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Book Review Comprehensive Medicinal Chemistry. The Rational Design Mechanistic Study and Therapeutic Application of Chemical Compounds. Six volumes. Edited by C. Hansch P. G. Sammes and J. B

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[8] J. W. Bausch, G. K . Surya Prakash, G. A. Olah, D. S . Tse. D. C. Lorents,
Y K. Bae. R. Malkotra, J. Am. Chem. Soc. 113 (1991) 3205.
[9] a) J. Cioslowski, J. Am. Chem. Soc. f 13 (1991)4139; b) J. Cioslowski, E. D.
Fleischmann, J. Cliem. P/iys. 94 (1991) 3730; c) A. H. H. Chang. W. C.
Ermler. R. M. Pitzer, hid. 94 (1991) 5004.
[lo] a) I. R. Heath. S . C. O’Brien, Q. Zhang, Y Lin, R. E Curl, H. W. Kroto,
F. K. Tittel. R. E. Smalley. J. Am. Cheni. Soc. 107 (1985) 7779; b) F. D.
Weiss. J. L. Elkind, S. C. OBrien. R. F. Curl, R. E. Smalley, J. Am. Chem.
Soc. 110 (1988) 4464.
[ I l l a) D. M . Cox. D. J. Trevor. K . C. Reichmann, A. Kaldor. J Am. Cliem.
So(.. 108 (1986) 2457; b) D. M . Cox, K. C. Reichmann, A. Kaldor. J.
Cliem. Pli1.s. 88 (1988) 1588; c) A. Rosen. B. Wlstberg, J. Am. Cl7m1.Soc.
/10 (1988) 8701.
[I21 Presented for the first time: D. K . Bohme, T. Weiske, J. HruSAk, W.
Krltschmer. H. Schwarz, 371h Annu. Conference on Moss Sppclrum. und
Allied Top. IASMS).Nashville,TN. USA,May21,1991.-Wehave heard
from Dr. M. M. Ross, Naval Research Laboratories, Washington. D.C.,
that he has repeated our experiment after the ASMS conference and obtained the same results.
[I31 a) P. P. Radi. M. T. Hsu, J. Brodbelt-Lustig, M. Kincon, M. T. Bowers. J.
Cliem. P h w 92 (1990)4817; b) A. B. Young, L. M. Cousins, A. G. Harrsion. RupIdCommun. Mus.s Spectrum. 5 (1991) 226: c) D. R. Luffer. K . H.
Schram. ibid. 4 (1990) 552; d) P. P. Radi, M.-T. Hsu, M. E. Rincon. P. R.
Kemper, M. T. Bowers. Chem. PI7w Lett. 174 (1990) 223; e) C. Lifshitz.
M. Iraqi. T. Peres, J. E. Fischer. I n f . J. Mass Spectrom. fun Proccsse.?,in
press; f ) C . Lifshitz, M. Iraqi. T. Peres, J. E, Fischer. RuppidCommun.
Spectrorn.5(1991)238:g)D.Schroder.D.SiilzIe,J. Chrm. Phys. 94(1991).
6933, h) R. J. Doyle. Jr., M. M. Ross, J. Plirs. Cliem., in press.
[14] Reviews: a) R. G . Cooks (Ed.): Collision Spectroscopy. Plenum. New York
1978; b) K. Levsen. H. Schwarz, Muss Spectrum. Rev. 2 (1983) 77: c) J.
Bordas-Nagy, K. R. Jennings, Inst. J. Muss Spectrum. Ion Processes 100
(1990) 105.
[I51 a) R. Srinivas, D. Siilzle, T. Weiske, H. Schwarz, fnr. J Mass Spectrom. Ion
Processes, in press; b) R. Srinivas, D. Siilzle, W. Koch, C. H. DePuy, H.
Schwarz, J. Am. Chem. Soc., in press.
(161 J. R. Chapman: Praclical Orgunk Mass Spectrometry, Wiley, Chichester,
England 1985. Chapter 6.
[ I 71 The “center of mass”-energy (ECJdetermines the maximum energy which
can be transferred in a collision of a projectile A with a stationary particle
m J , where
N. The following relationship holds: E,, = E,[m,/(m,
E,, = kinetic energy of A (corresponding to 8000 eV in the experiments
described here) and m, the masses of A and N.
[18] Direct production of CJ/He o r C;t/He according to Equation (a) in
a high-energy collision experiment is fundamentally impossible on
kinematic grounds. However, we are planning experiments with
“slow” C;’ ions. Furthermore, we intend to expose the Cie/He species
to a neutralization~reionization (NRMS) experiment. The experiment (which has not yet been performed because of insufficient intensities) will answer the question about the existence of neutral C,He clusters.
[I91 S . C. O’Brien. J. R. Heath, R. F. Curl, R. E. Smalley, J. Cl7em. Phys. 88
(1988) 220.
