The scientific collaboration between the United States and Japan in the field of cancer goes back many years. In this successful international collaboration cancer chemotherapy has been one of the most productive areas. Pioneers such as YOSHIDA, UMEZAWA, SHEAR, and GOLDIN established firm links of mutual trust and respect in the period after the Second Great War. Japanese drugs, such as mitomycin C and bleomycin have become mainstays of clinical oncology in the U. S. and throughout the world. Many drugs developed in the U. S. have become established in Japanese cancer therapy. Within the cancer chemotherapy field the antitumor antibiotics rank as one of the most important groups. In the U . S. -J apanese collaboration this group of drugs has taken the paramount role. The Japanese, under the leadership of U mezawa, are considered to be among the most innovative and productive in this area which has also had great emphasis in the United States as part of the National Cancer Institute's drug development program and in the pharmaceutical industry. This extended collaboration in general oncology, and chemotherapy in particular, has received increased impetus by and support from the official U . S. -J apan Joint Agreement on cancer research, which was established in 1974 between the National Cancer Institute and the Japanese Society for the Promotion of Science. One of the subsections of this agreement is cancer therapy with emphasis on chemotherapy.

This two-volume treatise, the collected effort of more than 50 authors, represents the first comprehensive survey of the chemistry and biology of the set of molecules known as peptide growth factors. Although there have been many symposia on this topic, and numerous publications of reviews dealing with selected subsets of growth factors, the entired field has never been covered in a single treatise. It is essential to do this at the present time, as the number of journal articles on peptide growth factors now makes it almost im anyone person to stay informed on this subject by reading the possible for At the same time it is becoming increasingly apparent that primary literature. these substances are of universal importance in biology and medicine and that the original classification of these molecules, based on the laboratory setting of their discovery, as "growth factors," "lymphokines," "cytokines," or "colony-stimulating factors," was quite artifactual; they are in fact the basis of a common language for intercellular communication. As a set they affect es sentially every cell in the body, and in this regard they provide the basis to develop a unified science of cell biology, germane to all of biomedical research."

Over the past two decades a number of attempts have been made, with varying degrees of success, to collect in a single treatise available information on the basic and applied pharmacology and biochemical mechanism of action of antineoplastic and immunosuppressive agents. The logarithmic growth of knowledge in this field has made it progressively more difficult to do justice to all aspects of this topic, and it is possible that the present handbook, more than four years in preparation, may be the last attempt to survey in a. single volume the entire field of drugs em ployed in cancer chemotherapy and immunosuppression. Even in the present instance, it has proved necessary for practical reasons to publish the material in two parts, although the plan of the work constitutes, at least in the editors' view, a single integrated treatment of this research area. A number of factors have contributed to the continuous expansion of research in the areas of cancer chemotherapy and immunosuppression. Active compounds have been emerging at ever-increasing rates from experimental tumor screening systems maintained by a variety of private and governmental laboratories through out the world. At the molecular level, knowledge of the modes of action of estab lished agents has continued to expand, and has permitted rational drug design to playa significantly greater role in a process which, in its early years, depended almost completely upon empirical and fortuitous observations."

The intestine, particularly the small bowel, represents a large surface (in the adult 2 human approximately 200m ) through which the body is exposed to its environment. A vigorous substrate exchange takes place across this large surface: nutrients and xenobiotics are absorbed from the lumen into the bloodstream or the lymph, and simultaneously, the same types of substrate pass back into the lumen. The luminal surface of the intestine is lined with a "leaky" epithelium, thus the passage of the substrates, in either direction, proceeds via both transcellular and intercellular routes. Simple and carrier-mediated diffusion, active transport, pinocytosis, phagocytosis and persorption are all involved in this passage across the intestinal wall. The term "intestinal permeation" refers to the process of passage of various substances across the gut wall, either from the lumen into the blood or lymph, or in the opposite direction. "Permeability" is the condition of the gut which governs the rate of this complex two-way passage. The pharmacologist's interest in the problem of intestinal permeation is twofold: on the one hand, this process determines thebioavailability of drugs and contributes significantly to the pharmacokinetics and toxicokinetics of xeno biotics; on the other hand, the pharmacodynamic effects of many drugs are manifested in a significant alteration of the physiological process of intestinal permeation.

