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 entire 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 impossible for anyone person to stay informed on this subject by reading the primary literature. At the same time it is becoming increasingly apparent that 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 com mon language for intercellular communication. As a set they affect essentially 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. This treatise is divided into four main sections. After three introductory chapters, its principal focus is the detailed description of each of the major peptide growth factors in 26 individual chapters."

About 1958, the late Professor R. E. ALSTON and Professor B. L. TURNER, both of the Department ofBotany, The University ofTexas at Austin, initiated a general systematic investigation ofthe legurne genus Baptisia. They found that flavonoid patterns, as revealed by two-dimensional paper chromatography, were valid criteria for the recognition of the Baptisia species and for the documentation of their numerous natural hybrids. Later, they showed that the flavonoid chemistry could be used for the analysis of gene flow among populations. At that time no attempt was made to even partially identify the flavonoids which were detected chromatographically. Neverthe1ess, it soon became apparent that the full value of the chemical data for systematic purposes required knowledge of the structures of the flavonoids. In 1962, one of us (T.J.M.) in collaboration with Drs. ALSTON and TURNER beg an the chemical analysis of the more than 60 flavonoids which had been chromatographi- cally detected in the 16 Baptisia species. In the intervening years, a number of chemists and botanists, inc1uding Drs. K. BAETCKE, B. BREHM, M. CRANMER, D. HORNE, J. KAGAN, B. KROSCHEWSKY, J. MCCLURE, H. ROSLER, and J. WALLACE, participated in the devel- opment of techniques and procedures for the rapid identification of known flavonoids and in the structure determination of new flavonoids. In addition, the flavonoid chem- istry of many plants other than Baptisia was investigated.

This book is based on the proceedings of the symposium entitled "Di rected Drug Delivery: A Multidisciplinary Problem," which was held in Lawrence, Kansas on October 17-19, 1984. The purpose of the sym posium and this book is to focus on the multidisciplinary nature of drug delivery. Development of a successful drug delivery system re quires contributions from various scientific disciplines, including pharmaceutical chemistry, analytical chemistry, medicinal chemistry, biochemistry, pharmacology, toxicology, and clinical medicine. The contents of this volume illustrate the importance of the various disci plines in identifying the problems and approaches for the develop ment of a rational and effective drug delivery system. Thus the infor mation provided herein will be of value not only to the pharmaceutical chemists who are responsible for dosage form design, but also to the pharmacokineticists, pharmacologists, and clinicians involved in bio logical evaluation of drug delivery systems. The volume should also be of interest to the analytical chemists who must provide technology to quantitcltively evaluate drug delivery. Additionally, this work will also interest the biochemists and medicinal chemists involved in drug dis covery, since the drug delivery system often plays a major role in determining the success or failure of a new drug entity. Each speaker at the symposium was requested to contribute a chapter reviewing the contribution of their major discipline to the de velopment of a successful drug delivery system."

The volumes of this classic series, now referred to simply as "Zechmeister" after its founder, L. Zechmeister, have appeared under the Springer imprint ever since the series was founded in 1938. The volumes contain contributions on various topics related to the origin, distribution, chemistry, synthesis, biochemistry, function or use of various classes of naturally occurring substances ranging from small molecules to biopolymers. Each contribution is written by a recognized authority in his field and provides a comprehensive and up-to-date review of the topic in question. Addressed to biologists, technologists and chemists alike, the series can be used by the expert as a source of information and literature citations and by the non-expert as a means of orientation in a rapidly developing discipline.

Volume 31 of "Progress in Drug Research" contains 13 articles, a sub ject index, an index for all articles that have been published so far in this series of monographs, as well as an author and subject index for all 31 volumes. The reviews in this volume are particularly concerned with the therapy of helminth diseases, with pyramidinones as biody namic agents, and with quinolones which are of interest in the treat ment of infections. For a deeper understanding of the pharmacokinet ic actions of modem drugs, the articles on cooperative binding of drug molecules to DNA, on in vitro models for the study of antibiotic activi ties, on inhibitors of the renin-angiotensin system, on GAB A-drug in teractions, and on the mechanism of action of anxiolytic drugs provide a wealth offacts and new findings. The pharmacology of caffeine is re viewed from the viewpoint of its role in combination with other phy siologically active substances, and the chapter on high resolution nuc lear magnetic resonance spectroscopy demonstrates the importance of this method in the development of new drugs. Finally, the article on light and dark touches border problems of the therapy of psychic dis orders. With these contributions, the authors aim to summarize latest achieve ments in important and actual fields of drug research. Researchers who are actively engaged in the same or in similar fields of research are sure to benefit from these efforts."

