More than 70 years have elapsed since U. S. von Euler and I. H. Gaddum dis- covered an unidentified depressor substance in the brain and gut. The effects of the powdery extracts were marked as 'P' on the kymograph tracings, and the nondescript name of 'substance P' still carries the breath of this adventurous period. In the 1960s, substance P returned in another disguise, staging as a hypothalamic peptide that causes copious salivary secretion (see chapter by F. Lembeck and I. Donnerer). This time, though, the mysterious substance was tracked down by S. E. Leeman and her collaborators as an undecapeptide, after it had eluded its identification for some 40 years. Substance P turned out to be the mammalian counterpart of a family of peptides which had been extracted from amphibian and nonvertebrate species and which had been given the name 'tachykinins' by V. Erspamer. Soon novel members of this peptide family were discovered, and in mammals substance P was joined by neurokinin A and neu- rokinin B. The presence of tachykinins in frog skin as well as in venoms and toxins of microbes and arachnids raises the possibility that these peptides re- present an old system of biological weapons that have been transformed to a particular messenger system in mammals.

The book explores cutting-edge strategies to overcome proteasome inhibitor resistance, including the second generation 20S proteasome inhibitors, novel combinational therapies, and new targets in the ubiquitin-proteasome pathway (e.g., ubiquitin E3 ligases, deubiquitinases, 19S proteasomal ATPases, histone deacetylases, oxidative stress and proteotoxic stress pathways and pharmacogenomic signature profiling) in resistant cancer cells. The mechanisms of action and resistance of proteasome inhibitors, such as bortezomib and carfilzomib in human cancers, including multiple myeloma, mantle cell lymphoma, acute leukemia, and solid tumors are explored in depth in this volume.

This timely volume unveils the most current discoveries of the mechanisms behind proteasome inhibitor resistance, which will help illuminate the future of cancer therapies.

Topics covered in this volume include pheromone reception in mammals, elucidation of mammalian bitter taste, synaptic modulation in pain pathways, the vertebrate phototransduction cascade, and amplification and termination mechanisms.

Managing the Drug Discovery Process: How to Make It More Efficient and Cost-Effective thoroughly examines the current state of pharmaceutical research and development by providing chemistry-based perspectives on biomedical research, drug hunting and innovation. The book also considers the interplay of stakeholders, consumers, and the drug firm with attendant factors, including those that are technical, legal, economic, demographic, political, social, ecological, and infrastructural. Since drug research can be a high-risk, high-payoff industry, it is important to researchers to effectively and strategically manage the drug discovery process. This book takes a closer look at increasing pre-approval costs for new drugs and examines not only why these increases occur, but also how they can be overcome to ensure a robust pharmacoeconomic future. Written in an engaging manner and including memorable insights, this book is aimed at redirecting the drug discovery process to make it more efficient and cost-effective in order to achieve the goal of saving countless more lives through science. A valuable and compelling resource, this is a must-read for all students and researchers in academia and the pharmaceutical industry.

This volume discusses the latest advancements and technologies used in cancer drug resistance research. Cancer Drug Resistance: Overviews and Methods contains chapters that cover topics such as: studying the mechanics of resistance to DNA damaging therapeutic drugs; studies to delineate the role of efflux transporters; expression of drug transporters; resistance to targeted therapies in breast cancer; the role of microRNAs in current pancreatic cancer treatment; and cancer exosomes as mediators of drug resistance or clinical and molecular methods in drug development and the use of bioinformatics in the management of cancer drug resistance data. Written in the highly successful Methods in Molecular Biology series format, chapters include overviews of the main issues in cancer drug resistance and the respective mechanisms, as well as introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls. Authoritative and practical, Cancer Drug Resistance: Overviews and Methods, is a valuable resource to researchers, oncobiologists and clinical oncologists or anyone else who is interested in the study of cancer and its drug resistances.

