Cyclic nucleotides are intimately involved in the consequences of either stimulation or blockade of receptors; therefore, an understanding of the biochemistry of cyclic nucleotides ought to be important for pharmacologists. Pharmacology is a science that among other things investigates chemical compounds that affect the physiology of cells, tissues and organs. Frequently pharmacologists account for the effect of low concentrations of a drug upon a tissue by invoking the presence of a receptor upon the surface of the cell. Traditional pharmacologists excelled at identifying and classifying the properties of receptors. A. J. CLARK'S monograph in the earlier series of the Handbook of Experimental Pharmacology (CLARK 1937) summarized the mathematics underlying the traditional pharmacological approach towards receptors. By its nature, however, classic pharmacology provided little useful information about the intracellular events occurring as a consequence of occupying a receptor; for example, ALQUIST (1948) identified the beta-adrenocep tor, but he did not provide any insight into how stimulation of the receptor produces tissue-specific physiological responses. The discovery of cyclic AMP by RALL and SUTHERLAND (see RALL, Vol. I) led to biochemical investigations of many different receptors (including ALQUIST'S beta-adrenoceptor) that share a cyclic nucleotide as a common factor in the biochemical mechanisms that translate the occupancy of receptors into physiological effects. Ten years ago, in the introduction to their monograph on cyclic nucleotides, ROBISON et al. (1971) commented on the rapid growth of interest in cyclic nucleotides over the preceding years."

Wenn uber Fortschritte der Chemie der Gallotannine berichtet werden soll, so muss ein Ausgangspunkt gewahlt werden, von dem aus die neu gewonnenen Erkenntnisse geschildert werden. Das ist in unserem Falle nicht schwer. EMIL FISCHER hatte fur das chinesische Gallotannin (aus den Blattgallen von Rhus semialata) und das turkische Gallotannin (aus den Zweiggallen von Quercus infectoria) das bekannte Bauprinzip der polygalloylierten Glucosen herausgearbeitet. Aber weder ihm noch KARRER (43, 44) ist es moglich gewesen, aus dem Gemisch von Substanzen, die sie untersuchten, einzelne Individuen zu isolieren, deren exakte Konstitution man hatte aufklaren und angeben konnen. Auch mit den modernen Methoden der Gegenstromverteilung und Verteilungschromato graphie ist eine Auf trennung dieser Gemische offenbar bis heute noch nicht gelungen. Ahnlich liegen die Verhaltnisse beim Sumach-Gerbstoff (aus Rhus coriaria), von dem MUNz (58) gezeigt hat, dass der Hauptteil der Substanz aus einer Pentagalloyl-glucose besteht. Erwahnt man noch das Glucogallin und Tetrarin, die GILSON (30, 30a) aus chinesischem Rhabarber isoliert hat, und das Acertannin, ein Digalloyl-anhydrohexit aus koreanischem Acer ginnale, von PERKIN und UYEDA (65), so hat man die im Jahre 1929 bekannten Forschungsergebnisse zusammengestellt, mit Ausnahme des Hamameli-tannins und der Chebulinsaure, die aber im nachstehenden Bericht noch ausfuhrlicher behandelt werden. Somit kann also das Jahr 1929 als Ausgangspunkt fur die vorliegende Berichterstattung gewahlt werden. 11. Gallotannine: Ellagsaure-freie Gerbstoffe. I. Hamameli-tannin."

Eleven years have elapsed since the appearance of the first Volume and it is with great pleasure that the Editor is now able to present Volume 14. During these eleven years various fields of drug research have undergone important, partly revolutionary, changes. A number of these have already been dealt with, so that the series PROGRESS IN DRUG RESEARCH contains a comprehensive review of a substantial part of our current knowledge. The Editor is particularly grateful for the opportunity of transmitting to those connected with the development of drugs the extensive knowledge of the Authors, who, without exception, are themselves actively engaged in research. Drug research is currently in a state of transformation: reconsideration in the light of the past and reorientation with a view to the future. To a large extent this is due to the tumultuous developments in the last 20 years, developments which are unparalleled in the history of medicine and the consequences of which cannot yet be completely evaluated. Unfortunately, however, the current situation is not devoid of its unpleasant and even tragic aspects, aspects which fall outside the research worker's sphere or influence. Those connected with drug research, be they in industry, in universities or in clinics, are aware of these problems, and, as a result of this awareness, are all the more in need of an aid which will assist them in ascertaining the current position and in fixing future goals.

