Table Of ContentProgress in Drug Research
Fortschritte der Arzneimittelforschung
Progres des recherches pharmaceutiques
Vol. 41
Progress in Drug Research
Fortschritte der Arzneimittelforschung
Progres des recherches pharmaceutiques
Vol. 41
Edited by / Herausgegeben von / Redige par
Ernst Jucker, Basel
Authors / Autoren / Auteurs:
Mont R. Juchau . Robert J. Walker and J. Paul Fawcett· R. Sutherland·
Noel W. Preston· Sanjay Batra, Manju Seth and A. P. Bhaduri . Wilhelm
Schoner . James W. Fisher· Hiroshi Ohtaka and Toshio Fujita
1993 Birkhauser Verlag
Basel· Boston· Berlin
Ausgeschieden
kiz Univ. Ulm
The publisher cannot assume any legal responsibility for given data, especially
as far as directions for the use and handling of chemicals and drugs are concerned.
This information can be obtained from the manufacturers.
The use of registered names, trademarks, etc. in this publication does not imply,
even in the absence of a specific statement, that such names are exempt from the
relevant protective laws and regulations and therefore free for general use.
This work is subject to copyright. All rights are reserved, whether the whole or part
of the material is concerned, specifically those of translation, reprinting, re-use of
illustrations, broadcasting reproduction by photocopying machine or similar means,
and storage in data banks. Under § 54 of the German Copyright Law where copies
are made for other than private use a fee is payable to "Verwertungsgesellschaft
Wort", Munich.
© 1993 Birkhauser Verlag Basel
Softcover reprint of the hardcover 1st edition 1993
P.O. Box 133
4010 Basel
Switzerland
ISBN-13 :978-3-0348-7152-5 e-ISBN-13: 978-3-0348-7150-1
DOl: 10.1007/978-3-0348-7150-1
Contents . Inhalt . Sommaire
Chemical teratogenesis . . . . . . . . . . . . . . . . . . . . . .. 9
By MontJ.Juchau
Drug nephrotoxicity - The significance of cellular
mechanisms ............................. 51
By Robert J. Walker and J. Paul Fawcett
Bacterial resistance to p..lactam antibiotics:
Problems and solutions . . . . . . . . . . . . . . . . . . . . . .. 95
By R. Sutherland
Eradication by vaccination: The memorial to smallpox could
be surrounded by others . . . . . . . . . . . . . . . . . . . . . .. 151
By Noel W. Preston
Chirality and future drug design . . . . . . . . . . . . . . . 191
By Sanjay Batra, Manju Seth and A. P. Bhaduri
Endogenous digitalis-like factors . . . ... . . . . . . . . 249
By Wilhelm Schoner
Recent advances in erythropoietin research . . . . . . . 293
By James W. Fisher
Structural modification patterns from agonists to antagonists
and their application to drug design - A new serotonin (5HT3)
antagonist series . . . . . . . . . . . . . . . . . . . . . . . . . . . 313
By Hiroshi Ohtaka and Toshio Fujita
Index· Sachverzeichnis· Table des matieres . Vol. 41 359
Index oftitles . Verzeichnis der Titel· Index des titres .
Vol. 1-41 . . . . . . . . . . . . . . . . . . . . . . . . . 369
Author and paper index· Autoren und Artikelindex .
Index des auteurs et des articles, Vol. 1-41 . . . . . . 379
Foreword
Volume 41 of "Progress in Orug Research" contains eight reviews
and the various indexes which facilitate its use and establish the con
nection with the previous volumes. The articles in this volume deal
with teratogenesis; nephrotoxicity; bacterial resistance to P.lactam
antibiotics; eradication of diseases by vaccination; chirality and drug
design; endogenous digitalis-like factors; erythropoietin; and sero
tonin (5HT)-antagonists.
3
All these articles give an excellent overview of the respective fields of
research.
In the 33 years that POR has existed, the Editor has enjoyed the valu
able help and advice of many colleagues. Readers, the authors of the
reviews, and last but not least, the reviewers have all contributed
greatly to the success of this series. Although the comments received
so far have generally been favorable, it is nevertheless necessary to
analyze and to reassess the current position and the future direction
of such a review series.
So far, it has been the Editors intention to help disseminate informa
tion on the vast domain of drug research, and to provide the reader
with a tool with which to keep abreast of the latest developments and
trends. The reviews in POR are useful to the non-specialists, who can
obtain an overview of a particular field of research in a relatively
short time. The specialist readers of POR will appreciate the reviews'
comprehensive bibliographies, and, in addition, they may even get
fresh impulses for their own research. Finally, the readers can use the
41 volumes of POR as an encyclopedic source of information.
