The recent symposium and the appearance of this new book on Drugs Affecting Lipid Metabolism take place at a very unusual time for the development of this area. After the publication and wide acceptance of the results of the cholestyramine study by the Lipid Clinics in the USA, showing for the first time a direct association between drug induced reduction of plasma levels of total and LDL cholesterol and coronary heart disease in a high risk population, an unparalleled interest in drugs and other procedures able to control plasma cholesterol levels has been activated. Two other significant events occurred during 1986 and 1987: the availability of compact instruments for the immediate determination of total cholesterol in plasma or total blood and the developments of new agents such as the inhibitors of HMG-CoA (hydroxymethyl glutaryl CoA) reductase and ACAT inhibitors, with potentially great effect on plasma lipid levels after oral administration. These new advances, together with the combined efforts of cell biologists and lipoprotein chemists, have set the pace for an exciting period of research and clinical applications of diets and drugs af fecting lipids. This volume, which includes the work of many of the leading world laboratories, represents an authoritative and up-to-date ap praisal of the status of the art and a stimulus to future research at laboratory and clinical level in an area of opportunity for clinical and preventive medicine."

Die Befruchtung spielt eine bedeutende Rolle im Entwicklungsgang der Organismen. In ihrem Verlauf werden die Gametenkerne, und damit das genetische Material zweier Individuen, vereinigt. Durch die Meiose (Reduktionsteilung) wird der Ausgangszustand wiederhergestellt, jedoch in einer solchen Weise, daB die elterlichen Erbfaktoren in den verschiedensten Kombinationen neu verteilt werden konnen. Die Beob- achtung von Befruchtungsvorgangen zeigt, daB der eigentlichen Ver- schmelzung der Geschlechtszellen Reaktionen vorausgehen, an denen offensichtlich chemische Wechselwirkungen beteiligt sind. Besonders deutlich lassen sich solche stoffiichen Wechselwirkungen bei niederen Pflanzen beobachten, bei denen beispielsweise Geschlechtsorgane nur gebildet werden, wenn der entsprechende Partner oder Filtrate seines Kulturmediums vorhanden sind. In anderen Fallen kann man beobachten, daB Geschlechtsorgane durch Luft oder Wasser gerichtet aufeinander zu- wachsen oder, daB freibewegliche mannliche Gameten sich gezielt zu stationaren weiblichen Gameten hinbewegen. Solche biologischen Reak- tionen sind auBerordentlich empfindlich, und die Konzentration der beteiligten Stoffe ist entsprechend gering. Dies macht die Ansammlung von gentigenden Mengen fUr die StrukturaufkIarung zu einem auBerst mtih- samen Unternehmen. Obwohl auch in der alteren Literatur zahlreiche Hinweise auf chemische Wechselwirkungen zwischen Sexualpartnern vor- handen sind (42, 43), konnten bisher erst wenige derartige Geschlechts- stoffe identifiziert werden. Erst die hochleistungsnihigen modernen Ana- lysenmethoden, wie Massen- und Kernresonanz-Spektroskopie, haben hierbei die Forschung wesentlich vorangetrieben. Man kennt heute die Molekularstruktur von vier Sexualhormonen, die nunmehr auch synthe- tisch zuganglich sind.

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.

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."

This book deals with principles in g

From beach encounters, aquaculture perils, and processed-food poisoning to snake bites and biological warfare, natural toxins seem never to be far from the public's sight. A better understanding of toxins in terms of their origin, structure, structure-function relation ships, mechanism of action, and detection and diagnosis is of utmost importance to human and animal food safety, nutrition, and health. In addition, it is now clear that many of the toxins can be used as scientific tools to explore the molecular mechanism of several biological processes, be it a mechanism involved in the function of membrane channels, exocytosis, or cytotoxicity. Several of the natural toxins have also been approved as therapeutic drugs, which has made them of interest to several pharmaceutical companies. For example, botulinum neurotoxins, which have been used in studies in the field of neurobiology, have also been used directly as therapeutic drugs against several neuromus cular diseases, such as strabismus and blepherospasm. Toxins in combination with modem biotechnological approaches are also being investigated for their potential use against certain deadly medical problems. For example, a combination of plant toxin ricin and antibodies is being developed for the treatment of tumors. The great potential of natural toxins has attracted scientists of varying backgrounds-pure chemists to cancer biologists-to the study of fundamental aspects of the actions of these toxins."

This publication of a symposium held on 24 th and 25 th of June 1988 in Munich th is dedicated to Nepomuk Zollner on the occasion of his 65 birthday, expressing the best wishes of the authors. Nepomuk Zollner was born in the northern part of Bavaria. While a medical student in Munich he was called up to military duty in the last year of World War II. After achieving excellent results on his examinations he served as a physician in several hospitals in Munich and soon became interested in inborn errors of metabolism. In order to receive the best education possible at that time he joined the group of S. J. Thannhauser, the famous German emigrant, in Boston where he worked from 1951 to 1953. There he was able to continue his studies on lipids, which he had started in 1948, and begin with his studies on purine metabolism. While working in Thannhauser's laboratory he learned to think and act according to the strict laws of natural SCIence. After returning to Europe he concentrated his scientific work on purines and lipids. Gout and hyperlipoproteinemias from the genetic to the therapeutic aspects remained the dominating topics of his research activities. In spite of many obligations as head of the Medical Polyclinic of the University of Munich and many activities at the university and in scientific societies Zollner's foremost intent continued to be the development and progress of natural science in medicine.