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Rapid advances in computer science, biology, chemistry, and other disciplines are enabling powerful new computational tools and models for toxicology and pharmacology. These computational tools hold tremendous promise for advancing applied and basic science, from streamlining drug efficacy and safety testing, to increasing the efficiency and effectiveness of risk assessment for environmental chemicals. "Computational Toxicology" was conceived to provide both experienced and new biomedical and quantitative scientists with essential background, context, examples, useful tips, and an overview of current developments in the field. This two-volume set serves as a resource to help introduce and guide readers in the development and practice of these tools to solve problems and perform analyses in this area.

Divided into six sections, "Volume II" covers a wide array of methodologies and topics. The volume begins by exploring the critical area of predicting toxicological and pharmacological endpoints, as well as approaches used in the analysis of gene, signaling, regulatory, and metabolic networks. The next section focuses on diagnostic and prognostic molecular indicators (biomarkers), followed by the application of modeling in the context of government regulatory agencies. Systems toxicology approaches are also introduced. The volume closes with primers and background on some of the key mathematical and statistical methods covered earlier, as well as a list of other resources. Written in a format consistent with the successful "Methods in Molecular Biology" series where possible, chapters include introductions to their respective topics, lists of the necessary materials and software tools used, methods, and notes on troubleshooting and avoiding known pitfalls.Authoritative and easily accessible, "Computational Toxicology" will allow motivated readers to participate in this exciting field and undertake a diversity of realistic problems of interest."

N eurotoxicology is a broad and burgeoning field of research. Its growth in recent years can be related, in part, to increased interest in and concern with the fact that a growing number of anthropogenic agents with neurotoxic potential, including pesticides, 1ead, mercury, and the polytypic byproducts of combustion and industrial production, continue to be spewed into and accumulate in the environment. In addition, there is great interest in natural products, including toxins, as sources of therapeutic agents. Indeed, it is well known that many natural toxins ofbroadly differing structure, produced or accumulated for predatory or defensive purposes, and toxic agents, accumulated incidentalIy by numerous species, function to perturb nervous tissue. Components of some of these toxins have been shown to be useful therapeutic agents and/or research reagents. Unfor of some neurotoxicants of anthropogenic ori tunately, the environmental accumulation gin, expecialIy pesticides and metals, has resulted in incidents ofhuman poisoning, some of epidemic proportion, and high levels of morbidity and mortality. Furthermore, an increasing incidence of neurobehavioral disorders, some with baffling symptoms, is confronting clinicians. It is not clear whether this is merely the re suit of increased vigi lance and/or improved diagnostics or a consequence of improved health care. In any case, the role of exposure to environmental and occupational neurotoxicants in the etiology of these phenomena, as well as neurodegenerative diseases, is coming under increasing scrutiny and investigation.

This book provides BoNT treatment menus for symptom-oriented therapy in 14 different disease categories.Each chapter starts with a brief description of the disease and its current treatment followed by an evidenced-based upon the published assertions of the Therapeutic Subcommittee of the American Academy of Neurology. Each chapter includes case histories from editor's vast experience of over 25 years with BoNT therapy and description of injection techniques enhanced by illustrative figures. Botulinum Toxin Treatment in Clinical Medicine includes an additional introductory chapter that discusses molecular structure, mechanism of action, toxin serotypes, immunogenicity and safety issues. Meanwhile, a concluding chapter provides information on potential future application of these toxins' for treating symptoms of other specific diseases.

Currently, there are tremendous advances being made in understanding the basic science of both the structure and function of botulinum neurotoxins. This knowledge is opening up opportunities in regard to both therapeutic uses and treatment and protection options for civil and bio-defense applications. This volume fully evaluates the status of neurotoxin research and exploitation with a focus on clinical application. The book is a multi-authored collection of chapters written by the leading authorities responsible for the current scientific and clinical research that is advancing the understanding and exploitation of the neurotoxins and is both up to date and authoritative.

