It is quite amazing that the oldest group of medically useful antibiotics, the fJ-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 fJ-Iactams 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 fJ-Iactams. Later in the 1970s came the discoveries of nocardicins from Nocardia, clavulanic acid from Streptomyces, and the carbapenems from Streptomyces. Now in the 1980s we learn that fJ-Iactams 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 fJ-Iactam family seems brighter with each passing decade.

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""

Volume XXV of the Handbook of Experimental Pharmacology series entitled "Bradykinin, Kallidin, and Kallikrein" was published in 1970. My aim in editing this volume of the series is not to replace, but to update the 1970 edition. During the decade preceding the publication of Vol. XXV, the existence of kinins and kallikreins gained acceptance, the protein components of the system were purified and characterized and the peptides were synthesized. Even after these accomplish ments, interest in the subject has not abated, but has increased substantially. We have learned a great deal about the role that components of the kallikrein-kinin system play in other systems and about the immensely complex and intricate inter actions in blood. Directly or indirectly, kallikrein and kinins affect the coagulation of blood, the activation of complement, and the generation of angiotensin. Kinins release or modulate the actions of other agents, including prostaglandins, histamine, and catecholamines. Inhibitors of kallikrein or kininase II are employed, for example, in extracorporeal circulation or in hypertension. Kallikrein, kinins, and kininases, present in urine, were described first in 1925 and 1954, but have been ignored for decades. These substances are now studied extensively because of their possible role in blood pressure regulation. The evidence that kinins have a metabolic function is also increasing. The abundance of active components of the system in genital organs suggests a role in the fertilization process. The book is organized into chapters which bear upon these issues.

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.

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.

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

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.

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."

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.

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

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

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.""

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

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

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

Volume 29 of 'Progress in Drug Research' contains 10 articles, a sub- ject index for this volume, an alphabetic index of articles for volumes 1-29, and an author und subject index for all the volumes which have so far been published. The contributions of volume 29 are particularly concerned with drugs in general, hypertension and cardiovascular drugs, atherosclerosis, teratogenic hazards and carcinogenecity, hist- amine, dopamine agonists, tetrahydroquinolines and /J-carbolines, and meddicinal research. The authors have tried, and I think they have succeded, not only to summarize the current status of particular fields of drug research, but also to provide leads for future research activity. The articles of this vo- lume will be of special value to those actively engaged in drug re- search, and to those who wish to keep abrest of the latest developments influencing modern therapy. In addition, it is believed that the 29 vo- lumes of 'Progress in Drug Research' now available represent a useful reference book of encyclopedic character. The editor would like to take the occasion of the publication of this volume to express his grati- tude both to the authors and to the readers. The authors have willingly . undertaken the great labor of writing significant topical contributions, and many readers have helped the editor with criticism and advise. With these thanks, the editor would like to express his gratitude to the publishers, Birkhauser Verlag Basel, particularly to Messrs. H. 1. Ben- der, C. Einsele and A.

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

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

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

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."

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

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

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

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