Before the late 1970s, interest in caffeine among both the general public and the scientific community was at a relatively low level for many years, even though it was recognized that caffeine was an al most universal component of the diet. The National Coffee Associa tion was supporting a continuing program of research, some re search was being conducted by a few of the largest companies selling coffee, and an occasional university researcher became inter ested in caffeine and conducted experiments, often on effects of caf feine in very high concentration in vitro on skeletal muscle fibres or on dividing cells. Since 1978, however, there has been a mighty up surge in both public and scientific interest in caffeine. It is interest ing to note that this was prompted not by discovery of hitherto un known effects or hazards of caffeine, but by the actions of a regulatory agency, the Food & Drug Administration (FDA) of the U. S. Public Health Service. The U. S. Congress passed new laws on foods and drugs in 1958. One of the provisions was for testing of food additives to assess risk to health. As it was clearly impracticable to require immediate test ing of all additives already in use, a list was drawn up of some hun dreds of additives that were generally recognized as safe (GRAS)."

Today, the basic mood of researchers and clinical investigators, both at the center and on the periphery of interferon studies, is optimistic regarding the future of interferons as therapeutic substances. Many also feel these polypeptides will prove invaluable probes in unraveling certain fundamental biochemical processes which control the life cycle and developmental pattern of many human cells. In contrast, only a year or two ago, this optimism had given way to an attitude almost of disenchantment as public and scientific expectations were raised steeply, then rapidly waned, as it turns out, prematurely. Both the mUltiple actions of interferons (a virtual cascade of biochemical reactions may be induced, as documented herein) and the high visibility of interferon research provided by the millions of dollars invested both by national health agencies and by multinational pharmaceutical companies, contributed to an upsweep in public attention to drug development probably unprecedented in this century. Virtually every oncologist, it would seem, was plagued by requests for the experimental agent, although they already had therapies of more proven value. As recently as 1980, even though interferon had achieved success against certain cancers and certain viral diseases, the variability in clinical results was seemingly ever present and little evidence emerged to suggest interferons could cure advanced diseases. Why then the resurgence of an optimistic mood? There are almost always many elements which contribute to happiness, and this is certainly true of the broad frontier of interferon and its place in biochemical research and treatment.

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."

The history of arterial hypertension is both long and short; long, since BRIGHT (1827) first related hardness of the pulse to hardness of the kidneys and hyper. trophy of the heart; short in that modern research began in the late twenties. Most of what we know of these diseases has been discovered in the past fifty years. The modern story should have begun in 1897 when an extract of kidney was shown to be pressor. But little was done with knowledge until about 1929 when the relationship of this kidney extract called "renin" to hypertension was pos. tulated. The pressor effects were, however, unlike most of those seen with sub. stances such as epinephrine or vasopressin. Plasma was required for action of renin and the active substance appeared to be protein. In 1939, it was shown that renin was not in itself a pressor substance but rather a proteolytic enzyme which produced a powerful pressor substance acting on a substrate synthesized by the liver. Later it was noted that the first definable step after the formation of this peptide was cleaving of the decapeptide which had little or no demonstrable activity, with loss of two amino acids to form the octapeptide called "angiotensin." Within a decade synthesis was achieved which made the substance available for world.wide study."

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."

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.

If the numerous therapeutic acquisitions of the past few years have enriched very different fields of human pathology, it does seem that coronary pathology has been given very special attention, as witness the wide variety of antianginal medications placed at the disposal of the medical profession. There are various explanations for this state of affairs, one of them probably being that the medica- tions successively proposed do not fully satisfy the practitioner and another that the total number of individuals suffering from the clinicaI manifestations of coronary heart disease offers, by its size, a vast profit potential for the pharma- ceuticaI industry. This field of applications opens up such prospects that it has encouraged a prolific amount of competition between various research laborato- ries, and it is no exaggeration to say that every major firm has its individuaI anti- anginaI drug in its therapeutic cataIogue. A further factor has aIso contributed enormously to this proliferation of medi- cinal preparations intended for the treatment of angina pectoris: this is the rapid advance in our knowIedge of the physiopathoIogy of angina, which in turn has produced originaI concepts of pharmacological and biochemical research. As a result, there have emerged new substances whose action mechanisms have claimed to be best suited to the cardiovascular disorders responsible for cardiac pain.