[20] The a h initio MO calculations were performed at the MP2/6-31Ga’/:
MP2/3-21G * level of theory. We expect that calculations with larger
basis sets will lead to smaller values for the binding energy of C,Hia/He
as well as for the energy required to pass He through a C,H, or C6H;@
[?I] For M N D O calculations of the barrier for the endo + e m migration of
Lie In C,clusterssee: D. Bakowies, W.Thiel. J. Am. Chem. Soc. 113(1991)
[22] Note added in proof (12 June 1991): First experiments with C,: and Ne
(ECM= 216 eV) show that this noble gas can also be incorporated into the
cavity (appearance of [C, .,,Ne]’@.n = 2 - lo), but the “yield” is a factor
10 smaller than in the case of He.
Comprehensive Medicinal Chemistry. The Rational Design,
Mechanistic Study and Therapeutic Application of Chemical Compounds. Six volumes. Edited by C. Hansch, P. G.
Sammes and J. B. Taylor. Pergamon, Oxford 1990. Hardcover $ 1995.00. (Individual volume: $ 350.00 each).ISBN 0-08-032530-0 (complete work)
Volume 1 : General Principles. Volume Editor: P.D . Kennewell. xv, 81 l pp.-ISBN 0-08-037057-8
The first section of this volume is very heterogeneous in
content; it sets out to describe the development of medicinal
chemistry by giving a chronology of drug introductions and
tracing the history of the pharmaceutical industry. It shows
how the different initial conditions and environments existing
in German-speaking countries, in Great Britain and in the
USA have led to the industry developing in different ways.
The important role of legislation and of public regulatory
i> VCH Verlagsgesellsrhafi mbH, W-6940 Weinheim, 1991
agencies such as the FDA in imposing quality standards is
emphasized, and it is shown how this led to a strengthening
of the German and North American pharmaceutical companies even before the First World War.
The account of drug introductions is not in chronological
order, nor is it complete. Admittedly it would not be possible
to cover this subject exhaustively within the space allowed,
but it is surprising that some important milestones such as
the introduction of antihyperlipidemic aryloxycarboxylic
acids (“Fibrates”), HMG-CoA-reductase inhibitors (“Lovastatin”) and calcium antagonists of the dihydropyridine
type are not included. On the other hand the space devoted
to compounds such as LSD, tetrahydrocannabinol and chloramin-T is disproportionately large in relation to their importance. Antibacterial agents and their development are
discussed in detail, but only penicillins and cephaalosporins
are covered. Neither quinolones nor carbapenemes are mentioned. The important contribution of the azoles in
antifungal therapy is also ignored. This not entirely successful historical introduction ends with brief accounts of Egyptian, Greek and Arabic medicine, plus two separate chapters
on traditional Chinese and Indian medicine.
The second section on “Targets of Biological Active
Molecules” follows a logical sequence, starting with the essentials of anatomy and physiology and proceeding via cell
architecture to the identification of specific macromolecular
targets. Principles of general pharmacology, such as the receptor theory, are derived in the course of the discussion.
Although the introduction to anatomy and physiology is
pleasingly concise, this means that the non-biologists for
whom this chapter is mainly intended will find that their
needs are not fully satisfied here; it would have been useful
to include references to suitable books covering these topics.
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Angeu. Chem. lnr. Ed. Engl. 30 (1991) N o . 7
It is difficult to understand why a topic so important to
pharmacology as the smooth muscular system is given such
little emphasis, hidden away under the headings “Musculoskeletal System” and “The Neuromuscular Junction”.
The otherwise good introduction to renal physiology lacks a
clear and full explanation of the renin-angiotensin-aldosterone system. The physiology of the central nervous system is treated systematically from an anatomical standpoint.
The same also applies to the discussion of endocrine glands
and of hormones, although here some new findings such as
those concerning ANP, EDRF and endothelin are not mentioned. As the treatment is so concise, one expects that it
should be clear and unambiguous, and should not conflict at
any point with the textbooks (as, for example, in the cases of
the Hagen-Poiseuille equation or of renal autoregulation).
The chapter provides good basic information in the simplified account of the complex relationships in the immune
system. However, only a relatively small amount of space is
devoted to the AIDS problem. Basic concepts of general
pharmacology and their quantitative aspects are explained
with the help of examples. The contents of the articles entitled “The Concept of Bioselectivity” and “Bioselectivity”
could have been presented more concisely by either
combining them or relating them more effectively.