Disturbances of haemostasis and thromboembolic disorders still constitute a great problem in clinical practice. Increasing insight into the mechanism of blood coagula tion has led to more effective therapy and prophylaxis. Particularly, the understand ing of the biochemistry of fibrinolysis has provided possibilities for the pharma cological interference of these processes, which has resulted in effective haemostatic agents and useful antithrombotic ones. The development of antifibrinolytics for interfering with pathological fibrinolytic processes is nearly complete and has led to the development of drugs essential to the therapy of hyperfibrinolytic bleeding. The search for fibrinolytics for dissolving intravascular thrombi has led to highly effective compounds. This development is still under way and promising results are hoped. Spontaneous dissolution of blood clots is a phenomenon which was described a century ago. First investigations of this process assured that there is in the organism a system capable of removing the fibrin which is formed during blood coagulation after it has fulfilled its physiological function. This fibrinolytic system is specifically adapted to the degradation of insoluble fibrin into soluble degradation products. In the past 30 years, thorough investigation of this system has clarified the fibrinolytic process, its physiological role and its meaning as a pathogenetic principle. A good knowledge of these processes is required for an understanding of the effects and side effects of fibrinolytics and antifibrinolytics, which comprise the basis of methods for the detection of fibrinolytic processes in the organism and of the control of therapy with these drugs."

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 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.

The European School of Oncology came into existence to respond to a need for information, education and training in the field of the diagnosis and treatment of cancer. There are two main reasons why such an initiative was considered necessary. Firstly, the teaching of oncology requires a rigorously multidisciplinary approach which is difficult for the Universities to put into practice since their system is mainly disciplinary orientated. Secondly, the rate of technological development that impinges on the diagnosis and treatment of cancer has been so rapid that it is not an easy task for medical faculties to adapt their curricula flexibly. With its residential courses for organ pathologies and the seminars on new techniques (laser, monoclonal antibodies, imaging techniques etc.) or on the principal therapeutic controversies (conservative or mutilating surgery, primary or adjuvant chemotherapy, radiotherapy alone or integrated), it is the ambition of the European School of Oncology to fill a cultural and scientific gap and, thereby, create a bridge between the University and Industry and between these two and daily medical practice. One of the more recent initiatives of ESO has been the institution of permanent study groups, also called task forces, where a limited number of leading experts are invited to meet once a year with the aim of defining the state of the art and possibly reaching a consensus on future developments in specific fields of oncology.

The development of a new antiarrhythmic drug involves many people with disparate skills. The organic chemist who makes it is guided not only by the structure-action relations of previous compounds, but by anticipation of a requirement for a particular type of action. In fact several of the best-known antiarrhythmics, including lidocaine, mexiletine, amiodarone and verapamil, were originally synthesized for other purposes. Physicians have to determine whether the new drug works, and pharma cologists how it works. For some years I have believed that there was room for a work which could be understood by all these groups and which could enlighten each about the point of view of the others. Thus when I was invited by Springer-Verlag to prepare a volume in their series Handbook of Experimental Pharmacology, I already had a firm conception of what its form should be. In any multi-author work there are two objectives which cannot always readily be reconciled. The first is to select topics which would relate to each other in a coherent manner. to give a logical and orderly shape to the volume as a whole. The second is to offer authors the greatest possible freedom to express themselves as they wish. When the general design was complete, prospective contributors were invited to write specific chapters, being provided with a complete list of their coauthors and chosen topics, so that they could avoid overlap."

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.

