc.; www.healthnotes.com Inhaled Corticosteroids Source: Healthnotes, Inc.; www.healthnotes.com Interferon Source: Healthnotes, Inc.; www.healthnotes.com IP-6 Source: Healthnotes, Inc.; www.healthnotes.com Ipriflavone Source: Prima Communications, Inc.www.personalhealthzone.com Isoniazid Alternative names: Laniazid, Nydrazid Source: Prima Communications, Inc.www.personalhealthzone.com Ispaghula Alternative names: Psyllium Source: Integrative Medicine Communications; www.drkoop.com
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Ivy Leaf Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10112,00.html Kava Alternative names: Piper methysticum Source: Healthnotes, Inc.; www.healthnotes.com Kava Source: Prima Communications, Inc.www.personalhealthzone.com Ketorolac Source: Healthnotes, Inc.; www.healthnotes.com Klamathweed Alternative names: St. John's Wort Source: Integrative Medicine Communications; www.drkoop.com Knitbone Source: Integrative Medicine Communications; www.drkoop.com Kudzu Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,858,00.html Lamivudine Source: Healthnotes, Inc.; www.healthnotes.com Lansoprazole Source: Healthnotes, Inc.; www.healthnotes.com Lemon Balm Alternative names: Melissa officinalis Source: Healthnotes, Inc.; www.healthnotes.com Levodopa/Carbidopa Alternative names: Sinemet Source: Prima Communications, Inc.www.personalhealthzone.com Levofloxacin Source: Healthnotes, Inc.; www.healthnotes.com Licorice Alternative names: Glycyrrhiza glabra, Glycyrrhiza uralensis Source: Healthnotes, Inc.; www.healthnotes.com Licorice Alternative names: Glycyrrhiza glabra, Spanish Licorice Source: Integrative Medicine Communications; www.drkoop.com
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Licorice Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,801,00.html Lindane Source: Healthnotes, Inc.; www.healthnotes.com Lipoic Acid Source: Prima Communications, Inc.www.personalhealthzone.com Loop Diuretics Source: Healthnotes, Inc.; www.healthnotes.com Loracarbef Source: Healthnotes, Inc.; www.healthnotes.com L-tyrosine Source: Healthnotes, Inc.; www.healthnotes.com Luffa Alternative names: Luffa sp. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Lutein Source: Healthnotes, Inc.; www.healthnotes.com Lycopene Source: Healthnotes, Inc.; www.healthnotes.com Lysine Source: Prima Communications, Inc.www.personalhealthzone.com Ma huang Source: The Canadian Internet Directory for Holistic Help, WellNet, Health and Wellness Network; www.wellnet.ca Macrolides Source: Healthnotes, Inc.; www.healthnotes.com Maidenhair Tree Alternative names: Ginkgo Biloba Source: Integrative Medicine Communications; www.drkoop.com Maitake Source: Prima Communications, Inc.www.personalhealthzone.com Marsh Pennywort Alternative names: Centella asiatica , Centella, March Pennywort, Indian Pennywort, Hydrocotyle, Brahmi (Sanskrit), Luei Gong Gen (Chinese)(Note: Gotu kola should not be confused with kola nut.) Source: Integrative Medicine Communications; www.drkoop.com
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Marshmallow Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10042,00.html Matricaria Alternative names: Chamomile; Matricaria chamomilla Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Matricaria Recutita Source: Integrative Medicine Communications; www.drkoop.com Medium-chain Triglycerides Source: Prima Communications, Inc.www.personalhealthzone.com Melatonin Source: Healthnotes, Inc.; www.healthnotes.com Melatonin Source: Integrative Medicine Communications; www.drkoop.com Melatonin Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,804,00.html Melissa Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10043,00.html Menadione Source: Integrative Medicine Communications; www.drkoop.com Menaphthone Source: Integrative Medicine Communications; www.drkoop.com Menaquinone Source: Integrative Medicine Communications; www.drkoop.com Mesalamine Source: Healthnotes, Inc.; www.healthnotes.com Metformin Source: Healthnotes, Inc.; www.healthnotes.com Methionine Source: Healthnotes, Inc.; www.healthnotes.com Methotrexate Source: Healthnotes, Inc.; www.healthnotes.com
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Methyltestosterone Source: Healthnotes, Inc.; www.healthnotes.com Metoclopramide Source: Healthnotes, Inc.; www.healthnotes.com Milk Thistle Alternative names: Silybum marianum, Carduus marianus Source: Healthnotes, Inc.; www.healthnotes.com Minocycline Source: Healthnotes, Inc.; www.healthnotes.com Mirtazapine Source: Healthnotes, Inc.; www.healthnotes.com Mistletoe Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10109,00.html Moexipril Source: Healthnotes, Inc.; www.healthnotes.com Monascus Source: Integrative Medicine Communications; www.drkoop.com Nabumetone Source: Healthnotes, Inc.; www.healthnotes.com NADH Source: Healthnotes, Inc.; www.healthnotes.com Nadolol Source: Healthnotes, Inc.; www.healthnotes.com Natural Progesterone Cream Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10099,00.html Neomycin Source: Healthnotes, Inc.; www.healthnotes.com Nitrofurantoin Source: Healthnotes, Inc.; www.healthnotes.com Nitrous Oxide Source: Healthnotes, Inc.; www.healthnotes.com
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Ocimum Alternative names: Basil, Albahaca; Ocimum basilicum Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Oenothera Biennis Alternative names: Evening Primrose Source: Integrative Medicine Communications; www.drkoop.com Olive Leaf Alternative names: Olea europa Source: Healthnotes, Inc.; www.healthnotes.com OPCS (Oligomeric Proanthocyanidins) Source: Prima Communications, Inc.www.personalhealthzone.com Oral Corticosteroids Source: Healthnotes, Inc.; www.healthnotes.com Oregano/Wild Marjoram Alternative names: Origanum vulgare Source: Healthnotes, Inc.; www.healthnotes.com Osha Source: Prima Communications, Inc.www.personalhealthzone.com Oxaprozin Source: Healthnotes, Inc.; www.healthnotes.com PABA Source: Healthnotes, Inc.; www.healthnotes.com Paclitaxel Source: Healthnotes, Inc.; www.healthnotes.com Panax Alternative names: Ginseng; Panax ginseng Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Panax Ginseng Source: Integrative Medicine Communications; www.drkoop.com Passionflower Source: Prima Communications, Inc.www.personalhealthzone.com Pau d'Arco Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,811,00.html Penicillamine Source: Healthnotes, Inc.; www.healthnotes.com
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Penicillin V Source: Healthnotes, Inc.; www.healthnotes.com Penicillins Source: Healthnotes, Inc.; www.healthnotes.com Pennyroyal Alternative names: Hedeoma pulegoides, Mentha pulegium Source: Healthnotes, Inc.; www.healthnotes.com Peppermint Source: Prima Communications, Inc.www.personalhealthzone.com Perphenazine Source: Healthnotes, Inc.; www.healthnotes.com Phenylalanine Source: Integrative Medicine Communications; www.drkoop.com Phosphatidylserine Source: Healthnotes, Inc.; www.healthnotes.com Phosphatidylserine Source: Prima Communications, Inc.www.personalhealthzone.com Phosphorus Source: Integrative Medicine Communications; www.drkoop.com Phylloquinone Source: Integrative Medicine Communications; www.drkoop.com Pimpinella Alternative names: Anise; Pimpinella anisum (L) Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Piroxicam Source: Healthnotes, Inc.; www.healthnotes.com Plantago Isphagula Alternative names: Psyllium Source: Integrative Medicine Communications; www.drkoop.com Plantago Psyllium Alternative names: Psyllium, Ispaghula; Plantago psyllium/ovata Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Plantain Alternative names: Plantago lanceolata, Plantago major Source: Healthnotes, Inc.; www.healthnotes.com Pollen Source: Healthnotes, Inc.; www.healthnotes.com
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Pregnenolone Source: Healthnotes, Inc.; www.healthnotes.com Prickly Ash Alternative names: Zanthoxylum clava-herculis, Zanthoxylum americanum Source: Healthnotes, Inc.; www.healthnotes.com Prochlorperazine Source: Healthnotes, Inc.; www.healthnotes.com Psyllium Alternative names: Ispaghula Source: Integrative Medicine Communications; www.drkoop.com Pueraria Alternative names: Kudzu; Pueraria lobata Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Quinolones Source: Healthnotes, Inc.; www.healthnotes.com Raspberry Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,1061,00.html Red Koji Source: Integrative Medicine Communications; www.drkoop.com Red Leaven Source: Integrative Medicine Communications; www.drkoop.com Red Raspberry Source: Prima Communications, Inc.www.personalhealthzone.com Red Rice Source: Integrative Medicine Communications; www.drkoop.com Red Yeast Rice Alternative names: Angkak, Beni-koju, Hong Qu, Hung-chu, Monascus, Red Leaven, Red Rice, Red Koji, Zhitai, Xue Zhi Kang Source: Integrative Medicine Communications; www.drkoop.com Red Yeast Rice Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10054,00.html Reishi Alternative names: Ganoderma lucidum Source: Healthnotes, Inc.; www.healthnotes.com
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Repaglinide Source: Healthnotes, Inc.; www.healthnotes.com Rifampin Alternative names: Rifadin, Rimactane Source: Prima Communications, Inc.www.personalhealthzone.com Risedronate Source: Healthnotes, Inc.; www.healthnotes.com Risperidone Source: Healthnotes, Inc.; www.healthnotes.com Rofecoxib Source: Healthnotes, Inc.; www.healthnotes.com Roman Chamomile Alternative names: Chamaemelum nobile Source: Integrative Medicine Communications; www.drkoop.com Rosmarinus Alternative names: Rosemary; Rosmarinus officinalis L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Royal Jelly Source: Healthnotes, Inc.; www.healthnotes.com Ruta Alternative names: Rue; Ruta graveolens L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Salsalate Source: Healthnotes, Inc.; www.healthnotes.com SAMe Source: Healthnotes, Inc.; www.healthnotes.com Selegiline Source: Healthnotes, Inc.; www.healthnotes.com Shark Cartilage Source: Integrative Medicine Communications; www.drkoop.com Siberian Ginseng Alternative names: Eleutherococcus senticosus, Acanthopanax senticosus, Eleuthero Source: Integrative Medicine Communications; www.drkoop.com Sitosterol Source: Prima Communications, Inc.www.personalhealthzone.com Sotalol Source: Healthnotes, Inc.; www.healthnotes.com
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Soy Isoflavones Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10057,00.html Spanish Licorice Source: Integrative Medicine Communications; www.drkoop.com St. John's Wort Alternative names: Hypericum perforatum Source: Integrative Medicine Communications; www.drkoop.com St. John's Wort Source: Prima Communications, Inc.www.personalhealthzone.com Stavudine Source: Healthnotes, Inc.; www.healthnotes.com Sulfamethoxazole Source: Healthnotes, Inc.; www.healthnotes.com Sulfasalazine Source: Healthnotes, Inc.; www.healthnotes.com Sulfonamides Source: Healthnotes, Inc.; www.healthnotes.com Sulindac Source: Healthnotes, Inc.; www.healthnotes.com Sun Drop Alternative names: Evening Primrose Source: Integrative Medicine Communications; www.drkoop.com Swertia Alternative names: Swertia sp Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Symphytum Officinale Source: Integrative Medicine Communications; www.drkoop.com Tacrine Source: Healthnotes, Inc.; www.healthnotes.com Tamoxifen Source: Healthnotes, Inc.; www.healthnotes.com Tanacetum V Alternative names: Tansy; Tanacetum vulgare (L.) Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org
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Tang Kuei Alternative names: Dong Quai Source: Integrative Medicine Communications; www.drkoop.com Taraxacum Officinale Alternative names: Dandelion Source: Integrative Medicine Communications; www.drkoop.com Taurine Source: Prima Communications, Inc.www.personalhealthzone.com Tetracycline Source: Healthnotes, Inc.; www.healthnotes.com Tetracyclines Source: Healthnotes, Inc.; www.healthnotes.com Thiazide Diuretics Source: Healthnotes, Inc.; www.healthnotes.com Thioridazine Source: Healthnotes, Inc.; www.healthnotes.com Thymus Extracts Source: Healthnotes, Inc.; www.healthnotes.com Ticlopidine Source: Healthnotes, Inc.; www.healthnotes.com Tobramycin Source: Healthnotes, Inc.; www.healthnotes.com Topical Corticosteroids Source: Healthnotes, Inc.; www.healthnotes.com Trace Minerals Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10061,00.html Trans-beta-carotene Alternative names: Beta-Carotene Source: Integrative Medicine Communications; www.drkoop.com Triazolam Source: Healthnotes, Inc.; www.healthnotes.com Tribulus Puncture Alternative names: Puncture Vine, Goathead; Tribulus terrestris L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org