This practical collection examines methodologies originating from the benefits of genome-wide approaches to studying epigenetics, which has opened the emerging field of epigenomics. Focusing on the areas of cancer, inflammatory and autoimmune disorders, chapters discuss three main components of the epigenome and their role in the regulation of gene expression and present a detailed method section specific to studying each component, including data analyses, troubleshooting, and feasibility in different experimental settings. The main topics are high-throughput and targeted methods for DNA methylation analysis, nucleosome position mapping, studying epigenetic effects of gut microbiota, optical imaging for detection of epigenetic aberrations in living cells, methods for microRNA, and histone code profiling. Written for the Methods in Pharmacology and Toxicology series, the book includes the kind of detail and implementation advice to encourage success in the lab. Authoritative and easily applicable, Epigenetics and Gene Expression in Cancer, Inflammatory and Immune Diseases aims to provide pharmacologists, molecular biologists, bioinformaticians, and toxicologists with a vital background on epigenetics and state-of-the-art techniques in epigenomics.

This book, the proceedings of a Falk Workshop on `Topical Steroids in Gastroenterology and Hepatology', held in Berlin, Germany, on 14 June 2003, critically discusses the current role of budesonide in gastroenterology, hepatology, surgery and oncology and focuses especially on potential new indications for the use of budesonide. A number of smaller clinical studies and anecdotal case reports with impressive clinical effects are reported in patients with gastrointestinal, hepatic, oncological and surgical problems. In addition, the use of budesonide for the treatment of distal ulcerative colitis and ileocolonic Crohn's disease is evaluated with respect to its role in an evidence-based management of IBD. Finally, as clinical experience with the use of budesonide is increasing, safety issues and the side-effect profile of budesonide is addressed.

This edition of the companion volumes Muscle Pain: Understanding the Mech- isms and Muscle Pain: Diagnosis and Treatment is essential reading for those interested in clinical approaches to acute and chronic pain conditions involving muscle tissues and in the mechanisms underlying these conditions. The volumes cover a very important topic in pain medicine, since muscle pain is very common and can often be dif?cult to diagnose and treat effectively. Furthermore, chronic pain involving muscle and other components of the musculoskeletal system increases with age, such that it is a common complaint of those of us who are middle-aged or older. Indeed, as changing population demographics in "west- nized" countries result in higher proportions of the population living longer and being middle-aged and elderly, chronic muscle pain will likely become even more of a health problem. In the case of acute muscle pain, this can often be very intense, and in the short term can limit or modify the use of components of the musculoskeletal system associated with the sensitive muscle. Chronic muscle pain can also be intense, as well as unpleasant and disabling, and it is in many cases the over-riding symptom of most musculoskeletal disorders that are associated with long-term deleterious changes in musculoskeletal function.

Second comprehensive volume focuses on anti-inflammatory nutraceuticals and their role in prevention and therapy of various chronic diseases. Food and drug administration (FDA) approved drugs such as steroids, non-steroidal anti-inflammatory drugs (NSAIDS), statins and metformin have been shown to modulate inflammatory pathways, but their long-term intake has been associated with numerous side effects. Thus dietary agents which can modulate inflammatory pathways in humans, are likely to exhibit enormous potential. Leading experts describe the latest results of anti-inflammatory nutraceuticals and their role in prevention and therapy of various chronic diseases.

Today, most people use prescription medications. Every year, the multi-billion dollar pharmaceutical industry produces new medicines that treat everything from arthritis to AIDS, from high cholesterol to depression. But, despite recent controversies regarding the safety of drugs, consumers know little about the medications that they ingest and inject. How are these new medicines invented? How do consumers know that drugs are safe and effective? How are they tested? Who regulates their production - and who watches the regulators? How do drug companies produce the vast quantities needed for the marketplace, and why do they market their drugs as they do? The New Medicines leads the reader through the maze of the modern drug industry - from bench to bedside - and provides consumers with a step-by-step understanding of how new medicines are created, approved, marketed, and sold. In addition to explaining how drugs reach the medicine cabinet, the author - an experienced researcher and teacher - provides the scientific and business background for understanding the current controversial issues surrounding new medicines, such as:

• The rise and fall of the COX-2 inhibitors, Vioxx and Celebrex, and the process by which they were invented, approved, and re-evaluated.
• The saga of the cancer drug Erbitux and its creator, the company Imclone, made famous as the centerpiece of the Martha Stewart insider-trading scandal
• The strengths and weaknesses of the approval process of the Food and Drug Administration
• The controversial new marketing techniques of the pharmaceutical industry

As governments seek to mitigate the cost of state-subsidized healthcare, branding in the pharmaceutical industry has become a critical issue. Drugs companies must change their methods of communication and distribution--focusing more on their direct relationship with the consumer. This requires fundamental changes in consumer behavior, access to information, freedom of choice, and value for money. Brands and brand values will play a leading role in this process, as has been seen with products such as Prozac and Viagra. This book by Interbrand Newell and Sorrell, the world's leading branding consultancy, provides cutting-edge thinking on this area and lessons for anyone involved in brand development and management.

Since the introduction of ciprofloxacin in 1987, fluoroquinolones have expanded far beyond their early role in the treatment of urinary tract infections. Clinical applications beyond genitourinary tract infections include upper and lower respiratory infections, gastrointestinal infections, gynecologic infec- tions, sexually transmitted diseases, and some skin and soft tissue infections. Their ease of administration, favorable pharmacokinetic properties, excellent tolerability, and efficacy give them enormous potential for use and misuse alike. Quinolones have few common adverse effects, most notably nausea, headache and dizziness. Less frequent but more serious adverse events include prolongation of the corrected QT interval, phototoxicity, liver enzyme abnor- malities, arthropathy, and cartilage and tendon abnormalities. While possess- ing many of the favorable properties of intravenous agents, most fluoro- quinolones offer the convenience of oral administration, thus contributing to decreased health-care costs through increased outpatient therapy and short- ened hospital stays. With the recent introduction of agents such as gatifloxacin and moxifloxacin, the traditional Gram-negative coverage of fluoroquinolones has been expanded to include Gram-positive organisms, most importantly Streptococcus pneumoniae.

The present monograph is devoted to the chemistry of nitroazoles, one of the most interesting series of heteroaromatic compounds. The azoles hold a special position in the chemistry of heterocycles. Their unique properties and specific biological activity attract much attention of research chemists all over the world. During the last years the interest in the chemistry of nitroazoles has increasing. The nitro derivatives of azoles have found a wide application in various fields of industrial chemistry, agriculture, and medicine. Medical products developed by nitroazoles incluce a- mycin, metronidazole, misonidazole, tinidazole, nitazole, etc. , ionic liquids, hi- energy materials, synthons for nanocompounds, universal bases in peptide nucleic acids, plant growth regulators, and intermediates for organic synthesis. The investigations in the field of energetic compounds have received enormous interest in recent years. Energetic materials on the base nitroazoles - explosives, propellants, and pyrotechnics - are widely used for both civilian and military applications. Nitroazoles, especially polynitroazoles, possess higher heat of for- tion, density, and oxygen balance than their carbocyclic analogs. A number of ongoing research programs worldwide are aimed for the development of new explosives and propellants with higher performance characteristics or enhanced insensitivity to thermal or shock insults and pyrotechnics with reduced smoke. The preparation of nitroazoles demonstrates its great synthetic potential. At the same time, feasibility and availability of the starting molecules make this strategy a p- erful method for high-energy material construction.