It is quite amazing that the oldest group of medically useful antibiotics, the p-Iactams, are still providing basic microbiologists, biochemists, and clinicians with surprises over 50 years after Fleming's discovery of penicillin production by Penicillium. By the end of the 1950s, the future of the penicillins seemed doubtful as resistant strains of Staphylococcus aureus began to increase in hospital populations. However, the development of semisynthetic penicillins provided new structures with resistance to penicillinase and with broad-spectrum activity. In the 1960s, the discovery of cephalosporin C production by Cephalosporium and its conversion to valuable broad-spectrum antibiotics by semisynthetic means excited the world of chemotherapy. In the early 1970s, the 40-year-old notion that p-lactams were produced only by fungi was destroyed by the discovery of cephamycin production by Streptomyces. Again this basic discovery was exploited by the development of the semisynthetic cefoxitin, which has even broader activity than earlier p-lactams. Later in the 1970 s came the discoveries of nocardicins from Nocardia, clavulanic acid from Streptomyces, and the carbapenems from Streptomyces. Now in the 1980s we learn that p-lactams are produced even by unicellular bacteria and that semisynthetic derivatives of these monobactams may find their way into medicine. Indeed, the future of the prolific p-lactam family seems brighter with each passing decade.

The resolution of links between exposure to components of our complex environmental and causation of reproductive effects in the population constitutes an important problem in the field of toxicology. The focus of this volume is developmental toxicology, which represents one aspect of reproductive toxicology dealing with the study of adverse effects on the developing conceptus. Developmental toxicology, which includes teratogenesis as one of its manifesta tions, provides a fertile field for research in several basic and clinical disciplines; this field also receives input from several disoiplines such as developmental and molecu lar biology, pathology, pharmacology and toxicology, pediatrics and neonatology, and epidemiology. More recently we h~ve seen an emergence of interest in other fields such as perinatal physiology and postnatal behavior which have now become incorporated into the mainstream of research in this discipline. The present volume is an effort to provide a sampling of concepts currently under active investigation in several of the above fields. The authors have endeavored to provide up-to-date in formation on the following topics: detection and analysis of potential hazards to the conceptus in the workplace, pharmacokinetic aspects of the maternal/placental! fetal complex and its relationship to human birth defects, and probable mechanisms of teratogenesis as uncovered in certain well-defined situations. Also included are summaries of newer investigations on the emerging field of postnatal functional evaluations, i. e. , adverse effects on adult activities resultant from in utero exposure to toxic substances.

The problems associated with the pharmacologic and physiologic regulation of neuromuscular transmission and of the morphofunctional organization of neuromuscular junctions have attracted a wide range of investigators. Numerous handbooks, monographs, and reviews are devoted to this subject. At the same time, many fundamental and applied aspects of this trend continue to progress succesfully. In recent years, new experimental and clinical data on the structure and function of neuromuscular junctions have been gained, and new, more perfect neuromuscular blocking agents have been designed. It is these data that the present handbook mainly deals with. A considerable number of chapters have been written by authors from eastern Europe. This was done intentionally since much of their work has previously been published only in their own languages, and is thus inaccessible to most Western readers. This is why some of the data included in the volume are not quite the latest, but they contain fruitful ideas or important results and are of value for further progress in the pharmacology of neuromuscular transmission. Naturally, the methodological level of the investigations differs, depending on when they were carried out. The handbook contains a number of selected chapters on the pharmacology of neuromuscular junctions; they comprise data otherwise insufficiently reviewed or not dealt with at all. They furthermore reflect the up-to-date state of the problem and probable directions of further developments in this field. D. A. KHARKEVICH Contents CHAPTER 1 Neuromuscular Blocking Agents: General Considerations D. A. KHARKEVICH . . . . . . . . . . . . . . . .