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Trigonella Alternative names: Fenugreek; Trigonella foenum graecum L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Trimethoprim Source: Healthnotes, Inc.; www.healthnotes.com Trimethoprim/Sulfamethoxazole Source: Healthnotes, Inc.; www.healthnotes.com Triotann-S Pediatric Source: Healthnotes, Inc.; www.healthnotes.com Turmeric Alternative names: Curcuma longa Source: Healthnotes, Inc.; www.healthnotes.com Turmeric Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10062,00.html Tyrosine Source: Integrative Medicine Communications; www.drkoop.com Uncaria Asian Alternative names: Asian species; Uncaria sp. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Uva Ursi Alternative names: Arctostaphylos uva ursi Source: Integrative Medicine Communications; www.drkoop.com Vacciniumb Alternative names: Bilberry; Vaccinium myrtillus L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Valproic Acid Source: Healthnotes, Inc.; www.healthnotes.com Valproic Acid Source: Prima Communications, Inc.www.personalhealthzone.com Venlafaxine Source: Healthnotes, Inc.; www.healthnotes.com Verapamil Source: Healthnotes, Inc.; www.healthnotes.com Warfarin Source: Healthnotes, Inc.; www.healthnotes.com
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Warfarin Alternative names: Coumadin Source: Prima Communications, Inc.www.personalhealthzone.com White Willow Source: Prima Communications, Inc.www.personalhealthzone.com Willow Bark Source: Integrative Medicine Communications; www.drkoop.com Yucca Alternative names: Yucca schidigera , Yucca spp. Source: Healthnotes, Inc.; www.healthnotes.com Zhitai Source: Integrative Medicine Communications; www.drkoop.com Zingiber Alternative names: Ginger; Zingiber officinale Roscoe Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Zue Zhi Kang Source: Integrative Medicine Communications; www.drkoop.com •
Vitamins Ascorbic Acid Source: Integrative Medicine Communications; www.drkoop.com Folic Acid Source: Healthnotes, Inc.; www.healthnotes.com Folic Acid Alternative names: Vitamin B9 (Folic Acid) Source: Integrative Medicine Communications; www.drkoop.com Folic Acid Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,887,00.html Niacin Alternative names: Vitamin B3 (Niacin) Source: Integrative Medicine Communications; www.drkoop.com Pantothenic Acid Source: Healthnotes, Inc.; www.healthnotes.com Pantothenic Acid and Pantethine Source: Prima Communications, Inc.www.personalhealthzone.com
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Provitamin A Alternative names: Beta-Carotene Source: Integrative Medicine Communications; www.drkoop.com Vitamin A Source: Healthnotes, Inc.; www.healthnotes.com Vitamin A Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10066,00.html Vitamin B1 Source: Prima Communications, Inc.www.personalhealthzone.com Vitamin B12 Source: Healthnotes, Inc.; www.healthnotes.com Vitamin B12 Source: Prima Communications, Inc.www.personalhealthzone.com Vitamin B2 Source: Prima Communications, Inc.www.personalhealthzone.com Vitamin B3 Source: Healthnotes, Inc.; www.healthnotes.com Vitamin B3 Source: Prima Communications, Inc.www.personalhealthzone.com Vitamin B3 (Niacin) Alternative names: Niacin Source: Integrative Medicine Communications; www.drkoop.com Vitamin B6 Source: Healthnotes, Inc.; www.healthnotes.com Vitamin B6 Source: Prima Communications, Inc.www.personalhealthzone.com Vitamin B9 (Folic Acid) Alternative names: Folate Source: Integrative Medicine Communications; www.drkoop.com Vitamin C Source: Healthnotes, Inc.; www.healthnotes.com Vitamin C Source: Prima Communications, Inc.www.personalhealthzone.com Vitamin C (Ascorbic Acid) Source: Integrative Medicine Communications; www.drkoop.com
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Vitamin D Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,905,00.html Vitamin E Source: Healthnotes, Inc.; www.healthnotes.com Vitamin E Alternative names: Alpha-Tocopherol Source: Integrative Medicine Communications; www.drkoop.com Vitamin E Source: Prima Communications, Inc.www.personalhealthzone.com Vitamin E Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,906,00.html Vitamin K Alternative names: Menadione, Menaphthone, Menaquinone, Phylloquinone Source: Integrative Medicine Communications; www.drkoop.com Vitamin K Source: Prima Communications, Inc.www.personalhealthzone.com •
Minerals Alpha-tocopherol Alternative names: Vitamin E Source: Integrative Medicine Communications; www.drkoop.com Beta-tocopherol Alternative names: Vitamin E Source: Integrative Medicine Communications; www.drkoop.com Biotin Source: Healthnotes, Inc.; www.healthnotes.com Boron Source: Healthnotes, Inc.; www.healthnotes.com Boron Source: Prima Communications, Inc.www.personalhealthzone.com Bromelain/quercetin Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,941,00.html
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Buspirone Source: Healthnotes, Inc.; www.healthnotes.com Calcium Source: Prima Communications, Inc.www.personalhealthzone.com Calcium Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,884,00.html Calcium Acetate Source: Healthnotes, Inc.; www.healthnotes.com Carnitine Source: Prima Communications, Inc.www.personalhealthzone.com Carnitine (l-carnitine) Alternative names: L-Carnitine Source: Integrative Medicine Communications; www.drkoop.com Cerivastatin Source: Healthnotes, Inc.; www.healthnotes.com Chondroitin Source: Integrative Medicine Communications; www.drkoop.com Chondroitin Source: Prima Communications, Inc.www.personalhealthzone.com Chondroitin Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10017,00.html Chromium Source: Healthnotes, Inc.; www.healthnotes.com Chromium Source: Prima Communications, Inc.www.personalhealthzone.com Chromium Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10018,00.html Cisplatin Source: Healthnotes, Inc.; www.healthnotes.com Copper Source: Healthnotes, Inc.; www.healthnotes.com
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Creatine Source: Prima Communications, Inc.www.personalhealthzone.com D-alpha-tocopherol Alternative names: Vitamin E Source: Integrative Medicine Communications; www.drkoop.com Delta-tocopherol Alternative names: Vitamin E Source: Integrative Medicine Communications; www.drkoop.com Fluoxetine Source: Healthnotes, Inc.; www.healthnotes.com Fluvastatin Source: Healthnotes, Inc.; www.healthnotes.com Folate Alternative names: Vitamin B9 (Folic Acid) Source: Integrative Medicine Communications; www.drkoop.com Gabapentin Source: Healthnotes, Inc.; www.healthnotes.com Gamma-tocopherol Alternative names: Vitamin E Source: Integrative Medicine Communications; www.drkoop.com Iron Source: Healthnotes, Inc.; www.healthnotes.com Iron Source: Prima Communications, Inc.www.personalhealthzone.com L-carnitine Source: Healthnotes, Inc.; www.healthnotes.com L-carnitine Alternative names: Carnitine (L-Carnitine) Source: Integrative Medicine Communications; www.drkoop.com Lovastatin Source: Healthnotes, Inc.; www.healthnotes.com Magnesium Source: Healthnotes, Inc.; www.healthnotes.com Magnesium Source: Integrative Medicine Communications; www.drkoop.com Magnesium Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com
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Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,890,00.html Manganese Source: Healthnotes, Inc.; www.healthnotes.com Manganese Source: Prima Communications, Inc.www.personalhealthzone.com Naproxen/Naproxen Sodium Source: Healthnotes, Inc.; www.healthnotes.com Potassium Source: Healthnotes, Inc.; www.healthnotes.com Potassium Source: Integrative Medicine Communications; www.drkoop.com Potassium Source: Prima Communications, Inc.www.personalhealthzone.com Potassium Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10086,00.html Pravastatin Source: Healthnotes, Inc.; www.healthnotes.com Quercetin Source: Prima Communications, Inc.www.personalhealthzone.com Retinol Alternative names: Vitamin A (Retinol) Source: Integrative Medicine Communications; www.drkoop.com Selenium Source: Prima Communications, Inc.www.personalhealthzone.com Sodium Fluoride Source: Healthnotes, Inc.; www.healthnotes.com Vanadium Source: Healthnotes, Inc.; www.healthnotes.com Vanadium Source: Prima Communications, Inc.www.personalhealthzone.com Vinpocetine Source: Prima Communications, Inc.www.personalhealthzone.com
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Vitamin A (Retinol) Alternative names: Retinol Source: Integrative Medicine Communications; www.drkoop.com Zinc Source: Healthnotes, Inc.; www.healthnotes.com •
Food and Diet Almond Butter Source: Healthnotes, Inc.; www.healthnotes.com Apples Source: Healthnotes, Inc.; www.healthnotes.com Arugula Source: Healthnotes, Inc.; www.healthnotes.com Arugula Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,123,00.html Asparagus Source: Healthnotes, Inc.; www.healthnotes.com Athletic Performance Source: Healthnotes, Inc.; www.healthnotes.com Avocado Source: Healthnotes, Inc.; www.healthnotes.com Barley Source: Healthnotes, Inc.; www.healthnotes.com Beef Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,85,00.html Beets Source: Healthnotes, Inc.; www.healthnotes.com Beets Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,10,00.html Berries Source: Healthnotes, Inc.; www.healthnotes.com
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Bibb Lettuce Source: Healthnotes, Inc.; www.healthnotes.com Blueberries Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,101,00.html Bluefish Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,164,00.html Bok Choy Source: Healthnotes, Inc.; www.healthnotes.com Broccoli Source: Healthnotes, Inc.; www.healthnotes.com Bruising Source: Healthnotes, Inc.; www.healthnotes.com Brussels Sprouts Source: Healthnotes, Inc.; www.healthnotes.com Cabbage Source: Healthnotes, Inc.; www.healthnotes.com Cancer Prevention and Diet Source: Healthnotes, Inc.; www.healthnotes.com Carp Source: Healthnotes, Inc.; www.healthnotes.com Carrots Source: Healthnotes, Inc.; www.healthnotes.com Carrots Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,14,00.html Cartilage Alternative names: Shark Cartilage Source: Integrative Medicine Communications; www.drkoop.com Cartilage Source: Prima Communications, Inc.www.personalhealthzone.com Cashew Butter Source: Healthnotes, Inc.; www.healthnotes.com
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Catfish Source: Healthnotes, Inc.; www.healthnotes.com Cheddar Source: Healthnotes, Inc.; www.healthnotes.com Cheese Source: Healthnotes, Inc.; www.healthnotes.com Chicken Source: Healthnotes, Inc.; www.healthnotes.com Chicken Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,86,00.html Chicory Source: Healthnotes, Inc.; www.healthnotes.com Chili Peppers Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,132,00.html Chocolate Source: Healthnotes, Inc.; www.healthnotes.com Chondroitin Sulfate Source: Healthnotes, Inc.; www.healthnotes.com Clams Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,159,00.html Coffee Source: Healthnotes, Inc.; www.healthnotes.com Collards Source: Healthnotes, Inc.; www.healthnotes.com Cream Source: Healthnotes, Inc.; www.healthnotes.com Dairy Substitutes Source: Healthnotes, Inc.; www.healthnotes.com Dandelion Greens Source: Healthnotes, Inc.; www.healthnotes.com
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Diabetes Source: Healthnotes, Inc.; www.healthnotes.com Eggs Source: Healthnotes, Inc.; www.healthnotes.com Eggs Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,98,00.html Emmenthaler Source: Healthnotes, Inc.; www.healthnotes.com Endive Source: Healthnotes, Inc.; www.healthnotes.com Game Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,88,00.html Garlic Source: Prima Communications, Inc.www.personalhealthzone.com Garlic Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,21,00.html Gluten-Free Diet Source: Healthnotes, Inc.; www.healthnotes.com Goose Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,89,00.html Grains Source: Healthnotes, Inc.; www.healthnotes.com Guinea Fowl Source: Healthnotes, Inc.; www.healthnotes.com Hot Cereals Source: Healthnotes, Inc.; www.healthnotes.com Hypertension Source: Healthnotes, Inc.; www.healthnotes.com Jarlsberg Source: Healthnotes, Inc.; www.healthnotes.com
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Kale Source: Healthnotes, Inc.; www.healthnotes.com Kale Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,127,00.html Kohlrabi Source: Healthnotes, Inc.; www.healthnotes.com Leeks Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,24,00.html Lettuce & Other Salad Greens Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,196,00.html Low Back Pain Source: Healthnotes, Inc.; www.healthnotes.com Low-Fat Diet Source: Healthnotes, Inc.; www.healthnotes.com Mackerel Source: Healthnotes, Inc.; www.healthnotes.com Mahi Mahi Source: Healthnotes, Inc.; www.healthnotes.com Miso Source: Healthnotes, Inc.; www.healthnotes.com Miso Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,201,00.html Monounsaturated Fats Source: Healthnotes, Inc.; www.healthnotes.com Monterey Jack Source: Healthnotes, Inc.; www.healthnotes.com Mullet Source: Healthnotes, Inc.; www.healthnotes.com Mushrooms Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com
