New Targets in Inflammation: Inhibitors of COX-2 or Adhesion Molecules Proceedings of a conference held on April 15–16, 1996, in New Orleans, USA, supported by an educational grant from Boehringer Ingelheim

154 Pages·1996·4.62 MB·English

by  J. R. Vane

New Targets
in Inflammation
Inhibitors of COX-2 or
Adhesion Molecules
The publishers are grateful to
Dr Michelle Browner,
Roche Bioscience, Palo Alto, California,
for the schematic diagram of the
human COX-2 dimer shown on the cover
New Targets in
In8ammation
Inhibitors of COX-2 or
Adhesion Molecules
Edited by
DR NICOLAS BAZAN*, DR JACK BOTTING and SIR JOHN VANE
The William Harvey Research Institute, Saint Bartholomew's Hospital
Medical College, London, United Kingdom
*Neuroscience Center, Louisiana State University, New Orleans, USA
Proceedings of a conference held on April 15 -16, 1996,
in New Orleans, USA, supported by an educational grant from
Boehringer ""
11111111
Ingelheim 80EHRINGfR
INGE~HEIM
SPRINGER-SCIENCE+BUSINESS MEDIA, B.V. WILLIAM HARVEY
PRESS
A catalogue record for this book is available from the British Library
ISBN 978-94-010-6265-7 ISBN 978-94-011-5386-7 (eBook)
DOI 10.1007/978-94-011-5386-7
Copyright
© 1996 by Springer Science+Business Media Dordrecht
Originally published by Kluwer Academic Publishers in 1996
Softcover reprint ofthe hardcover 1s t edition
Ali rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or
transmitted in any form or by any means, electronic, mechanical, photocopying, recording or
otherwise, without prior permission from the publishers,
Springer-Science+Business Media, B.Y.
Typeset by Lasertext Ltd, Stretford, Manchester.
Contents
List of contributors Vll
Preface ix
1 The history of anti-inflammatory drugs and their mechanism of action
l. R. Vane and R. M. Botting
2 Structure of prostaglandin H2 synthase-l (COX-I) and its NSAID
binding sites
p. l. Loll 13
3 Differential inhibition of cyclooxygenases 1 and 2 by NSAIDs
M. Pairet, L. Churchill and G. Engelhardt 23
4 Blockade of inflammatory hyperalgesia and cyclooxygenase-2
S. H. Ferreira 39
5 Brain COX-2 in experimental models of epilepsy and stroke:
signalling pathways leading to enhanced expression
N. G. Bazan, V. M. Marcheselli, G. Allan, K. Van Meter and
l. P. Moises 47
6 New highly selective cyclooxygenase-2 inhibitors
A. W. Ford-Hutchinson 55
7 Characteristics of cyclooxygenase-l and cyclooxygenase-2-deficient
mice
S. G. Morham and R. Langenbach 63
8 X-ray crystal structure of human cyclooxygenase-2
M. Browner 71
9 Risk of gastrointestinal side effects caused by non-steroid
anti-inflammatory drugs (NSAIDs)
H. lick 75
10 Expression and regulation of cyclooxygenase-2 in synovial
tissues of arthritic patients
L. l. Crofford 83
v
vi NEW TARGETS IN INFLAMMATION
11 Differential target tissue presentation and COX-I/COX-2 inhibition
by non-steroid anti-inflammatory drugs: a rationale for a new
classification
H. Fenner 93
12 Clinical experience with meloxicam, a selective COX-2 inhibitor
W Bolten 105
13 Enzymatic regulation of the prostaglandin response in a human
model of inflammation
B. F. Adam and G. A. Fitzgerald 117
14 Cyclooxygenase-2 and intestinal cancer
R. N. DuBois, A. Radhika, 1. Shao, M. Tsujii, H. Sheng,
O. Kobyashi, R. D. Beauchamp and C. S. Williams 123
15 Cytokines and adhesion molecules in the lung inflammatory response
P. A. Ward 131
16 Adhesion molecules as targets for therapy in rheumatoid arthritis
P. E. Lipsky, A. F. Kavanaugh, H. Schulze-Koops and L. S. Davis 139
Index 145
List of Contributors
N. G. Bazan
LSU Neuroscience Center, Louisiana State University Medical Center, School of
Medicine, New Orleans, LA 70112, USA
Co-authors: V. M. Marcheselli, G. Allan, K. van Meter and J. P. Moises
W. Bolten
Rheumaklinik Wiesbaden II, Leibnizstrasse 23, 65191 Wiesbaden, Germany
M. Browner
Molecular Structure Department, Roche Bioscience, 3401 Hillview Avenue,
Palo Alto, CA 94303, USA
L. J. Crofford
Department of Internal Medicine, University of Michigan, 200 Zina Pitcher Place,
Ann Arbor, MI 48109-0531, USA
R. N.DuBois
Department of Medicine, Vanderbilt University Medical Center, Nashville,
TN 37232-2279, USA
Co-authors: A. Radhika, J. Shao, M. Tsujii, H. Sheng, O. Kobyashi,
R. D. Beauchamp and C. S. Williams
H. Fenner
Swiss Federal Institute of Technology, Zurich, Switzerland
S. H. Ferreira
Departamento de Farmacologia, Faculdade de Medicina de Ribeirao Pre to, USP,
CEP 14.049-900, Ribeirao Preto, Sao Paulo, Brazil
A. W. Ford-Hutchinson
Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway,
Kirkland, Quebec H9H 3L1, Canada
G. A. Fitzgerald
The Center for Experimental Therapeutics, The University of Pennsylvania,
905 Stellar Chance Laboratories, 422 Curie Boulevard, Philadelphia, PA 19104, USA
Co-author: B. F. McAdam
vii
viii NEW TARGETS IN INFLAMMATION
H. Jick
Boston Collaborative Drug Surveillance Program, Boston University Medical
Center, 11 Muzzey Street, Lexington, MA 02173, USA
P. E. Lipsky
Harold C. Simmons Arthritis Research Center, University of Texas Southwestern
Medical School, 5323 Harry Hines Boulevard, Dallas, TX 75235-8884, USA
Co-authors: A. F. Kavanaugh, H. Schulze-Koops and L. S. Davis
P. J. Loll
Department of Pharmacology, University of Pennsylvania School of Medicine, 3620
Hamilton Walk, Philadelphia, PA 19104-6084, USA
