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.

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."

According to most studies, allergic reactions represent 35%-50% of all untoward reactions to drugs, yet the pharmacological literature concerning the clinical aspects, diagnosis, and pathophysiological mechanisms of drug allergy is markedly less extensive than reports dealing with the toxicological or pharmacological effects of drugs. The main reasons for this state of affairs may be on the one hand that until a few years ago the pathophysiological mechanisms of the various types of allergic reactions were not well understood, and on the other hand that objective diagnosis of a drug allergy is still fraught with serious difficulties. Drug allergy is still an unpopular topic for most allergologists and pharmacologists; this is reflected by the fact that despite their frequency, allergic reactions to drugs still occupy a relatively small proportion of space in most pharmacology handbooks and in classical books devoted to the side effects of drugs. There has recently been considerable progress in research into the immunologi cal and pathophysiological events occurring in allergic reactions, and on that basis investigations of various drug allergies have also yield d new objective findings. Consequently, it was natural to attempt a review of the most frequent and important drug allergies in the form of a handbook. We originally intended to present a comprehensive review of all drug allergies, but the realization of this goal soon became more difficult than we had at first imagined."

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

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

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.

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.

To comment at length on the importance of the benzodiazepines seems superfluous within the scope of this preface. No other class of active substances has experienced an even approximately compa rable advance in the past two decades. It is therefore not surprising that the formerly dominant barbiturates and bromocarbamides have had to give way in many fields to the benzodiazepines, which now rank first (Proudfoot and Park 1828]). Closely linked with the great therapeutic importance of the benzodia zepines are analytical problems. Detection and the determination of blood levels can be necessary under therapeutic aspects, for instance in working out optimally effective levels in the treatment of epileptic conditions ("drug monitoring"), but also in connection with questions at issue in toxicology and traffic medicine. A toxicological analysis can be subdivided into the following steps: Detection (identification including screening) Determination (e. g. blood, plasma or serum levels) Interpretation of the analytical results. This book is intended as a contribution to each of these chapters: The part "Analytical Data" (pp.I-122) gives a comprehensive collec tion of data, e.g. general and chromatographic data (TLC, GLC) as well as spectra (UV, IR, MS) of 19 commercial preparations, 23 important metabolites and 18 hydrolysis derivatives. Information about biotransformation and the possible formation of aminobenzo phenone derivatives is also given. The most important analytical methods are presented in an extensive review on pp.123-204 in order to make it possible to select the optimum method on the basis of the essential data."

Since the exhaustive Handbook of Physiology (Alimentary Canal, Section 6, Motility) edited by CHARLES F. CODE in 1968, no complete survey of the morphological basis and the physiological control of intestinal motility has been published, in spite of the enormous amount of new data in the literature on this topic. The new techniques and methodologies, the use of electron microscopy, radioimmunoassay and binding techniques, as weIl as ever more sophisticated electrophysiological procedures have made possible areal flood of discoveries in this field. Moreover, the possibility ofnew studies ofthe endocrine cells in biopsies of human intestinal mucosa even during routine endoscopies, has opened new horizons for gastroenterologists and generated a number of important contribu tions to our knowledge of the morphology and physiopathology of the gut. As usual, new discoveries have also revealed both ignorance and many new problems. For tbis reason, although many of the data reported in this volume can be considered as firmly established, others still require confirmation, and the results of new research in this field are awaited with extreme interest. Since advances are occurring so rapidly, even experts in the specific topics need frequent comprehensive reviews. To avoid an excessively large volume, considera tions ofthe pancreas, liver, and biliary system were not included in this Handbook, which, nevertheless, has attempted to off er the reader the essence of more than 1,500 papers."

