Table Of ContentSkin Pharmacology
and Toxicology
Recent Advances
NATO ASI Series
Advanced Science Institutes Series
A series presenting the results of activities sponsored by the NA TO Science Committee,
which aims at the dissemination of advanced scientific and technological knowledge,
with a view to strengthening links between scientific communities.
The series is published by an international board of publishers in conjunction with the
NATO Scientific Affairs Division
A Life Sciences Plenum Publishing Corporation
B Physics New York and London
C Mathematical Kluwer Academic Publishers
and Physical Sciences Dordrecht, Boston, and London
o
Behavioral and Social Sciences
E Applied Sciences
F Computer and Systems Sciences Springer-Verlag
G Ecological Sciences Berlin, Heidelberg, New York, London,
H Cell Biology Paris, and Tokyo
Recent Volumes in this Series
Volume 175-Vascular Endothelium: Receptors and Transduction Mechanisms
S.
edited by John D. Catravas, C. Norman Gillis, and Una Ryan
Volume 176-Processing of Sensory Information in the
Superficial Dorsal Horn of the Spinal Cord
edited by F. Cervero, G. J. Bennett, and P. M. Headley
Volume 177-Prostanoids and Drugs
edited by B. Samuelsson, F. Berti, G. C. Folco,
and G. P. Velo
Volume 178-The Enzyme Catalysis Process: Energetics, Mechanism,
and Dynamics
edited by Alan Cooper, Julien L. Houben, and Lisa C. Chien
Volume 179-lmmunological Adjuvants and Vaccines
edited by Gregory Gregoriadis, Anthony C. Allison,
and George Poste
Volume 180-European Neogene Mammal Chronology
edited by Everett H. Lindsay, Volker Fahlbusch,
and Pierre Mein
Volume 181-Skin Pharmacology and Toxicology: Recent Advances
edited by Corrado L. Galli, Christopher N. Hensby,
and Marina Marinovich
Series A: Life Sciences
Skin
Pharm~cology
and Toxicology
Recent Advances
Edited by
Corrado L. Galli
University of Milan
Milan, Italy
Christopher N. Hensby
Centre International de Recherche Dermatologique (C.I.R.D.)
Val bonne, France
and
Marina Marinovich
University of Milan
Milan, Italy
Plenum Press
New York and London
Published in cooperation with NATO Scientific Affairs Division
Proceedings of a NATO Advanced Study Institute on
Recent Advances in Skin Pharmacology and Toxicology,
held April 9-19, 1989,
in Riva del Garda, Italy
Library of Congress Cataloging in Publication Data
NATO Advanced Study Institute on Recent Advances in Skin Pharmacology and
Toxicology (1989: Riva, Italy)
Skin pharmacology and toxicology: recent advances I edited by Corrado L.
Galli, Christopher N. Hensby, and Marina Marinovich.
p. cm.-(NATO ASI series. Series A, Life sciences; v. 181)
"Proceedings of a NATO Advanced Study Institute on Recent Advances in Skin
Pharmacology and Toxicology, held April 9-19, 1989, in Riva del Garda, Italy"
T.p. verso.
"Published in cooperation with NATO Scientific Affairs Division."
Includes bibliographical references.
ISBN-13: 978-1-4684-7904-1 e-ISBN-13: 978-1-4684-7902-7
DOl: 10.1007/978-1-4684-7902-7
1. Dermatopharmacology-Congresses. 2. Dermatotoxicology-Congresses. I.
Galli, C. L. (Corrado L.) II. Hensby, C. N. (Christopher N.) III. Marinovich, Marina.
IV. North Atlantic Treaty Organization. Scientific Affairs Division. V. Title. VI.
Series.