The first three chapters of Vol. 3 of Bio-organic Marine Chemistry deal with the chemistry and function of peptides. Chapter 1 by Ireland and coworkers serves as an introduction to marine-derived peptides. It is arranged phyletically and encompasses the entire range from dipeptides to a compound with 95 amino acid residues. Peptides involved in primary metabolism and hence belonging to the realm of macromolecular biochemistry are excluded. However, it might be mentioned in passing that the dividing line between large and small molecule chemistry is continually becoming less distinct. Not only are more compounds of intermediate size, from 1,000 to 10,000 dalton, being discovered, but instruments and techniques, particularly in mass spectrometry and nuclear magnetic resonance have been developed for their structural elucidation by what is considered small molecule methodology. Two groups of peptides are discussed in separate chapters. Biologists who have observed and described the mating behavior of diverse species of marine invertebrates have long surmised that a chemical mechanism might be operating in many cases of individual as well as mass fertilization. The chemical activators of sea urchin sperm prove to be a series of peptides, whose structures and activity are discussed by Suzuki.

At the end of the initial meeting on Primary and Secondary Metabolism of Plant Cell Cultures at Schloss Rauischholzhausen, it was decided to convene similar events on a regular basis midway between the International Congress for Plant Tissue and Cell Cul ture. We felt it was necessary to bring representatives of the research teams working in this field together to assess progress as well as to discuss future directions. The Plant Biotechnology Institute of the National Research Council of Canada in Saskatoon, Saskatchewan was chosen to be the site for the second symposium held in 1988. The theme of this meeting was "The Regulation of Primary and Secondary Metabol ism in Plant Cells" and judging by the contributions published in this volume it was a timely and actual one indeed. I would like to thank my organizing committee and my research group for their efforts, the National Research Council of Canada for the financial assistance and the participants for their contributions which all contributed to make this symposium a success. A special thank you to Mrs. L. -Blashill and R. Gallays for their assistance in hosting this event. Last but not least I would like to thank our publisher, Springer-Verlag, Heidelberg for their deci sion to publish the proceedings of this and future symposia.

Fever has always been recognised as the major sign of infectious disease as well as being associated with other illnesses. The suggestion of publishing a volume dedicated exclusively to the subject of fever in the Handbook of Experimental Pharmacology series was one that greatly appealed to me, and I felt very honoured when I was invited to edit it. The first ideas about this volume were conceived in the latter part of 1977 and by the middle of 1978 the first authors had been approached. As is usual with such publications, by the time the first manuscripts were beginning to arrive in the late spring of 1979 there were still a few chapters for which authors had not yet been found. Finally by the end of 1981 the volume was complete. Because of the span of time over which the chapters were written, some refer to more recent work than others; however, I do not feel that this detracts from the overall contribution of all the chapters.

It is quite amazing that the oldest group of medically useful antibiotics, the fJ-Iactams, are still providing basic microbiologists, biochemists, and clinicians with surprises over 50 years after Fleming's discovery of penicillin production by Penicillium. By the end of the 1950s, the future of the penicillins seemed doubtful as resistant strains of Staphylococcus aureus began to increase in hospital populations. However, the development of semisynthetic penicillins provided new structures with resistance to penicillinase and with broad-spectrum activity. In the 1960s, the discovery of cephalosporin C production by Cephalosporium and its conversion to valuable broad-spectrum antibiotics by semisynthetic means excited the world of chemotherapy. In the early 1970s, the 40-year-old notion that fJ-Iactams were produced only by fungi was destroyed by the discovery of cephamycin production by Streptomyces. Again this basic discovery was exploited by the deVelopment of the semisynthetic cefoxitin, which has even broader activity than earlier fJ-Iactams. Later in the 1970s came the discoveries of nocardicins from Nocardia, clavulanic acid from Streptomyces, and the carbapenems from Streptomyces. Now in the 1980s we learn that fJ-Iactams are produced even by unicellular bacteria and that semisynthetic derivatives of these monobactams may find their way into medicine. Indeed, the future of the prolific fJ-Iactam family seems brighter with each passing decade.

