"The chemical laboratory is actually not a dangerous place to work in, but it demands a reasonable prudence on the part of the experimenters and instructers, to keep it a safe place. Emphasis must be positive, indicating the proper, correct and safe procedure to be followed in all laboratory operations or when confron ted with an emergency situation. Too heavy stress upon the horrors associated with laboratory accidents or graphic descriptions of gory injuries or nasty fires should be avoided. Frightened, timid students are more likely to have accidents than the confident laboratory man who works with due regard to safety. " This statement, written by 1. R. Young (1) in 1971, in The Journal of Chemical Education, applies not only to students working in the chemical laboratory but can be extended to all scientists and technicians working with hazardous products, and in particular with chemical carcinogens. The hazards of handling toxic or dangerous chem icals have been well documented. Besides safety notices and articles in the scientific literature, a large number of books have been dedicated to this subject, among which can be cited Safety and Accident Prevention in Chemical Operations (2), Handbook of Laboratory Safety (3), Hazards in the Chemical Laboratory (4), 1 Handbook of Reactive Chemical Hazards (5), Safety in Working with Chemicals (6) and Prudent Practices for Handling Hazardous Chemicals in Laboratories (7).

The nitrates have remarkable clinical effects that have stood the test of time in the management of ischemic heart disease. What is unusual about this class of com pounds is that, after many years of clinical use, we are still exploring new avenues as to the vascular mechanisms of their effect, their applications in treating other clini cal conditions, and the development of products with more favorable pharmacoki netic properties. This volume represents the proceedings of a symposium held June 14-16, 1984, in Montreux. The papers were selected to explore the current state of knowledge re garding the mechanisms of action, pharmacokinetics, and clinical efficacy of ni trates. Particular attention has been given to newer studies utilizing the 5-mononi trate metabolite of isosorbide dinitrate, a drug whose pharmacokinetic properties may make it an important new agent in the treatment of angina and congestive heart failure. One of the benefits of an international meeting of experts sharing their views on an internationally used group of drugs is that differences in concepts and clinical practice become apparent and can be discussed. The Montreux forum made it clear that clinicians in North and South America and Europe have diverging views on how the nitrates should be used."

Trichloroethylene (TRI), administered orally at high doses for 18 months has been shown to increase the incidence of hepatocellular carcinoma in B6C3F 1 mice but not Osborne-Mendel rats (NCI, 1976). The interpretation of these studies has been confounded due to the presence of epoxide stabilizers in the TRI. However more recent studies have demonstrated that pure TRI also causes hepatocellular carcinoma in B6C3F mice (NTP, 1983) and Aldedey Park (Swiss) mice (Elcombe 1 and Pratt, unpublished data). Furthermore, no increase in the incidence of hepatocellular carcinoma was observed in Fisher 344 rats administered pure TRI (NTP, 1983). TRI has been extensively examined for mutagenic potential, but many studies were bedeviled by the presence of mutagenic epoxide stabilizers. However, in general, TRI has been found to be only 'marginally' mutagenic or non-mutagenic (Greim et ai., 1975; Simmon et ai., 1977; Bronzetti et ai., 1978; Waskell, 1978; Bartsch et ai., 1979; Slacik-Erben et ai., 1980). Covalent binding of trichloroethylene or its metabolites to protein, RNA and DNA has been illustrated in vitro (Van Duuren and Banerjee, 1976; Bolt et ai., 1977; Bolt and Filser, 1977; Uehleke and Poplawski-Tabarelli, 1977; Banerjee and Van Dauren, 1978). However, in vivo, only extremely low (indistinguishable from protein binding) or zero binding of TRI metabolites to DNA has been reported (Parchman and Magee, 1982; Stott et ai., 1982).

After a compound and its various effects - or, as the case may be, any particular one of these - have been discovered there is still a long way ahead until it is available for use in daily practice as a finished product. Before reaching the doctor, the substance is examined by chemists, pharmacologists and pharmacists - just to mention a few of the most important stages in a whole research sequence. Before the drug is finally made available on the market, the findings resulting from animal experiments must be confirmed in clinical studies. The expectations involved in its development must be met, and sufficient evidence has to be established as to the drug's effects and side effects, indications and contraindications, and the questions of safe use and appropriate dosage. Only then may the drug be registered and introduced to the market. In this respect Metipranolol eye drops, which have recently been launched on the market, formed no exception and had likewise to go through all these various stages. A series of investigators at many different centers participated in this procedure, and at the invitation of the manufacturers, Messrs. Dr. Gerhard Mann, they assembled for discussions at a symposium held in Berlin in January 1983, and reported on the substance and their experiences with it.

