K. D. Rainsford - Böcker

The role of trace metals, especially copper and zinc, in the pathogenesis of rheumatic conditions has continued to receive much interest following the initial upsurge of research activity in the 1970s. Meantime also copper and zinc complexes receive continued attention for their potential anti-inflam­ matory actions. Since the previous major titles were published in this field some years ago (e. g. 1,2) it was considered timely to consider progress which has been made in the interceding period. Thus in this volume aspects are re­ viewed of the metabolism and biodisposition of copper and zinc, especially as they may be influenced by inflammatory processes, the mode of action of copper and zinc compounds in inflammatory states, and the actions of some newer copper complexes. While we still understand relatively little about how copper and zinc complexes work in inflammation, and indeed what the fate of the ligands and their complexed ions is in inflammation, it is hoped that this volume will be useful for giving a current view of the "state of art" in the field. Special thanks are given to the valued efforts of the contributors, Dr Peter Clarke (Publishing Director, Kluwer Academic Publishers) and Mrs Veronica Rainsford-Koechli for her help in proof-reading the manuscripts. K D Rainsford Hamilton, Ontario, Canada February 1989 References 1. Rainsford, K. D. , Brune, K. and Whitehouse, M. W. (eds) (1981). Elements in the pathogenesis a treatment of inflammation.

Abnormal metabolism and distribution of both copper and zinc occurs in many inflammatory and degenerative diseases. The pattern of these changes varies at different stages of these diseases and with differing types of conditions. The corollary to this situation is the possibility of using drugs or metal complexes to modify both the perturbed status of copper and zinc and thus the disease states. This text comprehensively reviews the clinical and experimental data on the changes in copper and zinc status in different diseases and the use of various complexes of these metals or drugs to treat a diversity of inflammatory and degenerative conditions.

Adverse effects of anti-rheumatic and anti-inflammatory drugs are of major concern to all involved in the prescription, care and management of rheumatic and other patients receiving these important drugs. The 4th International Meeting on Side-Effects of Anti-Inflammatory Drugs, held in Sheffield, 7-9 August 1995, afforded an opportunity to hear current information and views on issues concerning the development of adverse effects from these drugs, the management of these effects, and the development of safer therapies. In addition to discussions on the safety relative to efficacy of established non-steroidal and steroidal anti-inflammatory drugs and disease-modifying agents, there was detailed consideration of the novel cyclo-oxygenase-2 selective NSAIDs which have recently been developed and introduced to the clinic. Also, the side effects from therapy with biologics, notably monoclonal antibodies and oral tolerance therapies, were considered.Among the other topics covered were: clinico-epidemiological studies on the adverse effects relative to use/efficacy of established and new anti-rheumatic drugs; procedures for reducing the gastrointestinal adverse effects; mechanisms and clinical significance of adverse effects in the gastrointestinal tract, liver, kidney, articular joints, skin and other organs from NSAIDs; and many more. The papers in this book were selected from those presented at the meeting.

The availability of analgesics and non-steroidal anti-inflammatory drugs (NSAIDs) sold over the counter (OTC) to the public without prescription has become an issue of major concern in recent years. The problem has been highlighted in the UK, USA and other countries because of the continuing high rates of cases of poisoning and the concern over the switch for many NSAIDs from prescription-only status to OTC sale, brought about, in large part, by governments and health maintenance organizations (especially in the USA) anxious to save on the costs of these drugs. This symposium, held at the South San Francisco Conference Center (USA) on March 17, 1997, enabled leading authorities from around the world to come together and discuss the central issues concerning the safety and efficacy of OTC analgesics and NSAIDs at a timely period. The conference opened with a series of presentations on the central themes - overall safety evaluation and assessment of the current status, the clinico-epidemiological evidence of adverse drug reactions from different drugs, pharmacokinetic and pharmacotoxicological mechanisms, and the expanding use of the drugs for pain and other states.Particular interest was addressed to the potential for NSAIDs to be used prophylactically to prevent certain chronic inflammatory/degenerative diseases (e.g. Alzheimer's and related dementias, and colon cancer). This symposium, held at the South San Francisco Conference Center (USA) on March 17, 1997, enabled leading authorities from around the world to come together and discuss the central issues concerning the safety and efficacy of OTC analgesics and NSAIDs at what was a timely period, for the reasons outlined above.

