Clinical Pharmacology &Therapeutics
Sponsored by the International Union 0/
Pharmacology and the British Pharmacological Society
President: Sir Arnold Burgen FRS
Chairman: Professor Colin Dollery
Proceedings ofPlenary Lectures
Symposia and Therapeutic Sessions
ofthe First World Conference on
Clinical Pharmacology & Therapeutics
Softcover reprint ofthe hardcover 1st edition 1980 978-0-333-31229-2
All rights reserved. No part ofthis publication may be reproduced or transmitted,
in any form or by any means, without permission
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The Ethical and Scientiüc Basis of Regulation Prof. L. Lasagna, USA 3
Predictive Value of Pre-Clinical Drug Prof. G. Zbinden,
Safety Evaluation Switzerland 9
The Pharmacology and C1inical Potential Dr. S. Moncada &
of Prostacyclin Dr . J. R. Vane , UK 15
Possible Physiological Roles ofthe Prof. H. W. Kosterlitz,
Enkephalins and Endorphins UK 33
Variability in Human Drug Metabolism A. H. Conney,
Gene-Environment Interactions in
Drug Metabolism E. S. Vesell 63
Importance of Purifrcation of Hepatic
Cytochrome P-450 for Studying Drug R. Kato&
Metabolism in Man T. Kamataki 80
Drug Metabolism at Various Ages - Young
Methodological Problems Associated with
Studies of Drug Metabolism in the Elderly
Renal Elimination of Drugs at Various Ages
Responsiveness to Drugs at Extremes of Age
ALTERATIONS IN RECEPTORS DURING
Chairmen: D. Grahame-Smith, UK
The Effects of Digoxin on Red Cell Digitalis
Mechanisms for Regulation of ß-Adrenergic
Receptor Function in Desensitization
Reversal of Pharmacological and Biochemical
Effects of Neuroleptic Drugs on
a-Adrenoceptors and the Clinical
The Effect ofOral Contraceptives on Platelet
Noradrenaline and 5-Hydroxytryptamine
Inotropic Drugs in Clinical Practice
Chairmen: J. F. Mustard, Canada
The Mechanism of Action of Drugs that Modify M. A. Packham &
Platelet and Vessel Wall Function 1. F. Mustard 197
The Effects of Platelet Regulatory Drugs in
Experimental Models ofThrombosis
Atherosclerosis and Myocardial Infarction
The Effectiveness of Drugs that Modify Platelet
Function in Peripheral Venous Thrombosis
Basic Current Evidence for the Use of Drugs
to Both Prevent and Treat Patients with
Venous Thrombosis and Pulmonary
The Value ofDrugs that Modify Platelet
and Vessel Wall Function for the
Clinical Complications of Atherosclerosis G. P. McNicol 242
Chairmen: J. Koch-Weser, France
Individualization of Antihypertensive Treatment 1. Koch-Weser 251
Does the Assay of Catecholamine Levels
Contribute to the Tailoring of W. H. Birkenhäger &
Antihypertensive Treatment? P. W. de Leeuw 256
ß-Adrenoceptor Blocking Drugs and the
Rational Approaches to Clinical Therapy
The Therapeutic and Toxic Effects of
Anti-Inflammatory Drugs Which Interfere
with Arachidonic Acid Metabolism
Clinical Effects and Interactions of the
Non-Steroid Anti-Inflammatory Drugs
Specific Therapy for Rheumatoid Arthritis
Immunological Modificatlon to Treat
Nociceptive Pathways and Transmitters
Analgesia Produced by Stimulation of the
Endorphins and Central Neurotransmitters
Clinical Pharmacological Actions and
Potential Therapeutic Effects of Marihuana
and Related Drugs L. Lemberger 353
Alcohol: The Old Rascal in New Clothes J.ldänpään-Heikkilä 360
Clinical Pharmacology of Benzodiazepine
Relationship of p-Endorphin in Physical
Methadone Maintenance Treatment of
Principles of Percutaneous Absorption H. Schaefer,
Biochemical Pharmacology of the Epidermis E. A. Duell 404
Drug Metabolism in Skin D. Rawlins ,
UV Inflammation and Anti-Inflammatory
Objective Comparison ofthe Response of S. Shuster,
Psoriasis to Treatment with PUVA and M. Rawlins,
Recent Studies on Bleomycin H. Umezawa 427
Regression Analysis of 4'-(9-Acridinylamino)
Methanesulphon-m-Anisidine (m-AMSA) B. F. Cain ,
Analogue Properties Providing High Dose B.C. Baguley
Potency in Leukaemia L1210 Assays W.A.Denny&
Chairmen: A. O. Lucas, Switzerland,
Therapy ofTropical Diseases - Schistosomiasis J. M. Kofl Ekue 445
Therapy ofTropical Diseases - Filariasis K. Awadzi 449
Chairmen: A. Kessler, Switzerland
Dilemmas in Contraceptive Development:
Variation in Endocrine Response to
Controversies in the C1inical Evaluation of
International Trials and Tribulations
The First Clinical Trial ofGossypol on
Comparative Pharmacodynamics and
Pharmacokinetics of Contraceptive
DRUGS FOR DEVELOPING COUNTRIES
Problems of Drug Evaluation in Developing
The World Health Organization Essential
Drug Concept - Three Years Afterwards
Drugs for Developing Countries - The Views
of a Practising Doctor in the Tropics
Drugs for Developing Countries: View of
ETHICS, LIABILITY, COMPENSAnON
M. N. G. Dukes , The Netherlands
Ethical and Legal Problems in Medicinal
Therapeutics M. N. G. Dukes 551
Principles of No-Fault or Strict Liability R. N. Williams 557
A No-Fault or Strict Liability Scheme in Action
Pharmaceuticallndustry B. Berde 572
Chairman ofthe Clinical Pharmacology Section ofIUPHAR .