[DNLM: 1. Dermatologic Agents-pharmacology-congresses. 2. Skin-drug
effects-congresses. 3. Skin Diseases-drug therapy-congresses. QV 60
N279s 1989]
RL801. N37 1989
616.5'061-dc20
DNLM/DLC 89-26614
for Library of Congress CIP
© 1990 Plenum Press, New York
Softcover reprint of the hardcover 1st edition 1990
A Division of Plenum Publlshing Corporation
233 Spring Street, New York, N.Y. 10013
All rights reserve,11
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
Major skin diseases, including acne, psoriasis and eczcma, affect the
majority of the population at some time in their lives. In general, these
diseases are physically and psychologically disfiguring for the sufferers;
furthermore, by their very chronic nature skin diseases, unlike most other
disease processes, present both acute and chronic therapy problems. In
addition, the chronic nature of these diseases can present certain economic
problems.
Firstly, chronic therapy is becoming increasingly expensive and secondly,
patients adhering to a strict treatment regimen will frequently be absent
from their gainful employment for either medical consultation or treatment.
Given that in all NATO countries the average age of the population is
continually increasing, these chronic skin diseases will increase in
importance in the coming years. Furthermore, as the average population age
increases, additional disease processes such as skin photodamage and
carcinogenicity risk becoming major areas of therapeutic concern.
This book reviews in detail the major scientific areas of interest for
research and clinical scientists working in skin pharmacology and toxicology.
The basic principles relating to an understanding of how drugs and chemicals
may influence either the skin or the body as a whole are discussed in detail
by recognized international scientific experts.
The Editors
March 1990
v
CONTENTS
Dermatological Drug Development - A Review of some Important Issues ...•. 1
J.R. Gibson
Carbohydrate, Protein and Lipid Metabolism in the Skin; Biochemical and
Molecular Aspects .•••••...•••.•••••••...••.••••.••.•••••...•••... 37
B. Berra and S. Rapelli
Hormone Receptors in the Skin .•..••••.•••.•••..•.•.••••.....•.••••...•. 53
M. Ponec
Skin Permeability and Models of Percutaneous Absorption ..•......••...• 77
H. Schaefer and C.N. Hensby
Skin as a Portal of Entry for Systemic Effect: Xenobiotic Metabolism .•• 85
D.R. Bickers and H. Mukhtar
Animal Models Used in Cutaneous Pharmacology ..•....•...•..•••........• 99
M. Bouclier, C.N. Hensby and D. Cavey
Hyperplastic Transformation: the Response of the Skin to Irritation
and Injury ..•...••...••••••.•.••••••...••.......•.••...•....••• 121
F. Marks
The Evaluation of Cutaneous Toxicity: Past and Future .....••..••.•..•. 147
G.J.A. Oliver
In Vitro Biochemical Markers of Skin Toxicity •.........•..••...••••.•• 165
C.L. Galli and M. Marinovich
The Use of Cultured Human Keratinocytes as a Model System for Skin
Pharmacology and Toxicology ...•••.••..•...••......•••••.•..••.. 181
U. Reichert and R. Schmidt
Pro-Inflammatory Mediators and Human Skin Disease ..••..••.....•.•••.•• 193
F.M. Cunningham
Studies of Photoaging •..•....••.•...•••••••.•.......••..•......•.....• 205
M. Yaar and B.A. Gilchrest
vil
Photosensitization Chemically Induced: Mechanisms and Clinical
Aspects ••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 211
P. Forlot
Molecular and Cellular Mechanisms of Multistage Carcinogenesis;
Role of Oncogenes and Intercellular Communication ••••••••••••••• 229
H. Yamasaki
Contact and Atopic Dermatitis ••••••••••••••••••••••••••••••••••••••••• 243
C. Gelmetti
In Vitro Expanded Human Keratinocytes: Clinical and Biological
Experiences ••••••••••••••••••••••••••••••••••••••••••••••••••••• 257
L. Andreassi, L. Donati, M. Malcovati, M.L. Tenchini and
E. Trabucchi
A Comparative Evaluation of Sun Protective Properties of a Shea
Butter by Reflectance Spectroscopy, Laser Doppler Flowmetry
and Visual Scoring •••••••••••••••••••••••••••••••••••••••••••••• 267
P.H. Andersen and P. Bjerring
A Computer System for Contact Dermatitis •••••••.•••.•••••••••••••••••. 277
A. Dooms-Goossens, J. Drieghe, H. Degreef and F. Dooms
Nuclear Aberrations in Anagen Hair Follicle Cells; a Novel in Vivo
Assay for the Detection of Genotoxic Agents •••••••••••••••••••.• 283