Das Buch enthalt Kapitel uber: M. Azria, Basel, CH: "Calcitonin - Physiologische und Pharmakologische Aspekte"U. Niemeyer, J. Engel, P. Hilgard, M. Peukert, J. Pohl, H. Sindermann, Bielefeld, FRG: "Mafosfamid - Ein Derivat des " "4-Hydroxycyclophosphamids"S. Grunwald, G.P. Pfeifer, Frankfurt, FRG: "Enzymatische DNA Methylierung""

From a logical point of view, cell division is regulated by the environment and by the ability of the cell to respond to the environmental signals. The terminology of the cell cycle, the elaborate mathematical models, and the kinetic analyses are all convenient notations and descriptions of the behavior of populations of cells. However, they tell us very little about the fundamental molecular mechanisms that control cell proliferation. Stated in other terms, what controls cell reproduction are growth factors in the environment and genes and gene products inside the cell or at its surface. This book examines the aforementioned growth factors, the study of which has made very rapid progress in the past few years. The selection of topics has been influenced by logistic considerations, but the book, as a whole, gives a broad survey of the state of the art of this exciting field. For this, thanks are due to the contributors, who have given much time to the preparation of the manuscripts and have met the deadline with a punctuality that is uncommon among biomedical scientists. I would also like to thank Ms. NORA PERRETT and the staff of Springer-Verlag for their help in editing the manuscripts and in preparing the production of the book.

The present 18th volume differs from previous volumes insofar as, with the exception of two contributions, it is exclusively concerned with problems of a single field, namely Tropical Medicine. This was occasioned by the Internatio nal Symposium on the investigation and treatment of infectious tropical diseases held in Bombay in January 1974 and organized by the editor in collaboration with the Minister of Health of the State of Maharashtra, Dr. Rafiq Zakaria, the Director of the Hafl'kine Institute, Dr. B. Gaitonde, and with Dr. J. N. Banerjee, Dr. S. K. Bhattacharya and Mr. P. D'Souza. The Hafl'kine Institute celebrated on this occasion the 75th year of its existence and everyone entrusted with the organisation of the Symposium considered themselves fortunate to have been able to help in strengthening the contacts between Indian and foreign research workers, in the hope of, in this way, making a contribution to the fight against infectious tropical diseases. The editor hopes that the present 18th volume will represent comprehensive information on the topics treated at the Symposium; the 19th volume, which will soon appear, is concerned with the same area, so that the two volumes together should give a good picture of the many still unsolved problems. The editor would also like to take this opportunity of expressing his gratitude to his collaborator, Dr. A. Niif, who, as usual, performed valuable services in working over the manuscripts."

Volume 28 of 'Progress in Drug Research' contains 8 articles, a subject index for this volume, an alphabetic subject index for volumes 1-28, and an author and subject index for all the volumes which have so far been published. The contributions of volume 28 are particularly con cerned with biogenic amines, with immunology and the pharmacology of the immune system, with antiviral agents, with amino-quinoline an timalarials, with the axoplasmic transport, with drug treatment of asthma and with the role of adipose tissue in the distribution and stor age of drugs. The authors have tried, and I think they have succeded, not only to summarize the current status of particular fields of drug research, but also to provide leads for future research activity. The articles of this volume will be of special value to those actively engaged in drug re search, and to those who wish to keep abrest ofthe latest developments influencing modern therapy. In addition, it is believed that the 28 volu mes of 'Progress in Drug Research' now available represent a useful reference work of encyclopedic character. l The editor would like to take the bccasion of the publication of this volume to express his gratitude both to, the authors and to the readers."

Volumes 18 and 19 of "Progress in Drug Research" differed from the earlier volumes insofar as they were concerned almost exclusively with problems in the field of Tropical Medicine. The editor and publishers believed that in this way some contribution could be made to the solution of some of the many problems with which the developing countries are burdened. The 20th volume, however, is in the customary form; it contains 17 contributions from various areas of drug research and therapy. Whereas the articles concentrate on a short representation of the progress which has already been made, nevertheless reference is also made to the many unsolved problems within the particular areas. The editor hopes that the 20th volume will not only represent a comprehensive review but will also be of some use in focusing further investigations on problems of medicine that have still not been overcome. The editor would also like to take this opportunity of expressing his gratitude to Dr. A. Naffor carefully working over the manuscripts and correcting proofs. Thanks are also due to the publishers and the printers, Druckerei Birkhauser, especially Dr. A. Birkhauser, Th. Birkhauser and C. Einsele, for their painstaking work on the printing and lay-out of the volume. August 1976 Dr. E. JUCKER Sandoz AG, Basel Vorwort Die Bande 18 und 19 der "Fortschritte der Arzneimitte1forschung" wichen insofern von den vorhergehenden Banden ab, a1s sie fast ausschliess1ich Prob1eme der Tropenkninkheiten behandelten.

