Of the porphyrinoid structures occurring in nature the most important and most widespread are the red blood pigment heme (1), the green pigment of plant photosynthesis chlorophyll a (2), the bacterial photo- synthetic pigment bacteriochlorophyll a (3), and the "antipernicious" red pigment vitamin BJ2 (4). The basic function of these cofactors are determined by the incorporation of the different metal ions into the macrotetracycles. The different oxidation levels of the macrocyclic ligand system regulate the fine tuning of these functions. The final adaptation of the cofactors to their special molecular environments in the cell compartments is effected by variation of the substitution patterns of the chromophores. HCO,C 3 CO,Phytyl 2 Heme Chlorophyll a CONH, CONH, ~ H,NOC 1 , CONH, /I(Y N~ 3 4 Bacteriochlorophyll a Vitamin B" HO References, pp. 42-51 Naturally Occurring Cyclic Tetrapyrroles 3 Until the mid-1970s the four classic cyclic tetrapyrrolic structures with their porphyrin, chi orin, bacteriochlorin, and corrin skeletons were almost the only representatives in the class of porphyrinoid natural products (1-10). Although other partially reduced porphyrins were conceivable, none of these partially saturated porphyrinoid structures had hitherto been found in nature.

This book deals with principles in g

From beach encounters, aquaculture perils, and processed-food poisoning to snake bites and biological warfare, natural toxins seem never to be far from the public's sight. A better understanding of toxins in terms of their origin, structure, structure-function relation ships, mechanism of action, and detection and diagnosis is of utmost importance to human and animal food safety, nutrition, and health. In addition, it is now clear that many of the toxins can be used as scientific tools to explore the molecular mechanism of several biological processes, be it a mechanism involved in the function of membrane channels, exocytosis, or cytotoxicity. Several of the natural toxins have also been approved as therapeutic drugs, which has made them of interest to several pharmaceutical companies. For example, botulinum neurotoxins, which have been used in studies in the field of neurobiology, have also been used directly as therapeutic drugs against several neuromus cular diseases, such as strabismus and blepherospasm. Toxins in combination with modem biotechnological approaches are also being investigated for their potential use against certain deadly medical problems. For example, a combination of plant toxin ricin and antibodies is being developed for the treatment of tumors. The great potential of natural toxins has attracted scientists of varying backgrounds-pure chemists to cancer biologists-to the study of fundamental aspects of the actions of these toxins."

This publication of a symposium held on 24 th and 25 th of June 1988 in Munich th is dedicated to Nepomuk Zollner on the occasion of his 65 birthday, expressing the best wishes of the authors. Nepomuk Zollner was born in the northern part of Bavaria. While a medical student in Munich he was called up to military duty in the last year of World War II. After achieving excellent results on his examinations he served as a physician in several hospitals in Munich and soon became interested in inborn errors of metabolism. In order to receive the best education possible at that time he joined the group of S. J. Thannhauser, the famous German emigrant, in Boston where he worked from 1951 to 1953. There he was able to continue his studies on lipids, which he had started in 1948, and begin with his studies on purine metabolism. While working in Thannhauser's laboratory he learned to think and act according to the strict laws of natural SCIence. After returning to Europe he concentrated his scientific work on purines and lipids. Gout and hyperlipoproteinemias from the genetic to the therapeutic aspects remained the dominating topics of his research activities. In spite of many obligations as head of the Medical Polyclinic of the University of Munich and many activities at the university and in scientific societies Zollner's foremost intent continued to be the development and progress of natural science in medicine.

Arthropod venoms have received much attention and have played an important role in folklore and medicine since ancient times. Scorpion envenomation, "tarant ism," bee and wasp stings are among those subjects about which most has been speculated and written in the past. In the last 50 years or so, a great number of scientific papers have been devoted to arthropod venoms, but only a few volumes have been designed to collect this rapidly increasing material, and these are not recent. Of late, the chemistry and mode of action of several arthropod venoms have been thoroughly studied, and some of these substances will probably be used as pharmacological tools and also as therapeutic agents. The aim of the present volume is to collect in manual form new information as well as the old notions on arthropod venoms. Even though it was our intention to present a volume on arthropod venoms, and not on venomous arthropods, inevitably we were forced to include information on venom-producing organisms as well. We assumed, in fact, that those scientists for whom the present manual is primarily intended (biochemists, particularly com parative biochemists, and pharmacologists) should be familiar with the biologic elements concerning the venom-producing species; which should show them how important it is to operate in close collaboration with biologists specialized in venomous arthropod systematics and biology."

