Current regulatory guidelines for cardiac safety utilize hERG block and QT interval prolongation as risk markers. This strategy has been successful at preventing harmful drugs from being marketed, but criticized for leading to early withdrawal of potentially safe drugs. Here we collected a series of articles presenting new technological and conceptual advances, including refinement of ex vivo and in vitro assays, screens and models, and in silico approaches reflecting the increasing effort that has been put forward by regulatory agencies, industry, and academia to try and address the need of a more accurate, mechanistically-based paradigm of proarrhythmic potential of drugs. This Research Topic is dedicated to the memory of Dr. J. Jeremy Rice, our wonderful friend and colleague.

Computational Toxicology for Drug Safety and a Sustainable Environment is a primer on computational techniques in environmental toxicology for scholars. The book presents 9 in-depth chapters authored by expert academicians and scientists aimed to give readers an understanding of how computational models, software and algorithms are being used to predict toxicological profiles of chemical compounds. The book also aims to help academics view toxicological assessment from the lens of sustainability by providing an overview of the recent developments in environmentally-friendly practices. The chapters review the strengths and weaknesses of the existing methodologies, and cover new developments in computational tools to explain how researchers aim to get accurate results. Each chapter features a simple introduction and list of references to benefit a broad range of academic readers. List of topics: 1. Applications of computational toxicology in pharmaceuticals, environmental and industrial practices 2. Verification, validation and sensitivity studies of computational models used in toxicology assessment 3. Computational toxicological approaches for drug profiling and development of online clinical repositories 4. How to neutralize chemicals that kill environment and humans: an application of computational toxicology 5. Adverse environmental impact of pharmaceutical waste and its computational assessment 6. Computational aspects of organochlorine compounds: DFT study and molecular docking calculations 7. In-silico studies of anisole and glyoxylic acid derivatives 8. Computational toxicology studies of chemical compounds released from firecrackers 9. Computational nanotoxicology and its applications Readership Graduate and postgraduate students, academics and researchers in pharmacology, computational biology, toxicology and environmental science programs.

This book gives professionals in clinical research valuable information on the challenging issues of the design, execution, and management of clinical trials, and how to resolve these issues effectively. It also provides understanding and practical guidance on the application of contemporary statistical methods to contemporary issues in safety evaluation during medical product development. Each chapter provides sufficient detail to the reader to undertake the design and analysis of experiments at various stages of product development, including comprehensive references to the relevant literature. Provides a guide to statistical methods and application in medical product development Assists readers in undertaking design and analysis of experiments at various stages of product development Features case studies throughout the book, as well as, SAS and R code

This book illustrates, in a comprehensive manner, the most current areas of importance to Safety Pharmacology, a burgeoning unique pharmacological discipline with important ties to academia, industry and regulatory authorities. It provides readers with a definitive collection of topics containing essential information on the latest industry guidelines and overviews current and breakthrough topics in both functional and molecular pharmacology. An additional novelty of the book is that it constitutes academic, pharmaceutical and biotechnology perspectives for Safety Pharmacology issues. Each chapter is written by an expert in the area and includes not only a fundamental background regarding the topic but also detailed descriptions of currently accepted, validated models and methods as well as innovative methodologies used in drug discovery.

The serious nature of cardiovascular adverse drug reactions occurring in patients makes assessment of a drug's cardiac safety profile a high priority during both development and post-approval monitoring. Integrated Cardiac Safety provides necessary guidance and methodology for professionals assessing cardiac safety of drugs throughout all stages of the drug's life, from discovery and development through postmarketing research. This self-contained, reader-friendly text is valuable to professionals in the pharmaceutical, biotechnology, and CRO industries, pharmacologists, toxicologists, government officials, and students.

This book helps readers integrate in silico, in vitro, and in vivo ADMET (absorption, distribution, metabolism, elimination and toxicity) and PK (pharmacokinetics) data with routine testing applications so that pharmaceutical scientists can diagnose ADMET problems and present appropriate recommendations to move drug discovery programs forward. The book introduces the current clinical practice for drug discovery and development along with the impact on early risk assessment; consolidates the tools and models to intelligently integrate existing in silico, in vitro and in vivo ADMET data; and demonstrates successful cases and lessons learned from real drug discovery and development. In short, it is a book aimed to provide a practical road map for drug discovery and development scientists to generate efficacious and safe drugs for unmet medical needs.

