Table Of ContentDrugs Affecting Leukotrienes
And Other Eicosanoid
Pathways
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Vo/ume 95-Drugs Affecting Leukotrienes and Other Eicosanoid Pathways
edited by B. Samuelsson, F. Berti, G. C. Folco, alld G. P. Velo
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Series A: Life Sciences
Drugs Affecting Leukotrienes
and Other Eicosanoid
Pathways
Edited by
B. Samuelsson
Karolinska Institute
Stockholm, Sweden
F. Berti
G. C. Folco
University of Milan
Milan, Italy
and
G. P. Velo
University of Verona
Verona, Italy
Plenum Press
New York and London
Published in cooperation with NATO Scientific Affairs Division
Proceedings of a NATO Advanced Study Institute entitled
Drugs Affecting Leukotrienes and Other Eicosanoid Pathways,
held September 9-20, 1984,
at the Ettore Majorana Center, Erice, Sicily, Italy
Library of Congress Cataloging in Publication Data
Main entry under title:
Drugs affecting leukotrienes and other eicosanoid pathways.
(NATO ASI series. Series A, Life sciences; v. 95)
Based on presentations at the International School of Pharmacology on
"Drugs Affecting Leukotrienes ahd Other Eicosanoid Pathways," held in Erice,
Sicily, at the Ettore Majorana Center, Sept. 9-20, 1984.
"Published in cooperation with NATO Scientific Affairs Division."
Includes bibliographies and index.
1. Arachidonic acid-Metabolism-Congresses. 2. Leukotrienes-Metab
olism-Congresses. 3. Arachidic acid-Metabolism-Congresses. I.
Samuelsson, Bengt. 11. North Atlantic Treaty Organization. Scientific Affairs
Division. 111. International School of Pharmacology on "Drugs Affecting
Leukotrienes and Other Eicosanoid Pathways" (1984: Ettore Majorana Center)
IV. Title: Eicosanoid pathways. V. Series. [DNLM: 1. Arachidonic Acid
metabolism-congresses. 2. Drug Therapy-congresses. 3. Eicosanoid Acids
-metabolism-congresses. 4. Leukotrienes B-metabolism-congresses. 5.
SRSA-metabolism-congresses. QU 90 D794 1984]
QP752.A7D78 1985 615.7 85-19217
ISBN 978-1-4684-7843-3 ISBN 978-1-4684-7841-9 (eBook)
00110.1007/978-1-4684-7841-9
© 1985 Plenum Press, New York
Softcover reprint of the hardcover 1st edition 1985
A Division of Plenum Publishing Corporation
233 Spring Street, New York, N.Y. 10013
All rights reserved
No part of this book may be reproduced, stored in a retrieval system, or transmitted;
in any form or by any means, electronic, mechanical, photocopying, microfilming,
recording, or otherwise, without written permission from the Publisher
PREFACE
This volume, the fourth in the series "The Prostagiandin System",
contains most of the presentations at the International School of
Pharmacology on "Drugs Effecting Leukotrienes and other
Eicosanoid pathways" held in Erice, Sicily, at the "Ettore
Majorana Center" on 9-20 September 1984.
The discovery of a new class of biologically active compounds is
always exciting even if at the present time knowledge is
advancing very rapidly; this is particu1arly true for the
eicosanoids. Evidence for a pivotal role of arachidonic acid as a
precursor of mediators and modulators of various cell functions
is now weil established. This broad knowledge has stimulated the
search for drugs capable of interfering with the eicosanoid
system and since the discovery of the mechanism of action of
Aspirin, new drugs have become available in order to act more
specifica11y not only at the level of different enzymes involved
in arachidonic acid conversion but also more selectively at the
receptor si tes where the acti ve metaboli tes are effecti ve. In
addition to this, several stable synthetic derivatives of
endogenous unstable prostanoids mimicking their functions in a
variety of physiopatho19gical processes are also of potential
therapeutic interest.