Recent progress in the fields of pharmacology and immunology has provided us with new possibilities for treating dermatological diseases. This book reviews the most important immunosuppressive and immunostimulatory drugs and gives helpful, practical information on the treatment of various dermatoses, including autoimmundiseases, atopic dermatitis, psoriasis, vasculitis, contact dermatitis, pyoderma gangrenosum, infectious diseases, and neoplasms of the skin - in particular, malignant melanoma.

Volume 29 of 'Progress in Drug Research' contains 10 articles, a sub- ject index for this volume, an alphabetic index of articles for volumes 1-29, and an author und subject index for all the volumes which have so far been published. The contributions of volume 29 are particularly concerned with drugs in general, hypertension and cardiovascular drugs, atherosclerosis, teratogenic hazards and carcinogenecity, hist- amine, dopamine agonists, tetrahydroquinolines and /J-carbolines, and meddicinal research. 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 vo- lume will be of special value to those actively engaged in drug re- search, and to those who wish to keep abrest of the latest developments influencing modern therapy. In addition, it is believed that the 29 vo- lumes of 'Progress in Drug Research' now available represent a useful reference book of encyclopedic character. The editor would like to take the occasion of the publication of this volume to express his grati- tude both to the authors and to the readers. The authors have willingly . undertaken the great labor of writing significant topical contributions, and many readers have helped the editor with criticism and advise. With these thanks, the editor would like to express his gratitude to the publishers, Birkhauser Verlag Basel, particularly to Messrs. H. 1. Ben- der, C. Einsele and A.

In 1906, Michael T. Sweet first developed the chromatographic method by using an adsorbant to separate pigments. Since that time, the technological advances in TLC and HPLC have brought about new definitions of purity in parallel with the advances. Radiopharmaceutical chemistry is especially dependent on the chromat ographic technique because of the relatively small amount of material in most radiopharmaceuticals-often so small that the usual physical methods of analytical chemistry cannot be used. As a result, this collection of papers represents the key to successful radiopharmaceutical development by setting the standard for the pres of radiochemical purity. ent-day definition William C. Eckelman, Ph.D. Diagnostics Associate Director The Squibb Institute for Medical Research New Brunswick, New Jersey Preface The chapters herein are updated and expanded versions of presentations that the authors made at a symposium held on June 4, 1984 in Los Angeles, California under the sponsorship of the Radiopharmaceutical Science Council of the Society of Nuclear Medicine. All manuscripts were refereed. The intent of the symposium organizers was to enlist participants who work on a day-to-day basis with the analytical and chromatographic techniques to be discussed at the symposium. We feel confident that this distillation of hands-on experience will be of value to graduate students as well as experienced researchers in radio pharmaceutical chemistry and related fields which use radiotracer methodology."

This book contains a collection of quantitative procedures in common use in pharmacology and related disciplines. It is intended for students and researchers in all fields who work with drugs. Many physicians, especially those concerned with clinical pharmacology, will also find much that is useful. The procedures included may be considered "core" since they are generally applicable to all classes of drugs. Some of the procedures deal with statistics and, hence, have even wider application. In this new edition we have increased the number of procedures from 33 (in the first edition) to 48. Other procedures have been revised and expanded. Yet the basic philosophy of this new edition remains unchanged from the first. That is, the pharmacologic basis of each procedure is presented, along with the necessary formulas and one or more worked examples. An associated computer program is included for each procedure and its use is illustrated with the same worked example used in the text. The discussions of theory and the sample computations are brief and self-contained, so that all computations can be made with the aid of a pocket calculator and the statistical tables contained in Appendix A. Yet it is realized that the proliferation of lower-priced microcom puters is likely to mean that more and more readers will utilize a computer for most calculations. Accordingly, we have modified the format of the book to facilitate computer usage."

The conceptual process of drug discovery is one that is often the result of an identified need in a defined disease area. This need represents a mandate from the marketing department of a phar- maceutical company or a breakthrough at the research level that has agreed applicability in response to a valid therapeutic demand. Although the intelligent design and development of new thera- peutic entities, as evidenced by Sir James Black's H -receptor an- 2 tagonist cimetidine (Tagamet), is intellectually satisfying, many novel drugs arise from serendipity, from the chance observation of the research scientist or the clinician, that a compound has unex- pected actions of use for the treatment of human disease states. Drugs that have been identified by this route include the antipsy- chotic chlorpromazine and the putative anxiolytic buspirone. The events surrounding the process of drug discovery and de- velopment are the theme of the present volume, which attempts to present, in a logical and lucid manner, the complexity of a process that is often naively assumed to represent nothing more than the identification of a new compound and its rapid introduction into humans, free of such complications as efficacy, selectivity, safety, bioavailability, toxicity, and need.

