Six decades after the serendipitous discovery of chlorpromazine as an antipsychotic and four decades after the launch of clozapine, the first atypical or second generation antipsychotic, psychopharmacology has arrived at an important crossroad. It is clear that pharmacological research and pharmaceutical development must now focus on complementary or even alternative mechanisms of action to address unmet medical needs, i.e. poorly treated domains of schizophrenia, improved acceptance by patients, better adherence to medication, safety in psychoses in demented patients, and avoiding cardiac and metabolic adverse effects. The first completely novel mechanisms evolving from our insights into the pathophysiology of psychotic disorders, especially the role of glutamatergic mechanisms in schizophrenia, are now under development, and further principles are on the horizon. This situation, in many respects similar to that when the initial second-generation antipsychotics became available, can be rewarding for all. Preclinical and clinical researchers now have the opportunity to confirm their hypotheses and the pharmaceutical industry may be able to develop really novel classes of therapeutics.

When we were approached by the publishers of the Handbook of Experimental Pharmacology to prepare a new volume on antipsychotics, our intention was to capture both, the accumulated preclinical and clinical knowledge about current antipsychotics as well as prospects for new and potentially more specific antischizophrenia principles. These efforts should be based on the pathophysiology of the diseases and the affected neurotransmitter systems. Since preclinical research on antipsychotic compounds is only reliable when intimately linked through translational aspects to clinical results, we decided to include clinical science as well. It turned out that that this endeavor could not be covered by a single volume. We thank the editorial board and the publishers for supporting our decision to prepare two volumes: Current Antipsychotics and Novel Antischizophrenia Treatments. These topics cannot really be separated from one another and should be seen as a composite entity despite the somewhat arbitrary separation of contributions into two volumes. The continuing challenges of developing improved and safer antipsychotic medications remain of concern and are discussed in the first volume. The new opportunities for the field to develop and license adjunctive treatments for the negative symptoms and cognitive deficits that are treated inadequately by existing compounds have been incentivized recently and provide the focus for the second volume. We hope these collective contributions will facilitate the development of improved treatments for the full range of symptomatology seen in the group of schizophrenias and other major psychotic disorders.

Gerhard Gross, Ludwigshafen, Germany

Mark A. Geyer, La Jolla, CA

This volume will try 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 will also deal with respective experimental and clinical methodology, biomarkers, and translational aspects of drug development. Non-schizophrenia indications will be covered to some extent, but not exhaustively."

Due to the rapid and steady growth of available low-cost computer power, the use of computers for discovering and designing new drugs is becoming a central topic in modern molecular biology and medicinal chemistry. In Computational Drug Discovery and Design: Methods and Protocols expert researchers in the field provide key techniques to investigate biomedical applications for drug developments based on computational chemistry. These include methods and techniques from binding sites prediction to the accurate inclusion of solvent and entropic effects, from high-throughput screening of large compound databases to the expanding area of protein-protein inhibition, toward quantitative free-energy approaches in ensemble-based drug design using distributed computing. Written in the highly successful Methods in Molecular Biology (TM) series format, chapters include introductions to their respective topics, reference to software and open source analysis tools, step-by-step, readily reproducible computational protocols, and key tips on troubleshooting and avoiding known pitfalls. Thorough and intuitive, Computational Drug Discovery and Design: Methods and Protocols aids scientists in the continuing study of state-of-the-art concepts and computer-based methodologies.

Proof of the efficacy of dermatological products is a prerequisite for clinical testing and registration. Now, efficacy claims for cosmetics must be equally substantiated. This book provides a concise, practical but comprehensive overview of experimental models used to screen, develop and select dermatological and cosmetic formulations. The authors are recognized specialists in their field and use a standardized approach to the projects facilitating the reading for the stressed scientist, for the R+D managers general view as well as for the beginners in the field.

This book continues as volume 2 of a multi-compendium on Edible Medicinal and Non-Medicinal Plants. It covers edible fruits/seeds used fresh or processed, as vegetables, spices, stimulants, pulses, edible oils and beverages. It encompasses species from the following families: Clusiaceae, Combretaceae, Cucurbitaceae, Dilleniaceae, Ebenaceae, Euphorbiaceae, Ericaceae and Fabaceae. This work will be of significant interest to scientists, researchers, medical practitioners, pharmacologists, ethnobotanists, horticulturists, food nutritionists, agriculturists, botanists, herbalogists, conservationists, teachers, lecturers, students and the general public. Topics covered include: taxonomy (botanical name and synonyms); common English and vernacular names; origin and distribution; agro-ecological requirements; edible plant part and uses; botany; nutritive and medicinal/pharmacological properties, medicinal uses and current research findings; non-edible uses; and selected/cited references.