In October 1982, a small international symposium was held at the Gesellschaft fUr Strahlen- und Umweltforschung mbH (GSF) in Munich as a satellite meeting of the IX International Conference on Analytical Cytology. The symposium focussed on cytometric approaches to biological dosimetry, and was, to the best of our knowledge, the first meeting on this subject ever held. There was strong encouragement from the 75 attendees and from others to publish a proceedings of the symposium. Hence this book, containing 30 of the 36 presentations, has been assembled. Dosimetry, the accurate and systematic determination of doses, usually refers to grams of substance administered or rads of ionization or some such measure of exposure of a patient, a victim or an experimental system. The term also can be used to describe the quantity of an ultimate, active agent as delivered to the appropriate target material within a biological system. Thus, for mutagens, one can speak of DNA dosimetry, meaning the number of adducts produced in the DNA of target cells such as bone-mar row stem cells or spermatogonia."

The International Life Sciences Institute (ILSI) is a scientific foundation which addresses critical health and safety issues of national and international concern. ILSI promotes international cooperation by providing the mechanism for sci entists from government, industry and universities to work together on co operative programs to generate and disseminate scientific data. The members and trustees of the Institute believe that questions regarding health and safety are best resolved when scientists can examine and discuss issues, as an in dependent body, separate from the political pressures of individual countries and the economic concerns of individual companies. Frequently, meaningful assessment of the risk of a test substance is hindered by the inherent inconsistencies in the system. The development and refinement of methods and systems to evalute the safety of chemicals have evolved in a rapid and largely unplanned fashion. Attempts to improve the system have largely been directed toward broad general concerns, with little attention being given to specific problems or issues. A failure to resolve these problems has frequently resulted in increased testing costs and complications in the assessment and extrapolation of the results. In response to these difficulties, ILSI has assembled highly qualified and renowned scientists from research institutes, universities, government and in dustry, with relevant scientific knowledge and expertise regarding the issues that complicate risk assessment procedures."

"Rheumatic Disease" is the second monograph in a new series on management and treatment in major clinical subspecialties and patient groups. Further volumes will be published over the next few years. Each book is complete in its own right. The whole series, however, has been prepared to fill a gap, perceived by the publisher, myself and the volume authors, between standard text books of medicine and therapeutics and research reviews, sympo sia' and original articles in specialist fields. Each volume aims to provide a concise, up to date account of treatment in its subject area with particular reference to drug therapy. Wherever pos sible, authorship has been undertaken by practising clinicians who themselves have training and experience in clinical pharma cology. The volumes are intended to be guides to treatment, to assist in the choice of drug and other treatment and to provide easy references to drug interactions and adverse reactions. The aims of the series should be upheld by this volume on "Rheumatic Disease." The book has been prepared in Glasgow and Newcastle. The authors, Drs. Hilary Capell, Terry Daymond and Carson Dick, are not only respected clinicians and rheumato logists but have wide clinical and research experience in the clinical pharmacology of antirheumatic drugs and therapeutic management of connective tissue disease and other areas of rheumatology. This volume combines practical pragmatic man agement with new concepts in drug treatment."

Die pharmazeutische Industrie weist gegenuber anderen Branchen einige Besonderheiten auf, die in der allgemeinen Industriebetriebslehre nicht ausreichend berucksichtigt werden. Das vorliegende Buch befasst sich daher mit den speziellen volkswirtschaftlichen und betriebswirtschaftlichen Aspekten der pharmazeutischen Industrie. Neueinsteigern in diese Branche bietet es einen umfassenden Uberblick, gestandene Praktiker konnen sich uber Spezialaspekte und neuere Ansatze informieren. Beitrage von Autoren aus Wissenschaft, Unternehmen und Beratungspraxis."

The International Life Sciences Institute (lLSI) is a scientific foundation wh ich addresses critical health and safety issues of national and international concern. ILSI promotes international cooperation by pro viding the mechanism for scientists from government, industry and universities to work together on cooperative programs to generate and disseminate scientific data. The members and trustees of the Institute believe that questions regarding health and safety are best resolved when scientists can ex amine and discuss issues, as an independent body, se arate from the political pressures of individual countries and the economic concerns of individual companies. Frequently, meaningful assessment of the risk of a test substance is hindered by the inherent inconsistencies in the system. The development and refinement of methods and systems to evaluate the safety of chemicals have evolved in a rapid and largely unplanned fashion. Attempts to improve the system have largely been directed toward broad general concerns, with little attention being given to specific problems or issues. A failure to resolve these problems has frequently resulted in increased testing costs and complications in the assessment and extrapolation of the results. Publicity surrounding toxicologic issues has created chronic public apprehension about the ability of science and government to deal effectively with these problems. In response to these difficulties, ILSI has assembled highly qualified and renowned scientists from research institutes, universities, government and industry, with relevant scientific knowledge and expertise regarding the issues that complicate risk assessment procedures."

