This volume collects the invited lectures and some selected contributions presented at the 5th International Meeting on Clinical Pharmacology in Psychiatry, which was held 26-30 June 1988 at the University of Troms0, Norway. The 24 h of daylight at the northernmost university in the world al lowed for long, pleasant and productive sessions. The title of the conference as well as a number of the topics covered represent a continuation of four previous conferences, the first held in Chicago in 1979 and organized by the late Earl U sdin and colleagues. The earlier conferences have been documented in Clinical Pharmacology in Psychiatry, edited by E. Usdin (Elsevier, New York, 1981), Clinical Pharmacology in Psychiatry. Neuroleptic and Antidepressant Research, edited by E. Usdin, S. G. Dahl, L. F. Gram and o. Lingjrerde (Macmillan Publishers Ltd., London, 1981), Clinical Pharmacology in Psychiatry. Bridging the Experimental-Therapeutic Gap, edited by LF. Gram, E. Usdin, S.G. Dahl, P. Kragh-Sorensen, P. L. Morselli and F. Sjoqvist (Macmillan Publishers Ltd., London, 1983), and Clinical Pharmacology in Psychiatry. Selectivity in Psychotropic Drug Action - Promises or Problems? edited by S. G. Dahl, L.F. Gram, S.M. Paul and W.Z. Potter (Psychopharmacology Series 3, Springer, Heidelberg, 1987)."

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

At the end of the initial meeting on Primary and Secondary Metabolism of Plant Cell Cultures at Schloss Rauischholzhausen, it was decided to convene similar events on a regular basis midway between the International Congress for Plant Tissue and Cell Cul ture. We felt it was necessary to bring representatives of the research teams working in this field together to assess progress as well as to discuss future directions. The Plant Biotechnology Institute of the National Research Council of Canada in Saskatoon, Saskatchewan was chosen to be the site for the second symposium held in 1988. The theme of this meeting was "The Regulation of Primary and Secondary Metabol ism in Plant Cells" and judging by the contributions published in this volume it was a timely and actual one indeed. I would like to thank my organizing committee and my research group for their efforts, the National Research Council of Canada for the financial assistance and the participants for their contributions which all contributed to make this symposium a success. A special thank you to Mrs. L. -Blashill and R. Gallays for their assistance in hosting this event. Last but not least I would like to thank our publisher, Springer-Verlag, Heidelberg for their deci sion to publish the proceedings of this and future symposia.

Most often when the subject of antimicrobial resistance is discussed, the organizational emphasis is on individual antimicrobial agents or groups of agents. Thus we tend to see discussion of resistance to f3-lactams, tetracyclines, amino glycosides etc. In this book many of the authors were asked to emphasize the mechanism of resistance in their discussion and from that to show how susceptibility to various agents was affected. In part this was done to help emphasize the enormous contribution that the study of antimicrobial resistance has made to our understanding of fundamental physiologic and genetic processes in bacteria. When one looks back over the study of antimicrobial resistance, it is clear that it has been the birthplace of many fundamental advances in molecular biology and of an appreciation of the role of many key functions in the life of a bacterium. In addition, and hopefully to an increasing extent in the future, such study has also contributed to advances in antimicrobial chemotherapy. Through out the book resistance mechanisms have been placed in perspective as to their significance as causes of resistance to key drugs or groups of drugs. Some are of much greater significance than others in terms of the prevalence or the degree of resistance produced. Whatever their numerical significance, however, each of the mechanisms, without question, throws light on fundamental cellular processes and the way in which they interact with antimicrobial agents."

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 entired 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 im anyone person to stay informed on this subject by reading the possible for At the same time it is becoming increasingly apparent that primary literature. 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 common language for intercellular communication. As a set they affect es sentially 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."

A wide variety of hormones, neurotransmitters and growth factors exert their cellular effects by reacting first with membrane receptors resulting in an increase of intracellular calcium and the cellular response. The calcium signal in the cell is mediated by the high-affinity calcium binding proteins (characterized by the EF-hand structural element), and by the calcium and phospholipid dependent proteins. Many of these have been discovered most recently. Their purification, distribution, protein and gene structures as well as their physiological roles are discussed. The book is of interest to biochemists and molecular biologists as well as to clinicians and the pharmaceutical industry who can apply the results in this field.

