LEADER 05224nam 2200637 a 450 001 9910779277703321 005 20230802005204.0 010 $a1-280-66922-5 010 $a9786613646156 010 $a981-4317-46-2 035 $a(CKB)2550000000101695 035 $a(EBL)919080 035 $a(OCoLC)794328376 035 $a(SSID)ssj0000654806 035 $a(PQKBManifestationID)12321756 035 $a(PQKBTitleCode)TC0000654806 035 $a(PQKBWorkID)10674483 035 $a(PQKB)11268532 035 $a(MiAaPQ)EBC919080 035 $a(WSP)00007839 035 $a(Au-PeEL)EBL919080 035 $a(CaPaEBR)ebr10563572 035 $a(CaONFJC)MIL364615 035 $a(EXLCZ)992550000000101695 100 $a20120607d2012 uy 0 101 0 $aeng 135 $aurcuu|||uu||| 181 $ctxt 182 $cc 183 $acr 200 10$aCardiac drug safety$b[electronic resource] $ea bench to bedside approach /$fMatthew J. Killeen 210 $aSingapore $cWorld Scientific Pub. Co.$d2012 215 $a1 online resource (189 p.) 300 $aDescription based upon print version of record. 311 $a981-4317-45-4 320 $aIncludes bibliographical references and index. 327 $aContents; Foreword; "Et causae quoque aestimatio saepe morbum solvit"* [Celsus: Prooemium 69, De Medicina]; Preface; Chapter 1 Challenges Facing the Pharmaceutical Industry in the 21st Century; Introduction; The Impact of Cardiac Toxicity on the Pharmaceutical Industry; References; Chapter 2 The Cellular Basis of Cardiac Electrophysiology; Introduction; The Initiation of the Heart Beat; The Ventricular Cardiac Action Potential; The Relationship Between the Cardiac Action Potential and the Electrocardiogram; Ion Channels Underlying the Cardiac Action Potential; Sodium channels 327 $aCalcium channels Potassium channels; Cardiac potassium channels; The transient outward potassium channel; Delayed rectifier potassium channels; The ultra rapid delayed rectifier potassium channel; The HERG potassium channel; The slowly activating delayed rectifier potassium channel; Inwardly rectifying potassium channels; Species-dependent variability of potassium channels; Potassium channel subunits; Summary; References; Chapter 3 Clinical Arrhythmia Syndromes; Introduction; The Long QT Syndrome; Congenital Long QT Syndrome; Drug-Induced QT Prolongation; Summary; References 327 $aChapter 4 The Mechanisms Underlying Cardiac Arrhythmias Introduction; Mechanisms Underlying Cardiac Arrhythmias; Abnormal Automaticity; Early and Delayed After depolarizations; Re-entry; Transmural Dispersion of Repolarization; How does Action Potential and QT Prolongation Generate Arrhythmias?; Does the M-Cell Play a Role in Arrhythmia Induction in Humans?; Using Mouse Models to Study Arrhythmia Mechanisms; Experimental Studies Exploring the Relationship Between Changes in Transmural Repolarization Gradients and Arrhythmias in Mouse Hearts 327 $aArrhythmia Mechanisms and Novel Antiarrhythmic Approaches Identified Using the Hypokalemic Mouse Model Summary; References; Chapter 5 The Mechanisms Underlying Drug-Induced Arrhythmias; Introduction; The Classical Model of Drug-Induced QT Prolongation and Proarrhythmia: HERG Blockade; Additional Mechanisms Contributing to Drug-Induced Arrhythmias; Drug-Induction Activation of Depolarizing Ion Channels; Drug-Induced Changes in Ion Channel Expression; Drug-Induced Sodium Channel Dysfunction; Summary; References; Chapter 6 Assessing Cardiac Safety in Drug Development; Introduction 327 $aPreclinical Evaluation of Cardiac Drug Safety The ICH S7B Guidelines; Single Cell Safety Studies; The Purkinje Fiber Model; The Ventricular Wedge Model; Isolated Heart Models; In Vivo Models; The Impact of Species-Related Differences in Cardiac Electrophysiology on Preclinical Drug Safety Assessment; Methods to Provoke Arrhythmias in Preclinical Studies; Programmed electrical stimulation; Reductions in the extracellular K+ concentration; Clinical Evaluation of Cardiac Safety; The Thorough QT study; Thorough QT study design; Additional Biomarkers to Detect Drug-Induced Proarrhythmia 327 $aVariability of repolarization 330 $aEnsuring the safety of new medical products remains a major challenge for the pharmaceutical industry. Cardiac safety, particularly drug-induced heart rhythm abnormalities, remains an important cause of pipeline attrition and has resulted in countless major product recalls or label changes. The risk of encountering this major adverse event continues to shape the drug development and regulatory landscape. Extensive research over the past decade has shed light on the root causes of arrhythmias that are triggered by medications and has helped drive, and optimize, drug safety testing.However, 606 $aCardiovascular agents 615 0$aCardiovascular agents. 676 $a363.738/74 676 $a363.73874 676 $a615.71 700 $aKilleen$b Matthew J$01543238 801 0$bMiAaPQ 801 1$bMiAaPQ 801 2$bMiAaPQ 906 $aBOOK 912 $a9910779277703321 996 $aCardiac drug safety$93796592 997 $aUNINA