S.Morham
Department of Pathology, University of North Carolina at Chapel Hill,
NC 27599-7525, USA
Co-author: R. Langenbach
M. Pairet
Department of Biological Research, Boehringer Ingelheim Research Laboratories,
Birkendorfer Strasse 65, 88397 Biberach an der Riss, Germany
Co-authors: L. Churchill and G. Engelhardt
J.R. Vane
The William Harvey Research Institute, St Bartholomew's Hospital Medical
College, Charterhouse Square, London ECIM 6BQ, UK
Co-author: R. M. Botting
P.A. Ward
Department of Pathology, University of Michigan Medical School,
1301 Catherine Road, Ann Arbor, MI 48109-0602, USA
Preface
For the past 100 years the mainstay of therapy for rheumatoid arthritis (RA) has been
aspirin or other drugs of the non-steroid anti-inflammatory group. In 1971 Vane pro
posed that both the beneficial and toxic actions of these drugs was through inhibition
of prostaglandin synthesis. The recent discovery that prostaglandins responsible for
pain and other symptoms at inflammatory foci are synthesized by an inducible
cyclooxygenase (COX-2) that is encoded by a gene distinct from that of the consti
tutive enzyme (COX-I) provided a new target for therapy of RA. A drug that would
selectively inhibit COX-2 would hopefully produce the symptomatic benefit provided
by existing NSAIDs without the gastrointestinal and renal toxicity due to the
inhibition of COX-I. Drugs selective for COX-2 are now available. Experimental
studies have shown them to be effective with minimal toxicity, and in clinical trials
gastric and renal toxicities are less. Highly selective COX-2 inhibitors, perhaps
designed with knowledge of the crystal structures of COX-I and COX-2, are also
available. Other experimental studies, including those in animals lacking effective
genes for COX-lor COX-2 and in experimental carcinomas, suggest there is still
much to be learned of the pathophysiological functions of these enzymes.
The inflammatory response is a complex reaction involving many mediators that
derive from white blood cells, endothelial cells and other tissues. Preliminary data
have revealed that inhibitors of the cytokines and adhesion molecules that play a
crucial role in the migration of white cells to inflammatory sites may be useful in RA.
These various issues are reviewed by experts who have contributed the following
chapters. Clearly such work will provide the basis for greatly improved treatments or
even cures for inflammatory disease.
Nicolas G. Bazan
Jack H. Botting
JohnR. Vane
ix
1
The history of anti-inflammatory
drugs and their mechanism of
action
J. R. VANE and R. M. BOTTING
The history of the anti-inflammatory drugs begins with the early use of decoctions or
preparations of plants containing salicylate. Salicylic acid and salicylates are
constituents of several plants long used as medicaments. About 3500 years ago the
Egyptian Ebers papyrus recommended the application of a decoction of the dried
leaves of myrtle to the abdomen and back to expel rheumatic pains from the womb.
A thousand years later Hippocrates recommended the juices of the poplar tree for
treating eye diseases and those of willow bark to relieve the pain of childbirth and to
reduce fever. All of these medicinal remedies contain salicylates.
In AD 30 Celsus described the four classic signs of inflammation (rubor, calor, dolor
and tumor; or redness, heat, pain and swelling) and used extracts of willow leaves to
relieve them. Throughout the Roman times of Pliny the Elder, Dioscorides and Galen
the use of salicylate-containing plants was further developed and willow bark was
recommended for mild to moderate pain. In China and other parts of Asia also,
salicylate-containing plants were being applied therapeutically. The curative effects
of Salix and Spir(£a species were also known to the early inhabitants of North
America and South Africa.
Through the Middle Ages further uses for salicylates were found, such as plasters
to treat wounds and various other external and internal applications, including the
treatment of menstrual pain and discomfort of dysentery. However, willows were
needed for basket making so the women herbalists of those days turned to other
related plants: they grew meadowsweet (Spir(£a ulmaria) in their herb gardens and
made decoctions from the flowers.
The first 'clinical trial' of willow bark to be published in England was made by a
country parson, the Reverend Edward Stone of Chipping Norton in Oxfordshirel. On
June 2, 1763, Edward Stone presented a report to the Royal Society on the use of
willow bark in fever. He had accidentally tasted it and was surprised by its extraordinary
bitterness, which reminded him of the taste of cinchona bark (containing quinine),
then being used to treat malaria. He believed in the 'doctrine of signatures' which
dictated that the cures for diseases would be found in the same locations where the
malady occurs. Since the "willow delights in a moist and wet soil, where agues
chiefly abound", he gathered a pound of willow bark, dried it over a baker's oven for
three months then ground it to a powder. His greatest success was with doses of I
dram (1.8g), which he reported using in about 50 patients with safety and success. He
concluded his paper by saying "I have no other motives for publishing this valuable