A cutting-edge review of the major research areas of adjuvant discovery, design, development, and use. The authors lay down a rational basis for vaccine adjuvant function and analyze a number of significantly distinct adjuvant-active molecules to illuminate the principles of their function and use. The focus is on specific receptor-ligand interactions, including the molecular features needed for a compound to possess adjuvant activity. The critical interface zone between the innate and adaptive immune systems is also analyzed to show how adjuvants exert their effects on T- and B-cell activation. Additional chapters address the possibility of tailoring adjuvants to yield optimally safe and effective responses.

Ocular toxicity is routinely assessed in toxicology studies conducted for regulatory purposes. Ocular anatomy and physiology and the assessment of ocular toxicity itself can be challenging to scientists involved in the safety assessment of pharmaceuticals, pesticides and other agents. Anatomical and physiological differences between species can impact the nature of ocular effects observed following intended or unintended exposure of ocular tissues to xenobiotics. "Ocular Toxicity in Laboratory Animals" provides a concise reference addressing ocular anatomy and physiology across species that will enhance the design and interpretation of toxicology studies conducted for regulatory purposes.

The book provides an overview of routine and advanced techniques that are used to assess ocular toxicity including slit lamp biomicroscopy, indirect ophthalmoscopy, electrophysiology and imaging methods for the anterior and posterior segments of the eye. Additionally, the book defines the regulatory expectations for pharmaceuticals intended to treat ocular diseases and for other non-pharmaceutical regulated chemicals. With contributions from experts in the field, "Ocular Toxicity in Laboratory Animals" is an authoritative, accessible guide for toxicologists and other scientists involved in conducting toxicology studies for regulatory purposes and/or reviewing data from such studies."

This book highlights current approaches and future trends in the use of mass spectrometry to characterize protein therapies. As one of the most frequently utilized analytical techniques in pharmaceutical research and development, mass spectrometry has been widely used in the characterization of protein therapeutics due to its analytical sensitivity, selectivity, and specificity. This book begins with an overview of mass spectrometry techniques as related to the analysis of protein therapeutics, structural identification strategies, quantitative approaches, followed by studies involving characterization of process related protein drug impurities/degradants, metabolites, higher order structures of protein therapeutics. Both general practitioners in pharmaceutical research and specialists in analytical sciences will benefit from this book that details step-by-step approaches and new strategies to solve challenging problems related to protein therapeutics research and development.

H. Wegele, L. M ller, and J. Buchner: Hsp70 and Hsp90 A Relay Team for Protein Folding

R. Sch lein: The Early Stages of the Intracellular Transport of Membrane Proteins: Clinical and Pharmacological Implications

L. Schild: The Epithelial Sodium Channel: From Molecule to Disease

Alkaloids are a major group of natural products derived from a variety of organisms, which are widely used as medicinal and biological agents. This Series is world-renowned as the leading compilation of current reviews of this vast field. Internationally acclaimed for more than 40 years, this Series, founded by the late Professor R.H.F. Manske, continues to provide outstanding coverage of the rapidly expanding field of the chemotaxonomy, structure elucidation, synthesis, biosynthesis, and biology of all classes of alkaloids from higher and lower plants, marine organisms, or various terrestrial animals.
Each volume provides, through its distinguished authors, up-to-date and detailed coverage of particular classes or sources of alkaloids. Over the years, this Series has become the standard in natural product chemistry to which all other book series aspire. The Alkaloids: Chemistry and Biology endures as an essential reference for all natural product chemists and biologists who have an interest in alkaloids, their diversity, and their unique biological profile.
Key Features
* Indispensable reference work written by leading experts in the field
* Provides up-to-date, timely reviews on compounds and classes of great interest
* Covers synthesis, biosynthesis, biology, as well as isolation and structure elucidation
* An essential research tool for anyone working with alkaloids from a chemical or biological perspective

Drug metabolism and transport are very important facets within the discipline of pharmaceutical sciences, with enzyme kinetic concepts utilized regularly in characterizing and modeling the disposition and elimination of drugs. Enzyme Kinetics in Drug Metabolism: Fundamentals and Applications focuses on very practical aspects of applying kinetic principles to drug metabolizing enzymes and transporters. Divided into five convenient sections, topics include the fundamental principles of enzyme kinetics, the kinetics of oxidative and conjugative drug metabolizing enzymes and drug transporters, modeling approaches for both drug metabolizing enzymes and transporters including novel systems biology approaches, understanding of variability both experimental and interindividual (pharmacogenomic), and case studies that provide real life examples of applying these principles. Written in the successful Methods in Molecular Biology series format, chapters include introductions to their respective topics especially suitable for the novice, in some cases step-by-step, readily reproducible protocols, and insights to help with troubleshooting and avoiding known pitfalls with extensive cross referencing to assist in learning. Authoritative and easily accessible, Enzyme Kinetics in Drug Metabolism: Fundamentals and Applications serves as a very practical teaching tool for novice, non-mathematically trained scientists interested in these fundamental concepts and as an aid for their supervisors in teaching these principles.