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."

Catecholamines 1922 -1971 H. BLASCHKO Adrenaline and related substances were discussed in the 1924 edition of Hefl'ter's Handbook by PAUL TRENDELENBURG. On 164 pages he described what was then known not only of adrenaline and its closest relatives but also of the sympathomimetic compounds such as tyramine and ephedrine. When the present Editors of the Handbook entrusted us with the task of editing the present Volume it was decided to restrict it to adrenaline and the other naturally occurring catecholamines. The sympathomimetic amines in general will be discussed only in their relation to the catecholamines. Since TRENDELENBURG completed his review this field has undergone an enormous expansion. There has been a wealth of new findings, and a succession of new ideas. The new theories that have been built into contemporary thought will be fully discussed in the succeeding contributions. But many of the hypotheses that have been put forward since 1924 have long been discarded and yet, they have often led to important observations that we still consider as valid.

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.

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 volume places more emphasis on endogenous mediators of gut motility than on drugs used to treat patients with deranged motility. In this respect it resembles most other books on gastroenterology, for while only a relatively small number of drugs are really useful for a rational therapy, a tremendous amount of data is available on neural and hormonal factors regulating the motility of the alimentary canal. Moreover, it must be considered that some of the drugs which can routinely be employed to modify deranged motility of the digestive system are represented by pure or slightly modified endogenous compounds (e. g. , cholecystokinin, its C terminal octapeptide and caerulein), and it is easy to foresee that their number is destined to increase in the near future. Other drugs are simply antagonists of physiological substances acting on specific receptors (e. g. , histamine H -blockers 2 and opioid compounds). The real explosion of research in this field and the extreme specialization often connected with the use of very sophisticated techniques and methodologies would probably have required a larger number of experts to cover some very specific fields from both an anatomical (lower esophageal sphincter, stomach, pylorus, small and large intestine) and a biochemical (hormones, candidate hormones, locally active substances, neurotransmitters etc. ) point of view.

Over the past two decades a number of attempts have been made, with varying degrees of success, to collect in a single treatise available information on the basic and applied pharmacology and biochemical mechanism of action of antineoplastic and immunosuppressive agents. The logarithmic growth of knowledge in this field has made it progressively more difficult to do justice to all aspects of this topic, and it is possible that the present handbook, more than four years in preparation, may be the last attempt to survey in a. single volume the entire field of drugs em ployed in cancer chemotherapy and immunosuppression. Even in the present instance, it has proved necessary for practical reasons to publish the material in two parts, although the plan of the work constitutes, at least in the editors' view, a single integrated treatment of this research area. A number of factors have contributed to the continuous expansion of research in the areas of cancer chemotherapy and immunosuppression. Active compounds have been emerging at ever-increasing rates from experimental tumor screening systems maintained by a variety of private and governmental laboratories through out the world. At the molecular level, knowledge of the modes of action of estab lished agents has continued to expand, and has permitted rational drug design to playa significantly greater role in a process which, in its early years, depended almost completely upon empirical and fortuitous observations."

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.