Volume 26 of 'Progress in Drug Research' contains 10 articles, a subject index for this volume, an alphabetic subject index for volumes 1-26, and an author and subject index for all the volumes which have so far been published. The contributions of volume 26 cover a wide field of drug research and therapy, and some are directed towards tropical deseases. As in previous volumes, the authors have also tried not only to summa rise the current status of particular fields of drug research, but also to provide leads for future research activity. The articles in this volume will be of special value not only to those actively engaged in resolving the diverse problems in drug research, but also to those who wish to keep abrest of the latest developments influencing modern therapy. In addition, it is believed that the 26 volumes of "Progress in Drug Research" now available represent a useful reference work of an encyclo paedic character."

Two aspects of the biotechnology of medicinal and aromatic plants are of immediate application. (1) Micropropagation under controlled germ- free conditions which enables their fast multiplication and availability throughout the year irrespective of external environment - this is specially useful for elite and rare plants. (2) A large-scale culture and low-temperature storage of cells enables retention of their biosynthetic potential for the production of important secondary metabolites, med- icines, flavours and other pharmaceutical products. This book has been compiled with a view to bringing together information and literature on the biotechnology and the present state of the art of plant cell cultures for their potential use in the pharmaceutical industry. This volume comprises 29 chapters on the biotechnology of med- icinal and aromatic plants grouped into three sections, (1) microprop- agation, immobilization, cryopreservation, bioreactors, production of secondary metabolites and their impact in pharmacy, (2) production through cell cultures of antitumour compounds, lrDopa, shikonin, an- thraquinone, morphinan alkaloids, caffeine, berberine, valeoptriates, rosmarinic acid, quinine, tropanes, hypoxoside, ellipticine, paeoniflorin, saponins, cardenolides etc, and (3) distribution, economic importance, conventional propagation, review of the tissue culture work on micropropagation and the in vitro production of compounds of medicinal and pharmaceutical interest in various species of Cannabis, Centaurium, Cinchona, Digitalis, Duboisia, Hypoxia, Lithospermum, Ochrosia, Paeonia, Panax, Papavar, Rehmannia, Rhamnus and Rhaza.

" . . . the motto for the therapeutics of the future will have to be de sedibus et causis pharmacorum. " P. EHRLICH, 1909 Exciting events in the basic disciplines of virology, immunology, and pharmacology continue to advance the understanding of the pathogenesis and control of virus diseases. At the same time, the rational development of antiviral agents is attracting, to an increasing extent, the interest of workers in other disciplines. Improvements in technology facilitate the definition of potential target sites for antiviral intervention and unmask new viral and host genes. The outcome is a further steady development of new antiviral agents which approach the "magic bullets" first proposed by PAUL EHRLICH. Remarkable advances in protein synthetic methods that yield polypeptides which inhibit active sites of viral proteins have aided substantially in the basic and clinical study of these antiviral agents. In addition, the extremely rapid progression in recombinant DNA techniques, leading to the synthesis of large quantities of gene products, is also increasing our opportunities at a dashing pace. New information and developing technology facilitate research on the mechanism of action, toxicity, pharmacokinetics, and pharmacodynamics of new agents. The list of clinically effective antiviral agents is expanding and the number of potentially useful compounds is growing rapidly. This book is a combined theoretical text and practical manual which, it is hoped, will be of use to all who have an interest in virus diseases, particularly scientists, physicians and graduate students.