The third section, “Bioactive Materials”, begins with an
excellent discussion of structure-activity relationships, their
importance for classifying active substances, and the problems that this entails. The two following chapters illustrate,
for the benefit of outsiders, the complex nature of the search
for new structural types with pharmaceutical activity. However, the expert too will undoubtedly discover here stimulating viewpoints for example the discussion of the advantages
and disadvantages of different types of organizational structures for finding and evaluating new active agents in an
interdisciplinary way. Two chapters deal with natural products, but these are devoted exclusively to hormones. In some
parts the discussion becomes lost in experimental details that
are of little interest to the outsider. On the other hand the
chapter on analytical methods is clearly presented. Unfortunately, however, the great advances made possible by the use
of molecular biological techniques in this field are only
touched on briefly. This is followed by a rewarding chapter
in which the many problems that nowadays confront a
chemist engaged in process development are described. Even
readers unfamiliar with this field will gain a clear impression
of the factors that often force one to adopt a synthetic strategy far removed from the laboratory method.
The field of gene molecular biology, gene structure and
cloning techniques is only covered in a very patchy fashion,
as is evident from the fact that there are only 40 literature
references altogether. It would have been better to save this
space by referring the reader to appropriate textbooks, and
to devote it instead to gene expression and manipulation,
which is only treated very briefly in the following chapter.
Although many topics are touched on, the information content remains rather meager. The final chapter (“Genetic Engineering: Commercial Applications”) deals with the therapeutic applications of recombinant proteins and fits very
well into the subject area of this series. However, it does not
make any reference to antibodies produced by genetic engineering.
The last section, “Socio-Economic Factors of Drug Development”, is again very heterogeneous. The topics covered
are regulatory authorities, the organization and funding of
pharmaceutical research, health care systems, clinical pharmacology, animal experiments, and patenting. Nearly all the
material on the first four subjects named above relates to the
A n ~ e n . .Clicwr Int. Ed. Engl. 30 ( 1 9 9 t ) No. 7
situations in Great Britain and the USA. For an international standard source it would have been desirable to also discuss the situation in the European Community, which will
become an increasingly important factor in the future, and
also to describe, at least briefly, the special features of the
Japanese licensing mechanisms for pharmaceuticals. Apart
from these reservations most of the chapters provide good
concise reviews of their subjects. There are special sections
devoted to the now highly interesting topics of “Good Clinical Practice” (GCP), “Good Manufacturing Practice”
(GMP) and “Postmarketing Surveillance” (PMS).
To summarize, in aiming to present a comprehensive account of this broad area the authors have in general given
basic information, but the chapters vary greatly in their provision of references to literature covering the topics in greater
depth. One would have liked to find more cross-references to
more detailed discussions to be found in other chapters or in
other volumes of this series, and this would undoubtedly
have added greatly to the usefulness of the volume.
John E. Butler, Ruiner GroJ
Gert Gruenewaldt, Peter Rounding,
Axel Unterbeck. Thomas Weihrauch
Volume 2: Enzymes and other Molecular Targets. Volume
Editor: P. G. Sammes. xvii, 887 pp.-ISBN 0-08-037058-6
Volume 2 deals with enzymic processes, and also describes
agents that interfere with the synthesis of the bacterial cell
wall or produce changes in nucleic acids. It begins with a
general introduction describing the structures, nomenclature
and classification of enzymes, the mechanisms of catalysis
and inhibition, and the development of resistance and tolerance towards antimicrobial agents. This is followed by descriptions of particular enzymes and enzyme systems of importance. It is, of course, not possible within this relatively
limited space (a little over 500 pages) to give an exhaustive
survey of this complex field. The criteria used in making the
selection have clearly been based mainly on pathophysiological importance and on the ability to influence systems by
pharmacological means. In the following commentary several chapters will be picked out as examples.
The article on protease inhibitors (D.H . Rich, University
of Wisconsin) is confined to inhibitors of low molecular
mass, with the main emphasis on renin and ACE inhibitors.
Unfortunately there is not much discussion of the relationship to biology and medicine. Good features are the inclusion of X-ray structural data and the discussion of “molecular mechanics” calculations. The chapter on enzyme cascades, coagulation, fibrinolysis and hemostasis agents
( M . P. Taylor, Warner Lambert Company) gives a very good
overall description of the processes of hemostasis, fibrinolysis and coagulation. Less satisfactory, however, are the formula schemes and diagrams, which could have been set out
more clearly, and are too small relative to the typeset formulas. Whereas the account of fibrinolysis therapy includes
references to the latest developments in molecular biology
(e.g. the use of rTPA), the discussion of blood coagulation
does not give enough information about developments of
this kind (e.g. the treatment of hemophilia using rFVIII as an
alternative to plasma concentrates). In general molecular
biological aspects are underrepresented; for example, the
cloning of blood factors and the techniques that have
grown from it are not adequately covered. In contrast the
chapters on the arachidonic acid cascades (G. A. Higgs, E. A .