M.T. Goldberg, E.A. Goldberg, R. Church and M.H. Hardy
A New Evaluation Method of Skin Plastoelasticity •••.•••••••••••..•••.• 295
A. Sparavigna and M. Setaro
An Interspecies Comparison of Skin Structure (Hair Follicle Area
as Determined by a Novel Technique) and Skin Permeability •••.••• 299
F.M. Smith, R.C. Scott and J.R. Foster
Chemical-Induced Differentiation of Cultured Human Keratinocytes
as Measured by Cell Size Distribution ••.•••.•••••••••••••••••••• 307
F. Van Pelt, M. Stelling, I. Hassing, R. Van De Heijden and
B. , Blaauboer
Contributors .•.•..••••••••••..••••.••••••••••••••••.•••••••••••••••••• 313
Index •..•••••••.••••••.•.••.•••••.••.•••••..•••••••.••..•.•••••..••.•• 315
viii
DERMATOLOGICAL DRUG DEVELOPMENT - A REVIEW OF SOME IMPORTANT ISSUES
John R. Gibson
The Wellcome Research Laboratories
Langley Court
Be~~enham, Kent, BR3 3BS.
It'j"TRODUCTION
In this chapter, a view of the skin from a drug developer's per
spective will be presented and a variety of issues pertinent to dermato
logical therapeutics will be discussed. The author is an experienced
pharmaceutical physician who practises as a clinical dermatologist and
is therefore well placed to provide a commentary on these subjects but
will, naturally, be strongly influenced by his background.
It is logical to assume that the key end point of skin pharmacology
and toxicology is to benefit mankind by making available new, effective
and well tolerated medicinal agents for the treatment of skin diseases.
In order to do this, we must carefully integrate fundamental knowledge
concerning both healthy and diseased skin, approaching our task in an
energetic, problem-oriented manner. It certainly requires the fusion of
knowledge, direction and drive, accompanied by a slice of good fortune,
to develop novel therapeutic agents for dermatology, which must be
currently recognised as a "Cinderella specialty" competing for finite
resources within the pharmaceutical industry against such giants as the
cardiovascular system, the central nervous system and the gastro
intestinal tract.
The theme of this NATO Advanced Study Institute "Skin Pharmacology
and Toxicology - Recent Advances" begs for a fresh and innovative
approach to be made. The starting point for this exercise is to care
fully re-examine our perception of the skin. Following this, a critical
look at the key structural and functional aspects of healthy skin should
be combined with a deeper understanding of the clinical features and
pathophysiological basis of the most important, or commonest, derma
toses. Dermatological dogma and "mythology", so often applied in the
past with devastatingly negative and long-lasting effects on skin
therapeutics, must no longer be permitted to act as stumbling blocks to
genuine progress. The energies of the synthetic chemist and
biotechnologist must be harnessed to produce novel agents worthy of
advancement through the long and arduous drug development process. This
effort requires team-work of the highest degree by professionals of
varied disciplines. Recognition of the deleterious effects of skin
disease on both the soma and the psyche of those afflicted, coupled with
an understanding of the massive scale of the problem in terms of the
numbers affected, should act as a spur for our endeavours.
Of necessity, this review cannot be exhaustive and therefore the
author has selected points for discussion which he considers of impor
tance and which, in some cases, tend to be neglected.
OUR PERCEPTION OF THE SKIN
The skin is indeed a remarkable and many faceted organ. It is so
exposed to the enquiring eye, a fact only too well recognised by those
suffering from dermatological disorders, and yet so easily overlooked or
taken for granted when in a normal condition. When one gazes, for
example, at a naked figure one rarely recognises the skin as being an
important and quite distinct entity. It is the sheer accessibility of
this large and important organ that rendered it for years the subject of
descriptive diagnoses and poorly structured therapeutic attempts. Yet
it is this feature which should also make the skin so attractive to the
drug developer. For it is the organ, par excellence, which is "treated"
extensively both in health and disease. It offers unsurpassed scope for
topically applied therapy, and yet is amenable to systemic medication.