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Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10046,00.html Mustard Greens Source: Healthnotes, Inc.; www.healthnotes.com Non-Nutritive and Artificial Sweeteners Source: Healthnotes, Inc.; www.healthnotes.com Nori Source: Healthnotes, Inc.; www.healthnotes.com Nuts Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,84,00.html Okra Source: Healthnotes, Inc.; www.healthnotes.com Omega-3 Fatty Acids Source: Integrative Medicine Communications; www.drkoop.com Omega-3 Fatty Acids Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,992,00.html Orange Roughy Source: Healthnotes, Inc.; www.healthnotes.com Oysters Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,160,00.html Partridge Source: Healthnotes, Inc.; www.healthnotes.com Perch Source: Healthnotes, Inc.; www.healthnotes.com Pike Source: Healthnotes, Inc.; www.healthnotes.com Pistachio Butter Source: Healthnotes, Inc.; www.healthnotes.com Polyunsaturated Fats Source: Healthnotes, Inc.; www.healthnotes.com
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Potatoes Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,270,00.html Quail Source: Healthnotes, Inc.; www.healthnotes.com Rabbit Source: Healthnotes, Inc.; www.healthnotes.com Radishes Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,33,00.html Raisins & Currants Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,67,00.html Red Leaf Lettuce Source: Healthnotes, Inc.; www.healthnotes.com Romaine Lettuce Source: Healthnotes, Inc.; www.healthnotes.com Rutabagas Source: Healthnotes, Inc.; www.healthnotes.com Rye Source: Healthnotes, Inc.; www.healthnotes.com Sablefish Source: Healthnotes, Inc.; www.healthnotes.com Salmon Source: Healthnotes, Inc.; www.healthnotes.com Sausage Source: Healthnotes, Inc.; www.healthnotes.com Scallops Source: Healthnotes, Inc.; www.healthnotes.com Scallops Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,184,00.html Sea Bass Source: Healthnotes, Inc.; www.healthnotes.com
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Sesame Seed Butter Source: Healthnotes, Inc.; www.healthnotes.com Shark Source: Healthnotes, Inc.; www.healthnotes.com Shrimp Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,177,00.html Snow Peas Source: Healthnotes, Inc.; www.healthnotes.com Soy Products Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,135,00.html Spinach Source: Healthnotes, Inc.; www.healthnotes.com Spinach Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,35,00.html Sprouts Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,36,00.html Summer Squash Source: Healthnotes, Inc.; www.healthnotes.com Sweet Peppers Source: Healthnotes, Inc.; www.healthnotes.com Sweet Potatoes Source: Healthnotes, Inc.; www.healthnotes.com Tendinitis Source: Healthnotes, Inc.; www.healthnotes.com Tilefish Source: Healthnotes, Inc.; www.healthnotes.com Tomatoes Source: Healthnotes, Inc.; www.healthnotes.com
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Tropical Fruit Smoothie Source: Healthnotes, Inc.; www.healthnotes.com Trout Source: Healthnotes, Inc.; www.healthnotes.com Tuna Source: Healthnotes, Inc.; www.healthnotes.com Turkey Source: Healthnotes, Inc.; www.healthnotes.com Turkey Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,92,00.html Turnips Source: Healthnotes, Inc.; www.healthnotes.com Vegetarian Diet Source: Healthnotes, Inc.; www.healthnotes.com Water Source: Healthnotes, Inc.; www.healthnotes.com Water Chestnuts Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,43,00.html Wheat Source: Healthnotes, Inc.; www.healthnotes.com Whitefish Source: Healthnotes, Inc.; www.healthnotes.com Winter Squash Source: Healthnotes, Inc.; www.healthnotes.com Yams Source: Healthnotes, Inc.; www.healthnotes.com Yogurt Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,97,00.html Zucchini Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,183,00.html
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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 3. DISSERTATIONS ON ETHER Overview In this chapter, we will give you a bibliography on recent dissertations relating to ether. 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 “ether” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on ether, we have not necessarily excluded non-medical dissertations in this bibliography.
Dissertations on Ether 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 ether. You will see that the information provided includes the dissertation’s title, its author, and the institution with which the author is associated. The following covers recent dissertations found when using this search procedure: •
A Comparison between Lorentz's Ether Theory and Special Relativity in the Light of the Experiments of Trouton and Noble (Hendrik Antoon Lorentz, Frederick T. Trouton, Henry R. Noble) by Janssen, Michael Heinrich Paul, PhD from University of Pittsburgh, 1995, 312 pages http://wwwlib.umi.com/dissertations/fullcit/9529160
•
Ability of Oxygenases in Rhodococcus Rhodochrous to Degrade Methyl Tert-Butyl Ether by Sorrell, John Kaiser; MS from Mississippi State University, 2003, 55 pages http://wwwlib.umi.com/dissertations/fullcit/1414600
•
Administering the Ether, and the Aesthetic of the Absolute by Milutis, Joseph; PhD from The University of Wisconsin - Milwaukee, 2001, 215 pages http://wwwlib.umi.com/dissertations/fullcit/3008797
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An Ether Search by King, Martin Edward; PhD from Carleton University (Canada), 1977 http://wwwlib.umi.com/dissertations/fullcit/NK35515
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•
Aspects of Ether Theory: A Study in the Philosophy of Science. by Leibowitz, Flora Lynn, PhD from The Johns Hopkins University, 1979, 233 pages http://wwwlib.umi.com/dissertations/fullcit/7924621
•
Cultivating the Ludic: 'Through the Air, with the Water, of the Earth, in the Fire, Ether' by Linan Vallecillos, Rafael Ramon, PhD from University of California, San Diego, 1996, 146 pages http://wwwlib.umi.com/dissertations/fullcit/9707350
•
Dynamics and Structure of Benzyl Ether Dendritic Macromolecules by Huang, Joseph Siang Huey; PhD from Stanford University, 2003, 332 pages http://wwwlib.umi.com/dissertations/fullcit/3104243
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Education in the Ether: a Historical Study of 'the Alberta School Broadcasts'; Circa 1929--1959 by Stotyn, Ronald Irwin; PhD from Southern Illinois University at Carbondale, 2003, 566 pages http://wwwlib.umi.com/dissertations/fullcit/3100779
•
Exploring Pathways in the Ether: the Formative Years of Radio in America, 1896-1912 by Douglas, Susan Jeanne, PhD from Brown University, 1979, 376 pages http://wwwlib.umi.com/dissertations/fullcit/8007003
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Kinetic Studies of Enol Ether Radical Cations: Mechanistic Studies of Pyruvate Formate Lyase by Taxil, Elsa Marine; PhD from University of Illinois at Chicago, 2003, 142 pages http://wwwlib.umi.com/dissertations/fullcit/3083893
•
Kinetic Studies on the Etherification of C(5)-alkenes to Fuel Ether Tame by Paakkonen, Paivi Kristiina; DSC (Tech from Teknillinen Korkeakoulu (Helsinki, Finland)), 2003, 47 pages http://wwwlib.umi.com/dissertations/fullcit/f248145
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Modeling Source Area Diffusivity of Methyl Tert-Butyl Ether (MTBE) in Groundwater Systems by Lefkowitz, Daniel Keith; PhD from Rutgers the State University of New Jersey - New Brunswick, 2003, 210 pages http://wwwlib.umi.com/dissertations/fullcit/3077107
•
Process and Part Optimization of Poly(ether) Block Amide 63d Microbore Tubing by Lareau, Raymond Joseph; MSEng from University of Massachusetts Lowell, 2003, 118 pages http://wwwlib.umi.com/dissertations/fullcit/1413363
•
Radical Ions in Photochemistry the Photosensitized (electron Transfer) Carboncarbon Bond Cleavage of Radical Cations : The Phenylethyl Ether and Acetal Systems by Lamont, Laurie J; PhD from Dalhousie University (Canada), 1989 http://wwwlib.umi.com/dissertations/fullcit/NL56239
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Radiolysis of Diethyl Ether and Ethanol Vapors Temperature Effects by Bansal, Krishan Murari; ADVDEG from University of Alberta (Canada), 1968 http://wwwlib.umi.com/dissertations/fullcit/NK03357
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Sodium Binding to Crown Ether Derivatives Bulk Membrane Transport and Sodium23 Nuclear Magnetic Resonance Studies by Stoumlver, Harald D. H; PhD from University of Ottawa (Canada), 1986 http://wwwlib.umi.com/dissertations/fullcit/NL36535
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•
Space, Time, Ether, and Kant (Metaphysics, Immanuel Kant) by WOng, Wing-Chun Godwin, PhD from University of Illinois at Urbana-Champaign, 1994, 224 pages http://wwwlib.umi.com/dissertations/fullcit/9512598
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Structural Studies on Phytanyl-Ether Membrane Lipids in Halobacterium Cutirubrum by Hancock, Anthony John; PhD from University of Ottawa (Canada), 1972 http://wwwlib.umi.com/dissertations/fullcit/NK14172
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Synthesis and Binding Studies of New N-Aryl Aza-Crown Ether Derivatives As Possible Sensing Devices by Xiao, Wenjing; PhD from Case Western Reserve University, 2003, 210 pages http://wwwlib.umi.com/dissertations/fullcit/3092039
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Synthesis and Characterization of Novel Amphiphilic Networks Based on Poly(Ethylene Glycol) and Poly(Benzyl Ether) Dendrimers by Zhu, Chao; , PhD from State University of New York Col. of Environmental Science & Forestry, 2003, 186 pages http://wwwlib.umi.com/dissertations/fullcit/3099389
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Synthetic Studies on Polyether Antibiotics: New Approaches to OligoTetrahydrofurans and Complex Spiroketals by Dabideen, Darrin Rajesh; PhD from City University of New York, 2003, 200 pages http://wwwlib.umi.com/dissertations/fullcit/3074643
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The Effect on Interfacial Energy on the Crystallisation and Melting Behaviour of Poly (Ether)-silica Composites by Cole, John Henry; PhD from McGill University (Canada), 1978 http://wwwlib.umi.com/dissertations/fullcit/NK38197
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The Larger Ether: a Study of Henry James's Romantic Fiction by Brina, Robert Richard, PhD from University of California, Berkeley, 1980, 332 pages http://wwwlib.umi.com/dissertations/fullcit/8029338
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The Medical Uses of Ether and Chloroform in the Nineteenth Century: How Medical Uses Contrasted with Surgical Uses by Kent, Donald Frederick, PhD from Drew University, 1995, 132 pages http://wwwlib.umi.com/dissertations/fullcit/9536138
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The Synthesis of Racemic Daunomycinone Trimethyl Ether, Racemic 4-0demethyldaunomycinone and Racemic Daunomycinone by Schwenk, Robert Joseph; PhD from The University of Manitoba (Canada), 1972 http://wwwlib.umi.com/dissertations/fullcit/NK12194
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Transport of the Oxidising Agent Permanganate in the Subsurface and the Investigation of Its Potential to Degrade Methyl Tert-Butyl Ether in Situ by Damm, Jochen H.; PhD from Queen's University of Belfast (United Kingdom), 2003, 301 pages http://wwwlib.umi.com/dissertations/fullcit/f254529
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Tridodecyl Glyceryl Ether As a Fat Absorption Indicator by Carlson, Walter E; ADVDEG from University of Guelph (Canada), 1970 http://wwwlib.umi.com/dissertations/fullcit/NK06670
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Vibrational Spectra of Several Isotopic Forms of Dimethyl Ether, Hydrogen Chloride and Ethylene Sulphide by Falk, Michael Victor; PhD from University of Alberta (Canada), 1974 http://wwwlib.umi.com/dissertations/fullcit/NK21008
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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 4. PATENTS ON ETHER 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.7 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 “ether” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on ether, we have not necessarily excluded non-medical patents in this bibliography.