This volume will certainly help scientists and students wi th
different interests related to those diseases that stern from
arachidonic acid metabolites interactions in hypersensitivity
phenomena and in host defence mechanisms.
We like to take this opportunity to expresse our gratitude to all
the speakers for their important contributions and to NATO
ADVANCED STUDY INSTITUTE for making this Course possible.
B. Samuelsson
F. Berti
G.C. Foleo
G.P. Velo
v
CONTENTS
Introduetion •.•..•...•..••.••....•... '. . . • . . • • . . • . • . • • • . . . . . . 1
B. Samuelsson
Measurement of Thromboxane Produetion in vivo: Metabolie
and Analytieal Aspeets...................................... 5
E. Granström, P. Westlund, M. Kumlin and A. Nordenström
High Pressure Liquid Chromatography_125J-Ria, a Sensitive
and Specifie Prostaglandin Assay............................ 19
T. Mourtis-Andersen, R. Jensen, and J. Dyerberg
Enzyme Immunoassays of Icosanoids Using Acetylcholinesterase 31
P. Pradelles, J. Maelouf, and J. Grassi
Syntheses and Biologieal Effeets of Leukotrienes and Analogs 39
B. Spur, A. Crea and W. Peters
Pharmacologic Modulation of Leukotriene Biosynthesis by
Ineorporation of Alternative Unsaturated Fatty
Acids (20:5 and 22:6)....................................... 55
R.A. Lewis, Tak H. Lee, and K. Frank Austen
Studies with Inhibitors of Leukotriene Biosynthesis with
Special Reference to Piriprost (U-60,257)................... 73
M.K. Bach
Pulmonary and Vascular Effects of Leukotrienes; Involvement
in Asthma and Inflammation.................................. 87
P. Hedqvist and S.E. Dahlen
vii
Modulation of the Release of Leukotrienes and Prostaglandins
and of their Functional Effects in Human and Guinea-Pig Lung
Parenchyma. . • . • . . . • • . • • . . . . . • • • • • • . . . . . . • . . • • . • . . . . • • . • • . . . . 103
G.C. Folco, L. Sautebin, G. Rossoni, T. Vigano,
M.T. Crivellari, G. Galli, F. Berti and M. Mezzetti
Comparative Effects of Leukotrienes in Respiratory Tissue
of Various Species.......................................... 121
M.N. Samhoun, P.J. Piper and N.C. Barnes
The Effects of Low-Dose Aspirin and Selective Inhibitors of
Thromboxane-Synthase on Eicosanoid Production in Man........ 131
C. Patrono, P. Filabozzi and P. Patrignani
Manipulation of Pro- and Antiaggregating Prostaglandins: New
Anti thrombotic Strategies................................... 141
H. Deckmyn, P. Gresele, J. Arnout and J. Vermylen
Flavonoids - Lipoxygenases - Platelet Aggregation........... 149
R.J. Gryglewski, J. Robak and J. Swi~s
Transformation of 15-Hydroperoxyeicosapentaenoic Acid Into
Mono- and Dihydroxyeicosapentaenoic Acids by Human Platelets 167
B. Lam, E. Marcinkiewicz and P.Y-K Wong
Metabolism of Arachidonic Acid by 12- and 15-Lipoxygenases
in Human Platelets and Polymorphonuclear Leukocytes......... 181
P. Y-K Wong, P. Westlund, M. Hamberg, E. Granstrom,
P. H-W Chao and B. Samuelsson
Epoxidation of Arachidonic Acid and Prostacyclin in the
Kidney...................................................... 197
P. Y-K Wong, J.C. McGiff, M. Schwartzman and F.F. Sun
The Effect of 9 a -Fluorohydrocortisone on the Urinary
Excretion of 6-Keto-PGF 1 in Man........ . . . • . . . • • . . . . • . . . . . . 211
P. Minuz, G. Capuzzo, M. Degan, C. Lechi, G. Covi,
G.P. Velco and A. Lechi
Prostacyclin in Therapy of Vascular Disease................. 221
R.J. Gryglewski and A. Szczeklik
viii
LTC4 Induces Hyperreactivity of the Isolated Vascular Tissue
to Histamine, Serotonin and Norepinephrine.................. 239
L. Daffonchio, C. Omini, G. Brunelli, and F. Berti
Evidence for a Thromboxane Antagonist in Selected in vitro
and in vivo Systems......................................... 249
P.E. Malo, M.A. Wasserman, and R.R. Osborn.