The toxic properties of cadmium compounds have been well recognized in many species. There is little evidence to suggest a physiologic role for the metal. Rather, because of its long biologic half-life, cadmium acts as a cumulative poison, and even at quite low ambient concentrations, it can accumulate in mammals to values not insignificant in terms of critical toxic levels. The problem of cadmium toxicity has become especially important, as cadmium concentrations in the environment have begun to rise owing to a variety of human activities such as mining, the metallurgical industry, coal combustion, and the use of cadmium-containing fertilizers. It seemed appropriate, therefore, to assemble in one volume an up-to-date analysis of the mechanism of action of cadmium on biologic systems. Aspects of this field have repeatedly been reviewed in the past, and particular reference must be made to the volumes prepared by FRIBERG and collaborators from Sweden. Much outstanding work on cadmium has also been reported from Japan, and I am happy that investigators from both countries were able to contribute to the present volume. Obviously, this volume does not report a consensus by its contributors. The purpose of the work was to permit leading investigators in the field to present a critical review with sufficient documentation to support their interpretations and conclusions. A certain amount of overlap and disagreement between chapters was therefore unavoidable. The result, I hope, will be a useful state-of-the-art discussion.

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."

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."

In the preface to Part I of this volume, which appeared in 1966, we stated: " ... we had to leave the Antihistaminics for another volume of unpredictable dimensions. In 1924, eight pages inserted in a Chapter on Mutterkorn by Arthur R.Cushing were considered enough, in Vol. II, Part II, pp. 1319-1326 of the Hand buch. Now 922 pages did not suffice to cover all aspects of the subject ... the subject has been expanded in so many directions, that the anti histaminic part had to be excluded from the present volume. Possibly, another thousand pages will be necessary to cover what remains of the subject."* This prediction was fulfilled, and the subject of histamine has grown to such an extent that dealing with the antihistaminics only in Part II would be quite inadequate. It is imperative to include the large number of recent findings on the subject of histamine, namely the splitting of its pharmacologic receptors, and the great variety of new contributions on, its participation in physiopathologic phenomena, metabolism and interaction with newly found mediators."

The Editorial Board of the Handbook of Experimental Pharmacology apparently did not hurry in suggesting production of a volume on glucagon since the present opus is number sixty-six in the series. This fact is even more striking if we consider that 34 volumes published over about eight years will separate the books on glucagon from those on insulin on library shelves, whereas only a few microns separate the cells manufacturing these two polypeptides within the islets of Langerhans in the pancreas! Numerous factors have probably caused this dicrimination; four of them are: First, insulin deficiency or resistance is the cause of one of the most serious and distressing diseases, diabetes mellitus, which affects millions of people, whereas glucagon deficiency is apparently an extremely rare disorder, for which detailed reports are published of individual cases whenever they occur. Second, since its discovery in 1921 by BANTING and BEST, insulin has been irreplaceable for the treatment of the most severe forms of diabetes, whereas, in contrast, glucagon was until recently considered a relatively minor therapeutic agent. Third, whereas insulin is a compound which has been well characterized since the pioneering work of SANGER and its biosynthesis clearly identified by STEINER and his co-workers, glucagon, also well characterized chemically, has suffered from its parenthood with the so-called "glucagon-like immunoreactive substances", an incompletely defined series of immunologically related polypeptides present in the gut, the pancreas and some other parts of the body.

Thirty years have elapsed since the first description by S. A. BERSON and R. S. Y ALOW of the basic principles of radioimmunoassay (RIA). During this period of time, RIA methodology has been instrumental to the growth of many areas of biomedical research, including endocrinology, oncology, hematology, and pharmacology. It has done so by providing a relatively simple universal tool allowing, for the first time, the detection of endogenous mediators that are present 12 10 in body fluids at concentrations as low as 10- _10- M. The fundamental nature of this discovery and the wide-ranging fall-out of basic and clinical knowledge derived from its application have been acknowledged by the many honors tributed to its pioneers, including the Nobel Prize awarded to Dr. Y ALOW 10 years ago. Although several excellent books have been published during the past decades covering various aspects of RIA methodology, we felt the need, as pharmacologists, for a comprehensive discussion of the methodological and conceptual issues related to the main classes of mediators of drug action and to drugs themselves. Thus, we gladly accepted the challenge provided by the invitation to edit a volume of the Handbook of Experimental Pharmacology on Radioimmunoassay in Basic and Clinical Pharmacology. We tried to balance the emphasis placed on more general aspects of the RIA methodology and that on specific mediators.