Patents on Ether By performing a patent search focusing on ether, 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
7Adapted
from the United States Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm.
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tell you how to obtain this information later in the chapter. The following is an example of the type of information that you can expect to obtain from a patent search on ether: •
Acidic hard-surface antimicrobial cleaner Inventor(s): Hilgers; Debra S. (Racine, WI), Rees; Wayne M. (Caledonia, WI) Assignee(s): S.c. Johnson & Son, Inc. (racine, Wi) Patent Number: 6,699,825 Date filed: January 12, 2001 Abstract: A low residue antimicrobial solution containing about 0.2 percent by weight of an acid selected from the group consisting of organocarboxylic acids; and about 2 percent of a volatile solvent selected from the group consisting of n-butanol, benzyl alcohol, phenylethanol, and sparingly soluble glycol ether solvents is disclosed. Preferred compositions may also contain about 0.1 percent anionic sulfated or sulfonated surfactants and about 5 percent co-solvent selected from the group consisting of completely water soluble monoprotic aliphatic alcohols and glycol ethers. The solution may be also employed as a low-residue cleaner for soiled hard surfaces. Excerpt(s): Not applicable. This invention relates to aqueous liquid cleaning and antimicrobial compositions which leave a low residue of material on the surface to be cleaned. The compositions of the present invention contain a synergistic combination of specific amounts of certain organocarboxylic acids and sparingly water-soluble monohydric aliphatic alcohol solvents, such as benzyl alcohol and certain low molecular weight glycol ethers. Anionic sulfated or sulfonated surfactants and co-solvents are also included in the preferred compositions. Eliminating pathogenic micro-organisms on various surfaces, especially hard surfaces where such organisms may stay active for relatively long periods of time, continues to be a desire of consumers. Traditionally, quaternary ammonium compounds, high levels of certain alcohols, and oxidizing agents have been used in anti-microbial household cleaning products. Disadvantages of utilizing these types of agents include their tendency to cause eye and skin irritation, unpleasant odor, high levels of volatile organic compounds (VOC's), and potential surface damage effects. Some types of hard surfaces, notably glass, glazed ceramic, and polished metal present an additional problem for cleaning and disinfecting. The visible appearance of these surfaces after cleaning is negatively affected by residues left on the surface by the cleaning composition, even after wiping by the user. Rinsing the surface with fresh water after cleaning would help remove these unsightly residues, but this step adds additional work to the cleaning process. Thus, there exists a need for cleaning and disinfecting compositions which can be used on various hard surfaces, especially glass, glazed ceramic, and polished metals, without leaving unsightly residues. Additionally, it is advantageous that such compositions are comprised largely of water, avoiding the use of large amounts of alcohols such as ethanol or isopropanol for reasons of cost, safety, and minimization of formulation VOC's. Web site: http://www.delphion.com/details?pn=US06699825__
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Activated carbon molded body and use thereof Inventor(s): Wolff; Thomas (Munchberg, DE) Assignee(s): Helsa-werke Helmut Sandler Gmbh & Co. KG (gefrees, De) Patent Number: 6,699,561 Date filed: January 31, 2002 Abstract: An activated carbon molded body, more particularly in honeycomb form and for use as an adsorption filter, can be produced from a mixture including activated carbon, water, novolak powder, clay, cellulose ether, liquid starch, wax, polyacrylamide and soap, by a procedure involving thoroughly mixing the constituents, extruding the mixture to form a monolithic molded body and cutting same to size, drying the body and effecting pyrolysis thereof. The adsorption filter produced therefrom can be regenerated by electrical heating under specified conditions. Excerpt(s): This application asserts the priority date of German Patent application No. 10104882.3, which was filed on Feb. 1, 2001. The present invention concerns an activated carbon molded or shaped body, referred to hereinafter as a molded body. The activated carbon molded body may be more particularly for example in honeycomb form and may be used as an adsorption filter. Web site: http://www.delphion.com/details?pn=US06699561__
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Alkaline carpet cleaning composition comprising a pyrrolidone-based solvent Inventor(s): Ryan; Tracy Ann (Ramsey, NJ), Taraschi; Frederic Albert (Skillman, NJ), Taylor; Candice Lida (Clifton, NJ) Assignee(s): Reckitt Benckiser Inc. (wayne, Nj) Patent Number: 6,693,068 Date filed: May 9, 2001 Abstract: Improved aqueous carpet cleaning compositions which are ideally suited for use in machinery designed or used in the mechanical cleaning of carpets. The compositions are alkaline, and include one or more detersive surfactants, preferably one or more nonionic surfactants and one or more anionic surfactants; at least about 2% wt. of aminopolycarboxylic acid salt; an organic solvent constituent, preferably which includes a pyrrolidone based organic solvent constituent and excludes glycol and glycol ether solvents; an anti-resoiling agent; and water in quantum sufficient to provide 100% wt. of the compositions, as well as further optional constituents. Excerpt(s): The present invention relates to cleaning compositions which are useful in the cleaning of carpet fibers, carpets and carpeted surfaces. The present invention is particularly directed to compositions useful in conjunction with machinery designed for the cleaning of such carpet fibers or carpets, as well as for a new process for the cleaning of carpet fibers or carpets. While carpet cleaning compositions are per se, known to consumers, many of these are directed to be used directly from their container, and to be applied to localized areas of carpets. Some are also known for use in the cleaning of broader areas of carpets or carpet surfaces, and these are typically used for cleaning such areas as rooms, hallways and the like where carpet surfaces are installed. A limited number of formulations are also known which are directed to be used with machines intended to clean carpets. The use of such machines is becoming widespread as consumers appreciate their labor saving benefits and cleaning effectiveness. In order to
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be successful for use in such a machine, a carpet cleaning formulation must perform well in the removal of stains, ideally both oleophilic stains, as well as oleophobic stains, and must be compatible with the materials of construction of the machine. However, as the known art will attest, the production of such a successful formulation is not a trivial problem. Further, it is desirable to also include one or more agents in such formulations which provide a barrier, or which resist resoiling of cleaned carpet surfaces. Certain such agents are known to the art, and these include certain classes of fluorocarbon materials such as those available as ZONYL (ex. DuPont Corp.) as well as FLUORAD materials (ex. 3M Corp.), as well as so-called antiresoiling agents based on certain polymers including acrylic polymers. However, the inclusion of one or more of these agents frequently is not possible due to incompatibilities with one or more other constituents which may be present in a formulation. Thus, their compatibility, in a formulation is rarely predicable to the formulator. Web site: http://www.delphion.com/details?pn=US06693068__ •
Bifunctional biphenyl and process for producing bifunctional phenylene ether oligomer compound using the same Inventor(s): Hiramatsu; Kiyonari (Tokyo, JP), Ishii; Kenji (Tokyo, JP), Miyamoto; Makoto (Tokyo, JP), Norisue; Yasumasa (Tokyo, JP), Yanagida; Katsuhiko (Tokyo, JP) Assignee(s): Mitsubishi Gas Chemical Company, Inc. (tokyo, Jp) Patent Number: 6,689,920 Date filed: October 16, 2002 Abstract: A process for producing 2,2',3,3',5,5'-hexamethyl-[1,1'-biphenyl]-4,4'-diol, which process comprises,while setting a pH of a reaction liquid containing an alkaline aqueous solution, a surfactant, a copper catalyst and 2,3,6-trimethylphenol during a reaction in the range of from 8 to 14 and controlling the variation range of the pH of the reaction liquid within.+-.1,oxidatively coupling the 2,3,6-trimethylphenol with an oxygen-containing gas, anda process for producing a bifunctional phenylene ether oligomer compound having a controlled average molecular weight, comprising carrying out oxidation polymerization under a proper oxygen concentration. Excerpt(s): The present invention relates to a process for producing 2,2',3,3',5,5'hexamethyl-(1,1'-biphenyl)-4,4'-diol (to be sometimes referred to as "HMBP" hereinafter) and a process for producing abifunctional phenylene ether oligomer having a phenolic hydroxyl group at each terminal by using HMBP. More specifically, it relates to a process for producing HMBP useful for applications such as an intermediate for electronic material and an agricultural chemical intermediate and to a process for selectively producing a bifunctional phenylene ether oligomer which is excellent in electric characteristics, toughness, compatibility with a thermosetting resin and molding-processability and has a predetermined number average molecular weight. Further, there is known a method which does not require a high-speed rotation thanks to an addition of a boron compound as a pH controlling agent (JP-A-60-152433). In particular, this method is effective for an oxidative coupling of an easily oxidizable phenol having substituents at 2- and 6-sites. Materials for use in an electric or electronic field are required to have low dielectric characteristic for processing high-volume data at high speed in the advanced information society and toughness for preventing the occurrence of microcracks due to thermal shock, etc. For the above requirements, the use of engineering plastic such as polyphenylene ether (to be sometimes referred to as "PPE" hereinafter) is proposed.