Higgs and B. Moncada, Wellcome Research Laboratories),
on phosphodiesterase inhibitors (R. E. Weishaar and 1 A
Bristol, Warner Lambert Company), on phospholipase-A2
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0S70-0833l9llO707-0887 8 3 . 5 0 t .25l0
( H . van den Bosch, Utrecht), and especially that on protein
kinases (K. J. Murray and B. A . Warrington, Smith, Kline
and French) contain comprehensive information, presented
concisely with clear tables and diagrams. In the last-named
chapter especially, a wealth of information on all the known
protein kinase inhibitors, including structure-activity relationships and a discussion of the biological effects, is clearly
and concisely presented. This chapter is of equal interest to
the chemist and the biologist. However, it would have been
useful, especially from the standpoint of up-to-dateness, to
include here a discussion of the protein phosphatases and
their inhibitors; this would undoubtedly have contributed to
giving a more complete picture of cellular regulatory mechanisms.
The clearly set out and succinct chapter on agents that
affect nucleic acids provides the reader with a soundly-based
insight into the various molecular mechanisms involved.
Suggestions are put forward for setting up selective therapeutic strategies to counteract tumor cells and pathogens.
The chapters that follow discuss other aspects of antimicrobial agents: the development of resistance and tolerance to
antibiotics, substances that intervene in metabolic processes,
and agents that affect cell walls. The discussions of these
include details on a wealth of chemical structures and pharmacological effects. However, this inevitably means that
some aspects are treated too briefly and without sufficient
attention to the latest state of knowledge. The disjointed
treatment is especially noticeable in the fact that there are
two chapters on p-lactams by different groups of authors.
There is no doubt that Volume 2 of this work again illustrates the general rule that length and up-to-dateness are
inversely related, despite the fact that quite a number of the
chapters contain references to recent literature (1986 to
1988). This, and the non-uniformity in the treatment due to
the large number of authors, are penalties that the reader
must incur along with the benefits of comprehensive books
of this kind. Nevertheless, the book is of considerable value
because of the wealth of information that it contains. The
biologist working in the pharmaceuticals area who needs to
find ways of controlling cellular or molecular processes will
find here many pointers to active compounds that are already known. Looked at from this standpoint, as a reference
source, the book is undoubtedly a valuable addition to the
Stefan Wohljeil, Erwin Bischoff,
Riidiger W Braun, Axel Dalhoff,
Detlef Schmidt
Volume 3: Membranes and Receptors. Volume Editor: J C.
Emmett. xvii, 1280 pp.-ISBN 0-08-037059-4
The third volume of the handbook deals with the pharmacology of the cell membrane and of membrane receptors.
The arrangement of the contents according to types of mechanisms is sensible and makes it easy to find the subject areas
one is seeking; unfortunately, though, sufficient cross-references are not provided to enable one to gather information
on processes that fall into several mechanistic categories (as
in the case of the “receptor operated ion channel”, for example). Also one searches in vain for membrane processes of
such central importance as active and passive ion transport.
These are in fact treated in Volume 2 with its vague title
“Enzymes and other Molecular Targets”.
The explanatory sections on methods and mechanisms
that introduce the volume as a whole and some individual
chapters are very useful, especially for readers new to the
field. For example, the introductory section on the structure
Verlagsgesellschofi mbH, W-6940 Weinhelm. 1991
and function of cell membranes gives a comprehensive and
very clearly set out overview of the current state of knowledge in this area. As well as indicating some general principles of membrane biochemistry with the help of examples,
the techniques used to study these systems are introduced in
an easily understandable way. These topics include the quantitative analysis of ligand-receptor interactions and a brief
review of methods for isolating and purifying membrane
receptors and investigating their molecular biology.
The chapter on transduction of signals and “second messenger” analogues unfortunately fails to live up to its
promise to introduce the reader to the mechanisms of signal
transduction. It seems that the adenylate cyclase, guanylate
cyclase and phospholipase C systems are only mentioned
here as a vehicle for including a few literature citations. The
discussion that follows deals only with “second messenger”
analogues, and here reference is continually made to “inosito1 1 ,4,5-triphosphate1’ instead of the correct name inositol
The authors of the chapters on neurotransmitters and
their receptors have succeeded in providing an excellent and
informative review of this field, which has now become very
complex. A pleasing feature here is the use of a standard
structure for each of the chapters. Starting with a description
of neuroanatomy and of the neurotransmitter pathways in
the brain and/or its periphery, the authors proceed to discuss
the biosynthesis and metabolism of each type of neurotransmitter. This is followed by the mode of action of the neurotransmitters and the ways in which they are influenced by
agonists and antagonists.
The traditional classification of receptors according to
their response to synthetic transmitter analogues is nowadays being replaced increasingly by one based on molecular
biological criteria. It has not been possible to cover this
aspect adequately here, in view of the rapid developments
that have occurred in the last few years.