Ibuprofen has become one of the foremost pain-relieving medications world-wide with its proven safety and efficacy in a wide variety of painful and inflammatory conditions. It has also been widely investigated for application in a variety of painful and non-pain inflammatory states including cancer and neurodegenerative conditions, reflecting the unique and novel properties of the drug that would never have been foreseen from knowledge of the properties when it was initially discovered. Edited by leading world expert with over 40 years record in research, teaching and as a scientific advisor in the field of anti-inflammatory/analgesic agents. Professor Kim Rainsford is also the founding Editor-in-Chief of the journal, Inflammopharmacology, as well as being an Associate Editor of The Journal of Pharmacy & Pharmacology.Provides a thorough coverage of the medicinal chemistry and pharmaceutics of ibuprofen, and its pharmacokinetics in both humans and animals.Includes molecular, pharmacological and toxicological studies, and discusses the safety and efficacy of non-prescription ibuprofen, including its side effects.Ibuprofen: Discovery, Development & Therapeutics provides a definitive reference on all the main aspects of the chemical and pharmaceutical properties, mechanisms of action and therapeutic uses of ibuprofen including its role in the prevention and treatment of rheumatic conditions, cancer and neurodegenerative conditions such as Alzheimer’s and Parkinson’s diseases. The book has its origins in a volume first published in 1999, since when there have been considerable advances in research and clinical studies on ibuprofen in the treatment of many inflammatory and even non-inflammatory states. This book will prove invaluable to scientists, clinicians, pharmacists and all those who need to know about the actions and uses of anti-inflammatory and analgesic drugs.

Ibuprofen is one of the most successful drugs used worldwide for the treatment of mild to moderate pain and various inflammatory conditions. Over the past 40 years, ibuprofen has been proven to be as safe or even safer and also as effective as the established non-steroidal anti-inflammatory drugs (NSAIDs) and the coxibs. This well-written book reviews the pharmacology, clinical uses and the various adverse effects of Ibuprofen, the disposition and unique modes of action in relation to clinical effects of the drug as well as various formulations. The use of combinations with other drugs (e.g. paracetamol, codeine, caffeine) are critically assessed and the impact of natural products and Chinese Medicines on the safety of ibuprofen.

Ibuprofen is one of the most successful drugs used worldwide for the treatment of mild to moderate pain and various inflammatory conditions.

In recent years there have been a number of significant developments of natural products for the treatment of rheumatic diseases, pain and gastro-intestinal ulcers and inflammation. The volume covers some of these novel developments of natural products which are of current and future interest as therapies for the above-mentioned conditions. Most available volumes cover a wide range of biological and technicological aspects of natural products and their discovery, some involving synthesis and properties of chemical compounds. The difference in this volume is that the natural products have a focus on their therapeutic effects on pain, arthritic and gastrointestinal diseases. Some of the natural products covered are either at the experimental stage of development while others are well-established clinically-used products. Each has its own unique place in therapy.

Nimesulide is a non-steroidal anti-inflammatory drug (NSAID) which acts as a cyclooxygenase- 2 inhibitor but also has other novel pharmacological features which account for its effect in the control of pain and inflammation. It has become a leading NSAID in over 50 countries worldwide. This book provides a comprehensive and fully up-to-date critical review of the published literature on nimesulide, including comparisons with anti-inflammatory, analgesic and antipyretic agents. The emphasis is on the action of nimesulide in relation to its therapeutic and side effects in comparison with other established NSAIDs, including the new class of Coxibs.The chapters are written by leading experts and cover development of nimesulide, including synthesis and production, introduction, and approved uses and applications, followed by pharmacokinetics and toxicological properties, adverse reactions and their mechanisms.

The contents of this book represent papers which were presented at the Third International Meeting on "Side-Effects of Anti-Inflammatory and Analgesic Drugs" which was held under the auspices of the University of Verona, Institute of Pharmacology in Verona on 8-11 May 1991. This meeting was held in conjunction with the 13th European Workshop on Inflammation and although publications from this part of the meeting are not published here (they appear in Agents and Actions), we were fortunate in having a group of people interested in inflammation from varying backgrounds. The success of the third meeting followed previous meetings held in Cambridge and Verona respectively and continue a tradition which has now become well established. The meeting brought together physicians, scientists and those concerned with the production and use of anti-inflammatory drugs to a very stimulating conference to discuss basic issues affecting all aspects of side-effects of anti-inflammatory and analgesic drugs as well as their detection and treatment. The meeting was held in the Auditorium of Glaxo Italy and we are very grateful to that company for use of their facilities as well as to the University of Verona, Institute of Pharmacology, for valuable secretarial and administrative help. The success of the conference would not have been possible without valuable financial assistance of the companies listed separately (under Acknowledgements) as well as to the organizers of the 13th European Workshop on Inflammation who collaborated with us.