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Web site: http://www.delphion.com/details?pn=US06689920__ •
Carbon dioxide-philic compounds and methods of synthesis thereof Inventor(s): Beckman; Eric J. (Aspinwall, PA), Sarbu; Traian (Pittsburgh, PA), Styranec; Thomas J. (Midland, MI) Assignee(s): University of Pittsburgh (pittsburgh, Pa) Patent Number: 6,686,438 Date filed: September 22, 2000 Abstract: A method of synthesizing a CO.sub.2 -philic analog of a CO.sub.2 -phobic compound, includes the step of: reacting the CO.sub.2 -phobic compound with a CO.sub.2 -philic compound selected from the group of a polyether substituted with at least one side group including preferably a Lewis base, a polycarbonate, a polycarbonate substituted with at least one side group including preferably a Lewis base, a vinyl polymer substituted with at least one side group including preferably a Lewis base a poly(ether-ester) or a poly(ether-ester) substituted with at least one side group including preferably a Lewis base, to create the CO.sub.2 -philic analog. A method of synthesizing a CO.sub.2 -phile includes the step of copolymerizing at least two monomers, wherein a polymer formed from homopolymerization of one of the monomers has a T.sub.g of less than approximately 250 K and a steric factor less than approximately 1.8, at least one of the monomers contains a group that results in a pendant group from the CO.sub.2 -phile backbone that contains a Lewis base group, and the resultant CO.sub.2 -phile does not contain both hydrogen bond donors and acceptors. Excerpt(s): The present invention relates to compounds that are soluble in or miscible in carbon dioxide and to methods of synthesizing such compounds. Various publications are referenced herein to, for example, clarify the general state of the art. Reference to a publication herein is not an admission that the publication is prior art or relevant to the patentability of the present invention. The feasibility of using carbon dioxide or CO.sub.2 as a process solvent has been extensively investigated in both academic and industrial circles because CO.sub.2 is considered to be an environmentally benign solvent. Previous solubility parameter calculations using equation of state information suggested that the solvent power of CO.sub.2 was similar to that of short n-alkanes, leading to hopes that CO.sub.2 could replace a wide variety of non-polar organic solvents. King, J. W., Poly. Mat. Sci. Eng. Prepr. (1984), 51, 707. Although such solubility parameter values precluded the use of CO.sub.2 for processing of polar or hydrophilic materials, it was believed that addition of conventional alkyl-functional surfactants could effectively deal with the problem. However, early attempts to employ conventional surfactants in CO.sub.2 failed as a result of the poor solubility of the amphiphiles, despite the fact that these same molecules exhibited adequate solubility in ethane and propane. Consani, K. A.; Smith, R. D.; J. Supercrit. Fl. (1990), 3, 51. It was later discovered that the early solubility parameter calculations, while mathematically correct, failed to note that the absolute value was inflated by as much as 20% by the strong quadropole moment of CO.sub.2 (which also inflates its critical pressure). Myers, A. L.; Prausnitz, J. M., Ind. Eng. Chem. Fundam. (1965), 4, 209. Web site: http://www.delphion.com/details?pn=US06686438__
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Catalysts for oxidative polymerization of fluorophenol, method of oxidative polymerization of fluorophenol, and poly(oxyfluorophenylene) derivative Inventor(s): Kumaki; Yosuke (Tokyo, JP), Oyaizu; Kenichi (Tokyo, JP), Saito; Kei (Tokyo, JP), Tsuchida; Eishun (Tokyo, JP) Assignee(s): Japan Science and Technology Corporation (saitama, Jp) Patent Number: 6,689,919 Date filed: September 7, 2001 Abstract: The synthesis of fluoropolyarylene ether with a high degree of polymerization is enabled, by using a copper complex catalyst with an oxidation potential in the range of -1V to 2V, for the oxidative polymerization of fluorophenols that contain at least one hydrogen atom as well as a fluorine atom bonded to the carbon atoms constituting the benzene ring. Excerpt(s): The present invention relates to catalysts for the oxidative polymerization of fluorophenols and a method for the oxidative polymerization of fluorophenols wherein such catalysts are used. More particularly, this invention relates to catalysts for the oxidative polymerization of fluorophenols useful for the synthesis of engineering plastics, such as fluoropolyarylene ether, with excellent heat resistance and flame resistance, as well as small friction factor, and a method for the oxidative polymerization of fluorophenols wherein such catalysts are used. Further, the present invention relates to poly(oxyfluorophenylene) compounds. More particularly, the present invention relates to soluble poly(oxyfluorophenylene) compounds with excellent heat resistance, membrane-formability and chemical stability. Polyarylene ethers are known as engineering plastics having characteristics such as excellent heat resistance, mechanical strength, drug resistance, dimensional stability, electric performance, and workability, and are used in various industrial fields, such as mechanical parts, gas separating membranes, conductive resins, and functional rubbers. Web site: http://www.delphion.com/details?pn=US06689919__
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Cleaning composition Inventor(s): Chernin; Vladimir (Green Bay, WI), Kubala; Ronald W. (Green Bay, WI), Martens; Richard (Green Bay, WI) Assignee(s): Cleaning Systems, Inc. (depere, Wi) Patent Number: 6,696,399 Date filed: October 15, 2002 Abstract: The present invention provides a low pH microemulsion cleaning composition, with methods for making and using the composition. The composition includes a salt of citric acid; at least one anionic surfactant such as a complex alkyl phosphate ester; at least one nonionic surfactant; a hydrotrope; a glycol ether; 5% to 25% by weight of glycolic acid, citric acid or lactic acid; 2% to 20% by weight of d-limonene, dl-limonene, pine oil, lemon oil, orange oil, grapefruit oil, lime oil, or bergamot oil; and water. Excerpt(s): The present invention is related, in general, to detergent compositions, and more particularly, to detergents utilized in transportation applications, such as automobile and truck washing. Detergent compositions are utilized in a wide variety of applications, all having differing requirements, such as detergents for household use,
Patents 171
detergents for industrial use, and detergents for vehicle washing and other transportation applications. Household and industrial detergents, for example, are being created to require one application and no rinsing, such as that disclosed in Aszman et al. U.S. Pat. No. 6,462,010, issued Oct. 8, 2002, entitled "All Purpose Liquid Cleaning Compositions Compromising Solubilizers", which illustrates a detergent for typical household use. Such detergents are unsuitable for a vehicle washing environment, in which the components to be removed include oily soils, mineral soils, innumerable types of organic and inorganic matter, mud, tar, grease, oil, and virtually any other item which may be found in a transportation environment, for automobiles, trucks, trains, airplanes, jets, boats, and ships. Vehicle washing has also evolved from various mechanical systems having physical contact with the vehicle, such as by using brushes and cloths, to non-mechanical washing systems which spray detergent on the vehicle and then rinse with water under high pressure, without the use of brushes, cloths or other mechanical aids. In addition, such non-mechanical systems may also use a twodetergent application washing process in which one detergent is applied, followed by a variable lag or dwell time, followed by application of a second detergent, again followed by a variable lag or dwell time, and then rinsing with high pressure water. In this environment, because of the absence of friction with the soiled surface from a mechanical device, more effective types of detergents are required to achieve comparable cleaning. Web site: http://www.delphion.com/details?pn=US06696399__ •
Composition for oral care Inventor(s): Endo; Toshio (Kuba, JP) Assignee(s): Daicel Chemical Industries, Ltd. (jp) Patent Number: 6,692,725 Date filed: February 19, 2002 Abstract: It was found that if a copolymer of maleic acid or maleic anhydride with an alkyl vinyl ether, which has a specific viscosity of 3.5 or more, is used as an antibacterial-enhancing agent, the action of an antibacterial agent in an oral composition is enhanced and the effect such as adhesion prevention of a soft deposit is improved. Excerpt(s): The present invention relates to an oral composition. In particular, it relates to an antibacterial antiplaque oral composition useful for toothpaste. More specifically, it relates to an oral composition containing an antibacterial agent effective to inhibit plaque, and an antibacterial-enhancing agent used therefor, which is a toothpaste composition containing a substantially water-insoluble noncationic antibacterial agent (NAA), and a copolymer of maleic acid or maleic anhydride with an alkyl vinyl ether operative as an antibacterial-enhancing agent (AEA) to enhance the antibacterial antiplaque activity of the NAA. As described in Japanese Patent Application Laid-open No. Hei 6-192060, unlike calculus which is a hard calcified deposit on tooth surface, dental plaque is a soft deposit that forms on any part from the tooth surface to soft oral tissue surface adjacent thereto, especially at the gingival margin. It is said that the plaque such as the soft deposit causes the occurrence of gingivitis. Moreover, the deposit of plaque appears to other persons as a dirt on the tooth so that they may find it unsightly and filthy during face-to-face conversation. Web site: http://www.delphion.com/details?pn=US06692725__
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Composition useful for the oxidation dyeing of keratin fibres, containing an oxyalkylenated carboxylic acid ether, a nonionic surfactant and a particular polymer Inventor(s): Bebot; Cecile (Clichy, FR), Desenne; Patricia (Bois Colombres, FR), Laurent; Florence (Bois Colombres, FR) Assignee(s): L'oreal (paris, Fr) Patent Number: 6,692,539 Date filed: December 20, 2002 Abstract: The invention relates to a composition useful for the oxidation dyeing of keratin fibers, in particular of human keratin fibers and more particularly the hair, containing, in a medium that is suitable for dyeing, at least one oxidation dye, at least one polyoxyalkylenated carboxylic acid ether or a salt thereof, at least one nonionic surfactant and at least one cationic or amphoteric polymer whose cationic charge density is greater than or equal to 2 meq/gram. The invention also relates to the dyeing devices and processes using the composition. Excerpt(s): The present invention relates to a composition useful for the oxidation dyeing of keratin fibres, in particular of human keratin fibres and more particularly the hair, comprising, preferably in a medium that is suitable for dyeing, at least one oxidation dye, and also at least one polyoxyalkylenated carboxylic acid ether or a salt thereof, at least one nonionic surfactant and at least one cationic or amphoteric polymer whose cationic charge density is greater than or equal to 2 meq/gram. The invention also relates to dyeing devices, kits, and processes using the composition. It is known practice to dye keratin fibres, and in particular human hair, with dye compositions containing oxidation dye precursors, generally known as "oxidation bases", in particular ortho- or para-phenylenediamines, ortho- or para-aminophenols, and heterocyclic bases. Web site: http://www.delphion.com/details?pn=US06692539__
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Compositions and methods for selectively binding amines or amino acid enantiomers over their counter-enantiomers Inventor(s): Bruening; Ronald L. (American Fork, UT), Krakowiak; Krzysztof E. (American Fork, UT) Assignee(s): Ibc Advanced Technologies, Inc. (american Fork, Ut) Patent Number: 6,686,479 Date filed: March 8, 2001 Abstract: Naphthyl crown ether ligand molecules containing at least two naphthyl groups that are covalently bonded to suitable solid supports and coated by hydrophobic organic solvents are disclosed. These compositions and associated methods are characterized by selectivity of desired amine or amino acid enantiomers over their counter-enantiomers and derivatives. The composition preferably has an.alpha.-value greater than or equal to 4. This allows for the separation of such enantiomers with nonchromatographic resin bed separations of three separation stages or less. Excerpt(s): The present invention is drawn toward compositions and methods for separating an amine or amino acid enantiomer from its counter-enantiomer in order to obtain a high degree of chiral purity. Effective methods for the separation and recovery of particular enantiomers of biochemicals such as amines and amino acids as well as other types of biochemicals is of great importance in modern technology. This