Recent advances in drug discovery have been rapid. The second edition of Bioinformatics and Drug Discovery has been completely updated to include topics that range from new technologies in target identification, genomic analysis, cheminformatics, protein analysis, and network or pathway analysis. Each chapter provides an extended introduction that describes the theory and application of the technology. In the second part of each chapter, detailed procedures related to the use of these technologies and software have been incorporated. Written in the highly successful Methods in Molecular Biology (TM) series format, the chapters include the kind of detailed description and implementation advice that is crucial for getting optimal results in the laboratory. Thorough and intuitive, Bioinformatics and Drug Discovery, Second Edition seeks to aid scientists in the further study of the rapidly expanding field of drug discovery.

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.

Covering topics from individual molecules to systemic diseases, from basic concepts to advanced technologies, Pharmacogenomics in Drug Discovery and Development , Second Edition provides a practical, state-of-the-art and integrative view of the application of pharmacogenomics in drug discovery and development. A wide range of theoretical and experimental approaches are introduced to meet the problem-solving objectives for understanding the complexity in health and diseases, from laboratory tests to computational analysis. The development of pharmacogenomics represents the evolution of biomedicine from treating the disease itself to treating the malfunction of an individual person, the "root" of diseases. With the change of focus from disease-centered to human-centric medicine, pharmacogenomics brings hope for the transformation from simple disease treatment to accurate prediction and effective prevention. Written in the 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 protocols, and notes on troubleshooting and avoiding known pitfalls. Authoritative and easily accessible, Pharmacogenomics in Drug Discovery and Development, Second Edition seeks to serve both professionals and novices with comprehensive resources and a holistic view for the translation of pharmacogenomics into better preventive and personalized medical care.

The currently available means of combating fungal infections are weak and clumsy. The application of fungal genomics offers an unparalleled opportunity to develop novel antifungal drugs. Interestingly, several novel antifungal drug targets have already been identified and validated. However, it is premature to expect a novel antifungal agent in clinical setting as drug discovery programs are still in their infancy. In addition to classical and genomic approaches to drug discovery, treasure trove based on natural products and phytomedicine can provide a multitude of alternative modes of combating fungal infection. This book incisively addresses essential topics on various aspects pertaining to fungal diseases in human and animals, their reservoir, fungal pathogenesis, their management and recent advances in their treatment. Issues of antifungal drug toxicity, especially nephrotoxicity, are also discussed. The development of resistance in fungal pathogens, including multidrug resistance and its mechanism, is dealt with in two chapters. Diverse diagnostic approaches to fungal infections are also reviewed. The combinational drug strategies used in combating invasive fungal infections are addressed in detail. The management of pulmonary mycoses in stem cell transplantation is also given special focus. Novel antifungal drugs (synthetic and herbal), fungal vaccines, and metabolic pathways as drug targets are discussed in detail in three different chapters. Subsequently the roles of innate immunity, cytokine therapy and immunomodulators in the treatment of fungal infections are elaborated upon. As novel drug delivery systems have a great potential for modifying the pharmacokinetics of medications, the last chapter takes this fact into consideration in its examination of state-of-the-art delivery systems in controlling fungal infections.

A consolidated and comprehensive reference on ligand-binding assays

Ligand-binding assays (LBAs) stand as the cornerstone of support for definition of the pharmaco-kinetics and toxicokinetics of macromolecules, an area of burgeoning interest in the pharmaceutical industry. Yet, outside of the Crystal City Conference proceedings, little guidance has been available for LBA validation, particularly for assays used to support macromolecule drug development. "Ligand-Binding Assays: Development, Validation, and Implementation in the Drug Development Arena" answers that growing need, serving as a reference text discussing critical aspects of the development, validation, and implementation of ligand-binding assays in the drug development field.

