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 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."

Today, our world increasingly is conceived of as being molecular. An ever widening range of phenomena are described logically in terms of molecular properties and molecular interactions. The majority of known molecules are heterocyclic and heterocycles dominate the fields of biochemistry, medicinal chemistry, dyestuffs, photographic science and are of increasing importance in many others, including polymers, adhesives, and molecular engineering. Thus, the importance of heterocyclic chemistry continues to increase and this three volume work by Drs. R. R. Gupta, Mahendra Kumar and Vandana Gupta is a welcome addition to the available guides on the subject. Its scope places it in a useful niche between the single-volume texts and monographs of heterocyclic chemistry and the multivolume treatises. The authors have retained the well tried classical approach but have succeeded in placing their own individual spin on their arrangement. They have put together a well selected range from among the most important of the vast array offacts available. This factual material is ordered in a clear and logical fashion over the three volumes. The present work should be of great value to students-and practitioners of heterocyclic chemistry at all levels from the advanced undergraduate upwards. It will be of particular assistance in presenting a clear and modem view of the subject to those who use heterocycles in a variety of other fields and we wish it well.

In the beginning of this century physiology witnessed the creation of a new concept, the hormonal regulation of the work of the digestive organs. It was found that such essential functions as the flow of pancreatic juice and emptying of bile into the intestine were regulated by two hormones, secretin and cholecystokinin, respectively. Already in 1925 French authors attempted to measure the functional capacity of the exocrine pancreas by means of stimulation with secretin. The use fulness of the secretin test in this connection was definitely established by Scandinavian workers in the 1930's. In spite of the difficulties in obtaining secretin American authors succeeded in keeping the interest in the secretin test alive. The development in the 1950's of counter-current, ion exchange and chromato graphic techniques offered new possibilities in this field. The intestinal hormones were known to be relatively low molecular peptides and these could now be isolated in pure form. Thus secretin was isolated in 1961, and cholecystokinin in 1964. The newly developed methods for peptide analysis likewise soon brought us full information about the primary structure of the peptides. Gastrin, the specific stimulant of the gastric acid secretion, which was discovered in 1905 and acknowledged as a hormone in 1938, was the first of the gastrointestinal hormones for which the structure became known. This was in 1964. Synthesis soon followed. These developments are reviewed in the first chapter of the present volume."

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.

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""

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.

The "First International Conference on Traditional Chinese Medicine: Science, Regulation and Globalization" was held from August 30 to September 2, 2000 at the University of Maryland at College Park, Maryland. There were approximately 250 participants from the Peoples Republic of China, Taiwan, Hong Kong and the United States. This objective of this conference was to promote international collaboration for the modernization of Traditional Chinese herbal medicines (TCM) and their introduction into the global health care system. It was mainly sponsored by the Ministry of Science and Technology of the People's Republic of China and the NllI National Center for Complementary and Alternative Medicine (NCCAM). It was organized by Dr. William Tai, then director of the Institute of Global Chinese Affairs at the University of Maryland and Dr. Yuan Lin, president of Marco Polo Technologies, Bethesda, MD. This conference was conceived by Dr. Tai two years earlier recognizing that this was an appropriate time and also the unique location of the University of Maryland. Today, there is a growing recognition of the of alternative medicine in modem societies and the rapid loss of importance knowledge about traditional methods for the treatment of the multitude of human illnesses found throughout the world. TCM has been in common use in China for thousands of years; and many of its formulations are well defined.

" . . . 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.

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.

The pharmacokinetics of digitalis glycosides have been the subject of extensive re view (IISALO, 1977; ARONSON, 1980; PERRIER et ai., 1977). Research on glycoside kinetics has progressed at a rapid pace, requiring continuing reevaluation of the state of our understanding of this problem. The present article focuses on the effect of disease states (renal, gastrointestinal, thyroid, and cardiac) on the absorption, distribution, and clearance of a number of digitalis glycosides. Evidence is critically reviewed, and interpreted with respect to possible clinical implications. A. Renal Insufficiency I. Strophanthin Strophanthin disposition in renal failure has been evaluated in only two studies. KRAMER et ai. (1970) determined an elimination half-life of 14 h in normals as com pared to 60 h in anuric patients. Similar results were reported by BRASS and Pm LIPPS (1970) using tritiated strophanthin. They found a half-life value of 18 h in healthy individuals as compared to 68 h in anuric patients. The findings clearly in dicate that the elimination half-life of strophanthin is prolonged in renal failure."

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.

When I was asked some years ago by the editors of the Handbook of Experimental Pharmacology to edit a new volume on Antianginal Drugs, I agreed on the condition that, in accordance with my scientific background, primary emphasis be given to clinical pharmacology and therapeutics. It soon turned out that, due to rapid developments in this field, nothing of the previous volume on Antianginal Drugs by Charlier (Vol. 31, 1971) could be retained apart from its basic idea of devoting considerable space to methodology. Since editors must operate within certain limits, I had to abstain from dealing with acute myocardial infarction in detail despite the well-known overlap between unstable angina, the preinfarction syndrome, and acute myocardial infarction. It was only possible for acute myocardial infarction and the concept of reduction of infarct size to be briefly discussed within the chapter on pathophysiology of acute coronary insufficiency. The chapter on invasive methods provided an opportunity to touch on new approaches to early intervention in acute myocardial infarction. Here, intracoronary streptokinase therapy and PTCA are considered, again with attention to the overlap between mechanical and pharmacological interventions.

Epileptic disorders need treatment for many years or even for life, and this makes a thorough understanding of the pharmacokinetics and possible hazards and side effects of the drugs used in treatment mandatory. During recent decades our knowledge in this field has considerably increased, not least as a result of the development of specific and sensitive methods for the determination of anti epileptic agents in biological material. The clinical pharmacology of this group of drugs has been studied extensively and can today be regarded as well established. This does not necessarily mean that drug treatment of epilepsy is without problems. For example, it has recently been shown that one of the newer anti epileptic drugs, greeted with great enthusiasm by clinicians, may in rare instances induce serious damage to the liver and the pancreas, and seems even to have a certain teratogenic potential. Clinical problems should be understood as a challenge to the experimental pharmacologist, who should try to find explanations for the clinical hazards, and, if possible, show new ways in which better drugs might be developed. In recent years interest has focused on the importance of the inhibitory transmitter 'l'-aminobutyric acid (GABA) in the pathophysiology of epilepsy, and there have been a series of attempts to find useful antiepileptic drugs among substances interfering with GABA metabolism in the CNS."

Held at Boppard, Germany, October 3-6, 1984

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.

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 27 of "Progress in Drug Research" contains 5 articles, a subject index for this volume, an alphabetic subject 4ldex for volumes 1-27, and an author and subject index for altthe volumes which have so far been published. The contributions of volume 27 are particularly concerned with fungal disease, with benzimidazole anthelmintics and with the chemistry and pharmacology of quinuclidines, azoles, and nitroimida- zoles. The authors have tried, 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 research, and to those who wish to keep abrest of the latest developments influencing modem therapy. In addi- tion, it is believed that the 27 volumes of "Progress in Drug Research" now available represent a useful reference work of encyclopedic charac- ter. The editor would like to take the occasion of the publication of this volume to express his gratitude both to the authors and to the readers. The authors have willingly1undertaken'the great labor of writing signifi- cant topical contributions, hnd many readers have helped the editor with criticism and advise. With these thanks, the editor would like also to express his gratitude to the publisher, Birkhauser Verlag Basel, particu- larly to Messrs. Th. Birkhauser and C. Einsele, and their associates for the excellent cooperation.