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importance is exemplified by the growing need and desire to produce and use optically pure pharmaceuticals and other biochemicals for human and other use. For example, often only one enantiomer of a chemical compound is biologically active or produces a desired effect. Thus, in order for a recipient of a pharmaceutical to receive enough of the biologically active enantiomer, twice the amount of pharmaceutical is generally given (assuming that the enantiomers are represented at about a 50:50 ratio). In other cases, the undesired enantiomer may be toxic or produce side effects. For example, the undesired enantiomer of thalidomide[4] has been known to cause severe malformation in children born to pregnant women who took the drug by prescription for the benefits of the desired enantiomer. Therefore, much research has been conducted in order to produce optically or enantiomerically pure pharmaceuticals such that the biologically active or desired enantiomer may be used in essentially pure forms in order to eliminate the drawbacks discussed above. There are essentially three theoretical methods that may be used to obtain optically pure compounds for pharmaceutical or other use. First, the desired enantiomer may be synthesized in the desired enantiomeric or optically pure form. Unfortunately this method is often impractical because, in many cases, these types of synthesis methods have not been discovered, or alternatively for those which have been discovered, the production cost of making the pure enantiomer has been prohibitive. Web site: http://www.delphion.com/details?pn=US06686479__ •
Compositions including ether-capped poly (oxyalkylated) alcohol wetting agents Inventor(s): Jordan, IV; Glenn Thomas (Indian Springs, OH), Kluesener; Bernard William (Harrison, OH), McKenzie; Kristen Lynne (Mason, OH), Scheper; William Michael (Lawrenceburg, IN), Sivik; Mark Robert (Mason, OH) Assignee(s): The Procter & Gamble Company (cincinnati, Oh) Patent Number: 6,686,330 Date filed: December 8, 2000 Abstract: Compositions including ether-capped poly(oxyalkylated) alcohol wetting agents. The wetting agents are low-foaming and have good biodegradability, and can be used in a variety of applications, for example in polymer, anti-foaming, biocidal, coating, fertilizer, pharmaceutical, and drilling fluid compositions. Excerpt(s): The present invention relates to compositions containing low-foaming nonionic wetting agents. Due to the varied nature of different compositions, different wetting agents are better suited for some applications while being less suited or totally unsuitable for other applications. While some wetting agents provide the desired properties, such as dispersion or suspension of other ingredients, they are high foaming or not readily biodegradable. Conversely, a wetting agent may be suitably low foaming, but provide less that suitable dispersion or suspension of other ingredients. Accordingly, the need remains for new wetting agents which are suitable for use in a variety of compositions and applications that can provide improve dissolution, improved rates of mixing with water, improved streaking and filming performance, good wetting, adequate dispersion and/or suspension, suds control and good biodegradability, while avoiding incompatibility with other components of the compositions. Web site: http://www.delphion.com/details?pn=US06686330__
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Die attach adhesives with vinyl ether and carbamate or urea functionality Inventor(s): Herr; Donald E. (Flemington, NJ), Musa; Osama M. (Hillsborough, NJ) Assignee(s): National Starch and Chemical Investment Holding Corporation (new Castle, De) Patent Number: 6,699,929 Date filed: August 10, 2001 Abstract: Compounds with both vinyl ether and carbamate, thiocarbamate or urea functionality are suitable for use in microelectronics applications and show enhanced adhesive strength compared to compounds that do not contain carbamate, thiocarbamate or urea functionality. Excerpt(s): This invention relates to die attach adhesives containing resins that contain both vinyl ether and either carbamate, thiocarbamate or urea functionality. Adhesive compositions, particularly conductive adhesives, are used for a variety of purposes in the fabrication and assembly of semiconductor packages and microelectronic devices. The more prominent uses are the bonding of integrated circuit chips to lead frames or other substrates, and the bonding of circuit packages or assemblies to printed wire boards. There exist electron acceptor/donor adhesives that contain vinyl ethers as the donor compounds for use in low modulus adhesives, particularly in fast-cure adhesives for die attach applications. However, die attach adhesives containing commercially available vinyl ethers frequently suffer from poor adhesion, resin bleed and voiding due to the volatility and non-polar nature of these commercial vinyl ethers. Thus, there is a need for improved die attach adhesives utilizing vinyl ethers containing polar functionality in order to address these performance issues. Web site: http://www.delphion.com/details?pn=US06699929__
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Diffraction devices and methods Inventor(s): Ballato; John (Central, SC), Foulger; Stephen (Clemson, SC), Shah; Hiren V. (Clemson, SC), Smith; Dennis W. (Seneca, SC) Assignee(s): Clemson University (clemson, Sc) Patent Number: 6,689,855 Date filed: July 16, 2002 Abstract: Fluoropolymers consisting of alternating perfluorocyclobutane and aryl ether linkages possess suitable properties for optical waveguides and other devices using refractive properties of the polymers. Perfluorocyclobutane (PFCB) polymers having aryl groups alternating on an ether chain have shown useful physical properties for optical waveguide applications. Processes for micromolding such polymeric films by replicating a pattern or image directly from a silicon master, rather than from a polydimethyl siloxane (PDMS) mold) are disclosed. Excerpt(s): This invention relates to the use of fluoropolymers and methods of applying fluoropolymers in making components for optical applications. In particular, the invention relates to copolymer compositions and methods for micromolding and microcontact lithographic printing. Polymeric large core waveguides for optical interconnects have been fabricated using rubber molding processes. Large core waveguides are prepared using photoresist patterning processes in a master fabrication procedure. In the electronics and optical fabrication technologies, optical interconnects
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have been used in backplane interconnections, board to board interconnections, clock distribution, and a variety of other applications. In particular, lithographic processes have been used because such processes are generally suitable for mass production, are usually insensitive to the polymer selection, and are of relatively low cost. Molding processes have in the past relied on micro-fabrication by traditional lithography. Web site: http://www.delphion.com/details?pn=US06689855__ •
Dispersant compositions Inventor(s): Nakamura; Norio (Takefu, JP), Shinohara; Shuichiro (Takefu, JP) Assignee(s): Nissin Chemical Industry Co., Ltd. (fukui-ken, Jp) Patent Number: 6,689,818 Date filed: August 29, 2002 Abstract: A dispersant composition comprising (A) 20-80% by weight of an acetylene glycol or ethoxylated acetylene glycol and (B) 20-80% by weight of a graft product of an allyl alcohol-maleic anhydride-styrene copolymer with a polyoxyalkylene monoalkyl ether, comprising (a) polyoxyalkylene monoalkyl ether units, (b) maleic anhydride units, and (c) styrene units, in a compositional ratio a:b:c of 25-40:25-40:25-40 in mole percent, and having a Mw of 1,000-50,000 exerts improved dispersing, anti-foaming and viscosity-reducing effects, when used in small amounts in dispersing of inorganic particulates. Excerpt(s): This invention relates to dispersant compositions, and more particularly, to dispersant compositions which exert improved dispersing, anti-foaming and viscosityreducing effects when added in small amounts in dispersing inorganic particulates such as ceramic particulates (e.g., alumina, ferrite) and calcium carbonate. Prior art methods of forming ceramic sheets involve dissolving a binder such as polyvinyl butyral resin in an organic solvent, admixing a finely divided ceramic raw material in the solution, and milling the mixture in a ball mill or suitable mixer for a long time for dispersion. After defoaming, the dispersion is applied to a film support of polyester or the like to a certain thickness to form a green sheet, which is fired. Because of the flammability and environmental problems of organic solvents, it was recently proposed to use aqueous binders to avoid the use of organic solvents. Water-soluble binders including polyvinyl alcohol and water-soluble polyurethane were developed as disclosed in JP-A 60-180955. They have found more frequent use. Web site: http://www.delphion.com/details?pn=US06689818__
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Extruded styrene resin foams, and methods for producing the same Inventor(s): Fujiwara; Hiroshi (Osaka, JP), Fukuzawa; Jun (Osaka, JP), Hayashi; Takahiro (Osaka, JP), Kobayashi; Osamu (Shiga, JP) Assignee(s): Kaneka Corporation (osaka, Jp) Patent Number: 6,696,504 Date filed: December 23, 1999 Abstract: Production of extruded styrene resin foams which are excellent in environmental compatibility and retain highly efficient thermal insulation property and have appropriate strength properties is disclosed which is characterized by using as a
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blowing agent a blowing agent comprising mainly 40% by weight or more and 85% by weight or less, based on the whole amount of the blowing agent, of at least one ether selected from the group consisting of dimethyl ether, methyl ethyl ether and diethyl ether, and 15% by weight or more and 60% by weight or less, based on the whole amount of the blowing agent, of at least one saturated hydrocarbon selected from the group consisting of saturated hydrocarbons having 3 to 5 carbon atoms. The production is further characterized by providing a more desirable cell structure such as a specified shape of cells or the presence of larger and smaller cells. Excerpt(s): The present invention relates to an extruded styrene resin foam and a method for its production. Particularly, the present invention relates to a board-like extruded styrene resin foam which is excellent in environmental compatibility, retains highly efficient thermal insulating property and has appropriate strength properties, and hence useful, especially, as a thermal insulation material, and to a method for the production thereof. Hitherto, extruded styrene resin foams have been widely used as thermal insulation materials for buildings because of their desirable workability and thermal insulation characteristic. Many prior patents proposed techniques which use flons typified by flon 12, flon 142b and flon 134a in order to impart excellent thermal insulation characteristic to styrene resin extruded foams, in combination with halogenated hydrocarbons which are easy to permeate through styrene resin, typified by methyl chloride and ethyl chloride in order to achieve desirable mechanical properties, thermal stability of foams and productivity. These techniques have been widely adopted as general production methods and have become common. On the other hand, in recent years, attention has been given to the ozone layer problem and the global warming problem. From such a viewpoint, the use of flon 134a, which is suitable for protection of the ozone layer, is proposed. However, there is further demand for selection of preferable blowing agent in view of a greenhouse effect. In addition, methyl chloride, ethyl chloride and the like are believed to be preferable to be replaced if possible from the viewpoint of environmental sanitation. Web site: http://www.delphion.com/details?pn=US06696504__ •
Flourine-containing copolymer Inventor(s): Fukuda; Kazuyuki (Osaka, JP), Hirao; Takayuki (Decatur, AL), Kono; Hideki (Osaka, JP), Lin; George (Orangeburg, NY) Assignee(s): Daikin America, Inc. (orangeburg, Ny) Patent Number: 6,703,464 Date filed: January 17, 2002 Abstract: A fluorine-containing copolymer obtained by copolymerizing tetrafluoroethylene, hexafluoropropylene and perfluoro vinyl ether as component monomers, wherein a weight ratio of tetrafluoroethylene, hexafluoropropylene and perfluoro vinyl ether units constituting the fluorine-containing copolymer is 70 to 95:5 to 20:0 to 10, respectively; the fluorine-containing copolymer having: a melt flow rate of 30 (g/10 minutes) or more; a volatile content index of 0.2% by weight or less; and a stress relaxation modulus G(t) (unit: dyn/cm.sup.2) which satisfies the following formula at t=0.1 second when measured at a temperature of 310.degree. C.:G(0.1)>7.times.10.sup.6.times.X.sup.-1.6143 -3000where X denotes the melt flow rate (unit: g/10 minutes). Also disclosed is an insulating material composed of the fluorinecontaining copolymer and an insulated cable having a core conductor coated with the fluorine-containing copolymer.
