In Vivo Models For Drug Discovery

This one-stop reference is the first to present the complete picture -- covering all relevant organisms, from single cells to mammals, as well as all major disease areas, including neurological disorders, cancer and infectious diseases. Addressing the needs of the pharmaceutical industry, this unique handbook adopts a broad perspective on the use of animals in the early part of the drug development process, including regulatory rules and limitations, as well as numerous examples from real-life drug development projects. After a general introduction to the topic, the expert contributors from research-driven pharmaceutical companies discuss the basic considerations of using animal models, including ethical issues. The main part of the book systematically surveys the most important disease areas for current drug development, from cardiovascular to endocrine disorders, and from infectious to neurological diseases. For each area, the availability of animal models for target validation, hit finding and lead profiling is reviewed, backed by numerous examples of both successes and failures among the use of animal models. The whole is rounded off with a discussion of perspectives and challenges. Key knowledge for drug researchers in industry as well as academia.

Animal models of diseases play a pivotal role in drug discovery and development, not only for proof of the concept studies of efficacy, PK/PD relationship but also for drug safety assessment. Since considerable differences in variables exist between animal models and human models (such as genetics, physiology, anatomy, gene expression, heterogeneity of disease conditions, etc.), not all the preclinical models are able to represent the pathophysiological conditions in human diseases. Therefore, partly due to the lack of congruency between animal and human disease models, several proposed therapeutic agents in the past decades have been demonstrated to be effective in preclinical models but failed in clinical studies. This e-book focuses on animal models of diseases from a translational perspective and highlights the key advantages and limitations of each model described to facilitate drug discovery and development. A unique feature of the volume is that it contains a selection of details disease models in various therapeutic niches with significant unmet medical needs, including inflammation, neurological diseases, cardiovascular and metabolic diseases, and oncology. This e-book is, therefore, of considerable value to researchers and clinicians involved in drug discovery and development as well as pathology.

Fruit flies are "little people with wings" goes the saying in the scientific community, ever since the completion of the Human Genome Project and its revelations about the similarity amongst the genomes of different organisms. It is humbling that most signalling pathways which "define" humans are conserved in Drosophila, the common fruit fly. Feed a fruit fly caffeine and it has trouble falling asleep; feed it antihistamines and it cannot stay awake. A C. elegans worm placed on the antidepressant flouxetine has increased serotonin levels in its tiny brain. Yeast treated with chemotherapeutics stop their cell division. Removal of a single gene from a mouse or zebrafish can cause the animals to develop Alzheimer’s disease or heart disease. These organisms are utilized as surrogates to investigate the function and design of complex human biological systems. Advances in bioinformatics, proteomics, automation technologies and their application to model organism systems now occur on an industrial scale. The integration of model systems into the drug discovery process, the speed of the tools, and the in vivo validation data that these models can provide, will clearly help definition of disease biology and high-quality target validation. Enhanced target selection will lead to the more efficacious and less toxic therapeutic compounds of the future. Leading experts in the field provide detailed accounts of model organism research that have impacted on specific therapeutic areas and they examine state-of-the-art applications of model systems, describing real life applications and their possible impact in the future. This book will be of interest to geneticists, bioinformaticians, pharmacologists, molecular biologists and people working in the pharmaceutical industry, particularly genomics.

Improving and Accelerating Therapeutic Development for Nervous System Disorders is the summary of a workshop convened by the IOM Forum on Neuroscience and Nervous System Disorders to examine opportunities to accelerate early phases of drug development for nervous system drug discovery. Workshop participants discussed challenges in neuroscience research for enabling faster entry of potential treatments into first-in-human trials, explored how new and emerging tools and technologies may improve the efficiency of research, and considered mechanisms to facilitate a more effective and efficient development pipeline. There are several challenges to the current drug development pipeline for nervous system disorders. The fundamental etiology and pathophysiology of many nervous system disorders are unknown and the brain is inaccessible to study, making it difficult to develop accurate models. Patient heterogeneity is high, disease pathology can occur years to decades before becoming clinically apparent, and diagnostic and treatment biomarkers are lacking. In addition, the lack of validated targets, limitations related to the predictive validity of animal models - the extent to which the model predicts clinical efficacy - and regulatory barriers can also impede translation and drug development for nervous system disorders. Improving and Accelerating Therapeutic Development for Nervous System Disorders identifies avenues for moving directly from cellular models to human trials, minimizing the need for animal models to test efficacy, and discusses the potential benefits and risks of such an approach. This report is a timely discussion of opportunities to improve early drug development with a focus toward preclinical trials.

