Table Of ContentDRUGS LOOKING FOR DISEASES
Developments in
Cardiovascular Medicine
VOLUME 120
The titles published in this series are listed at the end of this volume.
DRUGS LOOKING
FOR DISEASES
lnnovative Drug Research and the Development
of the Beta B/ockers and the Calcium Antagonists
by
REINVOS
Department of PharlT1flco!ogy and Pharmacolherapeutics,
University Centre for Pharmacy,
Universiry of Groningen,
Groningen, TIie Netherlonds
SPRINGER SCIENCE+BUSINESS MEDIA, B.V.
Library of Congress Cataloging-in-Publication Data
\/e s. Re i f\, 1955-
D'ugs l()o~ Ing for d 1seases , innova'1ve orug research anO the
develop~ent of the beta blockers and the calcium antagonists ! by
Reln Vos.
p. cm. -- (Develop~ents in card10vascular medicine : v. 120)
Includes bib110graphlcal references.
Inc ludes index.
ISBN 978-94-010-5689-2 ISBN 978-94-011-3796-6 (eBook)
DOI 10.1007/978-94-011-3796-6
1. Drugs~-Research. 2. Drugs--Des1gn. 3. Adrenerglc beta
blockers--ResearCh--History. 4. Calcium--Antagonists--Research-
-History. 1. 1i.le. II. Series.
[DNLM: 1. Adrenergic Beta Receptor Blockaders--history.
2. C~l:~u~ Ch3~nt~ e~o~k2~S' -1~;3ior~. 3, Drug TMerapy. q. Urugs.
5. Heart Dlsease--history. 6. Research. 7. Soclology, MedIcal.
Hl DE997VME v. 120 ! av 20.5 V959dl
RM301.25.V67 1991
615' . 19--oc20
DNLMrDLC
for Llbrary of Congress 90-5359
ISBN 978-94-010-5689-2
Printed on acid-free paper
AU Rights Reserved
©1991 Springer Science+Business Media Dordrecht
Originally published by Kluwer Academic Publishers in 1991
Softcover reprint of tbe bardcover lst edition 1991
No part of the material protected by this copyright notice may be reproduced or
utilized in any form or by any means, electronic or mechanical,
including photocopying, recording or by any information storage and
retrieval system, without written permission from the copyright owner.
FOREWORD
We all know how much time, effort and money it takes to develop a new drug. Hundreds of chemical
compounds have to be synthesized and thousands of different activities in biology, physiology,
pharmacology, clinical investigation, management and marketing have to be initiated and coordinated.
Each new drug starts a voyage of discovery through an unmapped terrain which is shrouded in mist
and beset by pitfalls, as Dr. Rein Vos puts it in his absorbing inside story of the development of the
beta-adrenoceptor blocking agents and the calcium antagonists.
Indeed we know, for example, how long it took before the theory of Ahlquist of the alpha and beta
adrenergic receptors was widely accepted. Similarly, it suffices to memorize shortly the difficulty of
expanding the new concept of calcium antagonism through the national German boundaries into the
world. This shows how laborious and complex pharmaceutical progress is, and we all will benefit from
a deeper understanding of the process of innovative drug research.
Dr. Vos provides an absorbing account of the origin of the pharmacodynamic concepts of beta
blockade and calcium antagonism, and of the further development of these concepts as a new
therapeutic rationale in cardiovascular medicine. The book is extremely interesting since it depicts the
dominant trends in Anglo-American and German coronary therapy and the underlying theoretical
concepts. I have never seen such a thorough study of cultural differences of medical thinking and their
relevancy for progress in cardiovascular medicine. In this respect it is also really surprising how
diligently my own work on calcium antagonism has been investigated in every detail. Such a
scrutinizing study has never been made before, and I am sure that the colleagues in the various fields of
cardiovascular and pharmaceutical research will have the same experience with respect to the subjects
of their own expertise which are described in this book. Further, Dr. Vos' treatise of the interactions
between industrial laboratory work, academic research and clinical investigation sheds light on the way
of thinking by medicinal chemists, pharmacologists and physiologists, and clinical investigators and
clinicians.
