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Cardiac Drug Safety : A Bench To Bedside Approach - Matthew J. Killeen

Cardiac Drug Safety

A Bench To Bedside Approach

Hardcover

Published: 30th November 2011
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At present, over 120 medications have been withdrawn from the major global pharmaceutical markets due to potentially lethal unwanted effects on the heart, namely ventricular fibrillation. With recent FDA guidelines recommending stringent testing of new pharmaceuticals on the heart, the importance of cardiac electrophysiology is affecting an increasing number of professionals in a range of industries. This book will equip readers with a clear and solid foundation in the fundamentals of electrophysiology and pharmacology of the heart, explore clinical disorders and treatments and relate this to the research and development of new medicines.Representing an integrative bench to bedside approach to understanding this critical drug safety phenomenon, this book begins with a comprehensive review of the mechanisms responsible for drug-induced arrhythmia, followed by an in-depth discussion of the current preclinical and clinical recording techniques. Additionally, a complete assessment of current methods to stratify cardiac risk in drug development is included. Most importantly, the book develops and outlines the novel strategies and key frameworks that increase the cardiac drug safety and drive down the risk of novel biopharmaceutical products in the future. Contents: Physiology of the Heart; Introduction to Electrophysiology: History, Ion Channels, Important Concepts; Electrophysiology of the Heart; Studying Cardiac Electrophysiology in the Laboratory and Clinic; Electrical Disorders of the Heart: From Cell to Bedside; The Impact of Cardiac Electrophysiology on Drug Development: History, Current Tests (Regulations, Requirements) and Their Shortcomings; Case Studies; The Future of Cardiac Drug Safety: Strategies to Reduce Risk and Ensure Continued Safety.

Forewordp. ix
Prefacep. xi
Challenges Facing the Pharmaceutical Industry in the 21st Centuryp. 1
Introductionp. 1
The Impact of Cardiac Toxicity on the Pharmaceutical Industryp. 4
Referencesp. 10
The Cellular Basis of Cardiac Electrophysiologyp. 11
Introductionp. 11
The Initiation of the Heart Beatp. 11
The Ventricular Cardiac Action Potentialp. 12
The Relationship Between the Cardiac Action Potential and the Electrocardiogramp. 15
Ion Channels Underlying the Cardiac Action Potentialp. 15
Summaryp. 26
Referencesp. 26
Clinical Arrhythmia Syndromesp. 31
Introductionp. 31
The Long QT Syndromep. 31
Congenital Long QT Syndromep. 32
Drug-Induced QT Prolongationp. 34
Summaryp. 40
Referencesp. 41
The Mechanisms Underlying Cardiac Arrhythmiasp. 43
Introductionp. 43
Mechanisms Underlying Cardiac Arrhythmiasp. 43
Abnormal Automaticityp. 44
Early and Delayed Afterdepolarizationsp. 44
Re-entryp. 45
Transmural Dispersion of Repolarizationp. 48
How does Action Potential and QT Prolongation Generate Arrhythmias?p. 51
Does the M-Cell Play a Role in Arrhythmia Induction in Humans?p. 53
Using Mouse Models to Study Arrhythmia Mechanismsp. 54
Experimental Studies Exploring the Relationship Between Changes in Transmural Repolarization Gradients and Arrhythmias in Mouse Heartsp. 57
Arrhythmia Mechanisms and Novel Antiarrhythmic Approaches Identified Using the Hypokalemic Mouse Modelp. 58
Summaryp. 67
Referencesp. 67
The Mechanisms Underlying Drug-Induced Arrhythmiasp. 73
Introductionp. 73
The Classical Model of Drug-Induced QTp. 73
Prolongation and Proarrhythmia: HERG Blockade Additional Mechanisms Contributing top. 74
Drug-Induced Arrhythmias Drug-Induction Activation of Depolarizing Ion Channelsp. 75
Drug-Induced Changes in Ion Channel Expressionp. 77
Drug-Induced Sodium Channel Dysfunctionp. 78
Summaryp. 80
Referencesp. 80
Assessing Cardiac Safety in Drug Developmentp. 83
Introductionp. 83
Preclinical Evaluation of Cardiac Drug Safetyp. 83
The ICH S7B Guidelinesp. 84
Single Cell Safety Studiesp. 87
The Purkinje Fiber Modelp. 88
The Ventricular Wedge Modelp. 89
Isolated Heart Modelsp. 90
In Vivo Modelsp. 92
The Impact of Species-Related Differences in Cardiac Electrophysiology on Preclinical Drug Safety Assessmentp. 95
Methods to Provoke Arrhythmias in Preclinical Studiesp. 97
Clinical Evaluation of Cardiac Safetyp. 100
Additional Biomarkers to Detect Drug-Induced Proarrhythmiap. 104
Recent Case Studies of Drug-Induced Proarrhythmiap. 109
Propoxyphene-Induced Cardiac Toxicityp. 110
Clinical and Experimental Studies of Propoxyphene-Induced Cardiac Toxicityp. 110
Regulatory Assessment of Propoxyphene's Cardiac Safety Profilep. 113
Dolasetron-Induced Cardiac Toxicityp. 113
Clinical and Experimental Studies of Dolasetron-Induced Cardiac Toxicityp. 114
Regulatory Assessment of Dolasetron's Cardiac Safety Profilep. 116
Summaryp. 117
Referencesp. 118
Pediatric Cardiac Safetyp. 123
Introductionp. 123
Cisapride-Induced Pediatric Cardiac Toxicityp. 124
Potential Mechanisms Underlying Cisapride-Induced Cardiac Toxicity in Pediatric Patientsp. 126
Drug-Induced Cardiac Toxicity in the Embryonic Heartp. 130
Summaryp. 132
Referencesp. 134
Drug-Induced Atrial Fibrillationp. 137
Introductionp. 137
Atrial Fibrillationp. 137
Bisphosphonate-Induced Atrial Fibrillationp. 138
Adenosine-Induced Atrial Fibrillationp. 142
Corticosteroid-Induced Atrial Fibrillationp. 144
Implications for Cardiac Safety Testing During Drug Developmentp. 146
Summaryp. 149
Referencesp. 149
Navigating the Future Path of Cardiac Drug Safetyp. 153
Introductionp. 153
Disease-Driven Approaches to Cardiac Safetyp. 153
Emerging Technologies for Cardiac Safety Assessmentp. 157
New Proarrhythmic Paradigmsp. 162
Engagement of Key Stakeholders to Advance Cardiac Safely Assessmentsp. 164
Referencesp. 166
Indexp. 169
Table of Contents provided by Ingram. All Rights Reserved.

ISBN: 9789814317450
ISBN-10: 9814317454
Audience: Tertiary; University or College
Format: Hardcover
Language: English
Number Of Pages: 188
Published: 30th November 2011
Publisher: World Scientific Publishing Co Pte Ltd
Country of Publication: SG
Dimensions (cm): 22.86 x 15.24  x 1.91
Weight (kg): 0.48