Precursor-Product Relationship in Vascular Eicosanoid
Formation after Manipulation of Dietary Fatty Acids in
Experimental Animals........................................ 265
C. Galli, E. Giani and I. Masi
Formation of Leukotrienes and other Eicosanoids in the
Gastrointestinal Tract and Effect of Drugs.................. 277
B.M. Peskar, K.W. Dreyling, K. Schaarschmidt,
H. Goebell
Role of Eicosanoids in the Pathogenesis of Inflammatory
Bowel Diseases.............................................. 295
B.J.R. Whittle, N.K. Boughton-Smith and C.J. Hawkey
Inhibition of 5'Lipoxygenase: Relevance to Inflammation •.... , 311
R.M.J. Palmer and J.A. Salmon
The Role of Glucocorticoid-Induced Phospholipase Inhibitory
Proteins ••. . •• • . . . . . • . .. ••• . . . . . . . .. .. . . • . • . . . • . . . .• . . . . . . . . 331
M. Di Rosa
Formation and Oxidative Degradation of Leukotrienes by
Eosinophils and Neutrophils................................. 339
William R. Henderson
Eicosanoids and Cancer...................................... 351
A. Bennet
Stimulated Human Colonic Synthesis of Arachidonate
Lipoxygenase and Cyclo-Oxygenase Products by Laxatives...... 359
F. Capasso, I.A. Tavares, and A. Bennett
ix
Correlation Between K+ Fluxes and the Arachidonic Acid
Cascade in Human Leukocyte Stimulated with A-23187 or
Melittin.................................................... 363
M. Braquet, M. D'Onofrio, R. Garay, and P. Braquet
Index. • • . • • . • . . • • . • • • • . • . • • . • • . • • • • • . . • • . • . . . • . . • • • . . . . . . . . . 381
x
INTRODUCTION
Bengt Samuelsson
Dept. of Physiological Chemistry
Karolinska Institutet
S-104 01 Stockholm, Sweden
ProstagIandin research has developed rapidly especially during
the past two decades. The elucidation of the chemistry, biosynthe
sis and metabolism of the prostagIandin system as weIl as advances
concerning the biological effects and physiological roles of
prostaglandins and related compounds are important areas in this
development (1). The new knowledge hasformed the basis for under
standing the role of prostaglandins in many pathophysiological
processes and for the therapeutic use of prostaglandins in various
diseases.
After the elucidation of the chemistry of the prostaglandins
and their biosynthesis from polyunsaturated fatty acids, studies
on the mechanism of prostagIandin biosynthesis demonstrated the
existence of unstable endoperoxide intermediates as PGG2 and PGH~.
The finding that the endoperoxides had unique biological effects
indicated that additional biologically active derivatives were
formed from the endoperoxides (2). These considerations formed the
basis for the discovery of thromboxane A2 and subsequently also
prostacyclin (3,4).
The leukotrienes constitute another group of biologically ac
tive derivatives formed from polyunsaturated fatty acids. They
were originally discovered in leukocytes (LTB4), however, studies
on their mechanism of biosynthesis resulted In the recognition of
an unstable intermediate (LTA4). This finding formed the basis for
the elucidation of the chemistry of slow reacting substance of
anaphylaxis (LTC~, LTD4, LTE4) (5). The leukotrienes have potent
biological effects related to inflammation and allergy.
