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A. CORBIN Investigations on LHRH and its analogs have just completed their first decade. We have witnessed a veritable explosion of chemical, physiologic and pharmacologic data on this hypothalamic peptide and the approximately 1500 agonist and antagonist analogs that have been synthesized. In order to track this expanding field, I was asked to organize an international symposium on basic and clinical aspects of LHRH analogs as part of the Reproductive Health Care: CDS Symposium held in Maui, Hawaii, in October 1982. This meeting brought together a number of the leading investigators in the field. Much new state-of-the-art information was presented which I and my colleagues felt deserved a wider audience. Drs Vickery, Nestor, and Hafez consented to undertake this task. Upon review of the literature, it was apparent that there was no recent text which fully covered the breadth of developments in the field. Accordingly, the editors decided to use the symposium as a nucleus on which to build a singular, comprehensive state-of-the-art analysis of this rapidly growing discipline, and the application of such knowledge to reproductive medicine. As exemplified by the various areas of expertise provided by the individual contributors, it becomes obvious that the scope of the subject matter, while relating solely to a well-defined chemical class (LHRH analogs) and a circumscribed physiologic and pharmacologic entity (reproduction), has expanded enormously.
Since the discovery of LHRH in 1971, research into the physiology and therapeutics of this compound can be divided into three dis tinctly different phases. In the first phase, attention was paid chiefly to the natural sequence hormone; efforts were channeled to explore its diagnostic use; and nearly all the clinical investigations were coordinated by a single pharmaceutical company. The successes in this area were quite limited and the interest in the promise of this agent as a diagnostic test has long since waned. This phase of research con sumed roughly the first seven years of clinical testing after the isolation and characterization of the compound by the two groups involved in the Nobel effort. With the appearance of long-acting LHRH agonists, the second phase of research on LHRH began in the late '70's. LHRH agonists were the only compounds available during this period of research and paradoxical desensitization was the predominant therapeutic basis for the discoveries. An ever-widening number of therapeutic applications using this approach were unearthed. A second theme which emerged during this second 5-7 year period was that the pulsatile administration of the natural sequence LHRH could be used to treat LHRH deficiency in men and women.
In the late 1980s, it became painfully evident to the pharmaceutical industry that the old paradigm of drug discovery, which involved highly segmented drug - sign and development activities, would not produce an acceptable success rate in the future. Therefore, in the early 1990s a paradigm shift occurred in which drug design and development activities became more highly integrated. This new str- egy required medicinal chemists to design drug candidates with structural f- tures that optimized pharmacological (e. g. , high affinity and specificity for the target receptor), pharmaceutical (e. g. , solubility and chemical stability), bioph- maceutical (e. g. , cell membrane permeability), and metabolic/pharmacokinetic (e. g. , metabolic stability, clearance, and protein binding) properties. Successful implementation of this strategy requires a multidisciplinary team effort, incl- ing scientists from drug design (e. g. , medicinal chemists, cell biologists, en- mologists, pharmacologists) and drug development (e. g. , analytical chemists, pharmaceutical scientists, physiologists, and molecular biologists representing the disciplines of pharmaceutics, biopharmaceutics, and pharmacokinetics/drug metabolism). With this new, highly integrated approach to drug design now widely utilized by the pharmaceutical industry, the editors of this book have provided the sci- tific community with case histories to illustrate the nature of the interdisciplinary interactions necessary to successfully implement this new approach to drug d- covery. In the first chapter, Ralph Hirschmann provides a historical perspective of why this paradigm shift in drug discovery has occurred.
Endocrine Disruption and Human Health starts with an overview of what endocrine disruptors are, the issues surrounding them, and the source of these chemicals in the ecosystem. This is followed by an overview of the mechanisms of action and assay systems. The third section includes chapters written by specialists on different aspects of concern for the effects of endocrine disruption on human health. Finally, the authors consider the risk assessment of endocrine disruptors and the pertinent regulation developed by the EU, the US FDA, as well as REACH and NGOs. The book has been written for researchers and research clinicians interested in learning about the actions of endocrine disruptors and current evidence justifying concerns for human health but is useful for those approaching the subject for the first time, graduate students, and advanced undergraduate students. - Provides readers with access to a range of information from the basic mechanisms and assays to cutting-edge research investigating concerns for human health - Presents a comprehensive, translational look at all aspects of endocrine disruption and its effects on human health - Offers guidance on the risk assessment of endocrine disruptors and current relevant regulatory considerations
Written by the foremost authority in the field, this volume is a comprehensive review of the multifaceted phenomenon of hepatotoxicity. Dr. Zimmerman examines the interface between chemicals and the liver; the latest research in experimental hepatotoxicology; the hepatotoxic risks of household, industrial, and environmental chemicals; and the adverse effects of drugs on the liver. This thoroughly revised, updated Second Edition features a greatly expanded section on the wide variety of drugs that can cause liver injury. For quick reference, an appendix lists these medications and their associated hepatic injuries. Also included are in-depth discussions of drug metabolism and factors affecting susceptibility to liver injury.
Groundbreaking, comprehensive, and developed by a panel of leading international experts in the field, Textbook of Assisted Reproduction provides a multidisciplinary overview of the diagnosis and management of infertility, which affects 15% of all couples around the world. The book aims to cover all aspects of assisted reproduction. Particular attention is given to topics such as the assessment of infertile couples; assisted reproductive techniques (ARTs) including ovulation induction, intra uterine insemination (IUI), in vitro fertilization (IVF) and intracytoplasmic sperm injection (clinical and laboratory aspects); reproductive genetics; and obstetric and perinatal outcomes.