The study of tumour resistance to anticancer drugs has been the subject of many publications since the initial discovery of the phenomenon by J. H. Burchenal and colleagues in 1950. Many papers have been published since then reporting development of resistance to most of the well-known anticancer agents in many different animal tumour systems, both in vivo and in vitro. Many different mechanisms of resistance have been described, and it is clear that the tumour cell has a wide diversity of options in overcoming the cell-killing activity of these agents. Definition of the magnitude of the phenomenon in the clinic is, however, much more problematical, and it is with this in mind that the initial chapter, seeks to out line the problem as the clinicians see it. It appears that the phenomenon of true resistance to a drug, as the biochemist would recognise it, is an important cause of the failure which clinicians experience in treating the disease. The extent of the contribution of this phenomenon to the failure of treatment cannot easily be evaluated at the present time, but it is hoped that the development and application of new and more sophisticated techniques for the analysis of cellular sub populations may help to give a more exact estimate and to shed some light on the causes of failure of many of the present therapeutic techniques."

One of the most impressive works of scholarship in the field of experimental pharmacology has been the Heffter-Heubner Handbuch der experimentellen Pharmakologie, internationalized some years ago under the title Handbook 0/ Experimental Pharmacology and kept up to date by a series of numbered Ergiin zungswerke or supplementary volumes which have now replaced in importance the original Handbuch. These volumes constitute a valuable and continuously up dated multi author review series of topics important in modern pharmacology and allied sciences. The Editorial Board of the Handbook invited me 2 years ago to undertake, as subeditor, the preparation of a new volume entitled The Cholinergic Synapse. A previous volume in this series, vol. 15, Cholinesterases and Anticholinesterase Agents, edited by GEORGE KOELLE, was published in 1963 and was far wider in scope than its title suggested: it was, in fact an authoritative summing up of the whole subject of cholinergic function and still has some value today as an account of the state of the art as it was at that time. Since then another excellent review, of a specific cholinergic synapse, has appeared in this series: this was vol. 42, Neuromuscular Junction, edited by ELEANOR ZAIMIS and published in 1976. A third volume, vol. 53, Pharmacology o/Ganglionic Transmission, which appeared in 1980 and was edited by D. A. KHARKEVICH, includes important aspects of autonomic cholinergic function.

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 resolution of links between exposure to components of our complex environmental and causation of reproductive effects in the population constitutes an important problem in the field of toxicology. The focus of this volume is developmental toxicology, which represents one aspect of reproductive toxicology dealing with the study of adverse effects on the developing conceptus. Developmental toxicology, which includes teratogenesis as one of its manifesta tions, provides a fertile field for research in several basic and clinical disciplines; this field also receives input from several disoiplines such as developmental and molecu lar biology, pathology, pharmacology and toxicology, pediatrics and neonatology, and epidemiology. More recently we h~ve seen an emergence of interest in other fields such as perinatal physiology and postnatal behavior which have now become incorporated into the mainstream of research in this discipline. The present volume is an effort to provide a sampling of concepts currently under active investigation in several of the above fields. The authors have endeavored to provide up-to-date in formation on the following topics: detection and analysis of potential hazards to the conceptus in the workplace, pharmacokinetic aspects of the maternal/placental! fetal complex and its relationship to human birth defects, and probable mechanisms of teratogenesis as uncovered in certain well-defined situations. Also included are summaries of newer investigations on the emerging field of postnatal functional evaluations, i. e. , adverse effects on adult activities resultant from in utero exposure to toxic substances.

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."

The synthetic chemistry of carbohydrates has advanced at a scarcely equalled rate in the last 25 years, due to the great interest of biologically active natural products coritaining sugar moieties. It suffices to note that in the review by J. D. Dutcher appearing in "Advances in Carbohydrate Chemistry" vol. 18, 1963, only the structures of less than ten aminodeoxy sugars were reported. This book deals exclusively with a single class of carbohydrates, namely the aminodeoxy sugars of antibiotics, the most popular of which is probably daunosamine, a compound for which more than 20 different synthetic approaches have been reported in the literature since the publication of its structure in 1964. No compound in the 3-amino-2-deoxY-L-hexose series had been prepared by chemical synthesis when we started our synthetic work in this field in 1972 on the wave of the successful therapeutic applications of adriamycin. The compounds with xylo stereochemistry were unknown even in the more easily accessible D-series. The size of this book documents the rapid development of the field. I wish to add that the improvements of chemical methodology reported in. the volume outspan the specific field and are of importance in the design of synthetic approaches to other carbohydrate structures. These also include compounds involved in chemical interactions of great biological interest, but hitherto un explained at the molecular level, such as those related with cell recognition, adhesiveness and differentiation."