The study of tumour resistance to anticancer drugs has been the subject of many publications since the initial discovery of the phenomenon by J. H. Burchenal and colleagues in 1950. Many papers have been published since then reporting development of resistance to most of the well-known anticancer agents in many different animal tumour systems, both in vivo and in vitro. Many different mechanisms of resistance have been described, and it is clear that the tumour cell has a wide diversity of options in overcoming the cell-killing activity of these agents. Definition of the magnitude of the phenomenon in the clinic is, however, much more problematical, and it is with this in mind that the initial chapter, seeks to out line the problem as the clinicians see it. It appears that the phenomenon of true resistance to a drug, as the biochemist would recognise it, is an important cause of the failure which clinicians experience in treating the disease. The extent of the contribution of this phenomenon to the failure of treatment cannot easily be evaluated at the present time, but it is hoped that the development and application of new and more sophisticated techniques for the analysis of cellular sub populations may help to give a more exact estimate and to shed some light on the causes of failure of many of the present therapeutic techniques."

The cells of the immune system generate a large variety of binding sites which differ in their binding specificities and can therefore react specifically with a large variety of ligands. These binding sites are part of receptor molecules, enabling the system to react to the universe of antigens. The classical antigen receptor is the antibody molecule, and accord ingly the first session of this colloquium deals with a classical sub ject, namely antibody structure. Dramatic recent advances in this field make it possible to interrelate primary and three-dimensional struc ture both to each other and to function, i.e. the binding of antigen and possible reactions occurring in the antibody molecule upon antigen binding. The latter point is of particular interest since it may be relevant not only for effector functions of antibodies such as the binding of complement, but also for the triggering of a lymphocyte through its antibody receptor for antigen."

Das Buch enthalt Kapitel uber: M. B. Bottorff, W. E. Evans, Memphis, TN, USA: "Uberwachung der Medikament-Konzentration"E. Truscheit, I. Hillebrand, B. Junge, L. Muller, W. Puls, D. D. Schmidt, Wuppertal, FRG: "Inhibitoren der mikrobiellen " "alpha-Glucosidase: Chemie, Biochemie und potentielle " "therapeutische Anwendungen"H. Will, Berlin-Buch, GDR: "Plasminogen-Aktivatoren: Molekuleigenschaften, biologische " "Zellfunktion und klinische Anwendung""

Table of Contents -Shape-Memory Polymers and Shape-Changing Polymers By M. Behl, J. Zotzmann, and A. Lendlein -Shape-Memory Polymer Composites By Samy A. Madbouly and Andreas Lendlein -Characterization Methods for Shape-Memory Polymers By W. Wagermaier, K. Kratz, M. Heuchel, and A. Lendlein -Shape-Memory Polymers for Biomedical Applications By Christopher M. Yakacki and Ken Gall -Controlled Drug Release from Biodegradable Shape-Memory Polymers By ChristianWischke, Axel T. Neffe, and Andreas Lendlein

Continuing the Respiratory Pharmacology and Pharmacotherapy series, this volume explores the pathophysiology and therapy of rhinitis. The volume is introduced by a chapter describing the normal anatomy and physiology of the nose and sinuses. Against this background the contributing authors describe and discuss the immunological and pathological changes which occur in rhinitis. The various causes and the types of rhinitis - such as allergic, vasomotor, and infectious - are discussed as are the treatments available (pharmacotherapy, immunotherapy, surgery). The book concludes with a description of the animal models of rhinitis which are now available. This book will be of interest to bench scientists and clinicians alike.