The protection of human health and food and fiber resources against the ravages of pests of many sorts is a continuous struggle by all people in the world. The use of chemical pesticides as an aid in this struggle is now also global. These chemicals are deliberately added to the environment for the purpose of killing or injuring some form of life. Because pesticides are generally less selectively toxic than would be desired, non-target species, including humans, must be protected from injury by these chemicals. This can only be achieved by thorough understanding of the comparative toxicology of these compounds, and by minimizing human (and other desirable species) exposure. The latter can only be achieved by sound regulatory policies that utilize scientific principles and data, properly tempered by both gaps in that data and sociologic and economic considerations. This book contains the proceedings of the NATO Advanced Study Institute on "Toxicology of Pesticides: Experimental, Clinical and Regulatory Perspectives" held in Riva del Garda on October 6-15, 1986. This NATO-ASI has been promoted by the School of Public Health and Community Medicine, University of Washington at Seattle, by the Institute of Pharmacological Sciences, University of Milano and by the Giovanni Lorenzini Foundation, and has been sponsored by both the Society of Toxicology (USA) and the Italian Society of Toxicology.

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

The description of the pharmacology of psychotomimetics, cannabis, and alcohol in this third volume concludes the discussion on psychotropic agents. As psychomotor stimulants these groups of psychotropic agents are of little or no therapeutic relevance, but since they are used in a nonmedical manner, or are even considered by some groups of the population as social commodities, their behavioral effects and psychopharmacological properties are not the concern of the pharmacol ogist alone. The same is true of psychotomimetics, as well as cannabis and its components. Psychotomimetics have a social history going back many hundreds of years and are among the most potent psychotropic agents known to man. The closing description of psychopharmacology also deals with the psychotropic effects of a number of drugs not primarily considered to be psychotropic. Their psychotropic effects are either an inherent constituent of their therapeutic profile, as is the case with opiates, hypnotics, and caffeine, or they may occur indirectly as side effects or accompanying effects during therapy. This applies to p-adrenoreceptor antagonists and anticholinergics. The editors are also aware that a description of psychotropic agents would not have been complete without discussing the medical, ethical, and legal aspects of the development, clinical testing, and use of such drugs."

The volumes on "psychotropic substances" in the Handbook of Experimental Phar macology series clearly show that the classical concept of this discipline has become too narrow in recent years. For instance, what substances are psychotropic is determined not by the criteria of the animal trial, i.e. by experimental pharmacology, but by their action on the psy che, which in the final analysis is only accessible to us in man. Psychotropic substances force experimental pharmacology (and thus also this Handbook) outside its tradition allimits, which have essentially depended on animal studies. The antipsychotics and antidepressants were not discovered in animal ex periments, but by chance (or more precisely, by clinical empiricism). Experienced psy chiatrists trained in the observation of patients recognised the efficacy of drugs, the beneficial effect of which nobody had dreamed of before: DELAY and DENICKER in the case of chlorpormazine, KLINE in the case of the monoamine oxidase inhibitors and KUHN in the case of imipramine. It was only after these discoveries that the pharma cologists developed experimental models of the psychoses in animal experiments. However, even today we still do not know with certainty which of the effects shown in animals is relevant for the clinical effect despite the vast abundance of individual investigations. For many years, this uncertainty led to the testing of antipsychotics (e.g. of the neuroleptic type) in models which actually produced the undesired effects."

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.""

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.