Many chemotherapeutic agents introduced for use in humans are carcinogenic in laboratory animals (Conklin et al. 1965; Shimkin et al. 1966; Griswold et al. 1968; Harris 1976). However, initially their beneficial effect in disseminated cancer was of such short duration that the inevitable death of the patient from his primary disease precluded any clinical manifestation of the carcinogenic potential. During the last decade, chemotherapy has radically changed the outlook for many patients with cancer. Combinations of drugs, administered as the primary treatment, have resulted in high rates of cure in patients with disseminated malignancies, such as stage IV Hodgkin's disease or childhood acute lymphocytic leukemia. In other disseminated forms of neoplasia, induction of a remission, a substantial palliation and a prolongation of survival have been achieved. In many instances of localised disease, where surgery with or without radiotherapy are the primary form of treatment, anticancer drugs have been used with success as adjuvant therapy for distant microscopic disease. With these spectacular achievements, secondary malignancies, in particular acute non-lymphocytic leukemia (ANLL), has become of major concern. Incidence Acute leukemia is the most frequent form of secondary neoplasia in patients treated for cancer (Penn 1981). In one large series, 5. 9% of all ANLL could be attributed to previous chemotherapy (Kapadia et al. 1980).

Drugs may cause disease, or they may aggravate the morbidity of the condition for which they are prescribed, and certain patients may for one or other reason be particularly liable to drug injury. The inextricable relationships between the toxic profiles of drugs, the natural history of the diseases for which they are given, and the adverse drug effects that may develop in the course of such diseases are of considerable interest. It is the study of these rather neglected aspects of pharmacology and therapeutics which has formed the basis of this book. An explanation is required of the approach and the style which have been followed. The monograph does not purport to be comprehensive. Only important drug groups which are commonly used in practice are considered. Emphasis has been placed on achieving maximum benefit and safety of the appropriate drugs in the management of common illnesses. When treatment fails, either ab initio or subsequent to an initial response, the risk-benefit relationship of drugs inevitably alters. For this reason the main factors responsible for treatment failure have been considered, with special attention to the possible contribution of or implications for drug therapy in such a situation. Finally, proposals have been put forward for improving the diagnosis and reporting of adverse drug effects. In order to be practical and, as far as possible, constructive it has been necessary for me to "take a position" on numerous issues.

Nervous system is in the most cases a likely target for the untoward effects of chemicals. The harmful consequences affect primarily the individual but may also considerably strain the whole society. The consumption of ethanol is a glaring example (National Institute on Alcohol Abuse and Alcoholism 1978). As ethanol, many organic liquids have similar immediate effects on the nervous system. The rapidity of the response suggests the involvement of the neuronal communication. The nervous system is also vulnerable to the depletion of oxygen, another common cause for the rapid deterioration of the brain function. It is quite impossible to list all the effects produced by the very large number of the individual chemicals. It would be more fruitful to try to understand the characteristics of the nervous system and the biochemical toxic mechanisms in the evaluation of the neurotoxicity of chemicals. Transfer of Xenobiotics in the Brain The adult central nervous system displays a functional barrier toward the blood-borne chemicals so that water-soluble compounds with an approximate molecular weight above 100 are largely prevented from directly entering the brain (Bradbury 1979). The functional barrier has morphological features typical to it and has a very close association of adjacent capillary cells separated by clefts of 12 A wide (Jacobs 1978). The nervous system capillaries are enveloped by glial cell tongues, and these pericytes contain contractile elements (Le Beux and Willemot 1978a, b) so that the capillaries can be constricted.

This book uncovers the principles behind optimal neonatal and paediatric prescribing.