The present volume represents the proceedings of the symposium on npyridine Nucleotide-Dependent Dehydrogenases" which was held on the campus of the re cently established University of Konstanz, Germany, from September 15 to 20, 1969. The aim of the symposium was to provide a forum for discussion among the experts interested in the various aspects of pyridine nucleotide-dependent de hydrogenases and the pyridine coenzymes, so as to evaluate the state of the present knowledge and to stimulate further progress in this field. In order to facilitate discussion and personal contact it was necessary to restrict the number of participants to 90 including the invited speakers, who came from fifteen countries (Australia, Austria, Denmark, England, Finland, France, Germany, Hungary, Israel, Italy, Japan, Netherlands, Sweden, Switzerland, USA). The printed lectures in this volume differ only in minor respects from those circulated be fore the meeting. In some cases speakers presented new experimen tal material during the symposium which was added as an addendum to the papers. The discussions were not recorded. The participants were requested to provide a written report of what they considered worth including in the published re port. This, together with the answers of the speakers is presented in this vo lume. I whish to thank all the speakers and discussants for their cooperativity in preparing the manuscript. The symposium was sponsored by the International Union of Biochemistry whose President, Professor Theorell, was also present and who was acting as one of the speakers and chairmen."

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.

Originally published in 1995, The History of Pharmacy is a critical bibliography of selected information on the history of pharmacy. The book is designed to guide students and academics through the history of science and technology. Topics range from medicine, chemical technology and the economics and business of pharmacy to pharmacy's influence in the arts. The bibliography includes an exhaustive selection of primary and secondary sources and is arranged chronologically. This book will be of interest to those researching in the area of the history of science and technology and will appeal to students and academic researchers alike.

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.

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."

Volume 36 of "Progress in Drug Research" contains 5 articles and the various indexes which facilitate its use and establish the connec tion with the previous volumes. While all articles deal with some of the topical aspects of drug research, the contribution by Robert R. Ruffolo et al. on "Drug receptors and control of the cardiovas cular system: Recent advances" is indeed in its own right a mono graphic presentation of this important domain. The remaining four reviews provide an overview of the work in volved in the search for new and better medicines, with a focus on chemical, pharmacological, toxicological, biological, biochemical and molecular modeling studies. In the 31 years this series has existed, the Editor has enjoyed the help and advice of many colleagues. Readers, the authors of the in dividual articles, and, last but not least, the reviewers have all con tributed greatly to the success of PDR. Although many comments received have been favorable, it is nevertheless necessary to analyze and to reconsider the current position and the direction of such a series. So far, it has been the Editor's aim to help spread informa tion on the vast domain of drug research, and to provide the reader with a tool helping him or her to keep abreast of the latest develop ments and trends."

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""

The recent interest in the pharmacology of the skin and the treatment of its diseases has come about for two reasons. The first is a realisation that many aspects of pharmacology can be studied as easily in human skin as in animal models, where they may be more relevant to human physiology and disease. Examples of this are the action of various vasoactive agents and the isolation of mediators of inflammation after UV irradiation and antigen-induced dermatitis. The second reason is the fortuitous realisation that a pharmacological approach to the treatment of skin disease need not always await the full elucidation of aetiology and mechanism. For example, whilst the argument continued un resolved as to whether the pilo-sebaceous infection which constitutes acne was due to a blocked duct or to a simple increase in sebum production, 13-cis retinoic acid, was found quite by chance totally to ablate the disease; again, whilst cyclosporin, fresh from its triumphs in organ transplantation, has been found able to suppress the rash of psoriasis, it has resuscitated the debate on aetiology. We are therefore entering a new era in which the pharmacology and clinical pharmacology of skin are being studied as a fascinating new way of exploring questions of human physiology and pharmacology as well as for the development and study of new drugs, use of which will improve disease control and at the same time help to define pathological mechanisms.