"Ligand-Binding Assays" covers essential topics related to ligand-binding assays, from pharmacokinetic studies, the development of LBAs, assay validation, statistical LBA aspects, and regulatory aspects, to software for LBAs and robotics and other emerging methodologies for LBAs. Highlights include:

A general discussion of challenges and proven approaches in the development of ligand-binding assays

More detailed examination of characteristics of these assays when applied to support of pharmacokinetic and toxicokinetic studies of compounds at different stages in the discovery or development timeline

A concise, but detailed, discussion of validation of ligand-binding assays for macromolecules

A practical approach to "fit-for-purpose" validation of assays for biomarkers, those molecules receiving increased attention as potentially demonstrating that the target chosen in discovery is being modulated by the candidate therapeutic, both in nonclinical and clinical studies

Written by a team of world-recognized authorities in the field, "Ligand-Binding Assays" provides key information to a broad range of practitioners, both in the pharmaceutical and allied industries and in related contract research organizations and academic laboratories and, perhaps, even in the field of diagnostics and clinical chemistry.

A Pharmacology Primer: Techniques for More Effective and Strategic Drug Discovery, Sixth Edition features the latest research surrounding the application of pharmacology in drug discovery in an effort to equip readers with a deeper understanding of complex and rapid changes in this field. Written by well-respected pharmacologist, Terry P. Kenakin, this primer is an indispensable resource for anyone involved in drug discovery. This edition has been reorganized for better flow and clarity and includes material on new technologies for screening (virtual, DNA encoded libraires, fragment-based) and a major section on phenotypic (target agnostic) screening for new leads and determination of drug targets. With full color illustrations as well as new examples throughout, this book remains a top reference for all industry and academic scientists and students directly involved in drug discovery or pharmacologic research. New material includes a discussion of the determination of target engagement, including numerous new ways to demonstrate the physical interaction of molecules with drug targets and new drug candidates such a mRNA, gene therapy, antibodies and information on CRISPR and genomics.

Advances in Molecular Toxicology features the latest advances in all of the subspecialties of the broad area of molecular toxicology. Toxicology is the study of poisons and this series details the study of the molecular basis by which a vast array of agents encountered in the human environment and produced by the human body itself manifest themselves as toxins. Not strictly limited to documenting these examples the series is also concerned with the complex web of chemical and biological events that give rise to toxin-induced symptoms and disease. The new technologies that are being harnessed to analyze and understand these events will also be reviewed by leading workers in the field.
Advances in Molecular Toxicology will report progress in all aspects of these rapidly evolving molecular aspects of toxicology with a view toward detailed elucidation of both progress on the molecular level and on advances in technological approaches employed.
* Cutting edge reviews by leading workers in the discipline.
* In depth dissection of molecular aspects of interest to a broad range of scientists, physisicans and any student in the allied disciplines.
* Leading edge applications of technological innovations in the chemistry, biochemistry and molecular medicine.

As cells mature they naturally stop dividing and enter a period called senescence. But cellular senescence can also be induced prematurely by certain oncogenes involved in cancer development. Cellular senescence, a growth-arrest program that limits the lifespan of mammalian cells and prevents unlimited cell proliferation, is attracting considerable interest because of its links to tumor suppression.

Thepresent work is a finecontribution to the broad field of environmental security in the context of risk assessment and management of obsolete pesticides for the region of Southeast Europe. The purpose of this book is to evaluate the existing knowledge of improper disposal of obsolete pesticides in the region, to estimate the associated impact on environmental health, and to develop recommendations to mitigate or eliminate threats posed to the environment, biodiversity and human life. The issues discussed in the book include: reviews of the transport and fate of pesticides and associated contaminated materials in different environmental media and identification of the principal sources, emission routes and patterns of environmental pollution with pesticides; a recognition of the most suitable methods for environmental sampling analysis and sample preparation; an evaluation of the current methods and techniques for chemical and mass analysis of environmental and biological samples and discussion of the metrological and quality aspects of trace analyses; a characterization of the environmental and human health impacts of pesticide pollution, the health effects associated with acute and chronic exposure and the use of epidemiological data for risk assessment; a revision of the existing chemical safety regulations and strategies for protection and management of obsolete pesticide stocks; a survey of the international conventions, directives and standards concerning pesticide use.