Published continuously since 1944, the Advances in Protein Chemistry and Structural Biology series has been the essential resource for protein chemists. Each volume brings forth new information about protocols and analysis of proteins. Each thematically organized volume is guest edited by leading experts in a broad range of protein-related topics.

This book provides a comprehensive discussion on the current information and evidence on the latest developments in the field of drugs resistance. Drug resistance is the reduction in effectiveness of a medication such as an antimicrobial or an antineoplastic in treating a disease or condition. This leads to negative outcomes at great risk of public health; therefore, increasing efforts are dedicated to the development of a new generation of medications that will help deal with this phenomenon. Decades of technological innovations in drug design have demonstrated the potential of resistance. Enormous information on various aspects of antibiotics resistance is available. However, literature on drug resistance specifically related to infectious and non-infectious diseases is rarely presented, particularly those focusing on the mechanisms, biochemistry, kinetics, dynamics, and management of drug resistance. Therefore, there is an immense need for a systematic compilation on the available information about this issue. All the chapters are logically selected and arranged to provide state-of-the-art information about all aspects of drugs resistance. After an introductory chapter, four chapters are dedicated to infectious microbial diseases, whereas two other chapters are complimenting this theme and focusing on drugs resistance in ear, nose and throat, and skin diseases. The recent advances in the understanding of drugs resistance in lung, neurological, kidney, heart, and liver diseases are also covered. Biochemistry of drugs resistance in cancer, HIV, ocular, reproductive, and diabetes diseases is also discussed. Finally, a chapter dedicated to the "management of drug resistance" has been included.

The past 6 years since the first edition of this book have seen great progress in the development of genetically engineered mouse (GEM) models of cancer. These models are finding an important role in furthering our understanding of the biology of malignant disease. A comfortable position for GEM models in the routine conduct of screening for potential new therapeutics is coming more slowly but is coming. Increasing numbers of genetically engineered mice are available, some with conditional activation of oncogenes, some with multiple genetic changes providing mouse models that are moving closer to the human disease.

This book illustrates the current state-of-the-art in histamine research, with a focus on the appropriate methodologies to investigate the pharmacological properties and the therapeutic exploitation of HRs and their ligands. In addition, the range of techniques described provides an introduction to complementary cross-methodological disciplines beyond these fields. This multi-disciplinary approach is required to define the 'decision gates' that determine the development of more effective and safer therapeutic options for many forms of highly prevalent and debilitating diseases, such as asthma, dementias, dermatitis, and arthritis. Written for the Methods in Pharmacology and Toxicology series, chapters concentrate on practical, hands-on protocols from experts in the techniques. Authoritative and thorough, Histamine Receptors as Drug Targets seeks to aid pharmacologists, biochemists, drug discovery researchers, molecular biologists, chemists, toxicologists, lab scientists, medical doctors, principle investigators, research scientists, lab directors and technicians, as well as graduate students around the world in pursuing the study of this vital scientific area.

Scientific interest in regulatory T cells has revived during the last decade. Initially described in the early seventies as suppressor T cells, the concept of suppressor/regulatory T cells went through turbulent times during the eighties when molecular analysis failed to identify putative suppressor genes. The constructive and elegant cellular experiments on regulatory T cells during the nineties, initiated by Shimon Sakaguchi and co-workers, however have brought these cells back into the limelight. Nowadays, regulatory T cells are regarded as essential components of the immune system, and several different subsets of regulatory T cells have been described. Considerable regulatory function has been attributed to the CD4+CD25+ T cell subset. These cells act by suppressing adaptive and possibly also innate immune responses thereby maintaining or restoring the balance between immunity and tolerance. The suppressive effects of CD4+CD25+ regulatory T cells are cell-contact dependent but a role for soluble factors, particularly in vivo, has been suggested as well.
The aim of this book is to bring together recent developments and viewpoints in the field of CD4+CD25+ regulatory T cells and to discuss the potential use of regulatory T cells in immunotherapy of inflammatory diseases. By linking data on regulatory T cells from experimental models with recent findings from the clinic, this topical book will be of interest to immunologists and other biomedical researchers as well as clinicians that are interested in regulation and manipulation of the immune response during (chronic) inflammatory disease.