However, the most important prospect, as outlined in the book, seem to arise from the author's view
point that the drug discovery process can be studied and modeled. Throughout the book the view is
developed that medical-pharmaceutical practice is an indispensable source of feedback to the discovery
process. In this way Dr. Vos counteracts current views of drug research, yet simultaneously provides us
with a new perspective on the shaping of new medicines.
Prof. Dr. A. Fleckenstein
Freiburg, West Gennany
November 1990
CONTENTS
Preface xiii
Acknowledgments xv
List of interviewed participants xix
Introduction xxiii
Chapter 1. The controlled clinical trial - a model for the
intricate relationships between clinical medicine
and drug research
1.1. Introduction 1
1.2. The evolution of the controlled clinical trial (CCT) 2
1.3 The implementation of the controlled clinical trial in
drug research 6
1.4. Criticism of the classical view of the controlled clinical trial 12
1.5. Conclusions 18
Chapter 2. The architecture of drug discovery
2.1. Introduction 21
Part 1. The discovery process
2.2. Current views of drug discovery 21
2.2.1. Basic concepts in drug discovery 21
2.2.2. Basic epistemologies in drug discovery 24
2.3. Scientific discovery from the viewpoint of cognitive science 29
2.4. The drug discovery process revisited 33
Part 2. The representation of knowledge about drugs and diseases
2.5. An epistemological analysis of the concept of drug and
disease profiles 35
2.5.1. Introduction 35
2.5.2. The concept of drug profile 35
2.5.2.1. The classification of drugs 35
2.5.2.2. Incursion of drug profiles into disease profiles 39
2.5.2.3. The nature of drug characteristics 40
CONTENTS
viii
2.5.3. The concept of disease profile 44
2.5.3.1. Disease profiles as pigeon holes of medical knowledge 44
2.5.3.2. The fundamental basis of taxonomy in medicine 46
2.5.3.3. Convergent and divergent forces in clinical taxonomy 47
2.5.3.4. The translation of everyday medical language into the 49
structure of profiles
2.5.4. Conclusions 51
Part 3. A set-theoretical model of drug discovery
2.6. A definition of the concept of profile in terms of set
theory 52
2.6.1. Introduction 52
2.6.2. The first aspect of a profile: membership 52
2.6.3. The second aspect of the concept of profile: values of
the disease characteristics 55
2.6.4. The third aspect of the concept of profile: ranking
order of characteristics 60
2.6.5. Conclusions 61
2.7. The drug discovery process -a set-theoretical model 61
2.7.1. Introduction 61
2.7.2. A naive definition 62
2.7.3. First adjustment of the naive defenition: structural and
functional characteristics of drugs 63
2.7.4. Second adjustment of the naive defenition:
disease characteristics 67
2.7.5. The improvement of toxic effects of drugs:
positive and negative aspects and their judgment 69
2.7.6. Conclusions 70
Chapter 3.Experimental and therapeutic profiling in drug innovation:
the early history of the beta blockers
3.1. Introduction 71
3.2. Historical overview of the development of the beta blockers 71
3.3. From Dale to Ahlquist: a new methodology in pharmacology 72
3.4. Change in the concepts of agonist and antagonist 74'
3.5. Experimental and therapeutic profiling in drug innovation 76
3.5.1. Cardiac arrhythmias 76
3.5.2. Angina pectoris 77
3.6. Conclusions 78
CONTENTS ix
Chapter 4. Industrial research and beta blockade
4.1. Introduction 81
4.2. Beta blocker research at Imperial Chemical Industries (ICI) 81
4.2.1. The early phase 81
4.2.2. The birth of pronethalol 84
4.2.3. The demise of pronethalol 85
4.2.4. The development of propranolol 87
4.2.4.1. A "clean" drug 87
4.2.4.2. The rapid expansion of a successful drug 90
4.2.4.3. Endangered drug 91
4.2.5. The development of practolol 94
4.2.5.1. Practolol: a tool in industrial research 94
4.2.5.2. Selectivity in industrial and academic research 95
4.2.5.3. The therapeutic interest 102
4.3. The beta blocker project of Eli Lilly & Co. 104
4.4. The beta blocker project of Mead Johnson 105
4.5. The beta blocker project of AB Hassle 107
4.5.1. The early phase 107
4.5.2. Intrinsic sympathomimetic activity of alprenolol 110
4.5.3. The profiling of alprenolol 112
4.5.4. Selective beta blockade 115
4.6. The beta blocker project at CIBA 117
4.7. Conclusions 119
Chapter 5. Verapamil: dying drug or sleeping beauty?