"

Aldehyde Dehydrogenases-The 1992 Perspective.- Metabolic Role of Aldehyde Dehydrogenase.- Effects of Aldehyde Products of Lipid Peroxidation on the Activity of Aldehyde Metabolizing Enzymes in Hepatomas.- Metabolic Interactions of 4-Hydroxynonenal, Acetaldehyde and Glutathione in Isolated Liver Mitochondria.- Biological Role of Human Cytosolic Aldehyde Dehydrogenase 1: Hormonal Response, Retinal Oxidation and Implication in Testicular Feminization.- Human Cytosolic Aldehyde Dehydrogenase in Androgen Insensitivity Syndrome.- The Use of Immortalized Mouse L1210/OAP Cells Established in Culture to Study the Major Class 1 Aldehyde Dehydrogenase-Catalyzed Oxidation of Aldehydes in Intact Cells.- Enhanced Transcription of the Cytosolic ALDH Gene in Cyclophosphamide Resistant Human Carcinoma Cells.- Attempts to Increase the Expression of Rat Liver Mitochondrial Aldehyde Dehydrogenase in E. coli by Altering the mRNA.- Preliminary Characterization of the Rat Class 3 Aldehyde Dehydrogenase Gene.- Human High-Km Aldehyde Dehydrogenase (ALDH3): Molecular, Kinetic, and Structural Features.- Overexpression or Polycyclic Aromatic Hydrocarbon-Mediated Induction of an Apparently Novel Class 3 Aldehyde Dehydrogenase in Human Breast Adenocarcinoma Cells and Its Relationship to Oxazaphosphorine-Specific Acquired Resistance.- Tumor-Associated Aldehyde Dehydrogenase (ALDH3): Expression in Different Human Tumor Cell Lines with and without Treatment with 3-Methylcholanthrene.- Sexual Differentiation in the Induction of the Class 3 Aldehyde Dehydrogenase.- Mouse Class 3 Aldehyde Dehydrogenases: Positive and Negative Regulation of Gene Expression.- Human Stomach Aldehyde Dehydrogenase, ALDH3.- Bovine Corneal Aldehyde Dehydrogenases: Evidence for Multiple Gene Products (ALDH3 and ALDHX).- Carbonyl-Metabolizing Enzymes and Their Relatives Recruited as Structural Proteins in the Eye Lens.- Members of the ALDH Gene Family are Lens and Corneal Crystalline.- Retinoic Acid Synthesis in the Developing Retina.- Human Liver High Km Aldehyde Dehydrogenase (ALDH4): Properties and Structural Relationship to the Yeast Glutamic ?-Semialdhyde Dehydrogenase.- Effect of Some Compounds Related to Disulfiram on Mitochondrial Aldehyde Dehydrogenase in Vitro and in Vivo.- Photoaffinity Labeling of Aldehyde Dehydrogenase from Horse Liver by P1-N6-(4-Azidophenylethyl) Adenosine-P2[4-(3-Azidopyridinio)Butyl] Diphosphate.- Aldehyde Dehydrogenase: Aldehyde Dehydrogenation and Ester Hydrolysis.- Is the Single Site Binding Model for Aldehyde Dehydrogenase an Oversimplification? The One-Site, Two-Site Debate Revisited.- Crystallization and Preliminary X-Ray Analysis of Bovine Mitochondrial Aldehyde Dehydrogenase and Human Glutathione-Dependent Formaldehyde Dehydrogenase.- Aldo-Keto Reductases: An Overview.- Location of an Essential Arginne Residue in the Primary Structure of Pig Aldose Reductase.- Cys298 Is Responsible for Reversible Thiol-Induced Variation in Aldose Reductase Activity.- Substrate Specificity of Reduced and Oxidized Forms of Human Aldose Reductase.- Kinetic Alteration of Human Aldose Reductase by Mutagenesis of Cysteine Residues.- Inhibition of Aldose Reductase by (2, 6-Dimethylphenylsulphonyl) Nitromethane: Possible Implications for the Nature of an Inhibitor Binding Site and a Cause of Biphasic Kinetics.- Sepiapterin Reductase and ALR2 ("Aldose Reductase") from Bovine Brain.- Polymorphisms of the Aldose Reductase Locus (ALR2) and Suseptibility to Diabetic Microvascular Complications.- Polycyclic Aromatic Hydrocarbons and Phenolic Antioxidants do not Significantly Induce Carbonyl Reductase in Human Cell Lines.- The Purification and Properties of a Novel Carbonyl Reducing Enzyme from Mouse Liver Microsomes.- Properties and Stereoselectivity of Carbonyl Reductases Involved in the Ketone Reduction of Warfarin and Analogues.- Activation of Pulmonary Carbonyl Reductase by Aromatic Amines and Pyridine Ring-Containing Compounds.- Unique Dihydrodiol Specific Dehydrogena...