Departm ent of Clinical Pharmacolo gy ofthe Karolinska Institute,
Huddinge Hospital. 5-14186 Huddinge, Sweden
When the first world congress in pharmacology was held in Stockholm in 1961
clinical pharmacology was barely visible in the scientific programme. The most
recent congresses in San Francisco (1972), Helsinki (1975) and Paris (1978) had
representative sessions in clinical pharmacology ofhigh scientific calibre. Due to the
medicine, paediatrics and psychiatry, a need developed to organize an international
meeting focussing entirely on clinical pharmacology matters . The original suggestion
by Professor Colin Dollery to organize such a meeting was therefore enthusiastically
received by our Section ofClinical Pharmacology and , even more important, by our
colleagues in basic pharmacology in IUPHAR.
The interdisc iplinary nature of clinical pharmacology is both a strength and an
inherent weakness. It is a strength in the sense that our research methodology often
penetrates into several branches ofmedicine. As an example - the controlled clinical
trial may be looked upon as one of the main advances of modern medicine and its
principles are today widely acknowledged in the scientific community. While the
cardiac catheter has remained an important identity tool for the cardiologists few
people today seem to recognize the link between controlled drug evaluation and
clinical pharmacology. Dr Franz Gross (1978) recently expressed this in a
commentary entitled 'The thorny path of clinical pharmacology' - 'despite the fact
that, in continuing education programmes therapeutic topics enjoy wide attention,
Let us carry out abrief retrospective critical analysis of the development (some
pessimists would say lack of development) of our discipline . This should not be
difficult since the past of clinical pharmacology is as short as 20 years, which is only
one half-life ofan average professional career in medicine!
'In the early and mid-sixties, a number ofwell-written articles appeared, mainly in
American and British medical journals that tried to foresee specific areas of research,
teaching and service in clinical pharmacology (Carr, 1963; Crout, 1965; Dollery,
1966; Lasagna, 1962, 1966; Wilson, 1963). It was pointed out that the preoccupation
with problems of diagnosis and pathogenesis had left the scientific study of drug
treatment relatively neglected (Dollery, 1966) and that therefore there was a great
need for drug oriented physicians in medicine. It was particularly underlined that
pharmacology units ought to develop and teach the methodology of controlled drug
evaluation in man in one or several areas (Lasagna, 1966). This point is equally
important today (Breckenridge, 1980).
InitiaIly too much time was spent on debating whether the skills of the clinical
pharmacologists ought to be those of the clinical investigator with a knowledge in
pharmacology or those of a pharmacologist with an interest in clinical medicine. At
the Anglo-Scandinavian symposium on 'Clinical pharmacology and patient care'
held in Newcastle in 1977, British and Scandinavian clinical pharmacologists
representing these two different schools with respect to basic training found that after
several years in the discipline they were doing very similar things and had similar
perspectives regarding the future directions.
'Clinical Pharmacology - Scope, organization, training', areport of a WHO study
group working in December 1969 under the chairmanship of Sir Derrick Dunlop,
might be the single most important publication on clinical pharmacology. Not only
does it contain a simple defmition ofclinical pharmacology as a field 'connected with
the scientific studies ofdrugs in man ' but also outlines the main functions ofa clinical
pharmacologist or rather a clinical pharmacology unit as:
I) to improve patient care by promoting the safer and more effective use of drugs
2) to increase knowledge through research
3) to pass on knowledge through teaching and
4) to provide services such as drug information, drug analysis, monitoring drug usage
and advice on experimental design.
Although clinical pharmacology operates in three distinct places: university
medical centres, the pharmaceutical industry and drug control, I shaIl limit most of
my comments to the problems and chaIlenges of clinical pharmacology as an
academic and health care discipline. WardeIl (1970) has reviewed, in agiobai
perspective, how the different functions listed by the WHO expert group are
implemented in the academic context. Not surprisingly he found that there are few
complete departments or divisions of clinical pharmacology having the broad
doctors to choose a field lacking a defmed career structure. One of the most
important reason s for the continuous growth of clinical pharmacology as an
integrated research , teach ing and health-care discipline in Great Britain and the
Nordic countries may very weIl be the creation of a subspeciality with a defmed
curriculum structure. EquaIly important is national, long-term planning regarding
the need and ava ilability of academic and other posit ions in clinical pharmacology.
The unsatisfactory recruitment to clinical pharmacology is of particular concern at a
time when clinical investigators are becoming an endangered species. Countries
paying attention to this problem have much to learn from the splendid achievements
ofclinical pharmacology in the UK .
While the controIled clinical trial and quantitative drug evaluation particularly in
hypertension were the main contributions of clinical pharmacology to medicine
during the early sixties, advances in human drug metabolism and pharmacokinetics
dominated the research contributions during the late sixties and early seventies.
Much credit for these developments should go to men like James Shannon and
Bernard B. Brodie at NIH who pioneered the development of drug analysis in body
fluids already while working at the Goldwater Hospital. Research on interindividual
Disease-mediated changes in kinetics and drug response were identified . Clinical
pharmacologists came to playa decisive role in research on drug interactions - and
they still do. The concept of individualization of drug therapy was born and as a
consequence rapid progress was seen in drug plasma level monitoring of a variety of
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