This book describes antibiotic resistance amongst pathogenic bacteria. It starts with an overview of the erosion of the efficacy of antibiotics by resistance and the decrease in the rate of replacement of redundant compounds. The origins of antibiotic resistance are then described. It is proposed that there is a large bacterial resistome which is a collection of all resistance genes and their precursors in both pathogenic and non-pathogenic bacteria. Ongoing resistance surveillance programs are also discussed, together with the perspective of a clinical microbiologist. The book then turns to specific themes such as the most serious area of resistance in pathogens, namely in Gram-negative organisms. The role of combinations of antibiotics in combating resistance emergence is discussed, particularly in the tuberculosis field, and then the importance of non-multiplying and persistent bacteria which are phenotypically resistant to antibiotics and prolong the duration of therapy of antibiotics which leads to poor compliance and resistance emergence. The role of anti-microbial compounds in textiles is covered, with its potential to exacerbate the spread of resistance. Then, efflux pumps are discussed. The final chapter describes the compounds which are in late stage clinical development, illustrating the paucity of the antibiotic pipeline, especially for Gram-negative bacteria.

This volume of Pharmacochemistry Library comprises the text of invited lectures presented at the 11th Noordwijkerhout-Camerino Symposium "Trends in Drug Research," held in Noordwijkerhout, The Netherlands, from 11-15 May 1997.

In the programme attention has been given to the generation of new biological target systems and the generation of new lead molecules, with presentations on e.g. combinatorial chemistry, compound libraries, database search, high throughput screening and molecular biology.

Other topics discussed were the perspectives for new medicines for the gastro-intestinal tract, the major developments in the search for effective anti-HIV drugs and new aspects in synthetic approaches. In a special session three topics which currently draw much attention were discussed: How to deal with the major problem of resistance against antimirobial agents? Can the apoptosis mechanism be used as a drug target? Is the newly observed phenomenon of inverse agonism a general principle and has it consequences for drug development (and use?)

The tetracyclines have an illustrious history as therapeutic agents which dates back over half a century. Initially discovered as an antibiotic in 1947, the four ringed molecule has captured the fancy of chemists and biologists over the ensuing decades. Of further interest, as described in the chapter by George Armelagos, tetracyclines were already part of earlier cultures, 1500-1700 years ago, as revealed in traces of drug found in Sudanese Nubian mummies. The diversity of chapters which this book presents to the reader should illus trate the many disciplines which have examined and seen benefits from these fascinating natural molecules. From antibacterial to anti-inflammatory to anti autoimmunity to gene regulation, tetracyclines have been modified and redesigned for various novel properties. Some have called this molecule a biol ogist's dream because of its versatility, but others have seen it as a chemist's nightmare because of the synthetic chemistry challenges and "chameleon-like" properties (see the chapter by S. Schneider).

''A wealth of information...these two volumes will be immensely valuable to anyone having to deal with this difficult group of compounds.'' ---Biochemical Systematics and Ecology, from a review of Saponins Used in Traditional and Modern Medicine and Saponins Used in Food and Agriculture

Vaso-occlusive disorders including unstable angina, myocardial infarction, transient ischemic attacks, stroke and peripheral artery disease remain the major sources of morbidity and mortality in western civilization. Platelet activation and resulting platelet aggregation play a major role in the pathogenesis of these thromboembolic diseases. Recognition of the contribution of platelets to the pathophysiology of cardiovascular disease has provided impetus for the continued search for new antiplatelet agents. Hence, over the past two decades many strategies have been evaluated in the search for efficacious mechanisms to reduce platelet function. The medical need for more efficacious antithrombotic drugs and the growing understanding of the role of platelets in vascular injury have catalyzed the extensive evaluation of novel approaches to control platelet function. Along these lines, the volume therefore provides an in-depth assessment of ongoing clinical trials, new and clinically established agents, and other developments in this rapidly developing field.

The first authoritative textbook specifically addressing issues of the field, this book delivers a focused discussion on several themes in psychiatry while providing a sound background on pharmacovigilance. Internationally-recognised researchers, clinicians and pharmacovigilance experts contributed to this textbook, giving it the benefit of different perspectives and years of experience. Pharmacovigilance in psychiatry provides a thorough introduction to this field but goes on to explore advanced themes such as methodologies and resources used for pharmacovigilance in psychiatry, challenges as well as most recent developments to this field, making it suitable for under-graduates, graduate and post-doctoral students and persons working pharmacovigilance who seek to broaden their knowledge on this subject.