The scientific community is increasingly recognising the skin as an
ideal organ for the in vitro and in vivo study of human tissue pharma
cology (Camp and Greaves, 1987) with therapeutic implications, for
example in the fields of inflammation, allergy, immunology and uncon
trolled cellular proliferation, that go well beyond the specialty of
dermatology. The pharmaceutical industry is beginning to awaken to
facts long recognised by the cosmetic houses, i.e the skin represents a
massive potential market-place which will handsomely reward genuine
innovation, even of a modest degree.
In order to motivate those with the potential to create important
new dermatological therapies, it is important that the skin is recog
nised by them as a dynamic and vital organ whose health is of funda
mental importance to human well-being, and the study of which carries
rewards, in terms of possibilities for ethical human experimentation and
the development of knowledge, with implications well beyond the borders
of the integument itself.
STRUCTURE AND FUNCTION
rt would clearly be impractical, and undesirable, to attempt to
present in this brief chapter a routine, comprehensive review of the
structure and function of the skin. Excellent standard texts covering
this subject already exist (Goldsmith, 1983; Jarrett, 1973-1986; Lever
and Schaumburg-Lever, 1983; Rook et al., 1986a; Schaefer et al., 1982).
The functions of the skin are summarised in table 1.
I would like to focus my attention on certain aspects of barrier
function, as this is of key importance in drug development and has
pharmacokinetic implications for both topically and systemically admin
istered drugs. The former is more often emphasised, but the latter is
of importance when considering, in particular, anti-dermatophytic drugs
(Shah, 1987) and other antimicrobial agents.
2
Table 1. Functions of the Skin
Barrier to foreign materials and radiat~on
Protection against mechanical stress
Mediation of sensation
Thermoregulatory control
Immunological role
Excretory/secretory activities
Metabolic role
Socio-sexual communication
Although obvious, I believe it is worth emphasising that research
in which the skin is viewed as a target tissue for topically applied
therapy must be clearly differentiated from that involving the use of
the skin as a route of administration for systemic agents. The latter
involves specific areas of normal human skin and utilises occlusive
patches, penetrating agents apd drugs which often bear no physico
chemical relationship to agents used in dermatology. The former intro
duces the scientifically devastating variables of the effects of varying
degrees of different diseases on barrier function, coupled with the well
known regional variation in skin permeability to different molecules
(Maibach, 1976).
The temptation to extrapolate the results of data obtained from
experimentation with animal skin in vitro and in vivo to the human
situation must be avoided unless scientific validation exists to show
that this is appropriate for the given agent (Gibson, 1985).
The stratum corneum provides the major, but not the only, barrier
to penetration of topically applied drugs (Schalla and Schaefer, 1987).
Much research has been performed concerning the route(s) by which they
are likely to penetrate the skin (Barry, 1983; Scheuplein and Bronaugh,
1983; Schaefer et al., 1982). There are three possible routes to target
sites in the viable epidermis or in the dermis. These are (1) via the
eccrine ducts (2) via the pilo-sebaceous apparatus and 3) through the
stratum corneum membrane itself. The relative importance of these three
pathways in the treatment of human skin disease with various agents is
not fully understood, although the weight of opinion places emphasis on
the latter due to the relatively tiny surface area presented by the
former two (Barry, 1983; Scheuplein and Bronaugh, 1983). This, however,
has been questioned recently (Illel and Schaefer, 1988). It must not be
forgotten, after all, that some drugs e.g. corticosteroids have potent
effects at low concentrations and it is not inconceivable that at least
the early effects of corticosteroid application may be achieved by the
"shunt" provided by the eccrine and follicular routes. Passage through
the stratum corneum membrane itself could theoretically be predominantly
via either an intercellular or intracellular pathway but, no matter the
route, occurs by passive diffusion (Schaefer et al., 1982). It was
initially considered that the latter pathway was the most likely one for
3