Arthropod venoms have received much attention and have played an important role in folklore and medicine since ancient times. Scorpion envenomation, "tarant ism," bee and wasp stings are among those subjects about which most has been speculated and written in the past. In the last 50 years or so, a great number of scientific papers have been devoted to arthropod venoms, but only a few volumes have been designed to collect this rapidly increasing material, and these are not recent. Of late, the chemistry and mode of action of several arthropod venoms have been thoroughly studied, and some of these substances will probably be used as pharmacological tools and also as therapeutic agents. The aim of the present volume is to collect in manual form new information as well as the old notions on arthropod venoms. Even though it was our intention to present a volume on arthropod venoms, and not on venomous arthropods, inevitably we were forced to include information on venom-producing organisms as well. We assumed, in fact, that those scientists for whom the present manual is primarily intended (biochemists, particularly com parative biochemists, and pharmacologists) should be familiar with the biologic elements concerning the venom-producing species; which should show them how important it is to operate in close collaboration with biologists specialized in venomous arthropod systematics and biology."

Vitamin C holds a unique place in scientific and cultural history. In this book, a group of leading scientific researchers describe new insights into the myriad ways vitamin C is employed during normal physiological functioning. In addition, the text provides an extensive overview of the following: the rationale for utilizing vitamin C in the clinic, updates on recent uses of vitamin C in cancer treatment through high-dose intravenous therapies, the role vitamin C plays in the treatment of sepsis and infectious disease, management of the ways vitamin C can improve stem cell differentiation, as well as vitamin C use in other important health situations. Features Includes chapters from a team of leading international scholars Reviews the history and recent research on the functions, benefits, and uses of vitamin C Focuses special attention on the way vitamin C can be used in the treatment of cancers Discusses how vitamin C can be employed against infectious disease

BARTON und COHEN haben r9S7 in einer Arbeit "Some Biogenetic Aspects of Phenol Oxidation" (3) Dienone der allgemeinen Formel (I) als biogenetische Vorstufen bestimmter Aporphin-Alkaloide postuliert (S. 260). Strukturen dieses Typs wurden erstmals r963 fUr die Alkaloide D-( +)-Pronuciferin und D-( +)-Crotonosin bewiesen [BERNAUER (II); HAYNES, STUART, BARTON und KIRBY (35)]. Der fur solche Verbin- dungen vorgeschlagene Sammelname "Proaporphine" (23, 65) bringt den in zwischen experimentell bewiesenen* biogenetischen Zusammenhang mit der Gruppe der Aporphin-Alkaloide zum Ausdruck, ist aber auch vom praparativ-chemischen Standpunkt sinnvoll, da sich Proaporphine (I) leicht in Aporphine (2) umwandeln lassen (S. 2S0). AuBer den Alkaloiden mit Dienongruppierung sind auch solche be- kannt geworden, in welchen eine oder mehrere Doppelbindungen des Dienonsystems aushydriert sind; sie werden sinnvollerweise den Pro- aporphinen zugerechnet. Dieser Aufsatz berucksichtigt alle natiirlichen Alkaloide und ihre wichtigsten Derivate sowie alle synthetischen Ver- bindungen, die das Skelett (3) besitzen (Tabellen I-3, SS. 270-279). Er macht ausschlieBlich von der in (3) angegebenen Bezifferung Gebrauch, welche der Nomenklatur der IUPAC und der Chemical Abstracts ent- spricht. Verbindung (I, R = H) ist wie folgt zu bezeichnen: 2',3',8',8'a-Tetra- hydro-S',6'-dihydroxy-spiro[2,S-cyclohexadien-r,7'(r'H)-cyclopent[ij]-iso- chinolin ]-4-on. R2 (2) K=H oder Alkyl (I) R=H oder Alkyl Rt=H,OH oder O-Alkyl Proaporphine Aporphine In den Originalarbeiten sind verschiedene, von der in (3) angegebenen ab- weichende Bezifferungsarten verwendet worden. Keine hat sich allgemein durch- gesetzt. Auch die von SLAViK (69) fur das sauerstofffreie Grundgerust der Pro- aporphine vorgeschlagene Bezeichnung Mecambran hat keinen Eingang in die Literatur gefunden.

Hepatic cells are involved in the metabolization and elimination of a variety of endogenous and exogenous substances. They mediate the uptake, processing and subsequent secretion of biliary compounds, such as various drugs or hormones, and the passage of metabolites to be released into different blood compartments. To perform vectorial passages hepatocytes show a strong polarity with sites for endocytotic processes or specific carrier molecules, and a specified system of organelles for intracellular transport and sorting, metabolization and secretion of compounds. Several aspects, e.g. regulation, control and mechanisms of hepatic traffic are reported in detail - complemented by methodological approaches to analyse and monitor these processes.

Protein-protein interactions are involved in muscle contraction and signal transduction. This book describes how synthetic peptides may be used, much like antibodies, both as specific inhibitors and as molecular probes to explore the cognitive interfaces between interacting proteins and their functional significance. This offers the prospect of very selective intervention in cellular mechanisms. These timely contributions by several experts will appeal to the researchers in muscle physiology, cardiovascular pharmacology and cell biology who are interested in this new approach.