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.

This volume addresses neuronal pain mechanisms at the peripheral, spinal and supraspinal level which are thought to significantly contribute to pain and which may be the basis for the development of new treatment principles. Chapters on nociceptive mechanisms in the peripheral nociceptive system address the concept of hyperalgesic priming, the role of voltage-gated sodium channels in different inflammatory and neuropathic pain states, the hyperalgesic effects of NGF in different tissues and in inflammatory and neuropathic pain states, and the contribution of proteinase activated receptors (PAR) to the development of pain in several chronic pain conditions. Chapters on nociceptive mechanisms in the spinal cord address the particular role of NO and of glial cell activation in the generation and maintenance of inflammatory and neuropathic pain and it discusses the potential role of local inhibitory interneurons, of the endogenous endocannabinoid system and the importance of non-neuronal immune mechanisms in opioid signaling in the control of pain. Furthermore, it is presented how spinal mechanisms contribute to the expression of peripheral inflammation.

Withtherecentlyperceivedincreaseinincidenceofautismandtherealizationthat "autism"mayactuallybe"autisms"withsubsetsofaffectedindividuals,researchers have been pursuing the possibility that there may be multiple etiologies for the disorder.Althoughmostautismstudieshavefocusedongeneticsandadvancedn- roimaging,thereisapaucityofresearchaimedatdeterminingtheneurochemical basisofautism.Identifyingcoreneuralsubstratesorkeybiomarkersisessentialto understandingthemechanisticbasisthatmayinpartunderlie"autisms."Alterations inmolecules,proteins,receptors,andsynapticelementsaresomeofthecontrib- ingsubstratesthatcouldresultinaltereddevelopmentalprocesses,changedsynaptic function,andaberrationsinconnectivity.Itisnowapparentthatmultiplebrainareas are affected in autism, and neuropathological defects have been described within corticalandsubcorticalnetworks.Althoughrecentprogresshasbeenmadeinid- tifyingsomeofthegenesthatmayunderliethedisorder,muchattentionhasalso beengiventoepigeneticand/orenvironmentalfactorsthatmaycontributetosubsets ofautisticindividuals. The contributors to this book were hand selected because of their expertise in their respective ?elds. Individually each chapter presents a unique perspective into the clinical, developmental, neurochemical, and/or physical chemical basis of autism. The contributing authors summarize current research ?ndings in their respective areas and also present novel ideas and propose hypotheses and p- sible mechanisms that may be operative during development and the potential consequencesofhavingdefectsinspeci?cmolecules,receptors,orgenes. Thesubtitle"FromMoleculestoMinicolumns"wasinsertedbecauseofmuch recent attention given to alterations in the basic organization of mini- or mic- columns of neurons in cerebral cortical areas in autism. These especially include prefrontalcorticalareasthatundergoanovergrowthduringearlypostnataldevel- mentinmanyindividualswithautism.Tothisend,theworldrenownedDr.Alan Peters,theneuroanatomistthatoriginallydescribedmini-ormicro-columnaror- nizationinthecerebralcortex,wasrecruitedtowriteachapterinthisbookgiving hisexpertperspectiveontheissueinautism. The book begins with highly respected clinician, Dr. Margaret L. Bauman, DirectoroftheLADDERSclinicintheBostonarea,withaclinicalandmedicalp- spectiveofautismdiscussingetiologies,clinicalpresentation,earlyidenti?cation, vii viii Preface advancementsinmedicalcare,andassociateddisorders. Inthechapter"TheMale Prevalence in Autism Spectrum Disorders: Hypotheses on its Neurobiological Basis",ItalianresearchersDrs.FlavioKellerandLilianaRutapresentneuroch- ical hypotheses as the basis for the predominance of male prevalence in autism discussing the possible roles of estrogen, testosterone, oxytocin, and vasopressin in the organization of brain circuits and hemispheric specialization. Psychiatrist Dr. Ricardo Vella relates neuropathologies in autism, in the limbic and cereb- lar regions, to speci?c behaviors and presents a developmental perspective and hypotheses regarding emotional and attachment behaviors in autistic individuals.

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.

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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.

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 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.

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.

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

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.

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.

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.