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ADVANCES IN Pharmacology and Chemotherapy VOLUME 13 ADVISORY BOARD D. BOVET J. F. DANIELLI Zstituto Superiore di Sanita Rome, Ztaly Worcester Polytechnic Institute Worcester, Massachusetts B. B. BRODIE National Heart Institute Bethesda, Maryland J. H. BURN Oxford University Oxford, England A. CARLSSON Department of Pharmacology University of Goteborg Goteborg, Sweden K. K. CHEN Department of Pharmacology University of Zndiana Indianapolis, Zndiana R. DOMENJOZ Pharmakologisches Znstitut Universitat Bonn Bonn, Germany B. N. HALPERN De'partement de Me'decine Expe'rimentale Collgge de France Paris, France A. D. WELCH Squibb Institute for Medical Research New Brunswick, New Jersey ADVANCES IN Pharmacology and Chemotherapy EDITED BY Silvio Garattini A. Goldin lstituto di Ricerche Farmacologiche “Mario Negri” Milano, Italy National Cancer Institute Bethesda, Maryland F. Hawking 1. J. Kopin Clinical Research Centre Harrow, Middlesex, England National Institute of Mental Health Bethesda, Maryland Consulting Editor R. J. Schnitzer Mount Sinai School of Medicine New York, New York VOLUME 13-1975 ACADEMIC PRESS New York San Francisco London A Subsidiary of Harcourt Brace Jovanovich, Publishers COPYRIGHT 0 1975, BY ACADEMIC PRESS,INC. ALL RIGHTS RESERVED. N O PART OF THIS PUBLICATION MAY BE REPRODUCED OR TRANSMITTED I N ANY F O R M OR BY ANY MEANS. ELECTRONIC OR MECHANICAL, INCLUDING PHOTOCOPY, RECORDING, OR ANY INFORMATION STORAGE AND RETRIEVAL SYSTEM, WITHOUT PERMISSION I N WRITING FROM T H E PUBLISHER. ACADEMIC PRESS, INC. 111 Fifth Avenue, New York, New York 10003 United Kingdom Edition published by ACADEMIC PRESS, INC. (LONDON) LTD. 24/28 Oval Road, London N W I LIBRARYOF CONGRESS CATALOG CARD NUMBER: 61-18298 ISBN 0-12-032913-1 PRINTED I N THE UNITED STATES OF AMERICA CONTENTS CONTRIBUTORS TO THIS VOLUME . . . . . . . . . . . . . . . . ix Chemotherapy of Trypanosoma cruzi Infections Z . BRENER I . Introduction . . . . . . . . . . . . . . . . . . . . I1. I11. IV . V. VI . VI . In Yivo Drug Testing . . . . . . . . . . . . . . . . . In Vitro Drug Testing . . . . . . . . . . . . . . . . . Compounds Active Against Trypanosoma cruzi Infections . . . . . Mode of Action . . . . . . . . . . . . . . . . . . . Clinical Trials . . . . . . . . . . . . . . . . . . . Concluding Remarks . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . 2 3 12 15 24 34 39 40 Enzyme Study As a Source of Strategy in Drug Design CORWINHANSCH I . Introduction . . . . . . . . . . . . . . . . . . . . I1. Problem of Drug Modification . . . . . . . . . . . . . 111. Type of Enzyme-Ligand Interactions . . . . . . . . . . . IV . Formulation of Quantitative Structure-Activity Relationships . . . V . Examples of Enzymic Quantitative Structure-Activity Relationships VI . Nature of Receptors . . . . . . . . . . . . . . . . VII . Therapeutic Index Problem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VIII . Conclusion References . . . . . . . . . . . . . . . . . . . . . . . . . . 45 47 48 51 52 75 76 77 78 The Cephalosporin Group of Antibiotics D . R . OWENS.D . K . LUSCOMBE.A . D . RUSSELL.AND P . J . NICHOLLS I . Introduction . . . . . . . . . . . . . . . . . . . . I1. I11. IV . V. VI . Chemical Aspects . . . . . . . . Antibacterial Activity . . . . . . . Pharmacology and Toxicology . . . . Clinical Aspects . . . . . . . . . Hypersensitivity and Allergenicity . . . R