After the discovery of endogenous NO formation in the late '80s and the 1998 Nobel Prize in Physiology or Medicine, many researchers and physicians again became interested in the NO/sGC interaction and cGMP-dependent signaling. This book is an enthusiastic celebration of cyclic guanosine monophosphate (cGMP) and amply illustrates the importance of this field of science to patients and the way in which the field has evolved. It is exclusively devoted to this exciting and important signaling molecule, addressing all recent advances in understanding guanylate cyclase regulation, NO/sGC interactions, cGMP effector mechanisms and their pathophysiological and pharmacological implications. Particular attention will also be given to clinical applications of the novel cGMP-elevating drugs which are on the horizon, thus spanning the continuum from basic science to clinic.

As the drug discovery process shifts more and more toward specifically targeting pathways and molecules, model systems continue to increase in importance, and the mouse, with its versatility, ease of use, and remarkable similarity to the human genome, has clearly risen to the forefront of animal model studies. In Mouse Models for Drug Discovery: Methods and Protocols, experts in the field present some background for those less familiar with mice as experimental model platforms as well as a collection of techniques involving general methods as well as specific disease topics such as type 1 and 2 diabetes, cardiovascular disease, arthritis, skin disorders, cancer, the use of behavioral models for depression and anxiety, neurodegenerative diseases, neuromuscular diseases, and infectious diseases. Written in the highly successful Methods in Molecular Biology series format, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and notes on troubleshooting and avoiding known pitfalls.

Authoritative and easy-to-use, Mouse Models for Drug Discovery: Methods and Protocols will stimulate those not familiar with the power of the mouse and its potential for the drug discovery process, and it will encourage the development of new models and new ways to utilize existing models in order to further the use of this dynamic animal in this vital field."

The goal of this work is summarize the contribution that insertional mutagenesis has made to our understanding of cancer. A variety of insertional mutagens are presented that have been used to study a variety of tumor types in several model organisms. In addition, the impact of insertional mutagenesis in several gene therapy trials is discussed along with strategies to avoid such complications in future clinical trials.

This book is a short and simple pedagogical guide to the diagnosis and management of epilepsy. After the headache, epilepsy is the second most common neurological disorder, and this book clarifies the many courses of action to take in treating patients with epilepsy. The book simplifies the classification, testing, and treatment of epilepsy, addresses important psychosocial issues and the efficacy of pharmaceutical and other interventions, and also includes an account of modern concepts of the aetiology of the disease. The Comprehensive Evaluation and Treatment of Epilepsy: A Practical Guide is an important reference work for all medical schools, hospitals, clinics and primary care centers. Features: * CONTAINS ESSENTIALS ON: * Initial management of patients with seizures * Psychosocial aspects of epilepsy * Neuropsychologic problems associated with epilepsy * Psychiatric disorders * Diagnosis and treatment of status epilepticus * Nonepileptic seizures * Ambulatory EEG monitoring * Epilepsy surgery * Endocrine aspects of partial seizures * Epilepsy in the elderly

Antibiotics are truly miracle drugs. As a class, they are one of the only ones that actually cure disease as opposed to most drugs that only help relieve symptoms or control disease. Since bacteria that cause serious disease in humans are becoming more and more resistant to the antibiotics we have today, and because they will ultimately become resistant to any antibiotic that we use for treatment or for anything else, we need a steady supply of new antibiotics active against any resistant bacteria that arise. However, the antibiotics marketplace is no longer attractive for large pharmaceutical companies, the costs of development are skyrocketing because of ever more stringent requirements by the regulatory agencies, and finding new antibiotics active against resistant strains is getting harder and harder. These forces are all combining to deny us these miracle drugs when we need them the most. I provide a number of possible paths to shelter from this perfect storm.