One of the most impressive works of scholarship in the field of experimental pharmacology has been the Heffter-Heubner Handbuch der experimentellen Pharmakologie, internationalized some years ago under the title Handbook 0/ Experimental Pharmacology and kept up to date by a series of numbered Ergiin zungswerke or supplementary volumes which have now replaced in importance the original Handbuch. These volumes constitute a valuable and continuously up dated multi author review series of topics important in modern pharmacology and allied sciences. The Editorial Board of the Handbook invited me 2 years ago to undertake, as subeditor, the preparation of a new volume entitled The Cholinergic Synapse. A previous volume in this series, vol. 15, Cholinesterases and Anticholinesterase Agents, edited by GEORGE KOELLE, was published in 1963 and was far wider in scope than its title suggested: it was, in fact an authoritative summing up of the whole subject of cholinergic function and still has some value today as an account of the state of the art as it was at that time. Since then another excellent review, of a specific cholinergic synapse, has appeared in this series: this was vol. 42, Neuromuscular Junction, edited by ELEANOR ZAIMIS and published in 1976. A third volume, vol. 53, Pharmacology o/Ganglionic Transmission, which appeared in 1980 and was edited by D. A. KHARKEVICH, includes important aspects of autonomic cholinergic function.

This book contains the papers that were presented at the "Crystallo graphic and Modeling Methods in Molecular Design Symposium" in Gulf Shores, Alabama, April 30 to May 3, 1989. During the past few years, there has been a burst of activity in this area, especially related to drug design and protein engineering projects. The purpose of the symposium and this book is to provide an up-to date review of the most recent experimental and theoretical approaches that are being used for molecular design. The book covers several re cent examples of approaches for using crystallography in conjunction with forefront modeling methods for guiding the development of en zyme inhibitors and of peptides and proteins with modified biological and physical properties. In addition, this book contains discussions of new approaches for combining crystallographic data and advanced computational techniques for aiding in the design of enzyme inhibitors and other compounds that bind to selected biological targets. This book is therefore of interest not only to molecular biologists and biochem ists, but is stimulating reading for anyone involved in structural biol ogy, pharmaceutical chemistry, enzymology, protein engineering, and biotechnology. The meeting was the third in a series of symposia initiated and spon sored by the Department of Biochemistry, University of Alabama at Birmingham.

In the first years of the existence of this series of monographs, during the so-called "Golden Age" of drug research, the majority of the pa pers published were mainly concerned with the traditional domains of drug research, namely chemistry, pharmacology, toxicology and pre clinical investigations. The series' aim was to give coverage to impor tant areas of research, to introduce new active substances with thera peutic potential and to call attention to unsolved problems. This objective has not changed. The table of contents of the present volume makes evident, however, that the search for new medicines has become increasingly complex, and additional, new disciplines have entered the research arena. The series now includes reviews on bio chemical, biological, immunological, physiological and medicinal aspects of drug research. Researchers actively engaged in the various scientific fields forming the entity of drug research can benefit from the wealth of knowledge and experience of the respective authors, and will be assisted in their endeavour to discover new pharmaceutical agents. Those simply wanting to keep abreast of new developments in the complex, multi-discipline science can turn to the "Progress in Drug Research" volumes as an almost encyclopaedic source of information without having to consult the innumerable original publications. Volume 32 contains 12 reviews, a subject index, an index for the close to 400 articles published in the series so far, and an author and titles index for all 32 volumes."

Catecholamines 1922 -1971 H. BLASCHKO Adrenaline and related substances were discussed in the 1924 edition of Hefl'ter's Handbook by PAUL TRENDELENBURG. On 164 pages he described what was then known not only of adrenaline and its closest relatives but also of the sympathomimetic compounds such as tyramine and ephedrine. When the present Editors of the Handbook entrusted us with the task of editing the present Volume it was decided to restrict it to adrenaline and the other naturally occurring catecholamines. The sympathomimetic amines in general will be discussed only in their relation to the catecholamines. Since TRENDELENBURG completed his review this field has undergone an enormous expansion. There has been a wealth of new findings, and a succession of new ideas. The new theories that have been built into contemporary thought will be fully discussed in the succeeding contributions. But many of the hypotheses that have been put forward since 1924 have long been discarded and yet, they have often led to important observations that we still consider as valid.