Patents 177
Excerpt(s): The present invention relates to a fluorine-containing copolymer which improves extrusion moldability for coating an electric cable with an insulating resin and which is capable of suppressing the occurrence of molding faults over long term operation even when coating at high speed. Tetrafluoroethylene (TFE)/hexafluoropropylene (HFP) copolymer has superior heat resistance, chemical resistance, extrusion moldability and the like, and in addition, has superior electric insulating property and high-frequency property with a low dielectric tangent. Therefore, it is used for insulating cable such as a cable and a wire, and such insulated cable is suitably used as a communication cable. The communication cable includes a data transmission cable such as a LAN cable. The insulated cable comprises a core wire such as a cable and an insulating material formed from a resin such as a TFE/HFP copolymer coating the core wire. In general, the insulated cable is manufactured by extrusion coating in which molten resin is extruded in the shape of a tube, drawn down by inserting a core wire through the center portion of the resin tube in its axial direction, and the core wire coated with the resin is then taken up. Web site: http://www.delphion.com/details?pn=US06703464__ •
Histologic visualization of cyanoacrylate embolization Inventor(s): Calvo; William J. (250 Kettering Dr., Buffalo, NY 14223), Lieber; Baruch B. (1662 Winterberry La., Weston, FL 33327) Assignee(s): None Reported Patent Number: 6,686,203 Date filed: September 11, 2001 Abstract: A histological staining technique that allows quantification of previously unmeasured parameters involved in surgical arteriovenous malformation (AVM) embolization. The invention allows the evaluation of the polymerization characteristics of various ratios of embolization agents, such as Lipiodol/n-butyl 2-cyanoacrylate (NBCA)/glacial acetic acid (GAA) mixtures, by virtue of a new tissue sample preparation protocol and staining technique. To determine the depth of NBCA penetration within the AVM model and to characterize the polymerization patterns of various mixtures within a model vessel, histologic cross-and longitudinal sections were prepared for microscopy using a new staining method including the use of europium aryl-.beta.-diketone complex and petroleum ether. Paraffin-embedded tissue sections were subjected to the staining protocol to improve differentiation between NBCA and Lipiodol. Excerpt(s): The present invention pertains to a method for histological staining of arteriovenous malformation (AVM) tissue samples in order to quantify parameters of surgical AVM embolization using an europium aryl-.beta.-diketone complex. Arteriovenous malformations (AVMs) are, in most patients, congenital lesions formed by tangled networks of blood vessels. The cause of AVMs is not known, but most AVMs are thought to be due to abnormal development of blood vessels during fetal development. While AVMs can potentially form anywhere in the body, those formed in the brain are particularly problematic. In normal brain tissue, blood enters through major cerebral arteries, passes through smaller arterioles, and subsequently moves into capillaries. Capillaries are tiny blood vessels that allow blood to deliver necessary oxygen and nutrients to the brain and remove waste products of brain metabolism. Normally, after passing through the capillaries, the blood enters the brain's venous system. When an AVM exists in the brain, blood is shunted directly from the arterial
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system to the venous system. There is normally a drop in pressure as blood travels from arteries to veins, but when an AVM is present, the rate of blood flow from arteries to veins can be high and the pressure can thus be elevated within the veins. This elevated pressure can contribute to a variety of complications, including stroke, seizures, bleeding, and disruption of the normal function of brain cells near the AVM. Web site: http://www.delphion.com/details?pn=US06686203__ •
Hypolipidemic and antioxidant morpholine derivatives Inventor(s): Chrysselis; Michael (Thessaloniki, GR), Kourounakis; Panagiotis (Thessaloniki, GR), Rekka; Eleni (Thessaloniki, GR) Assignee(s): Elpen S.a. (pikermi Attica, Gr) Patent Number: 6,693,192 Date filed: October 11, 2001 Abstract: The present invention relates to the synthesis and the evaluation of the antioxidant, hypocholesterolemic and hypolipidemic activity of substituted morpholine derivatives of formula (I) in which R.sub.1 =CH.sub.2 CH.sub.3, R.sub.2 =CH.sub.3, R.sub.3, R.sub.4 =H, R.sub.5 =C.sub.6 H.sub.5 (compound 1) or R.sub.1 =CH.sub.2 CH.sub.2 CH.sub.2 ONO.sub.2, R.sub.2 =CH.sub.3, R.sub.3, R.sub.4 =H, R.sub.5 =C.sub.6 H.sub.5 (compound 2) or R.sub.1 =H, R.sub.2 --R.sub.3 =(CH.sub.2).sub.4, R.sub.4 =H, R.sub.5 =C.sub.6 H.sub.5 (compound 3) or R.sub.1 =CH.sub.2 CH.sub.2 CH.sub.3, R.sub.2 --R.sub.3 =(CH.sub.2)4, R.sub.4 =H, R.sub.5 =C.sub.6 H.sub.5 (compound 4) or R.sub.1 =CH.sub.2 CH.sub.2 CH.sub.2 ONO.sub.2, R.sub.2 --R.sub.3 =(CH.sub.2).sub.4, R.sub.4 =H, R.sub.5 =C.sub.6 H.sub.5 (compound 5) or R.sub.1 =H, R.sub.2 =CH.sub.3, R.sub.3 --R.sub.4 =(CH.sub.2).sub.4, R.sub.5 =C.sub.6 H.sub.5 (compound 6) or R.sub.1 =CH.sub.2 CH.sub.2 CH.sub.3, R.sub.2 =CH.sub.3, R.sub.3 -R.sub.4 =(CH.sub.2).sub.4, R.sub.5 =C.sub.6 H.sub.5 (compound 7) or R.sub.1 =CH.sub.2 CH.sub.2 CH.sub.2 ONO.sub.2, R.sub.2 =CH.sub.3, R.sub.3 --R.sub.4 =(CH.sub.2).sub.4, R.sub.5 =C.sub.6 H.sub.5 (compound 8) or R.sub.1 =CH.sub.2 CH.sub.2 CH.sub.2 ONO.sub.2, R.sub.2 =CH.sub.3, R.sub.3, R.sub.4 =H, R.sub.5 =C.sub.6 H.sub.5 (compound 9) or R.sub.1 =H, R.sub.2 =p-NO.sub.2 --C.sub.6 H.sub.4 --CH.sub.2 CH.sub.2, R.sub.3, R.sub.4 =H, R.sub.5 =C.sub.6 H.sub.5 (compound 10). The 2-hydroxymorpholine derivatives 3, 6 and 10 are synthesised by the reaction of the appropriate aminoalcohol (22 mmol) and the 2-bromophenylacetophenone or the 2bromoacetophenone (10 mmol) in ether and acetone for 15 hours at room temperature. Me 2-alkoxy derivatives 1, 4 and 7 are synthesised by the reaction of the respective 2hydroxy derivative with the appropriate alcohol, in acid medium and reflux. Compounds 2, 5, 8 and 9 are synthesised by the reaction of the respective 2-hydroxy derivative with the 3-bromopropanol in acidic medium and reflux. The 2-(3bromopropoxy) derivatives thin reacted with silver nitrate in acetonitrile and reflux. The compounds of formula (I) decrease significantly total cholesterol, triglyceride and LDLcholesterol levels in plasma. The compounds of formula (I) possess potent antioxidant activity. The compounds of formula (I) with the above properties could be useful to the treatment of hypercholesterolemia, hyperlipidemia and atheromatosis. Excerpt(s): in which R.sub.1 =CH.sub.2 CH.sub.3, R.sub.2 =CH.sub.3, R.sub.3, R.sub.4 =H, R.sub.5 =C.sub.6 H.sub.5 (compound 1) or R.sub.1 =CH.sub.2 CH.sub.2 CH.sub.2 ONO.sub.2, R.sub.2 =CH.sub.3, R.sub.3, R.sub.4 =H, R.sub.5 =C.sub.6 H.sub.5 (compound 2) or R.sub.1 =H, R.sub.2 13 R.sub.3 =(CH.sub.2).sub.4, R.sub.4 =H, R.sub.5 =C.sub.6 H.sub.5 (compound 3) or R.sub.1 =CH.sub.2 CH.sub.2 CH.sub.3, R.sub.2 --
Patents 179
R.sub.3 =(CH.sub.2).sub.4, R.sub.4 =H, R.sub.5 =C.sub.6 H.sub.5 (compound 4) or R.sub.1 =CH.sub.2 CH.sub.2 CH.sub.2 ONO.sub.2 R.sub.2 --R.sub.3 =(CH.sub.2).sub.4, R.sub.4 =H, R.sub.5 =C.sub.6 H.sub.5 (compound 5) or R.sub.1 =H, R.sub.2 =CH.sub.3, R.sub.3 --R.sub.4 =(CH.sub.2).sub.4, R.sub.5 =C.sub.6 H.sub.5 (compound 6) or R.sub.1 =CH.sub.2 CH.sub.2 CH.sub.3, R.sub.2 =CH.sub.3, R.sub.3 --R.sub.4 =(CH.sub.2).sub.4, R.sub.5 =C.sub.6 H.sub.5 (compound 7) or R.sub.1 =CH.sub.2 CH.sub.2 CH.sub.2 ONO.sub.2, R.sub.2 =CH.sub.3, R.sub.3 --R.sub.4 =(CH.sub.2)4, R.sub.5 =C.sub.6 H.sub.5 (compound 8) or R.sub.1 =CH.sub.2 CH.sub.2 CH.sub.2 ONO.sub.2, R.sub.2 =CH.sub.3, R.sub.3, R.sub.4 =H, R.sub.5 =H (compound 9) or R.sub.1 =H, R.sub.2 =pNO.sub.2 --C.sub.6 H.sub.4 --CH.sub.2 CH.sub.2, R.sub.3, R.sub.4 =H, R.sub.5 =C.sub.6 H.sub.5 (compound 10). thrombogenesis, endothelial injury and haemodynamic factors. Especially, the oxidative modification of LDL appears to be the most risk atherogenic process, which induces inflammatory and apoptotic mechanisms and finally the formation of foam cells and fatty streaks. Web site: http://www.delphion.com/details?pn=US06693192__ •
Low molecular weight engineering thermoplastic polyurethane and blends thereof Inventor(s): D'Hooghe; Edward Louis (Hulst, NL), Moses; Paul J. (Lake Jackson, TX), van Pelt; Wilfred (Breda, GA) Assignee(s): The Dow Chemical Company (midland, Mi) Patent Number: 6,696,528 Date filed: August 7, 2001 Abstract: A low molecular weight engineering thermoplastic polyurethane (ETPU) can be homogeneously melt blended with a polyarylene ether (PAE) to give a low viscosity melt processable blend, and subsequently cooled to form a heterogeneous dispersion of the ETPU in the PAE that has two T.sub.g s, one that is close to the T.sub.g of the pure ETPU, and one that is close to the T.sub.g of the pure PAE. As such, the composite blend retains the properties of the polyarylene ether. Excerpt(s): The present invention relates to a low molecular weight engineering thermoplastic polyurethane and blends thereof. More particularly the invention relates to a dispersion of a low molecular weight engineering thermoplastic polyurethane in a polyarylene ether matrix. Polyarylene ethers (PAEs) are a class of thermoplastic resins with excellent mechanical and electrical properties, heat resistance, flame retardancy, low moisture absorption, and dimensional stability. These resins are widely used in automobile interiors, particularly instrument panels, and electrical as well as electronic applications. Epoxy resins have also been investigated as a reactive solvent for the PAE. (See Venderbosch, R. W., "Processing of Intractable Polymers using Reactive Solvents," Ph.D. Thesis, Eindhoven (1995); Vanderbosch et al., Polymer, Vol. 35, p. 4349 (1994); Venderbosch et al., Polymer, Vol. 36, p. 1167 (1995a); and Venderbosch et al., Polymer, Vol. 36, p. 2903 (1995b)). In this instance, the PAE is first dissolved in an epoxy resin to form a solution that is preferably homogeneous. An article is then shaped from the solution, and the solution is cured at elevated temperatures, resulting in a phase separation that can give a continuous PAE phase with epoxy domains interspersed therein. The properties of the finished article are primarily determined by the PAE; however, the use of an epoxy resin as a reactive solvent for the PAE is not practical in a continuous melt process like injection molding because the epoxy resin needs a curing agent to set. The curing agent will, over time, accumulate in the injection molding barrel,
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thereby fouling the machine. Furthermore, the cure and subsequent phase separation has to take place at at least 150.degree. C., which is impractical in a molder environment. Web site: http://www.delphion.com/details?pn=US06696528__ •