As a guide for pharmaceutical professionals to the issues and practices of drug discovery toxicology, this book integrates and reviews the strategy and application of tools and methods at each step of the drug discovery process. • Guides researchers as to what drug safety experiments are both practical and useful • Covers a variety of key topics – safety lead optimization, in vitro-in vivo translation, organ toxicology, ADME, animal models, biomarkers, and –omics tools • Describes what experiments are possible and useful and offers a view into the future, indicating key areas to watch for new predictive methods • Features contributions from firsthand industry experience, giving readers insight into the strategy and execution of predictive toxicology practices

Learn why some drug discovery and development efforts succeed . . . and others fail Written by international experts in drug discovery and development, this book sets forth carefully researched and analyzed case studies of both successful and failed drug discovery and development efforts, enabling medicinal chemists and pharmaceutical scientists to learn from actual examples. Each case study focuses on a particular drug and therapeutic target, guiding readers through the drug discovery and development process, including drug design rationale, structure-activity relationships, pharmacology, drug metabolism, biology, and clinical studies. Case Studies in Modern Drug Discovery and Development begins with an introductory chapter that puts into perspective the underlying issues facing the pharmaceutical industry and provides insight into future research opportunities. Next, there are fourteen detailed case studies, examining: All phases of drug discovery and development from initial idea to commercialization Some of today's most important and life-saving medications Drugs designed for different therapeutic areas such as cardiovascular disease, infection, inflammation, cancer, metabolic syndrome, and allergies Examples of prodrugs and inhaled drugs Reasons why certain drugs failed to advance to market despite major research investments Each chapter ends with a list of references leading to the primary literature. There are also plenty of tables and illustrations to help readers fully understand key concepts, processes, and technologies. Improving the success rate of the drug discovery and development process is paramount to the pharmaceutical industry. With this book as their guide, readers can learn from both successful and unsuccessful efforts in order to apply tested and proven science and technologies that increase the probability of success for new drug discovery and development projects.

Animal Models in Cancer Drug Discovery brings forward the most cutting-edge developments in tumor model systems for translational cancer research. The reader can find under this one volume virtually all types of existing and emerging tumor models in use by the research community. This book provides a deeper insight on how these newer models could de-risk modern drug discovery. Areas covered include up to date information on latest organoid derived models and newer genetic models. Additionally, the book discusses humanized animal tumor models for cancer immunotherapy and how they leverage personalized therapies. The chapter on larger animal, canine models and their use in and their use in pre-investigational new drug (pre-IND) development makes the volume unique. Unlike before, the incorporation of several simplified protocols, breeding methodologies, handling and assessment procedures to study drug intervention makes this book a must read. Animal Models in Cancer Drug Discovery is a valuable resource for basic and translational cancer researchers, drug discovery researchers, contract research organizations, and knowledge seekers at all levels in the biomedical field. Encompasses discussions on innovative animal models, xenograft, genetic models, primary models, organoid systems, humanized and other models in modern biology paradigms that are enhancing research in the field of drug discover Covers the use of these models in personalized medicine, immunotherapy, toxicology, pre-IND assessments and related drug development arenas Presents protocols, procedures, and a comprehensive glossary to help new readers understand technical terms and specialized nomenclature

This unique volume traces the critically important pathway by which a "molecule" becomes an "anticancer agent. " The recognition following World War I that the administration of toxic chemicals such as nitrogen mustards in a controlled manner could shrink malignant tumor masses for relatively substantial periods of time gave great impetus to the search for molecules that would be lethal to specific cancer cells. Weare still actively engaged in that search today. The question is how to discover these "anticancer" molecules. Anticancer Drug Development Guide: Preclinical Screening, Clinical Trials, and Approval, Second Edition describes the evolution to the present of preclinical screening methods. The National Cancer Institute's high-throughput, in vitro disease-specific screen with 60 or more human tumor cell lines is used to search for molecules with novel mechanisms of action or activity against specific phenotypes. The Human Tumor Colony-Forming Assay (HTCA) uses fresh tumor biopsies as sources of cells that more nearly resemble the human disease. There is no doubt that the greatest successes of traditional chemotherapy have been in the leukemias and lymphomas. Since the earliest widely used in vivo drug screening models were the murine L 1210 and P388 leukemias, the community came to assume that these murine tumor models were appropriate to the discovery of "antileukemia" agents, but that other tumor models would be needed to discover drugs active against solid tumors.