Bereits 3 Jahre nach dem ersten Adriamycin-symposium und 2 Jahre nach der Veroffentlichung der Referate jener Tagung erschien es angezeigt, Wissenschaftler aus aller Welt erneut zusammenzurufen, um tiber die inzwischen gewonnenen Erfahrungen mit Adriamycin zu berichten. Nachdem in einer ersten Phase die Wirkung dieses Chemotherapeutikums ftir die systemischen Krebserlaankungen erkannt und erforscht war, konnte in vielen kontrollierten Studien an bedeutenden, mit der Krebs- forschung befassten 1nstituten in aller Welt nachgewiesen werden, dass Adriamycin heute auch in der Bekampfung solider Tmnoren zu einem wich- tigen, in der Krebs-Therapie wirksamen Pharmakon gezahlt werden muss. Die Vortrage dieses Symposiums unterstreichen die wichtige Rolle die- ser ftir die moderne cytostatische Therapie bedeutsamen Substanz. Der Sinn dieser Tagung ist, auch ftir die Zukunft neue Anregungen ftir For- schung und internationa.le Zusammenarbei t beim Kampf gegen den Krebs zum Wohle des Patienten zu gewinnen. D. Schmahl Die Veroffentlichung der Referate des zweiten Adriamycin-Symposiums sollte moglichst rasch erfolgen und in kurzer Zeit dem interessier- ten und onkologisch tatigen Arzt zur Verftigung stehen. Deshalb haben wir uns entschlossen, auf ein Sachregister und ein ausftihrliches Li- teraturverzeichnis in diesem Buche zu verzichten, was dankenswerter- weise unter diesen Voraussetzungen vom Springer Verlag akzeptiert wurde. Allen Vortragenden und allen Beteiligten bei der Durchftihrung des Symposiums mochten wir an dieser Stelle unseren besonderen Dank sagen.

This second volume continues the description of the psychotropic agents and discusses anxiolytics, gerontopsychopharmacological agents, and psychomotor stimulants. Of these groups of substances, most of this volume has been devoted to anxiolytics as the authors have endeavored to convey as complete a picture as possible. The editors are of the opinion that particular attention should be given to anxiolytics with regard to their range of administration as this is the most frequently prescribed group of psychotropic drugs. In contrast to neuroleptics and thymoleptics, anxiolytics are a class of psychotropic drugs whose therapeutic effect can be recognized in animal experiments to some extent. This, together with the analysis of the biochemical mechanisms of their actions, permits a better understanding of material processes in the brain accompanying the emotions: anxiety and tension. For the first time in the history of the Handbook the editors have devoted a whole chapter to gerontopsychopharmacological agents. In doing so they are also aware of the risk they are taking, at least from a pharmacological point of view, as gerontopsychopharmacological agents are an insufficiently defined and extremely heterogeneous group of substances. The only denominator the various subgroups of these agents have in common is that they are given in cases of dysfunctions, disorders, and diseases of the brain occurring mainly in the elderly.

The history of antibiotics may weIl have begun with the ancient Sudanese-Nubian civilization (see Chapter 1, "Historical Introduction"), but this volume reflects a more contemporary appraisal of the antibiotic era. We have compiled a comprehensive review of the tetracyclines which includes all the major sub divisions of these chemically important and clinically useful antibiotics. There can be little doubt about the contribution of antibiotics to both the increase in human life span and the alleviation of much human suffering. The tetracyclines are still playing an important role in these areas and will continue to do so in the foreseeable future. We hope this volume will be an important contribution to a better under standing of the chemistry, biochemistry, and medical aspects of tetracycline antibiotics. We are indebted to the individual authors who have given so much of their time and effort in the preparation of the chapters. Pearl River, NY J OSEPH J. HLA VKA Ocean Gate, NJ JAMES H. BOOTHE Contents CHAPTER 1 Historical Introduction. J. H. BOOTHE and J. J. HLAVKA References. 3 CHAPTER 2 Fermentation and Mutational Development of the Tetracyclines J. J. GOODMAN A. Introduction 5 B. The Producing Microorganisms . 6 I. Morphology and Ultrastructure 6 11. Mutation and Strain Selection 8 111. Cosynthesis. 13 The Fermentation Process 14 C. I. Inoculum 14 11. Contamination 16 Complex Media. 18 111. IV. Synthetic Media. 27 V. Stimulators and Inhibitors 30 Directed Fermentations 32 VI."

