Table Of ContentMEDICINAL CHEMISTRY
A Series of Monographs
EDITED BY
GEORGE DESTEVENS
C1BA Pharmaceutical Company, A Division of CIBA Corporation
Summit, New Jersey
Volume 1. GEORGE DESTEVENS. Diuretics: Chemistry and Pharmacology. 1963
Volume 2. RUDOLFO PAOLETTI (ED.). Lipid Pharmacology. 1964
Volume 3. E. J. ARIENS (ED.) . Molecular Pharmacology: The Mode of Action
of Biologically Active Compounds. (In two volumes.) 1964
Volume 4. MAXWELL GORDON (ED.). Psychopharmacological Agents. Volume
I. 1964. Volume II. 1967. Volume III. 1974.
Volume 5. GEORGE DESTEVENS (ED.). Analgetics. 1965
Volume 6· ROLAND H. THORP AND LEONARD B. COBBIN. Cardiac Stimulant
Substances. 1967
Volume 7. EMIL SCHLITTLER (ED.). Antihypertensive Agents. 1967
Volume 8. U. S. VON EULER AND RUNE ELIASSON. Prostaglandins. 1967
Volume 9. G. D. CAMPBELL (ED.). Oral Hypoglycaemic Agents: Pharma-
cology and Therapeutics. 1969
Volume 10. LEMONT B. KIER. Molecular Orbital Theory in Drug Research.
1971
Volume 11. E. J. ARIENS (ED.). Drug Design. Volumes I and II. 1971. Vol-
ume III. 1972. Volume IV. 1973
Volume 12. PAUL E. THOMPSON AND LESLIE M. WERBEL. Antimalarial
Agents: Chemistry and Pharmacology. 1972
Volume 13. ROBERT A. SCHERRER AND MICHAEL W. WHITEHOUSE (Eds.).
Antiinflammatory Agents: Chemistry and Pharmacology. (In two vol-
umes.) 1974
ANTIINFLAMMATORY
AGENTS
Chemistry and Pharmacology
VOLUME I
Edited by
ROBERT A. SCHERRER
RIKER LABORATORIES, INC.
3M CENTER
ST. PAUL, MINNESOTA
MICHAEL W. WHITEHOUSE
DEPARTMENT OF EXPERIMENTAL PATHOLOGY
THE JOHN CURTIN SCHOOL OF MEDICAL RESEARCH
THE AUSTRALIAN NATIONAL UNIVERSITY
CANBERRA A.C.T., AUSTRALIA
ACADEMIC PRESS New York San Francisco London 1974
A Subsidiary of Harcourt Brace Jovanovich, Publishers
COPYRIGHT © 1974, BY ACADEMIC PRESS, INC.
ALL RIGHTS RESERVED.
NO PART OF THIS PUBLICATION MAY BE REPRODUCED OR
TRANSMITTED IN ANY FORM OR BY ANY MEANS, ELECTRONIC
OR MECHANICAL, INCLUDING PHOTOCOPY, RECORDING, OR ANY
INFORMATION STORAGE AND RETRIEVAL SYSTEM, WITHOUT
PERMISSION IN WRITING FROM THE PUBLISHER.
ACADEMIC PRESS, INC.
Ill Fifth Avenue, New York, New York 10003
United Kingdom Edition published by
ACADEMIC PRESS, INC. (LONDON) LTD.
24/28 Oval Road, London NW1
Library of Congress Cataloging in Publication Data
Scherrer, Robert Allan, Date
Antiinflammatory agents.
(Medicinal chemistry; a series of monographs, )
Includes bibliographies.
1. Antiphlogistics. I. Whitehouse, Michael W.,
joint author. II. Title. III. Series.
[DNLM: 1. Antiinflammatory agents. W1ME64/QV55
A629]
RM121.S37 615'.7 73-9447
ISBN 0-12-623901-0 (v.l)
PRINTED IN THE UNITED STATES OF AMERICA
To all those investigators who paved the way for our present under-
standing of inflammation and its regulation, and to our wives, secre-
taries, and others without whose loyal support these chapters would not
have been written
List of Contributors
Numbers in parentheses indicate the pages on which the authors' contributions begin.
MICHAEL J. DIMARTINO (209), Smith Kline & French Laboratories, Phila-
delphia, Pennsylvania
J. D. FISHER (363), Biochemistry Research Department, Armour Phar-
maceutical Co., Kankakee, Illinois
THOMAS J. FITZGERALD* (295), Department of Pharmacology, University
of Kansas Medical Center, Kansas City, Kansas
PETER F. JUBY (91), Bristol Laboratories, Division of Bristol-Myers Com-
pany, Syracuse, New York
JOSEPH G. LOMBARDINO (129), Pfizer Central Research, Pfizer, Inc., Gro-
ton, Connecticut
GEORGE G. I. MOORE (159), Riker Laboratories, Inc., 3M Center, St. Paul,
Minnesota
HAROLD E. PAULUS (3), Department of Medicine, University of California
School of Medicine, Los Angeles, California
THOMAS L. POPPER (245), Schering Corporation, Bloomfield, New Jersey
ROBERT A. SCHERRER (29, 45), Riker Laboratories, Inc., 3M Center, St.