When this book was first conceived as a project the expanding interest in the clinical use of platinum and gold complexes made a survey of the relevant biological properties of metal complexes timely and appropriate. This timeliness has not diminished during the gestation and final publica tion of the manuscript. The introduction contains an explanation of the layout and approach to the book, which I wrote as an overall survey of the wide variety of biological properties of metal complexes. Hopefully, the reader will see the parallels in mechanisms and behavior, even in different organisms. The writing was considerably helped by the enthusiasm and confidence (totally unearned on my part) in the project of Professor Brian James and lowe him my special thanks. I also owe a great debt of gratitude to my colleagues, and especially to Eucler Paniago, of the Universidade Federal de Minas Gerais, for their comprehension and for the initial leave of absence which allowed me to begin the project. To those who read some or all of the manuscript and made suggestions, Bernhard Lippert, Kirsten Skov, and Tom Tritton, as well as the editor's reviewer I am also grateful. As usual, the final responsibility for errors or otherwise rests with the author."

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.

Die Arzneimittelforschung hat sich in den letzten zwanzig J ahren stiirmisch ent- wickelt und bewegt sich nicht mehr nur auf den naheliegenden Disziplinen der Chemie, Pharmakologie, Toxikologie und Medizin, sondern greift auch auf die der Physiologie, Biochemie, physikalischen Chemie und Physik iiber. Dem einzelnen ist es deshalb kaum noch moglich, die Originalliteratur zu verfolgen, soweit sie auBerhalb seiner eigenen Forschungsrichtung liegt, und auch da besteht die groBe Gefahr der aIlzu engen Spezialisierung. Die Erkenntnis dieser Entwicklung und ihrer Folgeerscheinungen hat den Herausgeber vor einigen J ahren dazu bewogen, diese Monographienreihe ins Leben zu rufen, und er empfindet groBe Genugtuung, hiermit bereits den sechsten Band seinen Lesern iibergeben zu konnen. Er ergreift freudig die Gelegenheit, nicht nur den Autoren flir ihre Bereitwilligkeit, mit welcher sie einzelne Forschungsgebiete in Ubersichtsreferaten dargestellt haben, sondern auch befreundeten Forschern und Fachkollegen fiir ihre vielen wertvollen Anre- gungen, Kritiken und Vorschlage zu danken, ist es ihm doch nur dank dieser Unter- stiitzung von seiten der Fachwelt ermoglicht worden, diese Zusammenarbeit auf internationaler Ebene zu organisieren und die Fortschritte der Arzneimittel/orschung zu einem niitzlichen Werk auszugestalten. Er hofft, daB ihm diese wertvolle Unter- stiitzung, ohne die die Fortsetzung eines derartigen Werkes unmoglich ware, auch weiterhin in vollem Umfang erhalten bleibt. In den bis jetzt vorliegenden sechs Banden wurden ganz verschiedene Gebiete der Arzneimittelforschung dargesteIlt, und die Arbeiten flir die Berichterstattung werden nach verschiedenen aktuellen Richtungen hin weiter vorgetrieben.

Sulfonium compounds have been known to the organic chemist for almost 90 years. During most of this period they remained curiosities, well suited for didactic purposes to illustrate certain similarities to ether adducts and to organic ammonium compounds. Their exploration remained largely in the academic realm, because no unusual practical applications were found in spite of a steady increase in the attention paid to them. An event that occasionally puts a class of compounds into the center of interest is the recognition of its occurrence in nature and of special biological significance. The first natural sulfonium compound was discovered less than 20 years ago, somewhat by chance rather than as the climax of some coveted biochemical problem. Gradually, however, the unique role of sulfonium compounds, especially of S-adenosyl- methionine, in enzymatic group transfer reactions such as trans- methylation was recognized, and the recent upsurge of interest has been exceptional. The present review is directed toward an interpretation of the properties and functions of biological sulfonium compounds with frequent reference to their structural chemistry. The data presented here may suggest novel or improved analytical techniques and new interpretations of the mechanism of group transfer. Furthermore, a stimulus may be derived for the design of sulfonium compound analogues. The availability of competitive analogues of biochemical key compounds has aided in the understanding of the function of virtually all metabolic intermediates, prosthetic groups of enzymes, vitamins, amino acids, and other compounds. The pattern will be similar in sulfonium biochemistry.