The purpose of the present volume, the first of two on the pharmacology, biochemistry, and physiology of cyclic nucleotides, is to provide a comprehensive and up-to-date anthology on the nature and role of these important chemical regulators. Each of the chapters is the work of internationally known researchers who present a lucid and detailed review of their subject and not merely a single laboratory's viewpoint. The chapters emphasize critical assessments of the field rather than mere listings of experimental findings. By so doing, the contributors present the role of cyclic nucleotides in relationship to other intracellular regulators. Each chapter begins with a detailed summary to allow the reader to obtain a rapid overview of subsequent material. In addition, there are extensive bibliographies and a detailed subject index. Wherever pertinent, the chapters contain sections on drug mechanisms, physiological relevance, and disease processes. The Volume is divided into two sections, each beginning with an overview written by Professors T. W. RALL and P. GREENGARD, respectively. The first section focuses on the detailed pharmacology and chemistry of cyclic nucleotides, including their formation, degradation, measurement, and interaction with various modulatory agents, such as receptors and calcium. The second section is concerned with the biochemistry of protein phosphorylation, a process which appears to be one of the most important mechanisms for the intracellular expression of cyclic nucleotide action in eukaryotic cells.

D.A. KHARKEVICH The history of the study of ganglionic substances begins with the paper of LANGLEY and DICKINSON (1889), who established the ability of nicotine to block the neurones in the superior cervical ganglion. This was a considerable discovery as the authors ascertained that impulses were transmitted from pre- to postganglionic neurones in the autonomic ganglia. Simultaneously they indicated the possibility of pharmaco logical influence upon interneuronal transmission in autonomic ganglia. The idea of ganglionic receptors specifically sensitive to nicotine followed logically. Later, LANGLEY (1905, 1906) considered the problem of receptors with respect to neuro-effector synapses. It is remarkable that he was one of the first to put forward the theory of chemical mediation of excitation (" ... the nervous impulse should not pass from nerve to muscle by an electric discharge, but by the secretion of a special substance at the end of the nerve" LANGLEY, 1906, p. 183). In addition, LANGLEY JOHN N. LANGLEY (1852-1926) D.A. KHARKEVICH 2 and his collaborators managed to define the topography of autonomic ganglia more precisely by means of nicotine. It should be mentioned that it was he who introduced the terms "autonomic nervous system" and "parasympathetic nervous system.""

Research on purine derivatives as potent and selective modulators of physiologic functions has moved to center stage. This volume covers the biology and chemistry of purines and of their receptors broadly under these section headings: - Adenosine Receptors and Effector Systems - Adenine Nucleotide Receptors and Effector Systems - Phosphodiesterase Enzymes and Inhibitors The presentations focus on the potential development of clinically useful drugs and powerful agents that activate or block purinergic receptors or that inhibit phosphodiesterases. Xanthines (caffeine and theophylline) represent one class of such agents. This volume is for pharmacologists, biochemists, and medical chemists in research labs of universities, gov- ernment, and the pharmaceutical industry.

In the approach to the analysis of disease, including, of course, cancer, two major thrusts may be distinguished. These may be referred to, in shorthand, as agents and processes: the causative agents (chemical, microbial, physical, environmental, and psychosocial) and the organismic processes, initiated and furthered by the agents, culminating in observable pathology (at the macromolecular, cytological, histological, organ function, locomotor, and behavioral levels). The past 25 years, since the appearance of the first volume of the predecessor series (1) authored by the Editors of this present volume, have seen an impressive number of studies on chemicals (and other agents) as etiologic factors in the induction of cancer. The major emphasis has been on the discovery of many chemical carcinogens of widely different structures, their metabolism by various tissues and cells, and, in turn, their molecular-biochemical effects on the cells. This rapidly expanded body of information, as effectively covered in the predecessor volumes, is an excellent entree to the second half of the overall problem of chemical carcinogenesis, the processes. The active agents trigger a large array of molecular-biochemical alterations to which the target cells, target tissues, and target organisms respond in many select and common ways. This second major aspect of the induction of cancer by chemicals (and by other agents)- the sequence of cellular and tissue changes clearly relevant to cancer-remains the challenge for the future.