The study of the biological effects of foreign chemicals (whether therapeutic drugs or chemicals present at work or in the environment) interests the biologist from a number of different and complementary viewpoints. Apart from the more obvious pharmacological and toxicological interest, the experimentalist often uses foreign chemicals to produce in experimental animals disease states similar to naturally occurring diseases, so that their pathogenetic mechanisms and therapy can be studied under controlled conditions. In addition - as Claude Bernard pointed out over a century ago - foreign chemicals can be employed as instruments to analyze the most delicate vital processes; much can be learned about the physiological processes themselves by a careful study of the mechanisms by which these are altered by chemicals. The field of heme and hemoproteins offers an example of the interplay of these different approaches. Their metabolism can be altered by therapeutic drugs and other foreign chemicals and this results in a variety of biological responses that transcend the boundaries of pharmacology into the confines of clinical medi cine, genetics, toxicology, biochemistry and physiology. In this book a multidisciplinary approach to the study of heme metabolism is presented including the effect of chemicals on heme metabolism in patients, the results of experimental work in the whole animal, as well as in vitro studies."

This book has been developed from its earlier and far less formal presentment as the proceedings of a symposium entitled The Biochemistry of S-Adenosylmethionine as a Basis for Drug Design that was held at the Solstrand Fjord Hotel in Bergen, Norway on June 30-July 4, 1985. The purpose of the symposium was to bring together scientists from various disciplines (biochemistry, pharmacology, virology, immunology, chemistry, medicine, and so on) to discuss the recent advances that have been made in our understanding of the biological roles of S adenosylmethionine (AdoMet) and to discuss the feasibility of utilizing AdoMet-dependent enzymes as targets for drug design. Thus the information provided herein will be of value not only to basic scientists involved in elucidating the role of AdoMet in biology, but also to medicinal chemists who are using this basic knowledge in the process of drug design. The volume should also be of interest to pharmacologists and clinicians involved in biological evaluation of potential therapeutic agents arising from the efforts of the biochemists and medicinal chemists. Each plenary speaker at the symposium was requested to submit a chapter reviewing recent contributions of their discipline to our base of knowledge about the biological role of AdoMet. Topics covered in this volume include protein and phospholipid methylations (Section A), nucleic acid methyl ations (Section B), the regulation of AdoMet, S-adenosylhomocysteine, and methylthioadenosine metabolism (Section C), clinical aspects of AdoMet (Section D), and the design, synthesis, and biological evaluation of trans methylation inhibitors (Section E)."

Continuing the Respiratory Pharmacology and Pharmacotherapy series, this volume explores the pathophysiology and therapy of rhinitis. The volume is introduced by a chapter describing the normal anatomy and physiology of the nose and sinuses. Against this background the contributing authors describe and discuss the immunological and pathological changes which occur in rhinitis. The various causes and the types of rhinitis - such as allergic, vasomotor, and infectious - are discussed as are the treatments available (pharmacotherapy, immunotherapy, surgery). The book concludes with a description of the animal models of rhinitis which are now available. This book will be of interest to bench scientists and clinicians alike.