With the recent completion of the sequencing of the human genome, it is widely anticipated that the number of potential new protein drugs and targets will escalate at an even greater rate than that observed in recent years. However, identification of a potential target is only part of the process in developing these new next generation protein-based "drugs" that are increasingly being used to treat human disease. Once a potential protein drug has been identified, the next rate-limiting step on the road to development is the production of sufficient authentic material for testing, charact- ization, clinical trials, and so on. If a protein drug does actually make it through this lengthy and costly process, methodology that allows the production of the protein on a scale large enough to meet demand must be implemented. Furthermore, large-scale production must not compromise the authenticity of the final product. It is also nec- sary to have robust methods for the purification, characterization, viral inactivation and continued testing of the authenticity of the final protein product and to be able to formulate it in a manner that retains both its biological activity and lends itself to easy administration. Therapeutic Proteins: Methods and Protocols covers all aspects of protein drug production downstream of the discovery stage. This volume contains contributions from leaders in the field of therapeutic protein expression, purification, characterization, f- mulation, and viral inactivation.

PARP Inhibitors for Cancer Therapy provides a comprehensive overview of the role of PARP in cancer therapy. The volume covers the history of the discovery of PARP (poly ADP ribose polymerase) and its role in DNA repair. In addition, a description of discovery of the PARP family, and other DNA maintenance-associated PARPs will also be discussed. The volume also features a section on accessible chemistry behind the development of inhibitors. PARP inhibitors are a group of pharmacological inhibitors that are a particularly good target for cancer therapy. PARP plays a pivotal role in DNA repair and may contribute to the therapeutic resistance to DNA damaging agents used to treat cancer. Researchers have learned a tremendous amount about the biology of PARP and how tumour-specific defects in DNA repair can be exploited by PARPi. The "synthetic lethality" of PARPi is an exciting concept for cancer therapy and has led to a heightened activity in this area.

Cardiac Drug Development Guide outlines, in detail, the therapeutics of cardiac medicine currently at the cutting edge of scientific research and development around the world. This volume integrates basic and clinical cardiac pharmacology by c- bining, for the first time, both classical and molecular aspects of therapeutic drug development. The chapters comprise a broad spectrum of therapeutic areas and hence involve a comprehensive discussion of molecular, biochemical, and electrophy- ological concepts based on years of in vitro as well as in vivo pharmacological st- ies. In addition, the latter part of the book includes comprehensive clinical cardiac chapters that describe important topics in molecular medicine. These chapters also discuss current clinical therapeutic trends in medicine and provide an evaluation of the efficacy of novel drugs in these areas. Cardiac Drug Development Guide has many distinctive and outstanding features that set it apart from other cardiac pharmacology books. This book introduces topics in an easily understandable format for researchers in many varying disciplines by integrating and thereby simplifying concepts not usually discussed across a broad range of cardiac disciplines and in a highly technical field. Each chapter not only introduces and describes the physiology, pharmacology, and pathophysiology of the disease, but also overviews the clinical implications of drug development, what stages these areas are currently in, and also reviews some of the methodologies involved in drug discovery and development. As a result, this book provides a comprehensive overview of the most advanced procedures in cardiac pharmacology today.

This book focuses on recently developed High Throughput Screening (HTS) assay protocols, many involved in the ToxCast and/or Tox21 initiatives, and the relevant HTS data analysis techniques. Divided into three sections, in vitro assays, in vivo assays, and computational techniques to analyze HTS data are all examined. Written for the highly successful Methods in Molecular Biology series, most chapters include 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, High Throughput Screening Assays in Toxicology serves as a valuable reference resource for translating new HTS techniques into standardized chemical toxicity assessment tools in order to advance modern toxicology research to a new era where HTS techniques can partially replace the prevailing animal models.

Chemistry and Biology is a celebration of the outstanding contributions to the field by Professor R.H.F. Manske, who founded the series in 1950. This special volume demonstrates the dramatic changes in alkaloidchemistry since then. It also offers a unique overview of recent developments in major areas of alkaloid chemistry and biology and looks at how these areas will develop in the future. These fourteen contributions are written by many of the leading alkaloid chemists in the world, and thus comprise a unique view of alkaloids and their contributions to the health and well-being of humankind.
Key Features
* Unique contributions from twenty of the world's leading alkaloid chemists
* Critical reviews of the major progress in alkaloid chemistry
* Considered commentary on the future of alkaloid chemistry
* State-of-the-art insight into the role of alkaloids in the health sciences, biotechnology, and the elucidation of fundamental biological processes