It gives me great pleasure to present this new volume to our readers.
At the same time I would like to express my gratitude to Birkhauser
Verlag, and, in particular to Mrs. L. Koechlin and Mssrs. H.-P. Thiir
and A. Gomm. Without their personal commitment and assistance,
editing POR would be a nearly impossible task.
Basel, November 1993 OR. E. JUCKER
Vorwort
Der vorliegende 41. Band der Reihe «Fortschritte der Arzneimittel
forschung» enthalt acht Ubersichtsartikel sowie die verschiedenen
Register, welche das Arbeiten mit dies em Band erleichtem und den
Zugriff auf die vorhergehenden Bande ermoglichen. Die Artikel des
41. Bandes behandeln - wie das Inhaltsverzeichnis zeigt - verschie
dene aktuelle Gebiete der Arzneimittelforschung und ermoglichen es
dem Leser, sich rasch einen guten Uberblick iiber diese Gebiete zu
verschaffen.
Seit der Griindung der Reihe sind 33 Jahre vergangen. In dieser lan
gen Zeitspanne konnte der Herausgeber immer auf den Rat der Fach
kollegen, der Leser und der Autoren zahlen. Ihnen allen mochte ich
meinen Dank abstatten. In dies en Dank sind auch die Rezensenten
eingeschlossen, denn sie haben mit ihrer Kritik und mit ihren Vor
schlagen wesentlich zum guten Gedeihen der PDR beigetragen. Viele
Kommentare und Besprechungen waren lobend. Trotzdem ist es an
gebracht, die Frage nach dem Sinn und Zweck der «Fortschritte» zu
stellen und zu iiberpriifen.
Nach wie vor ist es unser Ziel, neueste Forschungsergebnisse in Form
von Ubersichten darzustellen und dem Leser auf diese Weise zu er
moglichen, sich verhaltnismaBig rasch und miihelos iiber bestimmte
aktuelle Richtungen und Gebiete zu informieren. Es wird ihm somit
die Moglichkeit gegeben, sich im komplexen Gebiet der Arzneimittel
forschung auf dem laufenden zu halten und den Kontakt zur aktu
ellen Forschung aufrechtzuerhalten. Die Ubersichten der «Fort
schritte» bieten dem Spezialisten eine wertvolle Quelle der Original
literatur dar, erlauben ihm niitzliche Vergleichsmoglichkeiten, und
sie konnen u. a. seine eigene Forschung befruchten. Fiir alle Leser
der «Fortschritte» stellt die Reihe mit ihren ausfiihrlichen Verzeich
nissen eine niitzliche Quelle von enzyklopadischem Wissen dar, so
daB das gesamte Werk auch als Nachschlagewerk dienen kann.
Zum Gedeihen der Reihe haben nicht zuletzt auch die Mitarbeiter
des Birkhauser Verlages beigetragen. Erwahnt seien insbesondere
Frau L. Koechlin und die Herren H.-P. Thiir und A. Gomm. Ihnen
mochte ich auch an dieser Stelle meinen Dank aussprechen.
Basel, November 1993 Dr. E. JUCKER
9
Chemical teratogenesis
By Mont R. luchau
Department of Pharmacology, School of Medicine SJ-30, University
of Washington, Seattle, Washington 98195, USA
1 Introduction: Definitions, scope and focus. . . . . . 10
2 Exposures of embryos and fetuses to chemicals . . . 11
3 Role of chemicals in the etiology of birth defects . . 15
4 Classes of chemicals with high teratogenic potential 17
5 Evaluation of chemicals for teratogenic activity 18
6 Chemicals recognized as teratogenic in humans 19
6.1 Thalidomide and congeners ... 20
6.2 Cancer chemotherapeutic agents . . 22
6.3 Retinoids/arotinoids...... 25
6.4 Anticonvulsant drugs . . . . . . 27
6.5 Alcohols/glycols/glycol ethers . 30
6.6 Antithyroid agents . . . . . . 31
6.7 Antimicrobial agents ...... 32
6.8 Heavy metals/organometals . . 34
6.9 Polyhalogenated aromatics . . . 35
6.10 Steroidal/nonsteroidal hormones 36
6.11 Coumarin derivatives . . . . . . . 38
6.12 Angiotensin-converting enzyme inhibitors 39
6.13 Recreational agents . . . . 40
6.14 Miscellaneous agents . . . 42
7 Future research ...... 44
8 Summary and conclusions 45
Acknowledgments 45
References . . . . . . . . . 45
10 Mont R. Juchau
1 Introduction: Definitions, scope and focus
For purposes of this treatise, the term chemical will refer both to en
dobiotics and xenobiotics and discussions will focus primarily on or
ganic chemicals of low molecular weight « 1000 daltons) but certain
inorganic chemicals will also be discussed (e. g., heavy metals, io
dides, lithium, etc.). Radiation and radiolabelled chemicals are not
discussed. The term teratogen will refer broadly to any agent capable
of eliciting deleterious effects, directly or indirectly, on developing
embryos or fetuses to the extent that permanent or semi-permanent
defects are manifest subsequent to the fetal period of development,
i. e., following parturition, hatching, metamorphosis, etc. Defects in
clude not only dysmorphic phenomena but also permanent/semi
permanent growth retardation, neoplasms and functional deficits in
volving the nervous system (e. g., behavioral, mental or motor defi
cits), the reproductive system, the immunologic system, metabolic
systems or any of the individual organs comprising the organism (kid
ney, heart, lung, etc.). Such permanent or semi-permanent deleterious
sequelae will be referred to as terata or also simply as birth defects.