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 intestine, particularly the small bowel, represents a large surface (in the adult 2 human approximately 200 m ) through which the body is exposed to its environ ment. A vigorous substrate exchange takes place across this large surface: nutrients and xenobiotics are absorbed from the lumen into the bloodstream or the lymph, and simultaneously, the same types of substrate pass back into the lumen. The luminal surface of the intestine is lined with a "leaky" epithelium, thus the passage of the substrates, in either direction, proceeds via both transcellular and intercellular routes. Simple and carrier-mediated diffusion, active transport, pinocytosis, phagocytosis and persorption are all involved in this passage across the intestinal wall. The term "intestinal permeation" refers to the process of passage of various substances across the gut wall, either from the lumen into the blood or lymph, or in the opposite direction. "Permeability" is the condition of the gut which governs the rate of this complex two-way passage. The pharmacologist's interest in the problem of intestinal permeation is twofold: on the one hand, this process determines the bioavailability of drugs and contributes significantly to the pharmacokinetics and toxicokinetics of xeno biotics; on the other hand, the pharmacodynamic effects of many drugs are manifested in a signigicant alteration of the physiological process of intestinal permeation.

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.

This book contains the papers that were presented at the "Crystallo graphic and Modeling Methods in Molecular Design Symposium" in Gulf Shores, Alabama, April 30 to May 3, 1989. During the past few years, there has been a burst of activity in this area, especially related to drug design and protein engineering projects. The purpose of the symposium and this book is to provide an up-to date review of the most recent experimental and theoretical approaches that are being used for molecular design. The book covers several re cent examples of approaches for using crystallography in conjunction with forefront modeling methods for guiding the development of en zyme inhibitors and of peptides and proteins with modified biological and physical properties. In addition, this book contains discussions of new approaches for combining crystallographic data and advanced computational techniques for aiding in the design of enzyme inhibitors and other compounds that bind to selected biological targets. This book is therefore of interest not only to molecular biologists and biochem ists, but is stimulating reading for anyone involved in structural biol ogy, pharmaceutical chemistry, enzymology, protein engineering, and biotechnology. The meeting was the third in a series of symposia initiated and spon sored by the Department of Biochemistry, University of Alabama at Birmingham.

In the first years of the existence of this series of monographs, during the so-called "Golden Age" of drug research, the majority of the pa pers published were mainly concerned with the traditional domains of drug research, namely chemistry, pharmacology, toxicology and pre clinical investigations. The series' aim was to give coverage to impor tant areas of research, to introduce new active substances with thera peutic potential and to call attention to unsolved problems. This objective has not changed. The table of contents of the present volume makes evident, however, that the search for new medicines has become increasingly complex, and additional, new disciplines have entered the research arena. The series now includes reviews on bio chemical, biological, immunological, physiological and medicinal aspects of drug research. Researchers actively engaged in the various scientific fields forming the entity of drug research can benefit from the wealth of knowledge and experience of the respective authors, and will be assisted in their endeavour to discover new pharmaceutical agents. Those simply wanting to keep abreast of new developments in the complex, multi-discipline science can turn to the "Progress in Drug Research" volumes as an almost encyclopaedic source of information without having to consult the innumerable original publications. Volume 32 contains 12 reviews, a subject index, an index for the close to 400 articles published in the series so far, and an author and titles index for all 32 volumes."

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."

The first useful antibiotic found by screening was streptomycin. The late Prof. WAKSMAN started screening for antibacterial antibiotics in 1940 and, after finding actinomycin in 1941, he and his collaborators discovered streptomycin in 1944. This antibiotic made a great contribution in saving human lives from tuberculosis and acute serious infections. About 1957, after wide usage of such antibiotics as penicillin, streptomycin, chloramphenicol, tetracycline, and erythromycin, staphy- lococci and Gram negative organisms resistant to all or most antibiotic drugs ap- peared in hospital patients. The origin and treatment of such resistant strains be- came a major topic of investigation. At that time, kanamycin was discovered and used in the treatment of resistant infections. It may be said that the appearance of resistant strains stimulated a resurgence of research on new antibacterial antibiot- ics and their derivatives. In 1965, kanamycin-resistant strains were found in hospital patients and, undertaking the study of the mechanisms of resistance, I found that resistant strains produce intracellular enzymes that can transfer either the terminal phos- phate of ATP or the acetate of acetyl-CoA to the 3' -hydroxyl or the 6' -amino group of 2-deoxystreptamine~containing antibiotics. These results, reported in 1967, made it possible to design new synthetic derivatives that would inhibit the growth of kanamycin resistant strains of microorganisms. Thus, a new research area was opened: the development of aminoglycosides useful in the treatment of drug-resis- tant infections.

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].