Conceptually unsavoury, airway mucus is vital to homeostasis in the respiratory tract. In contrast, when abnormal, mucus contributes significantly to the pathophysiology of a number of severe bronchial diseases, including asthma, chronic bronchitis and cystic fibrosis. This volume provides wide ranging and in-depth coverage of the scientific and clinical aspects of airway mucus. It commences with introductory chapters which address the biochemical and molecular biological basis of airway mucus and continues with comprehensive coverage of the various physiological and rheological aspects of respiratory secretions. The clinical aspects of the topic are then considered, with chapters discussing the involvement of mucus secretions in bacterial infection and in hypersecretory diseases of the airway. The volume concludes with a discussion of the therapeutic aspects of the topic, both in terms of the possible approaches to the treatment of mucus hypersecretion and the interaction of these drugs with airway mucus. Written by leading experts in the field, each contribution provides a comprehensive review of its particular subject. Reflecting the latest advances in this important area of respiratory research, this volume will be of great interest to scientists and clinicians working in the field of airway secretions and related areas.

Specialist Periodical Reports provide systematic and detailed review coverage of progress in the major areas of chemical research. Written by experts in their specialist fields the series creates a unique service for the active research chemist, supplying regular critical in-depth accounts of progress in particular areas of chemistry. For over 90 years The Royal Society of Chemistry and its predecessor, the Chemical Society, have been publishing reports charting developments in chemistry, which originally took the form of Annual Reports. However, by 1967 the whole spectrum of chemistry could no longer be contained within one volume and the series Specialist Periodical Reports was born. The Annual Reports themselves still existed but were divided into two, and subsequently three, volumes covering Inorganic, Organic, and Physical Chemistry. For more general coverage of the highlights in chemistry they remain a 'must'. Since that time the SPR series has altered according to the fluctuating degree of activity in various fields of chemistry. Some titles have remained unchanged, while others have altered their emphasis along with their titles; some have been combined under a new name whereas others have had to be discontinued. The current list of Specialist Periodical Reports can be seen on the inside flap of this volume.

The three years since our last conference in San Francisco have again seen a dramatic expansion of the number of antivirals either licensed or in the late stages of clinical trials. d4T is now licensed for HIV infection, famciclovir and the oral pro-drug of acyclovir, valacyclovir, are now licensed for VZV infections in some countries. Moreover. oral ganciclovir, cidofovir, and sorivudine are not far behind. Clinical trials with the second-site reverse transcriptase inhibitors and the protease inhibitors for HlV infection are proceeding rapidly and on a broad scale, and the preliminary results would suggest that several of these classes of drugs will be licensed as well. Despite this optimism, however, there is increasing evidence that antiviral-resistant strains of pathogenic viruses will be a significant problem, perhaps especially with therapy of HIV infection, and there remains a desperate need for improved drugs (with either improved efficacy or decreased toxicity, or both) for CMV and HIV infections. This book is the edited proceedings of the Fourth Triennial Conference on Antiviral Chemotherapy, held in San Francisco, in November 1994. The conference was sponsored by the University of California, San Francisco, and co-sponsored by the International Society for Antiviral Research (ISAR), the Macfarlane Burnet Centre for Medical Research in Melbourne, Australia, and the Australian National Centre for HIV Virology Research. The conference had been organized to present an overview of the field of antiviral chemotherapy.

Genetic Algorithms in Molecular Modeling is the first book available on the use of genetic algorithms in molecular design. This volume marks the beginning of an ew series of books, Principles in Qsar and Drug Design, which will be an indispensible reference for students and professionals involved in medicinal chemistry, pharmacology, (eco)toxicology, and agrochemistry. Each comprehensive chapter is written by a distinguished researcher in the field.
Through its up to the minute content, extensive bibliography, and essential information on software availability, this book leads the reader from the theoretical aspects to the practical applications. It enables the uninitiated reader to apply genetic algorithms for modeling the biological activities and properties of chemicals, and provides the trained scientist with the most up to date information on the topic.
. Extremely topical and timely
. Sets the foundations for the development of
computer-aided tools for solving numerous
problems in QSAR and drug design
. Written to be accessible without prior direct
experience in genetic algorithms

This work brigdges the compartmentalized undergraduate organic and biochemistry and biology subjects to the pharmacology and the clinical areas a modern pharmacy practice requires. The changes and constantly increasing responsibilities of today's pharmacist have dictated a restructuring of the pharmacy curriculum, including individual course content. This book reflects and addresses these developments. This is a well-written work that covers most major areas of pharmaceutical research. The text is presented in a logical and concise fashion being divided into chapters based upon therapeutic topic. This makes the work very useful for teaching a course in medicinal chemistry since therapeutic areas can be separately covered without having to make use of the entire book which overall contains a tremendous amount of information. This book is a significant contribution to understanding what medicinal chemistry is and how this science is used to develop new therapeutic agents.