Most of the authors conclude their discussion of the receptors concerned by describing the potential or already practised therapeutic applications of agents with specific activity
towards the neurotransmitter-receptor system. This means
that each chapter is a very useful and informative reference
source, not only for chemists, biochemists and pharmacologists but also for medical scientists, providing a clear
description of the sequence from the chemical synthesis
of a receptor-specific substance to a practical therapeutic
The treatment of peptide receptors is very clear and informative, and the division of this complex subject into ten
chapters is appropriate. These describe the characterization
of the receptors, their biosynthesis and metabolism, the ways
in which they are affected by the endogeneous peptides and
by peptide and non-peptide ligands, and, where appropriate,
the therapeutic applications of these substances. Structureactivity relationships are treated at considerable length.
In the chapter on angiotensin receptors one would have
liked to be given a rather more balanced treatment by the
inclusion of important research results from other groups.
Moreover, the non-peptide angiotensin-I1 antagonists are
underrepresented, being only mentioned in a single sentence.
One also searches in vain for a description of endothelin
In the treatment of ionic channels the pharmacology of the
sodium and calcium channels in particular is covered very
well and in great detail. However, the discussion of the
potassium channels fails to come up to standard because of
recent developments that are not included. Chloride channels are not treated at all.
$3.50+ ,2510
Angew. Chem. In?. Ed. Engl. 30 (1991) No. 7
The lymphokins and cytokins of the immune system are
treated separately. Although this makes for a clear division
of topics, it means that the complex interaction between
these mediators is not sufficiently brought out. Some of the
sub-chapters, such as the account of the physiological and
clinical importance of interleukins, are very informative. On
the other hand the importance of the role of T N F is understated; in the account of analytical techniques there is not
enough discussion of the advantages and disadvantages of
the various methods, and some of the literature references
are not mentioned in the text. The bibliographies are in many
cases more than five years out of date, and thereby fail to live
up to expectations in this respect, especially in the discussion
of pharamacological agents that affect the immune system.
The final chapter of this volume is devoted to the molecular structure, regulation and ligand chemistry of the most
important intracellular receptor systems, namely vitamin D,
thyroid hormone and steroid hormone. The treatment is for
the most part of an impressively high standard. An exception
to this is the physiology and pathophysiology of the steroid
receptors, which unfortunately has been subdivided and
placed in different parts of the chapter in a confusing way.
The literature references here are up-to-date and comprehensive, making it easy for the reader to refer to the original
papers when special questions arise.
To summarize, this volume is a substantial collection of
good review articles dealing with specific topics, but cannot
be regarded as a self-contained textbook or comprehensive
work of reference.
Martin Bechem, Arno Friedl,
Siegbert Hebisch, Gabriele Hecker,
Henning Sommermeyer, Hans-Peter Stasch
Volume 4: Quantitative Drug Design. Volume Editor: C. A .
Ramsden. xvi, 766 pp.-ISBN 0-08-037060-8
Volume 4 of this work contains 24 articles by well-known
authors. The main emphasis is on the “classical” methods of
investigating structure-activity relationships and on molecular modeling methods.
Methods for quantifying the physicochemical properties
of chemical structures and their interactions are treated in
detail. The discussion is concentrated mainly on computeraided theoretical methods, ranging from molecular fragment
approaches to predicting lipophilic behavior ( A . J. Leo),
through to molecular dynamics methods for calculating relative free energies of ligand-receptor complexes (J. A .
The quantitative description of biological data and the
transport of substances to the target site are each covered in
only one chapter, these being by I: C. Martin et al. and J. C.
Dearden respectively.
Several further articles are devoted to the models and
mathematical techniques used in correlating structure with
activity; for example, the Hansch approach and the FreeWilson method are described in detail with many examples
by 7: Fujita and H . Kubinyi respectively. Other articles are
concerned with the design of testing programs and methods
of pattern recognition. This group of articles is completed by
an account of some further methods, including the application of substructure analysis for predicting toxicity and
choosing suitable test compounds for screening tests ( P . N .
Craig), followed by a description of the distance-geometry
method ( A . K . Ghose and G . M . Crippen).
The use of models and molecular graphics techniques in
drug design is described in three articles by R . Langridge and
ir: E. Klein. by G . R. Marshall and C. B. Naylor, and by J. M .
Angew. Chem. Int. Ed. Engl. 30 (1991) No. 7
Blaney and C. Hansch. The relationship between these and
the quantitative methods is also discussed.
The editors do not appear to have set out to present a
balanced and comprehensive account of all the models and
methods that are in use in this field. In some cases the authors of the contributions seek to justify the omissions, as,
for example, in the case of the unduly brief treatment of
connectivity indices. In other topics, such as the treatment of
QSAR parameters for peptides or the study of structurepharmacokinetic relationships, the omissions are less easy to
The unavoidable instances of overlapping between the
contributions have mainly been kept to a reasonable minimum. However, this is not always the case in the introductory articles; for example, the information on chemical data
banks could have been shortened, as these were already
listed in Volume 1.