Between 1950 and 1960, remarkable advances were made in the develQpment Qf antihypertensive drugs, but since then, prQgress has been less rapid. This dQes nQt mean that no. new drugs have been intrQduced: Qn the cQntrary, their number has increased sharply; but since the advent Qf the beta-adrenergic blQckers no. new pharmacQdynamic principle has been discQvered that CQuid be applied widely as an antihypertensive. This has nQt been fQr want Qf effQrts, because many attempts have been made to. find new ways and means Qf influencing blQQd- pressure regulatiQn Qr the mechanisms invQlved in the pathQgenesis Qf hypertensiQn. HQwever, the results Qf these endeavQrs have mQstly been disapPQinting. Even thQugh high blQQd pressure can be treated mQre satisfactQrily tQday than many Qther diseases, the success achieved in cQmbating Qne Qf man's mQst frequent ailments shQuld nQt induce cQmplacency, but rather stimulate research tQwards further imprQvements. The present standstill affQrds an QPPQrtunity to. review the field Qf antihy- pertensive agents, fQr it is unlikely that fundamentally new drugs will appear in the near future. AlthQugh greater knQwledge has been gained Qf the mechanisms Qf blQQd-pressure regulatiQn and Qf the pathQgenesis Qf hypertensiQn, these ad- vances have had no. direct cQnsequences in the search fQr new therapeutics.

Local anesthetics are among the most widely used drugs. Their development over the past century ranges from a documented influence on Freud's Interpretation of Dreams 1 to the synthesis of the ubiquitously popular lidocaine, as described in Chapter 1. For surgical procedures the use of regional, epidural and intrathecal local anesthesia has increased continuously during the past decade. Local anesthetics are also applied by physicians to ameliorate unpleasant sensations and reactions to other procedures, such as tracheal intubation. The presence or the threat of cardiac arrhythmias is often countered by chronic administration oflocal anesthetic-like agents, such as lidocaine or procainamide. Relief of acute pain, accompanying dental manipulations, for example, and of chronic pain are also accomplished with traditional local anesthetics. And over-the-counter formula tions of topical local anesthetics provide practitioners of solar indiscretion welcome relief from their otherwise unaccommodating sunburn. In all these applications the final effect of the local anesthetic is an inhibition of electrical activity, accomplished as a reduction or total blockade of action potentials. The primary site of action is the sodium channel, a transmembrane protein which is essential for the influx of sodium ions that subserves impulse generation and propagation in nerves, skeletal muscle, and heart. The detailed mechanisms oflocal anesthetic action are still being investigated and Chapter 2 of this volume provides a current overview of that subject."

Isoquinolines form one of the largest groups of plant alkaloids and they in clude a number of valuable clinical agents such as codeine, morphine, eme tine and tubocurarine. Research into different aspects of isoquinolines con tinues in profusion, attracting the talents of botanists, chemists, bioche mists, analysts, pharmacists and pharmacologists. Many of these aspects are of an interdisciplinary nature, and in April 1984, The Phytochemical Society of Europe arranged a 3-day symposium on The Chemistry and Bi ology of Isoquinoline Alkaloids in order to provide a forum for scientists of differing disciplines who are united by a common interest in this one class of natural product. Each chapter in this volume is based on a lecture given at this symposium. Attempts have been made to make the aims and objectives, experimental findings and conclusions reached, intelligible to scientists of differing backgrounds. The introductory chapter, which is mainly based on a historical discus sion, stresses that plants containing isoquinolines have proved to be both a boon and a curse to mankind. The Opium Poppy, Papaver somniferum, produces the medicinally used alkaloids morphine, codeine, noscapine and papaverine whilst it also continues to provide drugs of abuse, particularly morphine and its readily prepared O, O-diacetyl derivative, heroin. Numer ous other alkaloids have been isolated from other members of the Papaver acea, and a knowledge of their presence and distribution within the various species has proved a useful adjunct to systematic botanical studies."