Over the last 25 years, few topics in medicine, and none in neurology, sur- pass Parkinson's disease from the viewpOInt of progress in understanding me- chanisms and treating symptoms. Our entire concept of anatomy (the very ex- istence of a nigrostriatal pathway) and physiology (dopaminergic trans- mission) has undergrone a revolution as the result of studies on Parkinson's disease leading to (a) the recognition of dopamine depletion as a crucial bio- chemical feature, and (b) the ability to alleviate symptoms by replenishing dopamine with levodopa. From this background has emerged a subclassifica- tion of dopamine receptors into Dl and D2 types, together with the develop- ment and therapeutic application of synthetic molecules that function as agonists at dopamine receptors. The pharmacological interrelationship be- tween parkinsonism (inadequate dopamine) and chorea (excessive dopamine) has been elucidated because dopaminomimetic agents were found to alleviate parkinsonism and induce chorea, while dopamine blocking drugs induced parkinsonism and alleviated chorea. Pharmacokinetic manipulation of levo- dopa achieved by adding extracerebral decarboxylase inhibitors (carbidopa, benserazide) decreased certain side effects and resulted in efficacy being at- tained with lower dosage. Extracerebral dopamine receptor blockers have proved invaluable in decreasing the emesis of dopaminomimetics, because the dopaminoceptive chemoreceptor trigger zone is located outside the blood- brain barrier. Recently, novel routes of administration of antiparkinson drugs, such as subcutaneous infusion, have been explored in an attempt to achieve more evenly sustained blood concentrations of therapeutic agents.

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.

Parasitic diseases are the most widespread of all the major diseases, currently 9 affecting about 3 x 10 people and innumerable domestic animals. There is no doubt that among these parasitic diseases, the helminthic infections of the gastrointestinal tract are about the most important because of their global distribution, their high prevalence, their effects on the nutritional status of men and animals, their effects on the physical and mental development of children, and their economic effects on the production of animals. Anthelmintics are important elements in the control of these gastrointestinal helminthic infections. In this volume the editors and authors have tried to find a way through the immense amount of information on anthelmintic drugs that is scattered throughout the literature. Different authors have critically examined this information from different angles. However, the aim of all has been to provide the information needed by veterinarians, physicians, and public health workers to select the most suitable drug for a given situation.

The literature on co-trimoxazole (TMP jSMX) is voluminous, but in the main it consists of research reports. The same can be said of various symposia that have appeared. This volume attempts to present the current status of this antibacterial combination in a series of topical reviews, each of which represents a comprehensive summary of a segment of the field. The editor acknowledges with appreciation the help provided by JACKIE, JENKS, LEE KUYPER, and particularly, RUTH Ross in the preparation of the Subject Index, and thanks Burroughs Wellcome Co. for providing access to library and word processing facilities. Research Triangle Park GEORGE H. HITCHINGS List of Authors Dr. J. F. ACAR, Hospital Saint-Joseph, 7, rue Pierre-Larousse, F-75674 Paris Cedex 14 Dr. N. ANAND, National Information Centre for Drugs and Pharmaceuticals, Central Drug Research Institute, Chattar Manzil, P. O. Box No. 173, Lucknow, 226001jIND Dr. D. W. BARRY, The Wellcome Research Laboratories, Burroughs Wellcome Co. , 3030 Cornwallis Road, Research Triangle Park, NC 27709jUSA Dr. R. E. BLACK, Center for Vaccine Development, University of Maryland, Division of Infectious Diseases, 29 S. Greene Street, Bressler Building, Room 404, Baltimore, MD 21201jUSA Dr. J. J. BURCHALL, Department of Microbiology, The Wellcome Research Laboratories, Burroughs Wellcome Co. , 3030 Cornwallis Road, Research Triangle Park, NC 27709jUSA Dr. S. R. M. BUSHBY, The Wellcome Research Laboratories, Burroughs Wellcome Co. , 3030 Cornwallis Road, Research Triangle Park, NC 27709jUSA Dr. M. L.

The construction of this volume has been guided by two personal convictions. Experience in the field of experimental chemotherapy, both in the pharmaceutical industry and academia, has convinced us that recent quantum technological advances in biochemistry, molecular biology, and immunology will permit and, indeed, necessitate an increasingly greater use of rational drug development in the future than has been the custom up to now. In Part l, therefore, we asked our contributors to provide detailed reviews covering the biology of the malaria parasites and their relation with their hosts, the experimental procedures including culture techniques that are necessary to take a drug from primary screening to clinical trial, and an account of antimalarial drug resistance. Our second conviction is that many research workers are all too loath to learn from the lessons of the past. For this reason we asked the contributors to Part 2 of this volume to review very thoroughly the widely scattered but voluminous literature on those few chemical groups that have provided the antimalarial drugs in clinical use at the present time. Much can be learned from the history of their development and the problems that have arisen with them in man. Some indeed may still have much to offer if they can be deployed in better ways than they are at present. This question has been taken up by several authors.