Membrane electrode assembly and method of its production Inventor(s): Blach Vizoso; Ricardo (Asua-Erandio, ES), Cadaval Fernandez De Leceta; Alfonso Carlos (Asua-Erandio, ES) Assignee(s): David Fuel Cell Components, S.l. (es) Patent Number: 6,685,806 Date filed: June 21, 2001 Abstract: Membrane-electrode assembly consisting of a cationic exchange membrane which contains fluorine (made of hydrolyzed copolymer of tetrafluoro-ethylene and vinyl ether which contains perfluorosulfur with PE=900-1300) and porous layers of electrode material (made of electrocatalyst), inactive electroconductor material and fluoropolymer agglutinating material arranged on both surfaces of the cationic exchange membrane. The cationic exchange membrane which contains the fluorine is made of hydrolyzed copolymer of tetrafluoroethylene with vinyl ether which contains perfluorosulfur, having a crystallinity grade between 2 and 8%; porous layers of the electrode material are obtained which have a porosity comprised between 40 and 70% and decreasing in the direction of the cationic exchange membrane surface with a porosity gradient from 5 to 15% par 1.mu. Said membrane-electrode assembly is used in fuel cells, in water electrolysis and in other electrochemical process. Excerpt(s): The present invention relates to the electrochemical industry in general, and more particularly to a membrane-electrode assembly ("MEA") based on fluorocontaining ion-exchange membranes and to a method for its production. Such MEAs are widely used in fuel cells, in water electrolyzers, and in other electrochemical processes. Our experiments showed that this copolymer has an equivalent weight (EW) of 1200 and a degree of crystallinity of 12%, as shown in control Example 1. The MEA is produced by applying an electrode composition on both sides of the CEM. The sedimentation method is used. The electrode composition consists of a mixture of an electrocatalyst and an ion-exchange polymer (polyantimonic acid) powder. The composition is fixed by electric current treatment in water at 90.degree. C., where the current density is 0.5-1 A/cm.sup.2. Web site: http://www.delphion.com/details?pn=US06685806__
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Metal film/aromatic polyimide film laminate Inventor(s): Amane; Takashi (Yamaguchi, JP), Anno; Toshihiko (Yamaguchi, JP), Nishino; Toshiyuki (Yamaguchi, JP), Yamamoto; Tomohiko (Yamaguchi, JP) Assignee(s): Ube Industries, Ltd. (yamaguchi, Jp) Patent Number: 6,699,572 Date filed: September 21, 2001 Abstract: A metal film/aromatic polyimide film laminate is composed of a composite aromatic polyimide film and a metal film, in which the composite aromatic polyimide film is composed of an aromatic polyimide substrate film having a linear expansion
Patents 181
coefficient of 5.times.10.sup.-6 to 30.times.10.sup.-6 cm/cm/.degree. C. in the temperature range of 50-200.degree. C. (measured in machine direction), and a thin aromatic polyimide layer of polyimide prepared from a carboxylic acid component comprising a mixture of 3,3',4,4'-biphenyltetracarboxylic dianhydride and 2,3,3',4'biphenyltetracarboxylic dianhydride in a molar ratio of 50:50 to 90:10 and an aromatic diamine component composed of 1,3-bis(4-aminophenoxy)benzene or a mixture of 1,3bis(4-aminophenoxy)benzene and p-phenylenediamine and/or diaminodiphenyl ether in a molar ratio of 10/90 or more. Tg of the thin polyimide layer is 210-310.degree. C. The metal film is fixed to the thin polyimide layer at a 90.degree. peel resistance of 0.5 kg/cm or higher, while the thin polyimide layer is bonded to the substrate film at a 90.degree. peel resistance higher than that between the metal film and the thin layer. Excerpt(s): This application claims priority of Japanese Application No. 2000-286456 filed Sep. 21, 2000, the complete disclosure of which is hereby incorporated by reference. This invention relates to a metal film/aromatic polyimide film laminate and further relates to a composite aromatic polyimide film. Aromatic polyimide films show good high temperature resistance, good chemical properties, high electrical insulating property, and high mechanical strength, and therefore are widely employed in various technical fields. For instance, an aromatic polyimide film is favorably employed in the form of a continuous aromatic polyimide film/metal film composite sheet for manufacturing a flexible printed circuit board (FPC), a carrier tape for tape-automatedbonding (TAB), and a tape of lead-on-chip (LOC) structure. Web site: http://www.delphion.com/details?pn=US06699572__ •
Method for anion-exchange adsorption and anion-exchangers Inventor(s): Andersson; Mikael (Uppsala, SE), Belew; Makonnen (Uppsala, SE), Gustavsson; Jan (Uppsala, SE), Johansson; Bo-Lennart (Uppsala, SE), Maloisel; Jean-Luc (Enebyberg, SE) Assignee(s): Amersham Biosciences AB (uppsala, Se) Patent Number: 6,702,943 Date filed: September 16, 2002 Abstract: A method for the removal of a substance carrying a negative charge and being present in an aqueous liquid (I). The method comprises the steps of: (i) contacting the liquid with a matrix carrying a plurality of ligands comprising a positively charged structure and a hydrophobic structure, and (ii) desorbing the substance. The characterizing feature is that (I) each of said ligands together with a spacer has the formula: --SP--[Ar--R.sub.1 --N.sup.+ (R.sub.2 R.sub.3 R.sub.4)] where (A) [Ar--R.sub.1 -N.sup.+ (R.sub.2 R.sub.3 R.sub.4)] represents a ligand a) Ar is an aromatic ring, b) R.sub.1 is [(L).sub.n R'.sub.1 ].sub.m where n and m are integers selected amongst zero or 1; L is amino nitrogen, ether oxygen or thioether sulphur; R'.sub.1 is a linker selected among 1) hydrocarbon groups; 2) --C(.dbd.NH)--; c) R.sub.2-4 are selected among hydrogen and alkyls; (B) SP is a spacer providing a carbon or a heteroatom directly attached to Ar--R.sub.1 --N.sup.+ (R.sub.2 R.sub.3 R.sub.4); (C)--represents that SP replaces a hydrogen in (Ar--R.sub.1 --N.sup.+ (R.sub.2 R.sub.3 R.sub.4); (D)--represents binding to the matrix; and (II) desorption. There is also described (a) anion-exchangers having high breakthrough capacities, (b) a screening method and (c) a desalting protocol.
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Excerpt(s): ii) desorbing said substance from said matrix by the use of a liquid (II). The invention also relates to novel anion-exchangers in which there are anion-exchange ligands comprising both a hydrophobic structure and a positively charged structure. The terms "carrying a negative charge" and "negatively charged" mean that the substance carries one or more negative charges and/or has a negative net charge. Web site: http://www.delphion.com/details?pn=US06702943__ •
Method of screening substances with a glycidyl methacrylate covered styreneglycidyl methacrylate polymer Inventor(s): Handa; Hiroshi (17-16, Sakurajosui 1-chome, Setagaya-ku, Tokyo, JP 156), Kawaguchi; Haruma (86-43, Nakazawa-cho, Asahi-ku, Yokohama-shi, Kanagawa, JP 241) Assignee(s): None Reported Patent Number: 6,703,207 Date filed: November 2, 2001 Abstract: A compound possessing physiological activity is coupled to a styrene-glycidyl methacrylate polymer through a spacer. Compounds that may be used include receptors such as proteins, and 3-[(5-(2,3-dimethoxy-6-methyl-benzoquinonyl)]-2-nonyl-2propionic a preferred spacer is an ethylene glycol diglycidyl ether derivative. Preferably, the whole surface of the styrene-glycidyl methacrylate polymer in microsphere form is covered with glycidyl methacrylate. The microsphere may be used for isolating and detecting substances such as proteins that bind to the coupled compound. Excerpt(s): The present invention relates to a microsphere which is prepared by coupling a substance possessing physiological activities to a styrene-glycidyl methacrylate polymer through a spacer as well as a process of isolating an objective or targeted substance by using the microsphere of the invention. Cells constituting a living body are exposed to various kinds of stimulation from the external environment all the time. To respond to such stimulation the cells lead some gene groups to expression. As a result, various living phenomena can occur, such as induction of cell growth and/or cell differentiation and maintenance of physiological homeostasis. Extracellular stimulation is transformed into an intracellular signal, which activates a specific proteinous transcription factor. The functionally activated transcription factor binds to a specific base sequence on a chromosome to induce a gene group under its regulation to expression. The product of the induced gene expression primarily functions to respond to the stimulation in some cases. In the other cases, the product of the induced gene expression further activates another transcription factor that induces another gene group under its regulation to expression to secondarily respond to the stimulation. In either case, cellular response to the stimulation from the external environment is concluded to be functional transformation of transcription factors. In recent years, an extremely interesting fact was revealed. That is, mechanisms of action of cyclosporin A (CysA) and FK506, immunosuppressive drugs, have been revealed. See J. Lin et al., Cell, 66:807-815 (1991); S. J. O'Keefe et al., Nature, 357:692 (1992); and N. A. Clipstone et al., Nature, 357:695 (1992). The first opportunity for revealing the mechanisms is the identification of intracellular receptors to these drugs. See R. E. Handschumacher et al., Science, 226, 554; and J. J. Sekierka et al., J. Immunol., 143:1580-1583 (1989). On the basis of these findings, a series of signaling pathway following stimulation by antigen was revealed in T-cell that is immunocompetent cell.
Patents 183
Web site: http://www.delphion.com/details?pn=US06703207__ •
Oxidation dyeing composition for keratin fibres Inventor(s): Maubru; Mireille (Chatou, FR) Assignee(s): L'oreal S.a. (paris, Fr) Patent Number: 6,682,572 Date filed: June 29, 1999 Abstract: The invention relates to a ready-to-use composition for the oxidation dyeing of keratin fibers, and in particular human keratin fibers such as the hair, comprising, in a medium which is suitable for dyeing, at least one oxidation base, at least one C.sub.4C.sub.8 ether of a C.sub.2 glycol and/or at least one C.sub.1 -C.sub.8 ether of a C.sub.3 C.sub.9 glycol and at least one enzyme of 2-electron oxidoreductase type in the presence of at least one donor for the said enzyme, and to the dyeing process using this composition. Excerpt(s): The invention relates to a composition for the oxidation dyeing of keratin fibres, and in particular human keratin fibres such as the hair, comprising, in a medium which is suitable for dyeing, at least one oxidation base, at least one C.sub.4 -C.sub.8 ether of a C.sub.2 glycol and/or at least one C.sub.1 -C.sub.8 ether of C.sub.3 -C.sub.9 glycol and at least one enzyme of 2-electron oxidoreductase type in the presence of at least one donor for the said enzyme, and to the dyeing process using this composition. It is known to dye keratin fibres, and in particular human hair, with dye compositions containing oxidation dye precursors, in particular ortho- or para-phenylenediamines, ortho- or para-aminophenols and heterocyclic bases, which are generally referred to as oxidation bases. Oxidation dye precursors, or oxidation bases, are colourless or weakly coloured compounds which, when combined with oxidizing products, can give rise to coloured compounds and dyes by a process of oxidative condensation. It is also known that the shades obtained with these oxidation bases can be varied by combining them with couplers or colour modifiers, the latter being chosen in particular from aromatic meta-diamines, meta-aminophenols, meta-diphenols and certain heterocyclic compounds. Web site: http://www.delphion.com/details?pn=US06682572__
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Perfluoro copolymers of tetrafluoroethylene and perflouro alkyl vinyl ethers Inventor(s): Kaulbach; Ralph (Emmerting, DE), Traunspurger; Helmut (Julbach, DE) Assignee(s): 3M Innovative Properties Company (st. Paul, Mn) Patent Number: 6,686,426 Date filed: August 28, 2001 Abstract: In preparing a fluorinated thermoplastic with good flex life, high thermal conductivity and low average spherolite diameter from tetrafluoroethylene and perfluoro n-alkyl vinyl ether, perfluoro 2-propoxyalkyl vinyl ether is additionally incorporated into the fluorinated thermoplastic. A semicrystalline, thermoplastically processable copolymer is prepared, made from units of the tetrafluoroethylene, from 2 to 10% by weight of units of perfluoro n-propyl vinyl ether and from 0.1 to 6% by weight of units of perfluoro 2-propoxypropyl vinyl ether. The novel copolymer
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preferably contains fewer than 70 unstable end groups per 10.sup.6 carbon atoms, has thermal conductivity of at least 0.19 W/mK at 23.degree. C. and has a smooth surface with an average spherolite diameter of
