The construction of this volume has been guided by two personal convictions. Experience in the field of experimental chemotherapy, both in the pharmaceutical industry and academia, has convinced us that recent quantum technological advances in biochemistry, molecular biology, and immunology will permit and, indeed, necessitate an increasingly greater use of rational drug development in the future than has been the custom up to now. In Part l, therefore, we asked our contributors to provide detailed reviews covering the biology of the malaria parasites and their relation with their hosts, the experimental procedures including culture techniques that are necessary to take a drug from primary screening to clinical trial, and an account of antimalarial drug resistance. Our second conviction is that many research workers are all too loath to learn from the lessons of the past. For this reason we asked the contributors to Part 2 of this volume to review very thoroughly the widely scattered but voluminous literature on those few chemical groups that have provided the antimalarial drugs in clinical use at the present time. Much can be learned from the history of their development and the problems that have arisen with them in man. Some indeed may still have much to offer if they can be deployed in better ways than they are at present. This question has been taken up by several authors.

The pharmacokinetics of digitalis glycosides have been the subject of extensive re view (IISALO, 1977; ARONSON, 1980; PERRIER et ai., 1977). Research on glycoside kinetics has progressed at a rapid pace, requiring continuing reevaluation of the state of our understanding of this problem. The present article focuses on the effect of disease states (renal, gastrointestinal, thyroid, and cardiac) on the absorption, distribution, and clearance of a number of digitalis glycosides. Evidence is critically reviewed, and interpreted with respect to possible clinical implications. A. Renal Insufficiency I. Strophanthin Strophanthin disposition in renal failure has been evaluated in only two studies. KRAMER et ai. (1970) determined an elimination half-life of 14 h in normals as com pared to 60 h in anuric patients. Similar results were reported by BRASS and Pm LIPPS (1970) using tritiated strophanthin. They found a half-life value of 18 h in healthy individuals as compared to 68 h in anuric patients. The findings clearly in dicate that the elimination half-life of strophanthin is prolonged in renal failure."

Held at Boppard, Germany, October 3-6, 1984

When I was asked some years ago by the editors of the Handbook of Experimental Pharmacology to edit a new volume on Antianginal Drugs, I agreed on the condition that, in accordance with my scientific background, primary emphasis be given to clinical pharmacology and therapeutics. It soon turned out that, due to rapid developments in this field, nothing of the previous volume on Antianginal Drugs by Charlier (Vol. 31, 1971) could be retained apart from its basic idea of devoting considerable space to methodology. Since editors must operate within certain limits, I had to abstain from dealing with acute myocardial infarction in detail despite the well-known overlap between unstable angina, the preinfarction syndrome, and acute myocardial infarction. It was only possible for acute myocardial infarction and the concept of reduction of infarct size to be briefly discussed within the chapter on pathophysiology of acute coronary insufficiency. The chapter on invasive methods provided an opportunity to touch on new approaches to early intervention in acute myocardial infarction. Here, intracoronary streptokinase therapy and PTCA are considered, again with attention to the overlap between mechanical and pharmacological interventions.

Epileptic disorders need treatment for many years or even for life, and this makes a thorough understanding of the pharmacokinetics and possible hazards and side effects of the drugs used in treatment mandatory. During recent decades our knowledge in this field has considerably increased, not least as a result of the development of specific and sensitive methods for the determination of anti epileptic agents in biological material. The clinical pharmacology of this group of drugs has been studied extensively and can today be regarded as well established. This does not necessarily mean that drug treatment of epilepsy is without problems. For example, it has recently been shown that one of the newer anti epileptic drugs, greeted with great enthusiasm by clinicians, may in rare instances induce serious damage to the liver and the pancreas, and seems even to have a certain teratogenic potential. Clinical problems should be understood as a challenge to the experimental pharmacologist, who should try to find explanations for the clinical hazards, and, if possible, show new ways in which better drugs might be developed. In recent years interest has focused on the importance of the inhibitory transmitter 'l'-aminobutyric acid (GABA) in the pathophysiology of epilepsy, and there have been a series of attempts to find useful antiepileptic drugs among substances interfering with GABA metabolism in the CNS."

-Encapsulation by Miniemulsion Polymerization By K. Landfester and C. K. Weiss -Enzyme-Encapsulated Layer-by-Layer Assemblies: Current Status and Challenges Toward Ultimate Nanodevices By K. Ariga, Q. Ji, and J. P. Hill -Non-LBL Assembly and Encapsulation Uses 1 of Nanoparticle-Shelled Hollow Spheres 2 By G.C. Kini, S. L. Biswal, and M. S. Wong -Polymersomes: A Synthetic Biological Approach to Encapsulation and Delivery By M. Massignani, H. Lomas, and G. Battaglia -Reaction Vessels Assembled by the Sequential Adsorption of Polymers By A.D. Price, A.P.R. Johnston, G.K. Such, and F. Caruso