The layout of the volume is excellent. However, the long
period required to prepare it has meant that only developments up to about 1988 are included. For this reason some
topics of current importance, such as 3D data banks, computer methods for designing ligands to match known receptor structures, and methods of quantifying chemical similarity, are unfortunately not included.
Despite the high price and the fact that some good monographs on this field already exist, especially in the QSAR
area, the eminence of the contributing authors ensures that
the book is of a high standard and will be successful.
Eike Moller, Martin Blunck
Volume 5: Biopharmaceutics. Volume Editor: 1 B. Taylor.
xvii, 756 pp.-ISBN 0-08-037061-6
Volume 5 is concerned with “Biopharmaceutics” and embraces a wide range of topics, from “Principles of Pharmacokinetics and Metabolism” through “Analytical Methodology” to matters of pharmacy and formulation in “Chemistry
and Pharmacy in Drug Development”.
The first part deals with the fundamentals of pharmacokinetics, beginning with general chapters on absorption,
distribution and metabolism. These chapters provide the scientist involved in pharmaceuticals development with a good
overview of the basic principles underlying pharmacokinetics. Especially useful is the concisely written chapter by 7:N .
Tozer, which forms an excellent introduction for the beginner. The emphasis that is placed on the physiological basis of
pharmacokinetic processes in these introductory chapters,
for example that on absorption (Dennis), is commendable.
However, it would have been desirable to include here
a more detailed treatment of bioavailability and bioequivalence, which has become a highly interesting theme in
recent years. The chapter on “Distribution and Clearance
Concepts” by Gaillot et al. contains an excellent summary of
current knowledge concerning the physiological basis and
importance of distribution processes, but clearance concepts
deserved to be treated at considerably greater length.
The section on “Sites of Drug Metabolism, Prodrugs and
Bioactivation” contains a well organized discussion of aims
and approaches in the design of prodrugs. The comprehensive bibliography and the tables listing details of review articles are useful for readers from other disciplines. The very
large field of bioactivation of chemicals to form reactive
intermediates, and the toxicological problems that this causes, is only treated in the form of a concise summary, which
is understandable.
These general review articles are followed by discussions
of some special areas, some of which are very up-to-date.
Verlagsgesellschafi mbH. W-6940 Weinheim, 1991
0570-0833/9ljO707-0889 8 3.50t.2Sl0
These short reviews also serve to provide the specialist with
a quick overview. Readers interested in following these up in
greater depth are helped by the mainly well selected bibliographies, which extend up to about 1988.
In the very informative chapter by Juchau on “Species
Differences in Drug Metabolism” the benefits and problems
arising in the use of various animal species as models for
predicting effects on humans are discussed. In drawing attention to the effects of extrahepatic biotransformation and to
differences in the isoenzyme patterns of different species. and
discussing enzyme systems that have received little study, the
authors make it clear that present knowledge still leaves
many gaps. Equally informative and interesting are the
chapters on “Developmental Drug Metabolism” (Juchau)
and “Stereoselectivity. . .” (Lennardet al.). There are further
specialized chapters on highly topical matters, such as that
on “Chronokinetics” (Reinberg et al.). The remarkable variations observed in pharmacokinetic processes according to
the time of day are described with many examples, and the
relative importance of endogenic factors (biorhythms) and
exogenic factors (e.g. food intake) is examined. To complete
the picture, some of the methodology used to investigate
these problems is described. It is pointed out that the regular,
and therefore predictable, cyclic changes that are observed in
chronokinetics studies are of practical importance in the development of programmed delivery devices, and the possible
therapeutic implications are also discussed.
The chapter by Paalzow on “Pharmacodynamics” discusses concentration-activity relationships by considering
numerous examples. The detailed description of the mathematical models used is sufficient to enable the reader to
become thoroughly involved in the theories of this area of
research; the comprehensive and up-to-date bibliography
offers further new ideas in this field.
The second part, entitled “Analytical Methodology”, suffers to a noticeable extent from the problems caused by the
complexity of this subject. The growth that has occurred in
analytical chemistry in recent years is such that there is a
danger of parts of this chapter being reduced to a mere
collection of technical terms. For example, under the title
“Isolation and Identification of Metabolites” the book covers, in only 18 pages, not only enzymic but also chromatographic and spectroscopic methods. Such a sketchy summary can at best only be of interest to beginners. The
introduction to biological analytical techniques by Chamberlain is excellent from a learning standpoint. However, one
would have preferred this chapter to be more up-to-date; for
example, the use of monoclonal antibodies only receives a
brief mention. Boobis et al. review techniques for in vitro
investigations of the metabolization of foreign substances,
including a detailed evaluation of alternative experimental
procedures. This chapter also includes a very comprehensive
bibliography. Vaughan describes the mathematical aspects of
pharmacokinetics from a strongly theoretically-orientated
standpoint. In view of the intended readership it would have
been desirable here to relate the discussion more closely to
the physiological background and the application of the theoretical model to practical situations.