Effective identification of patients at increased risk of malignant cardiac arrhythmia presently represents a clinically important unmet need. Existing guidelines for the selection of candidates for the prophylactic implantation of cardioverters-defibrillators (ICD) are based solely on the reduction of ventricular haemodynamic performance. Although this guidance is based on statistical results of previously conducted randomized clinical trials, available experience shows that it does not serve clinical needs efficiently. The majority of patients who are implanted with ICDs for prophylactic reasons never utilize the device during its technical longevity whilst, at the same time, many patients who succumb to sudden cardiac death do not have ventricular haemodynamic performance particularly compromised. Recent results also showed that the previous statistical findings of ICD efficacy are not fully reproducible in patients with non-ischemic heart disease and that the reduction of sudden cardiac death after myocardial infarction by external automatic defibrillation vests is lower than expected. Advances in cardiac electrophysiology are needed for better understanding of the mechanisms that are the basis of different arrhythmic abnormalities. Increased understanding of these mechanisms will allow them to be more effectively classified so that optimum therapeutic options can be offered. Likewise, better understanding of the underlying electrophysiology processes is needed so that novel and more focused randomized clinical trials can be designed. Compared to invasive electrophysiological studies, noninvasive cardiac electrophysiology offers the possibility of screening larger number of patients as well as healthy subjects investigated under different provocations and conditions. To advance the field, broad spectrum of studies is needed together with meta-analyses and reviews facilitating research interactions.

Over the past 25-30 years, deaths due to Torsades de Pointes (TdP) have resulted in numerous drugs being withdrawn from the market. However, nearly 200 drugs that may prolong the QT interval and cause TdP remain available. A number of drugs with the potential to cause TdP are among the top 200 most prescribed drugs in the US, whilst new information regarding TdP is emerging rapidly. The purpose of this book is to provide a comprehensive source of information on the topic of torsades de pointes (TdP), which is a life-threatening polymorphic ventricular tachyarrhythmia associated with QT interval prolongation on the electrocardiogram (ECG). Torsades de Pointes provides a detailed, up-to-date and emerging information related to the epidemiology, drug culprits, mechanisms, risk factors, and methods of prevention and management of the life-threatening polymorphic ventricular tachycardia, also known as torsades de pointes. The book contains current knowledge, incorporating recent and cutting-edge advances in understanding of topics including inherited channelopathies and congenital LQTS; drugs that cause QT interval prolongation and TdP; non-drug causes of acquired QT interval prolongation and TdP; epidemiology of inherited and acquired TdP; morbidity and mortality associated with TdP, particularly in association with specific antimicrobials, antidepressants and antipsychotics, and methadone; cellular and molecular mechanisms of TdP, traditional and emerging risk factors for TdP; methods of prevention and risk reduction for TdP; and clinical management of patients with TdP. This book is an essential reference for both clinicians and researchers – providing guidance for clinicians who care for patients receiving QT interval-prolonging drugs, as well as cutting edge information for scientists and investigators conducting research in the area. - Up-to-date information on TdP associated with inherited channelopathies and the multiple forms of congenital LQTS - Includes a wealth of new information emerging regarding TdP, including newly-described risk factors and cellular and molecular mechanisms, contributions of genetic polymorphisms to drug-induced TdP, methods of quantification of risk, and methods of risk reduction, including clinical decision support - Contains information on nearly 200 commonly used drugs that have the potential to cause torsades de pointes, including antimicrobials, antipsychotics, antidepressants, antiarrhythmic agents, methadone, and many others - An essential reference for clinicians and researchers – provides guidance for clinicians who care for patients receiving QT interval-prolonging drugs, as well as cutting edge information for scientists and investigators conducting research in the area

A Comprehensive Guide to Toxicology in Nonclinical Drug Development, Second Edition, is a valuable reference designed to provide a complete understanding of all aspects of nonclinical toxicology in the development of small molecules and biologics. This updated edition has been reorganized and expanded to include important topics such as stem cells in nonclinical toxicology, inhalation and dermal toxicology, pitfalls in drug development, biomarkers in toxicology, and more. Thoroughly updated to reflect the latest scientific advances and with increased coverage of international regulatory guidelines, this second edition is an essential and practical resource for all toxicologists involved in nonclinical testing in industry, academic, and regulatory settings. - Provides unique content that is not always covered together in one comprehensive resource, including chapters on stem cells, abuse liability, biomarkers, inhalation toxicology, biostatistics, and more - Updated with the latest international guidelines for nonclinical toxicology in both small and large molecules - Incorporates practical examples in order to illustrate day-to-day activities and the expectations associated with working in nonclinical toxicology

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