Paul, Minnesota
T. Y. SHEN (179), Merck Sharp & Dohme Research Laboratories, Rahway,
New Jersey
* Present address: School of Pharmacy, Florida Agricultural and Mechanical Univer-
sity, Tallahassee, Florida.
XI
xii LIST OF CONTRIBUTORS
BLAINE M. SUTTON (209), Smith Kline & French Laboratories, Philadel-
phia, Pennsylvania
DONALD T. WALZ (209), Smith Kline & French Laboratories, Philadelphia,
Pennsylvania
ARTHUR S. WATNICK (245), Schering Corporation, Bloomfield, New Jersey
Preface
Callimachus, the Alexandrian poet, once wrote: "A big book is a big
evil." On the whole, we must agree with this view. This two-volume work is
therefore a compromise between trying to lessen this evil while still doing
justice, with an adequate review, to the tremendous outlay of effort and inge-
nuity expended by physicians, chemists, and experimental biologists through
the years in seeking new drugs to treat arthritis and other severely debilitat-
ing chronic inflammatory diseases.
This treatise is a review of the current status of antiinflammatory research
from the laboratory to the clinic. It is directed toward the student and inves-
tigator concerned with the design of new and better agents and with their
critical evaluation in the laboratory and in man. Emphasis is given to factors
which could lead to new and better agents.
One of the advantages of having a multiauthored volume is to introduce
a variety of viewpoints. Authors have been encouraged to express their
personal opinions. Inevitably there is a certain amount of duplication and
even contradiction among some of the individual contributions. Some of the
reviews are the first generally available in English. We hope they may pro-
vide a suitable foundation and appropriate stimulus for the preparation of
more evenly balanced, second generation surveys at some time in the future.
Certainly this present offering owes much to its antecedents, the reviews and
literature surveys which have accumulated over the past twenty years. A
list of some of the more recent reviews can be found following the Introduc-
tion for the benefit of those who wish to read the earlier literature not detailed
in the succeeding chapters.
The work is divided into three parts, presented in two volumes. The first
part, comprising one chapter only, discusses the medical background and
describes the current therapy for the more prominent inflammatory diseases.
The chemistry of diverse types of compounds with antiinflammatory activity
Xlll
XIV PREFACE
is then surveyed in the remaining chapters of Volume I, comprising the
second part. The last four of these chapters deal with gold compounds, cor-
ticosteroids, colchicine, allopurinol, and some natural antiinflammatory
agents, including their special pharmacology as well as chemistry. The more
general biological properties of antiinflammatory (and immunosuppressive)
agents are then discussed in the third part which comprises the second vol-
ume. Two of the chapters are devoted to the clinical assessment of these
agents in man and the concluding chapter to some aspects of metabolism
related to the design and evaluation of antiinflammatory drugs.
Regrettably, it has not been feasible to include any systematic discussion
of topical antiinflammatory agents other than the steroids. The inadequacy
of current assays has necessarily obscured the possible utility of such agents
as dimethyl sulfoxide or glycyrrhetic acid derivatives, to mention but two
types of locally active agents, as "leads" in developing new drugs to treat
rather localized inflammatory states. Several topics have inevitably received
less attention than they deserve. To those investigators whose work has been
undervalued or, worse still, ignored, we offer our regrets and apologies.
Whatever merits this treatise possesses lie with the contributing authors,
each of whom found time amidst a full and active schedule to share his in-
sights and enthusiasm with us and cheerfully accepted the thankless burden
of authorship. For its shortcomings, only the editors are responsible.
We would like to acknowledge our gratitude to Riker Laboratories, Inc.,
for assisting us in many ways, to Rosemary Baatz for preparing the Subject
Index, and to the staff of Academic Press for their patience, encouragement,
and ready assistance in translating this book from a nebulous concept into
concrete reality.
While this work was in preparation we were saddened to hear of the death
of C. V. (Steve) Winder (1909-1972) who contributed greatly to our pres-
ent understanding of the pharmacological control of inflammation. Through
his life and his work he was an inspiration to many who knew him.
ROBERT A. SCHERRER
MICHAEL W. WHITEHOUSE
Contents of Volume n
Biological Properties and Clinical Evaluation
1. Introduction and Background to the Regulation
of Inflammation and the Immune Response
Michael W. Whitehouse
2. Evaluation for Antiinflammatory Activity
Karl F. Swingle
3. Evaluation for Immunosuppressive and
Antiallergic Activity
Marvin E. Rosenthale
4. Assessment of the Toxicity of Antiinflammatory Drugs
Louis Levy
5. Evaluation for Clinical Efficacy
Harold E. Paulus
6. Drug Kinetic Studies with Nonsteroidal Antiinflammatory Agents in
Animals and Man
Edward H. Wiseman
7. Inhibition of Blood Platelet Function
Richard /. Haslam
8. Molecular and Cellular Pharmacology of the Antiinflammatory Drugs:
Some in Vitro Properties Related to Their Possible Modes of Action
Martin Hichens
xv
XVI CONTENTS OF VOLUME II
9. Some Effects of Antiinflammatory Drugs on Connective Tissue
Metabolism
Karel Trnavsky
10. Metabolism of Selected Antiinflammatory Compounds
R. E. Ober
Author Index—Subject Index