The literature on co-trimoxazole (TMP jSMX) is voluminous, but in the main it consists of research reports. The same can be said of various symposia that have appeared. This volume attempts to present the current status of this antibacterial combination in a series of topical reviews, each of which represents a comprehensive summary of a segment of the field. The editor acknowledges with appreciation the help provided by JACKIE, JENKS, LEE KUYPER, and particularly, RUTH Ross in the preparation of the Subject Index, and thanks Burroughs Wellcome Co. for providing access to library and word processing facilities. Research Triangle Park GEORGE H. HITCHINGS List of Authors Dr. J. F. ACAR, Hospital Saint-Joseph, 7, rue Pierre-Larousse, F-75674 Paris Cedex 14 Dr. N. ANAND, National Information Centre for Drugs and Pharmaceuticals, Central Drug Research Institute, Chattar Manzil, P. O. Box No. 173, Lucknow, 226001jIND Dr. D. W. BARRY, The Wellcome Research Laboratories, Burroughs Wellcome Co. , 3030 Cornwallis Road, Research Triangle Park, NC 27709jUSA Dr. R. E. BLACK, Center for Vaccine Development, University of Maryland, Division of Infectious Diseases, 29 S. Greene Street, Bressler Building, Room 404, Baltimore, MD 21201jUSA Dr. J. J. BURCHALL, Department of Microbiology, The Wellcome Research Laboratories, Burroughs Wellcome Co. , 3030 Cornwallis Road, Research Triangle Park, NC 27709jUSA Dr. S. R. M. BUSHBY, The Wellcome Research Laboratories, Burroughs Wellcome Co. , 3030 Cornwallis Road, Research Triangle Park, NC 27709jUSA Dr. M. L.

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

This report on Future Trends in Inflammation IV records another of the multidisciplinary meetings organized by the European Biological Research Association. The organizers wish to record their thanks to all the participants and delegates who made this such an enjoyable meeting. Our thanks are due to a number of members of the pharmaceutical industry who so kindly donated funds. These funds were used to provide grants for young research workers to attend this meeting. Many people have kindly given their time and help to make this congress possible. It is impossible to list them by name, but we are profoundly grateful. We were dubious at the outset as to whether to hold this meeting in a period when many other meetings are being organized on inflammation. The enthusiastic attendance proves that we were right in going ahead. The next international meeting will be held in France in 1983. For further details please contact: Professor J. P. Giroud Department of Pharmacology, Hopital Cochin 75014 Paris, France D. A. Willoughby J. P. Giroud xxxiii Section I Future Trends CHAIRMAN: L. Chedid CO-CHAIRMAN: Dame Honor Fell 1 The participation of mononucleur phagocytes in immune based inflammatory processes with special reference to their secretory responses P. DAVIES AND R. J.

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

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

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

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

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

International Symposium. IFPMA Symposium, Geneva 30-31 October 1984

Following the monographs by STRAUB (1924) and LENDLE (1935), this is the third contribution to the "Pharmacology of Cardiac Glycosides" within the Handbook of Experimental Pharmacology, which was founded by ARTHUR HEFFTER and con tinued by WOLFGANG HEUBNER. Because of the need created by the length of time that had elapsed since LENDLE'S work, the editorial board requested the rapid ap pearance of this 56th volume, which represents current knowledge of the pharma cology and clinical pharmacology of cardiac glycosides. In order to avoid any delay, numerous authors were invited to contribute because shorter contributions take less time to prepare and are consequently more up-to-date. The disadvantage is that some overlap between certain chapters could not be avoided, despite the editor's efforts. Overlapping can, however, actually be useful, in that differing opinions may be provided and topical issues discussed from varying viewpoints. This re minds the reader that scientific horizons in medicine should often be widened or revised. I would like to thank DR. ALANNA Fox and DR. K. ANANTHARAMAN for their help and advice in the revision of certain chapters. I am also grateful to Springer Verlag, and particularly to MR. WINSTANLEY and MR. EMERSON, for their contribu tion to the completion of this volume through translation and corrections. In con clusion I would like to thank MRS. WALKER, MR. BISCHOFF, MRS. SEEKER, and MR. BERGSTEDT of Springer-Verlag for their helpful support."

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.

Contents/Information: N.P. Johnson, J.-L. Butour, G. Villani, F.L. Wimmer, M. Defais, V. Pierson, Toulouse, France; V. Brabec, Kralovopolska, CSSR: "Metal Antitumor " "Compounds: The Mechanism of Action of Platinum Complexes " "Pertaining to the Design of Anticancer Agents"B.K. Keppler, M. Henn, U.M. Juhl, M.R. Berger, R. Niebl, Heidelberg; F.E. Wagner, Garching, FRG: "New Ruthenium Complexes for the " "Treatment of Cancer"G. Mestroni, E. Alessio, Trieste, M. Calligaris, Pavia, Italy; W.M. Attia, Ismailia, Egypt; F. Quadrifoglio, S. Cauci, Udine, Italy; G. Sava, S. Zorzet, S. Pacor, C. Monti-Bragadin, M. Tamaro, L. Dolzani, Trieste, Italy: "Chemical, Biological and Antitumor Properties of " "Ruthenium (II) Complexes with Dimethylsulfoxide"N. Farrell, Burlington/VT, USA: "Metal Complexes as Radiosensitizers"S.C. Srivastava, L.F. Mausner, M.J. Clarke, Upton/NY, and Chestnut Hill/MA, USA: "Radioruthenium-Labeled Compounds for " "Diagnostic Tumor Imaging"P. Kopf-Maier, Berlin, FRG: "The " "Antitumor Activity of Transition and Main-Group Metal " "Cyclopentadienyl Complexes"E.V. Scott, G. Zon, L.G. Marzilli, Atlanta/GA and Foster City/CA, USA: "NMR Relaxation " "Footprinting: The ACr(NH3)6U3+ Cation as a Probe for Drug " "Binding Sites on Oligonucleotides"J.E. Schurig, H.A. Meinema, K. Timmer, Wallingford/CT, USA; B.H. Long, A.M. Casazza, Zeist, NL: "Antitumor Activity of " "BisABis(Diphenylphosphino)Alkane and AlkeneU Group VIII " "Metal Complexes"M.E. Heim, H. Flechtner, Mannheim; B.K. Keppler, Heidelberg, FRG: "Clinical Studies with Budotitane -" "A New Non-Platinum Metal Complex for Cancer Therapy""

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

The 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.