The discussions will be restricted to vertebrate organisms with focus
on mammals and particularly on humans. Emphasis will be upon re
cent research pertaining to the mechanisms whereby several chemi
cals or classes of chemicals currently regarded as having exhibited
significant teratogenicity in humans (often referred to as "esta
blished" human teratogens) elicit their respective teratogenic effects.
The capacity of exogenously administered chemicals to produce
permanent/semi-permanent birth defects has been recognized only
relatively recently. The concept that embryos and fetuses are either
killed by or are virtually completely insulated from damage due to en
vironmental influences was widely held until the early 1940's in spite
of a few earlier observations to the contrary. The extensive research
efforts ofWarkany and his colleagues [1] resulted in the realization by
many scientists that the concept was not valid but general public
awareness that chemicals could cause birth defects was not broadly
manifest until after the thalidomide tragedy [2, 3] that occurred in the
late 1950's and early 1960's. At present, more than twenty chemicals/
chemical classes (exclusive of radiochemicals and infectious agents)
are recognized as having shown the capability of eliciting teratogenic
effects in humans at feasibly expected exposure levels (Table 1).
Chemical teratogenesis 11
Several relatively recent additions to this list (ethyl alcohol, retinoids,
valproic acid, angiotensin-converting enzyme inhibitors, cocaine)
promise that a great many others will be added in the future. In spite
of this, vestiges of the aforementioned concept remain, even among
some otherwise knowledgeable health professionals who sometimes
appear to cling to the idea that the prenatal organism is not subject to
chemical teratogenesis except under the rarest of conditions. Indeed,
the extent to which embryos and fetuses often can be exposed to
many toxic chemicals without evidence of serious developmental de
fects is striking, possibly due to efficient embryonic defense/repair
systems (as yet largely unexplored in terms of dysmorphogenesis) and
it seems worth emphasis that the large majority of pregnancy-asso
ciated chemical exposures are probably without serious conse
quences. Nevertheless, demonstrations that chemicals can effect terata
and the possibility that birth defects can occur as a result of chemical
exposure should obviate complacency in this regard. It is hoped that
this article will contribute to a more rational view of the role that
chemicals may playas contributors in the etiology of birth defects.
A number of excellent discourses dealing with the general topic of
chemical teratogenesis have been published in recent years and these
are listed in the references [4-9]. Focus, emphasis and details of these
vary but each represents a valuable contribution to the literature. In
addition, a number of recently published texts catalog valuable sum
marized information with respect to the teratogenic activities (with
focus primarily on dysmorphogenic effects) of chemicals that have
been investigated in terms of their capacities to elicit such effects.
These are also listed in the references [10-16]. Increased demand for
information relative to the teratogenic activities of drugs and other
chemicals also has resulted in the generation of a number of excellent
computerized databases. These are discussed further in some of the
listed textbook references [10, 12, 14].
2 Exposures of embryos and fetuses to chemicals
Sources of exposures of embryos and fetuses to non-endogenous
chemicals (xenobiotics) are numerous and include physician-pre
scribed medications, non-prescription drugs, "recreational" agents
such as cocaine, amphetamines, narcotics, marijuana, ethyl alcohol,
tobacco, etc., workplace chemicals, chemical contaminants of food,