Beta-Rezeptorenblocker sind aus dem therapeutischen Arsenal zur Be- hand lung zahlreicher Erkrankungen nicht mehr wegzudenken. Die Be- miihung urn eine prazisere differentialtherapeutische Anwendung dieser Pharmaka-Gruppe, einschlie13lich der Erarbeitung von Dosierungsvor- schlagen und der Erkennung von therapeutischen Alternativen im Hin- blick auf Nebenwirkungen und Kontraindikationen, fUhrte eine Viel- zahl von Referenten aus dem In- und Ausland (U.S.A., England, Schweiz, Schweden) zu einem Symposion im November 1980 zusam- men. Mit dem Ziel, die praktische Anwendung von Beta-Rezeptorenblok- kern verstandlicher zu mach en und die therapeutische Sicherheit zu erh6hen, wurden zunachst pharmakologische Grundlagen und klinisch- pharmakologische Untersuchungsbefunde er6rtert. Ein wei teres wichti- ges Anliegen war es, M6glichkeiten und Grenzen, Nutzen und Risiko einer Therapie mit diesen Substanzen bei einzelnen Krankheiten aufzu- zeigen. Die Autoren der einzelnen Beitrage haben sich dankenswerterweise der Miihe unterzogen, ihre Manuskripte fUr die Publikation zu iiber- arbeiten und Anregungen und Erganzungen aus der Diskussion einzube- ziehen. Zusatzliche wichtige Gesichtspunkte aus der Diskussion wurden von den Herausgebern zusammengefaBt und sind am SchluB des Buches dargestellt. Dank und Anerkennung gebiihrt allen Mitarbeitern dieses Buches. Ferner danken wir den Damen und Herren des Springer-Verlages, ins- besondere Herrn Dr. Wieczorek und Herrn H. lakobi, fUr die ausge- zeichnete Zusammenarbeit.

During the early 1950's there appeared reports, from time to time of the presence among the products elaborated by actinomycetes of antifungal antibiotics which exhibited very similar and very characteristic multipeaked ultraviolet absorption spectra. In 1954, with a good number of examples on record, these spectra were analyzed and identified as those of straight-chain conjugated polyenes, comprising tetraenes, pentaenes, hexaenes and heptaenes (85, I30). These antibiotics have since been commonly referred to as the polyene antifungal antibiotics to distinguish them from a host of other miscellaneous antibiotics which also have antifungal properties. Within the next few years, reports of discoveries of new members of this class multiplied rapidly, and almost sixty are now known. Unquestionably, a number of these will eventually be found to be identical with others, as has already happened in several instances: for example, the tetraene "tennecetin" proved to be a rediscovery of pimaricin (34), and in the methyl- pentaenes "moldcidin E" has been identified with pentamycin (83), and "lagosin" appears to be indistinguishable from fungichromin (22). Those that have been purified have turned out to be of fairly high molecular weight (ca. 700-1300) and all appear to be substances of rather similar molecular structure. So far only three, pimaricin, fungi- chromin (lagosin) and filipin, have been structurally elucidated.

In their monumental work "The Cactaceae", BRITTON and ROSE (I9) record 1235 species belonging to the three tribes which constitute the family of the Cacti. The actual number of the species must be con- siderably higher. Cacti occur frequently in tlie more arid and less accessible regions of the American Continent, nearly always within very narrow and definite borderlines. The habitat of a species is in many instances a single valley located in a remote, uninhabited region of the Cordillera. Thus the collection of flowering specimens fit for botanical identification is some- times extremely difficult. On the other hand, cacti are apt to develop individual variations in their characteristic morphological features, rendering the definition of a species difficult and often illusory. Specimens taken from their normal habitat to botanical gardens or arboreta often die, degenerate or stop flowering. Taking into account all these difficulties, it is not surprising to find considerable differences of opinion among botanists on the taxonomy of the cactaceae. A considerable number of species have not been well defined and in many cases different names have been given to the same species. The index of BRITTON and ROSE records not less than 7000 binomials.

Das Buch enthalt Kapitel uber: M. B. Bottorff, W. E. Evans, Memphis, TN, USA: "Uberwachung der Medikament-Konzentration"E. Truscheit, I. Hillebrand, B. Junge, L. Muller, W. Puls, D. D. Schmidt, Wuppertal, FRG: "Inhibitoren der mikrobiellen " "alpha-Glucosidase: Chemie, Biochemie und potentielle " "therapeutische Anwendungen"H. Will, Berlin-Buch, GDR: "Plasminogen-Aktivatoren: Molekuleigenschaften, biologische " "Zellfunktion und klinische Anwendung""

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."

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