5.1 Introduction 123
5.2 The early history of verapamil 124
5.3 Verapamil: a coronary vasodilator? 124
5.4 Verapamil: a beta blocker? 126
5.5. Verapamil: a calcium antagonist! -The elucidation of
verapamil's mechanism of action by Fleckenstein 129
5.6. Citation analysis of the concept of calcium antagonism
elaborated by Fleckenstein 136
5.7. The application of the theory of drug and disease profiles 142
5.7.1. Changing views on the basic action of verapamil 142
5.7.2. The cardio-depressive effects of verapamil. 150
5.8. Conclusions 154
x CONTENTS
Chapter 6. Metamorphosis of a disease -Profiles of angina pectoris
in Anglo-American medicine
6.1. Introduction 157
6.2. Anglo-American medical views of angina pectoris 157
6.3. Disease profiles of angina pectoris in Anglo-American
medicine: cognitive dimensions. 170
6.4. Disease profiles of angina pectoris in Anglo-American
medicine: social dimensions 174
6.5. Anti-anginal drugs in the light of changing views of
angina pectoris 180
6.6. Conclusions 182
Chapter 7. Targeting in drug research and the medical scene
The beta blocker project at Boehringer against the background of
different views in German and Anglo-American medicine
7.1 Introduction 185
Part 1. The medical scene - different views in German and Anglo-American
medicine
7.2.1 The coronary vasodilator concept 186
7.2.1.1. Introduction 186
7.2.1.2. The early history of the coronary vasodilator concept 186
7.2.1.3. The rise and decline of the coronary vasodilator concept
in Anglo-American medicine 188
7.2.1.4. The coronary vasodilator concept -a firmly rooted
principle in German medicine 189
7.2.1.5 Bibliometrical analysis ~ 93
7.2.1.6 Conclusions 196
7.2.2. Medical views about heart failure 196
7.2.2.1. Introduction 196
7.2.2.2 Anglo-American medical views about congestive heart
failure: Starling's Law of the Heart. 196
7.2.2.3. German medical views about heart failure: The master
of the circulation? 199
7.2.2.4. Three clinical profiles of heart failure 202
7.2.2.5. Disease profiles of heart failure in Anglo-American and
German medicine 204
7.2.2.6. Conclusions 206
xi
CONTENTS
7.2.3. Angina pectoris and coronary insufficiency in German
medicine 207
7.2.3.1. Introduction 207
7.2.3.2. Coronary insufficiency 207
7.2.3.3. Organic and functional factors in German clinical
taxonomy 210
Part 2. The influence of medical perceptions on targeting in drug research
7.3. The beta blocker project at Boehringer Ingelheim 215
Part 3. Application of the theory of drug and disease profile
7.4. Theoretical analysis of the Boehringer project against
the background of medical views about angina pectoris
and heart failure 227
7.5. Conclusions 236
Chapter 8.Search processes, profiles and therapeutic practice in drug discovery
8.1. Introduction 239
8.2. The search process in drug discovery 239
8.3. Evaluation of the theory of drug discovery 244
8.3 .1. Introduction 244
8.3.2. The epistemological status of the concept of profile 245
8.3.3. Is the discovery process explicable in terms of profiles
and rules? 248
8.4. Practice - the contribution to drug discovery 250
8.4.1. Introduction 250
8.4.2. The conflict between controlled clinical trial and casual
experience in therapeutics 250
8.4.2.1. Toulmin's epistemological map of medicine 250
8.4.2.2. Application ofToulmin's map on the conflict between
controlled clinical trial and casual experience in medicine 252
8.4.2.3. Pragmatic attitude towards the controlled clinical trial 254
8.4.2.4. Dissection of the strong interpretation of the normative
claim about the CCT 255
8.4.3. Therapeutic treatment based on the individual patient 257
8.4.4. Accumulated experience and therapeutic intervention 259
8.4.5. Further explication of practice as a source of new
knowledge 261
8.5. Conclusions 265