Abnormal metabolism and distribution of both copper and zinc occurs in many inflammatory and degenerative diseases. The pattern of these changes varies at different stages of these diseases and with differing types of conditions. The corollary to this situation is the possibility of using drugs or metal complexes to modify both the perturbed status of copper and zinc and thus the disease states. This book comprehensively reviews the clinical and experimental data on the changes in copper and zinc status in different diseases and the use of various complexes of these metals or drugs to treat a diversity of inflammatory and degenerative conditions.

Concern in the UK about poisoning from paracetamol and the appreciable morbidity and mortality from aspirin was such that a major review was initiated in 1996 by the UK government's Medicines Control Agency (MCA).

3 The help of Mr Phil Johnstone and editorial staff at Kluwer Academic Publishers in producing this book and the publication in the Journal is most gratefully acknowl- edged. INFLAMMOPHARMACOLOGY Basic and clinical studies on Inflammation and its phannacologlcal control Aim. and Scope The joumal Innammopharmacology publishes papers on all aspects of inflammation and its phannacological control, emphasizing comparisons of (a) dillerent inflammatory states, and (b) the actions, therapeutic eflicacy and safety of dr\lgs employed in the treatment of inflammatory conditions. The comparative aspects of the types of inflammatory conditions include gastrointestinal disease (e. g. ulcerative colitis, Cmhn's dsease) i , parasitic diseases, toxicological manifestations of the effects of dr\lgs and envimnmental agents, and arthritic conditions. Inflammophannacology covers all the major aspects of the experimentally-induced clinical pathology, Its bkx:hemistry and cell biology, as well as the clinical and experimental phannacology and toxk:ology of therapeutic agents.The emphasis on comparative aspects of the actions of drugs Is intended to highlight their eflicacy and toxicity pmfiles as well as the variability In their clinical response and safety.

The scientific main programmes of these series of symposia changed from time to time following the international scientific trends. The main programmes of the First Symposium were: 1. Gastric and intestinal cytoprotection; 2. Hepatoprotection; 3. Pancreatic protection. For the second one: 1. Gastrointestinal mucosal 'cytoprotection'; 2. Liver 'cytoprotection'; 3. Pancreatic 'cytoprotection'; 4. Free radicals and scavangers; 5. Computer approach to cytoprotec­ tion. For the third one: 1. Basic, central, peripheral and cellular mechanisms of gastrointestinaol cytoprotection; 2. Esophagal protection; 3. Gastric protection; 4. Small intestinal injury and protection; 5. Large bowel injury and protection; 6. Liver injury and protection; 7. Pancreas injury and protection. The main scientific programmes of the Fourth International Symposium on 'Cell Injury and Protection in the Gastrointestinal Tract' are: 1. General mechanisms of gastrointestinal injury and protection; 2. Cell injury and protection in the stomach; 3. Cell injury and protection in the small intestine and in the large bowel; 4. Cell injury and protection in the liver and pancreas; 5. Cell injury and protection of the premalignant status and malignant diseases in the gastrointestinal tract. The presented papers are published in this book. The abstracts of this meeting were published in Digestive Diseases and Sciences, and we record appreciation of the Editor ofthatjoumal for their publication. Some of the papers published here have appeared in Inflammopharmacology 1996;4:331-398.

Recent concern about the adverse effects and relative risks of anti- inflammatory therapies has been such that another meeting was organized in the highly successful series of meetings on this topic. Adverse effects of anti-rheumatic and anti-inflammatory drugs are of major concern to all involved in the prescription, care and management of rheumatic and other patients receiving these important drugs. The IVth International Meeting on Side-Effects of Anti-Inflammatory Drugs, held in Sheffield, UK, 7-9 August 1995, afforded a unique opportunity to hear the latest information and views on issues concerning the development of adverse effects from these drugs, the management of these effects, and the development of safer therapies. In addition to discussions on the safety relative to efficacy of established non-steroidal and steroidal anti-inflammatory drugs and disease-modifying agents, there was detailed consideration of the novel cyclo-oxygenase-2 selective NSAIDs which have recently been developed and introduced to the clinic. Also, the side effects from therapy with biologics, notably monoclonal antibodies and oral tolerance therapies, were considered. Among the other highlights in the programme were:Clinico-epidemiological studies on the adverse effects relative to use/efficacy of established and new anti-rheumatic drugs. Procedures for reducing the gastrointestinal adverse effects. Mechanisms and clinical significance of adverse effects in the gastrointestinal tract, liver, kidney, articular joints, skin and other organs from NSAIDs. Clinical status and mechanisms of action of the newer (third generation) of NSAIDs (e.g. etodolac, nabumetone, meloxicam). Medico-legal aspects of adverse effects from anti-rheumatic drugs. The concept of `conditional pharmacology' or the disease-dependence of the toxicological and pharmacological activity of the anti-inflammatory drugs. The papers in this book were selected from those presented at the meeting.