Despite the long association of organohalogen compounds with human activities, nature is the producer of nearly 5,000 halogen-containing chemicals. Once dismissed as accidents of nature or isolation artifacts, organohalogen compounds represent an important and ever growing class of natural products, in many cases exhibiting exceptional biological activity. Since the last comprehensive review in 1996 (Vol. 68, this series), there have been discovered an additional 2,500 organochlorine, organobromine, and other organohalogen compounds. These natural organohalogens are biosynthesized by bacteria, fungi, lichen, plants, marine organisms of all types, insects, and higher animals including humans. These compounds are also formed abiogenically, as in volcanoes, forest fires, and other geothermal events.In some instances, natural organohalogens are precisely the same chemicals that man synthesizes for industrial use, and some of the quantities of these natural chemicals far exceed the quantities emitted by man.

Wir prtiften die Wirkung von Verapamil (V) auf die Reizleitungszeit innerhalb des akut ischamischen Myokards bei 10 Hunden (5 Kontrollgruppe, 5 behandelt mit V) nach Unterbindung des RIVA. Verapamil wurde in einer Dosis von 0,15 mg/kg in- travenos als Bolus, unmittelbar nach KoronarverschluB bei 5 Hunden verabreicht; anschlieBend wurde eine Dosis von 7,5 J. 1g/kg/Min infundiert. Die Unterbindung des RIV A erfolgte in zwei Stufen: in einer ersten Phase distal vom 2. R. diagonalis und in einer zweiten Stufe 30 Min spater distal vom 1. R. diagonalis. Endokardiale bipolare Elektrokardiogramme wurden mittels mehrerer Nadelelektroden vor sowie 5, 15 und 30 Min nach jeder Unterbindung aufgezeichnet. Die Untersuchung wurde bei konstanter Vorhofstimulation (200/Min) und vorzeitigen Stimuli mit einem Kopplungsintervall von 50070 durchgefiihrt. Die Reizleitungszeit (definiert als der Zeitintervall zwischen der vorzeitigen Schrittmacherstimulation und der ersten hochfrequenten Schwingung im endokardialen EKG) wurde im ischamischen sowie normalen Muskelareal beider Untersuchungsgruppen gemessen. Ergebnis: (1) Vor KoronarverschluB war die Reizleitungszeit innerhalb des normalen Myokardiums bei beiden Untersuchungsgruppen gleich. (2) Nach VerschluB des RIVA verzogerte sich die Reizleitungszeit signifikant innerhalb des ischamischen Areals bei der Kon- trollgruppe. (3) In der mit Verapamil behandelten Gruppe unterschied sich die Reiz- leitungszeit innerhalb des ischamischen Myokards nicht signifikant von Werten vor dem KoronarverschluB. Dies war signifikant unterschiedlich von Werten in der Ver- gleichsgruppe. Folgerung: Nach KoronarverschluB verhindert die intravenose Gabe von Verapa- mil die Verzogerung der Impulsfortleitung im ischamischen Areal.

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."

Volume 28 of 'Progress in Drug Research' contains 8 articles, a subject index for this volume, an alphabetic subject index for volumes 1-28, and an author and subject index for all the volumes which have so far been published. The contributions of volume 28 are particularly con cerned with biogenic amines, with immunology and the pharmacology of the immune system, with antiviral agents, with amino-quinoline an timalarials, with the axoplasmic transport, with drug treatment of asthma and with the role of adipose tissue in the distribution and stor age of drugs. 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 volume will be of special value to those actively engaged in drug re search, and to those who wish to keep abrest ofthe latest developments influencing modern therapy. In addition, it is believed that the 28 volu mes of 'Progress in Drug Research' now available represent a useful reference work of encyclopedic character. l The editor would like to take the bccasion of the publication of this volume to express his gratitude both to, the authors and to the readers."