Neurotoxicology is a broad and burgeoning field of research. Its growth in recent years can be related, in part, to increased interest in and concern with the fact that a growing number of anthropogenic agents with neurotoxic potential, including pesticides, lead, mercury, and the polytypic bypro ducts of combustion and industrial production, continue to be spewed into and accumulate in the environment. In addition, there is great interest in natural products, including toxins, as sources of therapeutic agents. Indeed, it is well known that many natural toxins of broadly differing structure, produced or accumulated for predatory or defensive purposes, and toxic agents, accumulated incidentally by numerous species, function to perturb nervous tissue. Components of some of these toxins have been shown to be useful therapeutic agents and/or research reagents. Unfor tunately, the environmental accumulation of some neurotoxic ants of anthropogenic ori gin, especially pesticides and metals, has resulted in incidents of human poisoning, some of epidemic proportion, and high levels of morbidity and mortality. Furthermore, an increasing incidence of neurobehavioral disorders, some with baffling symptoms, is confronting clinicians. It is not clear whether this is merely the result of increased vigi lance and/or improved diagnostics or a consequence of improved health care. In any case, the role of exposure to environmental and occupational neurotoxic ants in the etiology of these phenomena, as well as neurodegenerative diseases, is coming under increasing scrutiny and investigation.

This volume tries to put current therapy - achievements, shortcomings, remaining medical needs - and emerging new targets into the context of increasing knowledge regarding the genetic and neurodevelopmental contributions to the pathophysiology of schizophrenia. Some of the chapters also deal with respective experimental and clinical methodology, biomarkers, and translational aspects of drug development. The volume concentrates on reviewing the ongoing research attempting to identify novel treatments for the cognitive deficits and negative symptoms of schizophrenia, which are not treated adequately by current antipsychotic medications.

The book presents the current state of the art on phytocannnabinoid chemistry and pharmacology and will be of much use to those wishing to understand the current landscape of the exciting and intriguing phytocannabinoid science. The focus is on natural product cannabinoids which have been demonstrated to act at specific receptor targets in the CNS.

DNA Vaccines: An Introduction; M.R. Hilleman. Architecture of a DNA vaccine; G. Pavlakis. DNA vaccine delivery; S. Kaufmann. Adjuvanticity of DNA vaccines; A. Krieg. Immune responses to DNA vaccines: Antigen presentation; R. Steinman. Immune responses to DNA vaccines: Antigen processing; J. Yewdell. Immune responses to DNA vaccines: Induction of B cells; G. Kelsoe. Immune responses to DNA vaccines: Induction of CD4+ T cells; E. Shevach. Immune responses to DNA vaccines: Induction of CD8+ T cells; L. Whitton. Immune responses to DNA vaccines: Cytokines as immune mediators as part of the immune response and their potential as genetic adjuvants to DNA vaccines; H. Ertl. Immune responses to DNA vaccines: Chemokines as immune mediators as part of the immune response and their potential as genetic adjuvants to DNA vaccines; P. Murphy. DNA Vaccines to infectious agents: RNA viruses; J. Ulmer. DNA Vaccines to infectious agents: HIV/SIV; B. Wahren. DNA Vaccines to infectious agents: DNA viruses; B. Rouse. DNA Vaccines to infectious agents: Tumor-associated viruses (excluding HBV); R. Kennedy. DNA Vaccines to infectious agents: Bacteria; D. Lowrie. DNA Vaccines to infectious agents: Parasites; S. Hoffman. Use of DNA vaccines for neonatal/early childhood immunization; C.-A. Siegrist. The potential of DNA vaccines for developing countries; H. Wilde. DNA vaccines and their potential to counterbalance biological warfare/bioterrorism; A. Schmaljohn. DNA vaccines to cancer associated/specific antigens; DNA vaccines to autoimmune diseases; H. Wigzell. DNA vaccines to allergic diseases; Yan Chuah, P. Holt. DNA vaccines for gene therapy; K. High. Safety concerns for DNA; D. Klinman. DNA vaccines: Summary.

The International Symposia on Plant Lipids, the 15th of which was held in Okazaki, Japan, in May 12-17, 2002, is held every two years and is the only international meeting in this field. The contributions from the symposium collected in this book represent the most up-to-date research results on plant lipids,including their structure, analysis, biosynthesis, regulation, physiological function, environmental aspects, and biotechnology, obtained world-wide during 2000-2002.