Azapropazone is a chemically unique non-steroidal anti-inflammatory drug (benzotriazine oxide) which has found successful clinical applications in the therapy of a wide variety of arthritic conditions. This book summarizes the progress and critically reviews the clinical use and experimental studies since its introduction 20 years ago. Several studies focus on the physiochemical, pharmacological and toxico- logical properties of this drug. The studies suggest that it has some unique properties compared with other non-steroidal anti-inflammatory drugs. Among these the novel observations are that azapropazone inhibits several non-prostaglandin-related leucocyte functions, especially superoxide anion production. These serve as a basis for investigations which are reviewed showing the potential for the drug to prevent the pathological consequencies of myocardial ischaemia. The preparation of this book would not have been possible without the cooperation of the four companies who produce, market, or have research involvement with azapropazone, namely Siegfried AG (the manufacturers of the drug), A.H. Robins (U.K.) Co. Ltd., Robapharm AG (Switzerland) and E.!. duPont de Nemours (U.S.A.,Switzerland and F.R.G.).

At present we may be at the cross-roads in the therapeutic approaches we have for the treatment of the 100 or more rheumatic conditions. This is be­ cause we now recognise that although some advances have been made with the development of a large range of non-steroidal and steroidal drugs during the past two decades or so, we now recognise that many, if not all, of these have rather limited effects on many of the disease processes which underlie the manifestations of the various rheumatic states. Advances in molecular bi- 010gy in the past 5-10 years have enabled these tools to be applied extensive­ ly for developing further our understanding of the rheumatic disease processes. In some cases these molecular tools (e. g. ,),-interferon, interleukin- 2, T-cell antibodies) have been directly employed as therapies themselves. While the outcome from trials with such agents in rheumatoid arthritis in particular has not been as would have been hoped, these results as with cy­ closporin A and low-dose methotrexate in the therapy of rheumatoid arth­ ritis have given us important indications for the approach employing what are generally described as "immunomodulators" to control this disease. But this may not be the same type of approach which is desirable for all types of rheumatic conditions. Indeed, even the way which the present range of drugs and other therapies are applied may not be the most effective and safe means of treating different types of arthritic conditions.

The role of trace metals, especially copper and zinc, in the pathogenesis of rheumatic conditions has continued to receive much interest following the initial upsurge of research activity in the 1970s. Meantime also copper and zinc complexes receive continued attention for their potential anti-inflam­ matory actions. Since the previous major titles were published in this field some years ago (e. g. 1,2) it was considered timely to consider progress which has been made in the interceding period. Thus in this volume aspects are re­ viewed of the metabolism and biodisposition of copper and zinc, especially as they may be influenced by inflammatory processes, the mode of action of copper and zinc compounds in inflammatory states, and the actions of some newer copper complexes. While we still understand relatively little about how copper and zinc complexes work in inflammation, and indeed what the fate of the ligands and their complexed ions is in inflammation, it is hoped that this volume will be useful for giving a current view of the "state of art" in the field. Special thanks are given to the valued efforts of the contributors, Dr Peter Clarke (Publishing Director, Kluwer Academic Publishers) and Mrs Veronica Rainsford-Koechli for her help in proof-reading the manuscripts. K D Rainsford Hamilton, Ontario, Canada February 1989 References 1. Rainsford, K. D. , Brune, K. and Whitehouse, M. W. (eds) (1981). Elements in the pathogenesis a treatment of inflammation.

These two volumes contain the proceedings of a 3 day international meeting held at the University of Cambidge and Queens' College Cambridge from 31st July to 2nd August 1985 on the Side-Effects of Anti-Inflammatory Analgesic Drugs. The first meeting was held in Verona, (Italy) in 1982 and the organisers felt that, with a number of recent developments including the withdrawal of a num­ ber of new anti-inflammatory drugs, and concern being expressed in the lay and specialist medical press and other media about the safety of these drugs, that it was appropriate to have a second such meeting. The meeting was attended by some 300 delegates and the dis­ cussion focussed most intently on the recent issues, e. g. the value of adverse drug reaction reporting of the non-steroidal anti­ inflammatory (NSAI) drugs, certain side-effects associated with particular NSAI drugs, the predictive value of animal models etc. Organising a meeting de novo without outside help would not have been possible without the immensely valuable help given en­ thusiastically by people and financial assistance given most generously by those pharmaceutical companies listed below. These financial contributions were given despite current economic dif­ ficulties and moves to restrict the proportion of profits towards educational activities.