Neuropeptide Y (NPY) is a ubiquitous and important messenger in the nervous system, with a wide range of physiological roles. It is involved in the body energy balance and is one of the most potent stimuli of food intake known. NPY also acts to regulate central and peripheral autonomic functions.
This book, written by academic and industrial experts in the field, links the most recent basic experimental knowledge about NPY and its receptors with areas of clinical importance.
This book will be of interest to those working in all areas of research affected by NPY, such as food intake and energy homeostasis, cardiovascular regulation and G-protein-coupled receptors, as well as those interested in the development of drugs as NPY targets.
Key Features
* The hypothalamic role of NPY and its relationship with eating disorders and diabetes
* The sympathetic nervous system role of NPY and its involvement in cardiovascular disorders
* Characterization of NPY receptor types and their brain distribution, molecular biology and pharmacology
* Development of peptide and non-peptide receptor antagonists

This detailed volume brings together leading practitioners in the freeze-drying community to address recent progress, not only in new analytical tools and applications of the data derived in cycle design but also in the manufacturing of lyophilized products in the healthcare sector - whether these be therapeutics, vaccines or diagnostic products - and indeed the equipment to deliver this scale of freeze-drying. Areas of focus include analytical and formulation issues, process monitoring and control, as well as post-lyophilization analysis. Written for the Methods in Pharmacology and Toxicology series, chapters include the type of expert advice that leads to superior results in the lab. Authoritative and practical, Lyophilization of Pharmaceuticals and Biologicals: New Technologies and Approaches serves as an ideal guide for researchers working in or just seeking an update on this rapidly changing field.

Over the past ten years, a number of cytokines and growth factors have proven to be as effective therapeutics. While these products have certainly established recombinant biologics as a major pharmaceutical growth sector, the continued interest in this class of drugs arises from the fact that today we have a far better understanding of the human immune response, both at a cellular and molecular level. This has resulted in a more methodical characterisation of these factors which has given clinical researchers an opportunity to plan Phase 1 clinical trials that can provide substantial information on the activity of the cytokine in humans. Currently, a great deal of effort is also being channelled into identifying cytokines from the various DNA databases. Our major objective for this book is to profile cytokines that have been recently identified. The therapeutic potential of these cytokines based on their known properties will be discussed by the authors. The main aim of this book is to provide...

A comprehensive, state-of-the-art review of our current understanding of the molecular and structural biology of 5-HT receptors and their potential use for drug discovery. The authors describe the anatomical, cellular, and subcellular distribution of 5-HT receptors and demonstrate a powerful approach to elucidating their physiological role using knockout mice in which the 5-HT receptors were deleted. They also review our understanding of the physiological role(s) of 5-HT receptors based mainly on studies performed in genetically engineered mice. Highlights include discussions of the behavioral phenotypes of 5-HT receptor knockout animals, the molecular biology and pharmacology of 5-HT receptors, and insights into the complexity of 5-HT receptor signal transduction.

This volume comprehensively covers the multiplicity and diversity of mechanisms underlying patient resistance to currently approved anti-cancer drugs, including tyrosine kinase inhibitors and monoclonal antibodies, blockers of growth factor receptors and their downstream pathways, which play essential functions in cancer progression. Each chapter will cover a specific group of targets and the cognate drugs, along with molecular modes of innate and evolving resistance.

This book provides the most up-to-date review of the simian virus 40 (SV40) minichromosome as a model for the mammalian chromosome in studies of DNA replication. It focuses on disruption of DNA replication by anticancer drugs and DNA-damaging agents. There is a strong emphasis on the unique advantages of SV40 as an experimental system for the analysis of these classes of anticancer drug mechanisms. The new high-resolution gel electrophoresis methods for the analysis of SV40 DNA replication are covered in detail to aid readers in designing and interpreting similar experiments.
Key Features
* Presents unique advantages of SV40 as an experimental system for the study of classes of anticancer drugs
* Details new high-resolution gel electrophoresis methods for the analysis of SV40 DNA replication
* Provides details to help the reader design and interpret similar experiments