The last thirty years have seen an unprecedented increase in the discovery of new drugs, and moreover, these drugs, unlike many of the nostra of former times, have varied and powerful pharmacological actions. The occurrence of one or two "drug disasters," together with a change in public attitudes, has made it necessary for governments to introduce legislation to control the intro duction and release of new therapeutic agents, and most countries in the Western World have some form of drug licensing agency. Whole series of regulations have appeared which aim at discovering and defining the toxicity of new drugs. Many of these regulations rely heavily on testing drugs in animals before they are used in man, and at present very extensive and prolonged animal studies are required by most licensing authorities. It is most opportune that Professor Folb has decided to review the present position in this monograph. It is not only inhumane but also wasteful of time and money if extensive animal experiments which have little or no relevance to the human situation are carried out; furthermore, such results may even be dangerously misleading. There is little doubt that some preliminary animal investigations are necessary, but it is essential to keep their relevance under continuous review and to adopt a critical and flexible approach rather than heap regulation upon regulation."

Venomous Animals have been a threat to man at all times, in the warm and wilder regions more than in the temperate areas. People in especially dangerous regions know about these risks and live accordingly. However, with modern tourism and nearly unlimited travel oppor tunities more and more people without experience and knowledge about venomous animals come into contact with them; this book is intended to provide these people with an introduction to the subject. Venomous animals, their habits, their whole ecology and their venoms have been the object or research since the beginning of this century; truly intensive work, how ever, first started about thirty years ago. Medical treat ment therefore has been changed by new insights in the mechanism of action and the constituents of the various venoms. In this regard this book is also directed to physi cians, biologists and chemists to give them an introduc tion in this important and interesting field. New aspects of treatment of envenomations are reported. This book cannot replace bigger textbooks and monographs - they are cited in the references - but it gives an overview and an entry into this field. The original German edition was written at the request of colleagues and students of medicine, biology and chemistry as well as frequent travellers in tropical countries. It was sold out within eight months, thus showing that it really filled a gap."

"We pharmacologists must acquire a knowledge of the tools we use . . . Fortunately a surgeon who uses the wrong side of a scalpel cuts his own fingers and not the patient; if the same applied to drugs they would have been investigated very carefully a long time ago . . . More ceterum censeo is perhaps necessary in order to rouse pharmacology from its sleep. The sleep is not a natural one since pharma- cology, as judged by its past accomplishments, has no reason for being tired. " From R. Buchheim Beitrage zur Arzneimittel/ehre, Voss, Leipzig, 1849. Chapter 1 Preface and introduction Methods, clinical pharrnacology and the clinical pharmacologist In this book are brought together the proceedings from lecures and poster-demonstrations at the International Symposium on Methods in Clinical Pharmacology held in Frankfurt, May 6th-8th 1979. The symposium provided a forum for a group of invited clinical pharmacologist to speak on a topic of their own selection. They were asked to place special emphasis on the methodological aspects of their work they considered to be important. Seventeen of the speakers came from overseas. The sym- posium was thus an attempt to establish a methodological basis for further advancements in clinical pharmacology. This book, we hope, will be recognised as documentary evidence that this has been done. Owing to the considerable advancements that have been achieved, it may be forgotten or not realised that clinical pharmacology is a relativelyyoung discipline (7 to 10 years at the most).

Quality Assurance of Aseptic Preparation Services Standards Handbook (also known as the Yellow Guide) provides standards for unlicensed aseptic preparation in the UK, as well as practical information to aid implementation of the standards. The handbook delivers essential standards in a practical way and in a format that will be useful for pharmacy management, staff working in aseptic preparation units and those whose role it is to audit the services. The accompanying support resources help with understanding the complexities of relevant topics including microbiology, radiopharmaceuticals, advanced therapy medicinal products, technical (quality) agreements and capacity planning. All the standards have been revised and updated for this 5th edition. The text is produced on behalf of the Royal Pharmaceutical Society (RPS) and the NHS Pharmaceutical Quality Assurance Committee. New in this edition: Replaces the 4th edition standards and forms the basis for an ongoing audit program in the NHS Many new and revised standards Greater emphasis on Pharmaceutical Quality Systems; the responsibilities of pharmacy management, Chief Pharmacists (or equivalent), has been expanded in line with developments in Good Manufacturing Practice Reformatted into 2 parts: standards and support resources. This is a new collaboration between the RPS and NHS. Since the previous edition the RPS has become the professional body for pharmacists and pharmaceutical scientists. RPS launched these standards as part of a library of professional standards and a programme of work to create standards for all areas of pharmacy. The Handbook is essential for pharmacists, hospital pharmacy management and technical services teams, and auditors of unlicensed NHS hospital pharmacy aseptic preparation services in the UK, pharmacists and regulators. The text is used to inform standards used in several other countries.