The final part, entitled “Chemistry and Pharmacy in Drug
Development”, covers a variety of topics, ranging from the
properties of pharmaceutical substances, and their consequences for the formulation of products by conventional
methods, also taking physiological factors into account, to
new approaches such as drug targeting.
The first article, by Curry and Thukker, is entitled
“Physicochemical Principles”, and is mainly concerned with
the crystallinity and particle size distribution of pharmaceut890
‘9 VCH
Verlagsgesellschufi mbH, W-6940 Weinheim, 1991
ical compounds and their consequences for the method of
formulation. Here it would have been useful to include a
more detailed description of other important variables and
techniques for adjusting them at the pre-formulating stage.
In the chapter on “Formulation” Florence and Halbert emphasize the importance of in vitro tests on drug release for
arriving at the best formulation. This is followed in logical
sequence by a description of in vitro and in vivo correlation
methods, including a useful table listing many published
studies on this theme.
In their contribution on “Routes of Administration and
Dosage Regimens” Johnson and Lewis provide the newcomer to the subject of formulation with a comparative review of
the advantages and disadvantages of various alternative
routes of administration in pharmaceutical therapy. Newer
therapeutic routes such as the nasal administration of peptides, buccal administration, and transdermal absorption are
described. The second part of this article, which deals with
devising dosage regimens, seems out of place in the part of
the book concerned with pharmacy, especially as it has
already been treated in the first part, “Principles of
Pharmacokinetics and Metabolism”.
The article on “Delivery System Technology” discusses
various methods of retarding drug release and ways of
achieving improved absorption with peroral formulations.
Transdermal therapeutic systems are also discussed as a
modern formulation principle, together with the requirements that must be satisfied by the substances to be administered because of the structure of the skin; here the principles
are related to practical situations by describing a number of
commercial products.
In the noteworthy review of “Drug Targeting” by Crommelin and Storm the authors provide a comprehensive
overview of the current situation in this very active field of
research, including much information that is useful not only
for newcomers but for those already working in this area. A
commendable feature is the comprehensive and up-to-date
This volume must be evaluated in relation to the ambitious claim that the collection of articles represents “a milestone . . . in terms of coverage, clarity, and a sustained high
level of presentation”. In view of the wide range of topics
covered, it is understandable that it has not been possible to
treat all of these with equal thoroughness, although there has
clearly been an effort to achieve complete coverage. Taken as
a whole this collection, despite some weaknesses, offers a
good overall survey of the current state of knowledge in
biopharmaceutics, and it provides easy access to more advanced reading. It can therefore be recommended for all
scientists interested in the development of pharmaceuticals.
Hans-Peter Krause, Hans-Jurgen Ahr,
Michael Boberg, Jiirgen Giinther
Volume 6: Cumulative Subject Index and Drug Compendium.
Druyton. xv, 991 pp.-ISBN 0-08Volume Editor: C. .
This is a useful book.
The first 236 pages consist of a detailed subject index to
Volumes 1-5. This is followed by a “Drug Compendium” of
over 700 pages, compiled by P. N. Craig in a remarkably
laborious achievement. This lists over 5500 compounds (established and potential pharmaceuticals, pharmacological
agents, etc.) with their generic names and their structural
formulas produced by the ChemBase program. The principal sources that have been drawn on are U S A N and the U S P
Dictionary of Drug Names, while additional data have come
0570-0X33~91/0707-0X90$3.50+ 2510
Angew. Cliem. Int. Ed. Engl. 30 (1991) No. 7
from the Merck Index (10th edition), The National Formulary, Annual Reports in Medical Chemistry, The American
Drug Index, and Martindale: The Extra Pharmacopoeia.
Besides structure and generic name (from USAN o r INN)
further entries are given: the CAS Registry Number, the
molecular mass, molecular formula, partition coefficients
and indications of the physiological effects and therapeutic
It is evident that identifying the first manufacturer has
been problematic, and has led to numerous incorrect statements. In the author’s favor it must be admitted that outsiders can easily lose their way in the jungle of licensing,
cross-licensing. subsidiary companies, franchises, etc., but
more care should have been taken in this area. It is evident
that other authors should be warned against using the book
as their primary source with regard to first manufacturersit could lead to regrettable mistakes.
The entry classification is also not very clearly presented.
Insufficient attention has been given to consistently listing
not only the activities but also the mechanisms. It would
have been worthwhile to go into this matter thoroughly,
since the mechanism of action is particularly important to
the medicinal chemist involved in drug design; this is especially the case when making a search in the 3(D)-Database
(Molecular Design Ltd.), which is identical in content.
Despite the above teething troubles, which one hopes will
be overcome in the next edition, the verdict still remains: this
is a useful book.