This volume of the Handbook of Experimental Pharmacology (Concepts in Biochemical Pharmacology) will show that pharma cology has finally arrived as a true discipline in its own right, and is no longer the handmaiden of organic chemistry and physiology. Instead it is an amalgam of all the biological sciences including biochemistry, biophysical chemistry, physiology, pathology and clinical medicine. In the volumes that make up Concepts in Bioche mical Pharmacology we hope to convince Medical Schools what should now be obvious, that pharmacology is no longer that dull topic bridging the basic sciences with medicine, but is probably the most important subject in the medical curriculum. We are grateful for the advice of Dr. BYRON CLARKE, Director of the Pharmacology-Toxicology Program at the National Insti tutes of Health, whose support made possible much of the work described in this volume. Contents Section One: Routes of Drug Administration Chapter 1: Biological Membranes and Their Passage by Drugs. C. A. M. HOGBEN 1 References. . . . . . . . . . . . . . . . . . . . . . . . . . 8 Chapter 2: Absorption of Drugs from the Gastrointestinal Tract. L. S. SCHANKER. With 5 Figures. 9 I. Introduction. . . . . . . . . . . . . . . . . . . . . . . 9 II. Methods of Study. . . . . . . . . . . . . . . . . . . . . 9 III. Absorption from the Stomach . . . . . . . . . . . . . . . 11 IV. Intestinal Absorption of Non-Electrolytes and Weak Electrolytes 15 V. Absorption of Weak Electrolytes from the Colon and Rectum 18 VI. Intestinal Absorption of Organic Ions. . . . . . . . . . 19 VII. Intestinal Absorption of Macromolecules . . . . . . . . . . 19 VIII. Active Transport across the Intestinal Epithelium . . . . . 20 IX. Effect of EDTA on Drug Absorption from the Intestine . . . . . . .

Due tothedevelopmentofdrugresistanceandotherlimitationsinthe treat- ment of AIDS patients with reverse transcriptase (RT) inhibitors like zidovu- dineandothers, itbecamenecessarytoexploreantiviralagentsactingontar- getsotherthan RT. Inthepastfewyears, hundredsofHIVproteaseinhibitoLs have been synthesized and tested. Among these protease inhibitors, saquinavir, ritonavir, indinavir and nelfinavir have been marketed during 1995-1997. In this review, emphasis is placed on the development of HIV protease inhibitors as antiviral agents against HIV, structure-activity rela- tionship (SAR) analysis ofsaquinavirand relatedcompounds, comparisonof four marketed HIV protease inhibitors, and future prospect in developing new anti-HIV drugs. 2 Introduction HIV protease inhibitors 3 HIV protease as a target for chemotherapy HIV protease was first suggested as a potential target for AIDS therapy by Kramer et a1. in 1986 [5]. HIV protease is a proteolytic enzyme responsible for cleaving large numbers of amino acid sequences. This enzyme regulates conversionoftheselargeaminoacid sequencesintobiologicallyactive struc- tural and functional protein products. Specifically, HIV protease is responsi- the enzymatic processing of the gagand gag-pol genes of HIV, which ble for encode for functional core proteins and viral enzymes (reverse transcriptase, ribonuclease H, integrase, and HIV protease). The polyproteins encoded by the gagand gag-pol genes undergo post-translational processing by HIV pro- tease to form functional protein products as the viral particles budding out from infected cells. Therefore, inhibition of HIV protease by a protease inhibitor results in the release ofimmature, noninfectious viral particles [4].

Nitroglycerin and other organic nitrates have been used for over a century in the treatment of angina pectoris. Millions of patients, throughout the world, have placed nitroglycerin tablets under the tongue and have experienced rapid and dramatic relief from the chest pain that frequently occurs as a manifestation of disease of the coronary arteries. The empirical observation of the safe use of nitrates for tile alleviation of the symptoms of angina have led to their widespread medical acceptance. The use of organic nitrates preceded any knowledge of their mechanism of action or their ultimate metabolic fate. Thus, more simply stated, although sub lingual nitrates helped the patients, little was known concerning what these drugs do to the body or what the body does to the drugs. A substantial number of investigators have focused on these questions especially during the last two decades. We now have considerably more insight into the pathways of degradation of organic nitrates and the relationship of the metabolic processes to the biological action of these agents. Similarly, considerable effort has been expended in understanding the mechanism of action of these agents directly on vascular smooth muscle and on cardiac work and performance. Finally, there is a more substantive understanding of the physiology of the coronary circulation as well as the" pathophysiologic manifestations of myocardial disease."