Of all the parasitic diseases that beset man in the warmer parts of the world, malaria is still the major cause of morbidity and mortality. In spite of intensive efforts to interrrupt its transmission malaria still threatens over 800 million people, more than one-fifth of the world's population. Malignant tertian malaria caused by Plasmodium Jalciparum probably kills a million every year. Vivax malaria temporarily incapacitates millions more. The search for antimalarial drugs, both natural and syn. thetic, has been and continues to be one of the most challenging and, at times, rewarding exercises ever undertaken by ;:;hemists and biologists. The magnitude of the effort is reflected by the fact that, in the last 15 years, well over 250000 compounds have been screened for antimalarial activity in just one programme, that carried out under the auspices of the Walter Reed Army Institute of Research, not to mention sporadic studies undertaken by other research workers and organisations. While most people engaged in the search for new drugs agree that a rational approach based on knowledge of the intimate biochemical pathways of the target cells would be ideal as well as intellectually satisfying, most are reluctantly obliged to concede that, up to the present time, the chances of success following a more or less empirical search have been far greater. Spectacular advances in molecular biology and biochemistry in recent years, however, are rapidly changing this situation.

The first useful antibiotic found by screening was streptomycin. The late Prof. WAKSMAN started screening for antibacterial antibiotics in 1940 and, after finding actinomycin in 1941, he and his collaborators discovered streptomycin in 1944. This antibiotic made a great contribution in saving human lives from tuberculosis and acute serious infections. About 1957, after wide usage of such antibiotics as penicillin, streptomycin, chloramphenicol, tetracycline, and erythromycin, staphy- lococci and Gram negative organisms resistant to all or most antibiotic drugs ap- peared in hospital patients. The origin and treatment of such resistant strains be- came a major topic of investigation. At that time, kanamycin was discovered and used in the treatment of resistant infections. It may be said that the appearance of resistant strains stimulated a resurgence of research on new antibacterial antibiot- ics and their derivatives. In 1965, kanamycin-resistant strains were found in hospital patients and, undertaking the study of the mechanisms of resistance, I found that resistant strains produce intracellular enzymes that can transfer either the terminal phos- phate of ATP or the acetate of acetyl-CoA to the 3' -hydroxyl or the 6' -amino group of 2-deoxystreptamine~containing antibiotics. These results, reported in 1967, made it possible to design new synthetic derivatives that would inhibit the growth of kanamycin resistant strains of microorganisms. Thus, a new research area was opened: the development of aminoglycosides useful in the treatment of drug-resis- tant infections.

Resin glycosides are part of a very extensive family of secondary metabolites known as glycolipids or lipo-oligosaccharides and are constituents of complex resins (glycoresins) (1) unique to the morning glory family, Convolvulaceae (2). These active principles are responsible for the drastic purgative action of all the important Convolvulaceous species used in traditional medicine throughout the world since ancient times. Several commercial purgative crude drugs can be prepared from the roots of different species of Mexican morning glories. Their incorporation as therapeutic agents in Europe is an outstanding example of the assimilation of botanical drugs from the Americas as substitutes for traditional Old World remedies (3). Even though phytochemical investigations on the constituents of these drugs were initiated during the second half of the nineteenth century, the structure of their active ingredients still remains poorly known for some examples of these purgative roots. During the last two decades, the higher resolution c- abilities of modern analytical isolation techniques used in conjunction with pow- ful spectroscopic methods have facilitated the elucidation of the active principles of these relevant herbal products. This chapter describes the ethnobotanical information associated with the p- gative morning glory species and how traditional usages were instrumental in plant selection for chemical studies. The advantages and limitations of available analy- cal techniques for the isolation, puri?cation, and structure characterization of the individual constituents of these complex glycoconjugates are also discussed.