Oxidative damage appears to play a central role in the development of a wide range of tissue pathology, including neurodegenerative disease, drug side-effects, xenobiotic toxicity, carcinogenesis, and the aging process, to name just a few. Because of the centrality of oxidative processes to normal and abnormal tissue function, it has become imperative to develop appropriate analytical techniques to facilitate the quantitation of significant reactants. Without advances in methodology, corresponding advances in our knowledge of underlying biochemical events will be necessarily limited. Drs....

Since the pioneering discoveries of Hodgkin, Huxley, and Katz, it has been clear that specific ion conductance pathways underlie electrical act- ity. Over the ensuing 50 years, there has been ever increasing, and occasi- ally explosive, changes in the scope of efforts to understand ion channel behavior. The introduction of patch clamp technology by Erwin Neher and Bert Sakmann about 20 years ago led to the realization of the great variety of novel ion channel species, and the subsequent revolution in cl- ing has revealed an even greater diversity of the underlying molecular entities. Today,...

Dr. Myrtle A. Davis has assembled a panel of cutting-edge scientists to describe their best methods for detecting, illuminating, and quantifying apoptotic mechanisms in a way that is useful for the design of toxicology and pharmacology studies. These state-of-the-art techniques include flow cytometric, fluorometric, and laser scanning methods for quantifying and characterizing apoptosis, as well as protocols for the use of DNA microarray technology, high throughput screens, and ELISA. Immunocytochemical methods for measuring biochemical and molecular endpoints in tissue sections will be...

Well-respected leaders in the field of in vitro neurotoxicology take a fresh look at their own and other's work, critically and comparatively analyzing it across experimental systems and toxicants, and synthesizing essential principles for in vitro neurotoxicity testing. Neurotoxicants of significance to human health are emphasized, especially those for which metabolism and dose-responses are well well studied both in vivo and in vitro: lead, mercury, organophosphorous insecticides, polychlorinated biphenyls and dioxin, ethanol, and endogenous proteins. The goal is to set out new concepts and...

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...

A compendium of proven experimental approaches and strategies for studying the bioactivation, detoxification, tissue distribution, and elimination of xenobiotics in the metabolism and/or transport of various chemicals. The authors address several of the major drug metabolizing systems, including the cytochrome P450 family, flavin-containing monooxygenases, glutathione, S-transferase, glucuronidation, N-acetylation, and sulfotransferases. Additional chapters present novel approaches to the study of: signaling pathways in the regulation of drug metabolism enzymes, how the modulation of thiols...

Recent analyses of drug attrition rates reveal that a significant number of drug candidates fail in the later stage of clinical development owing to absorption, distribution, metabolism, elimination (ADME), and toxicity issues. Lead optimization in drug discovery, a process attempting to uncover and correct these defects of drug candidates, is highly beneficial in lowering the cost and time to develop therapeutic drugs by reducing drug candidate failures in development. At present, parallel synthesis combining with high-throughput screening has made it easier to generate highly potent...

concerns within the pharmaceutical industry about generating data that might be difficult to interpret in a regulated environment. There is also a growing apprec- tion for the challenges in translating this new information into clinical utility, including scientific, commercial, ethical, and policy challenges. Pharmacogenomics and Personalized Medicine, which is part of the Methods in Pharmacology and Toxicology series, comprises chapters on selected aspects of pharmacogenomics and personalized medicine. Our overall intent is to assist both novice and experienced investigators in...

The pharmaceutical industry has faced many significant challenges since the early 1990s. The fundamental issue that needs to be addressed is how to improve the efficiency of drug discovery and development. The current research and development (R&D) cost for developing a new therapeutic drug is greater than $800 million. Additionally, it takes an average of 12 years to get a new drug to market with an attrition rate greater than 90%. Reviewing the overall pharmaceutical R&D process, it has become clear that many of the drug failures are due to our lack of knowledge in population diversity,...