Wolfgang Hartwig [NB 1129 IE]
Address of all the reviewers of this work:
Bayer A G
Pharmaforschungszentrum Wuppertal (FRG)
Adolf Butenandt. Biochemiker, Hormonforscher, Wissenschaftspolitiker. By P . Karlson. Wissenschaftliche Verlagsgesellschaft, Stuttgart 1990. 336 pp., hardcover
D M 78.00. - ISBN 3-8047-0830-7
It is risky enough to write the biography of an eminent
scientist and individual during his lifetime, and even more so
when it comes from one of his closest students. Is it not
essential to stand at some distance to write a biography? Can
a student and close friend such as Peter Karlson write a
biography of his “boss” and teacher, without falling into the
traps of either excessive praise o r resentment? This book
proves that such doubts are unfounded.
Karlson spent 24 years close to Butenandt, years that
witnessed many changes in Butenandt’s many-sided life, including the beginnings of research into viruses, insect biochemistry, and hormones and the introduction of the geneproduct hypothesis. I t was in the latter studies that Karlson
was most closely involved. However, the lively and absorbing account is not confined to these years; the author
has carried out scholarly study into Butenandt’s childhood
and youth, his hometown, and his student days, and he has
continued this into Butenandt’s later years with devoted
interest. His factual and impressive account of the life of this
great researcher contains not only a wealth of scientific history and factual information, but also much personal detail
and historical background.
1first came to know AdolfButenandt personally during my
work in the Max-Planck-Gesellschaft from 1962 onwards,
although of course I was already familiar with his work
before this. For me an important criterion in assessing any
Ar7ge:L.M.Chem. Int. Ed. Engl. 30 (1991)No. 7
one of the older generation is how he behaved during the
Hitler regime, and therefore I will quote from Karlson’s book
the passage describing how Butenandt was forced to turn
down the Nobel Prize: “Butenandt was summoned to the
Reichskultursministerium. At the door stood a towering SS
man, who remained there silently o n guard duty. On the desk
lay a very harshly worded letter of refusal. Menzel said: ‘This
draft has been on the Fuhrer’s desk and he has approved it,
and therefore none of its text can be altered.’ Butenandt read
the letter, found it unacceptable, and said that he was unable
to sign it immediately. He was given three days to think it
over. Menzel dismissed him with the words: ‘But please consider carefully what consequences it will have for you and
your family if you fail to obey an order of the Fuhrer in
wartime!’ Adolf Butenandt went home with this moral
dilemma and discussed it with his wife. After much thought
they decided together that Butenandt would not sign this
letter, but would instead send a courteous and factual letter
to Stockholm. Shortly afterwards Alfred Kuhn and Fritz
von Wettstein arrived. They too were aware of the text of the
letter that Butenandt was supposed to sign. They both urged
him not to put up any foolish resistance in view of the
menacing political situation. Kuhn’s exact words were ‘I
shall not leave your house until you promise us that you will
not d o anything foolish. You would achieve nothing by refusing to sign, and you would risk bringing ruin on your
family and your academic institute. That would be stupid.’
These conversations, especially those with his friends Kuhn
and Wettstein, finally persuaded Butenandt to sign the letter.. . it still remains a painful recollection for Butenandt
that he yielded to the President’s [the President of the KaiserWilhelm-Gesellschaft] request and to his friends’ entreaties.
He said this was the only time that he had ever signed anything that was untrue!” Can any scientist of the younger
generation fully appreciate what was going on at that time in
the country and in the minds of many of its people? It is good
to find such matters treated so openly in this biography.
Reviewing this comprehensive and, at the same time, highly readable account of the life’s work of AdolfButenandt has
again evoked my admiration of the remarkable versatility of
this researcher. After earning a Nobel Prize for the discovery
and structure determination of sex hormones, he went on to
achieve at least two o r three further scientific successes of
comparable importance, in his research on viruses, in the
isolation and structure determination of insect hormones,
and finally in his research on gene products which was stimulated by his association with Kiihn. However, it is unfortunate from the standpoint of scientific history that
the scientific community has apparently forgotten that
Butenandt proposed the “one gene one enzyme” theory as
early as 1940, at least five years before George Beadle.
I experienced firsthand Butenandt’s activities in the
organizational aspects of science, especially his work as
president of the Max-Planck-Gesellschaft. Karlson describes
this period of Butenandt’s life from a thorough knowledge of
the facts, telling how for twelve years Butenandt guided the
fortunes of the Max-Planck-Gesellschaft in a way that was
both well-informed and personally honest-one can even say
in a noble and dignified way.
This discussion has now become not only a favorable
book review but also a eulogy of Butenandt himself-I hope
he will forgive me.
The book can be recommended to everyone with an interest in scientific history, from the student to the emeritus
professor. Their scientific knowledge will benefit from reading it, and it will extend their knowledge of scientific history
and of the turbulent period covered by Butenandt’s life from
0 VCH VerlagsgesellschaftmbH, W-6940 Weinheim,1991
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