Throughout the centuries, inflammation has been considered as a disease in itself. This misconception arose from the inability to distinguish between inflammatory changes and the insults which induce them. The understanding of the distinction between the genesis of inflammation and the tissue reactions that follow is attributed to JOHN HUNTER, who, at the end of the 18th century, substantially contributed to the analysis of inflammation in objective terms. Today, however, we are still trying to find explanations for Celsus' Signs in terms of structural and functional changes occurring in the inflamed tissue. There are drugs which modulate these signs but, without a detailed knowledge of the basic physiopathological events, it is impossible to understand their mechanism of action. Notwithstanding, the effects of anti inflammatory drugs provided new knowledge of the relevance of the signs and symptoms to the sequence of biochemical and morphological changes occurring in inflammation. When we accepted the invitation to edit a Handbook on Inflammation and Anti Inflammatory Drugs, we were aware of the magnitude of the task. We knew the impossibility of covering the whole field in detail, especially taking into account the rapid accumulation of experimental knowledge which would, in all likelihood, overtake the process of publication."

At present, there is growing interest in high pressure bioscience and biotechnology. The activities are nearly equally distributed between fundamental research and applications. With original work on marine and terrestrial microbiology, biochemicstry, molecular biology, deep-sea diving, food science and other industrial applications, this book covers the whole range of current high pressure bioscience. Advances in High Pressure Bioscience and Biotechnology will be welcomed by all industrial and academic researchers who are working in this field.

Leading scientists summarize the latest findings on signal transduction and cell cycle regulation and describe the effort to design and synthesize inhibiting molecules, as well as to evaluate their biochemical and biological activities. They review the relevant cell surface receptors, their ligands, and their downstream pathways. Also examined are the latest findings on the components of novel signaling networks controlling the activity of nuclear transcription factors and cell cycle regulatory molecules. Cutting-edge and highly suggestive, Signaling Networks and Cell Cycle Control: The Molecular Basis of Cancer and Other Diseases presents a wealth of information on the emerging principles of the field, as well as an invaluable guide for all experimental and clinical investigators of cell regulation and its rapidly emerging pharmacological opportunities today.

In 1970 I gave up the chairmanship of the Department of Pharmacology at Stanford University Schoel of Medicine to devote full time to basic and clinical research on problems of drug addiction. In 1971 I developed the method of radioligand binding that led to the important characterization of opioid receptors in several laboratories. The extraordinary specificity of these receptors for morphine and related opiates suggested the likelihood that there were naturally occurring morphine-like molecules in the brain and other tissues. The systematic search for these molecules culminated in 1979 in the discovery, by my group, ofthe dynorphin peptides-one of the three families of opioid peptides, the first of which (the enkephalin family) had been discovered in Aberdeen, Scotland, in 1975. I also became involved in clinical research on the pharmacologic treatment of heroin addicts, for which I established the first large methadone mainte nance treatment program in California. My basic and clinical research experience convinced me that an institution encompassing laboratory research, studies on normal human volunteers, and treatment research, under a single roof, could expedite progress in understanding the drug addictions. That concept was transformed into reality by the founding, in 1974, of the Addiction Research Foundation of Palo Alto, California. The funds for construction of a laboratory were provided by a generous grant from the Drug Abuse Council (a consortium of several foundations), the president of which was Thomas L. Bryant."

Has the neuromuscular junction been over-exposed or is it perhaps already a closed book? I asked myself this at a recent International Congress when an American colleague complained that the Journal of Physiology had articles on nothing but the neuromuscular junction, while another colleague asked why I was editing a volume on a subject about which everything was already known. It is worrying to think that these views may be shared by other people. I hope that this volume will convince my two colleagues and other readers that the neuromuscular junction is very much alive and continues to attract the interest of many workers from a variety of fields; strange as it may seem, the synapse between a motor nerve ending and muscle fibre, with its relatively simple architecture, is one of the most inter esting sites in the body-I do hope we have done it justice. The various chapters of this volume present a cross section of knowledge as viewed by a group of 13 individuals, actively engaged in research. Multi-author volumes such as this are frequently criticised on the grounds that chapters or sec tions overlap. I believe that such criticium is only valid where the overlap is repetitious. Where it results in the reader having available discussions of material from differing stand-points, overlap becomes a valuable feature of this type of publication."