Methods in Cardiovascular Safety Pharmacology
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I.D.1 I.D.1.1 I.D.2
I.D.2.1 I.D.2.2
I.D.2.3
I.D.3 I.D.3.1 I.D.3.1.1 I.D.3.1.2 I.D.3.1.3 I.D.3.1.4 I.D.3.2 I.D.3.2.1 I.D.3.2.2 I.D.3.2.3
I.D.3.2.4 I.D.3.3 I.D.3.3.1 I.D.3.3.2 I.D.3.3.3
Background . . . . . . . . . . . . . . . . . . . . . . General Considerations . . . . . . . . . . . . In vivo Experimental Models for Cardiovascular Safety Pharmacology . . . . . . . . . . . . . . . . . . . . Cardiovascular Safety Studies in Conscious Dogs and Other Species . Cardiovascular Safety Pharmacology Studies in Anesthetized Dogs and Other Species . . . . . . . . . . . . . . . . . . . . . . . . . . . Cardiovascular General Pharmacology Studies in Conscious Rats . . . . . . . . . . . . . . . . . . . . In vitro Cardiovascular Safety Pharmacology Models . . . . . . . . . . . . “High throughput” hERG Assays . . . Binding Competition Assays . . . . . . . Rubidium Flux Assays . . . . . . . . . . . . . Fluorescence Ion Channels Assays Using Voltage-Sensitive Dyes . . . . . . Automated Patch Clamp Systems. . . Voltage Clamp Studies on Potassium Channels . . . . . . . . . . . . . . . General Characteristics of the Voltage Clamp Technique . . . . . . . . . . Voltage Clamp Studies on Potassium Channels . . . . . . . . . . . . . . . Voltage Clamp Studies on hERG Potassium Channels in Heterologous Cell Systems . . . . . . . . Studies on Potassium Channels in Isolated Ventricular Myocytes . . . . . . Myocardial Action Potential Configuration . . . . . . . . . . . . . . . . . . . . . Studies in Isolated Purkinje Fibers . . Studies in Isolated Guinea Pig Papillary Muscles . . . . . . . . . . . . . . . . . Arterially Perfused Wedge of Canine Left Ventricle . . . . . . . . . . . . . .
61 62
I.D.4 I.D.4.1
65
I.D.4.2
65
I.D.4.3 I.D.4.4
68 I.D.5 70
I.D.5.1
72 72 72 73
I.D.5.2
73 74
I.D.5.3.2 I.D.5.4
74 74 75
76 78 79 80 82 84
I.D.5.3 I.D.5.3.1
Models for Proarrhythmic Potential . . . . . . . . . . . . . . . . . . . . . . . . . Studies of Arrhythmogenic Effects in Isolated Heart Preparations . . . . . . Langendorff Rabbit Heart (Screenit System) . . . . . . . . . . . . . . . . . Methoxamine-Induced Arrhythmia in Rabbits . . . . . . . . . . . . . Drug-Induced Proarrhythmic Effects in Dogs with Chronic AV Ablation . . . . . . . . . . . . . . . . . . . . . . . . . . Supplemental and/or Follow-Up Studies . . . . . . . . In-Depth Hemodynamic Analysis in Anesthetized Dogs . . . . . . . . . . . . . . Measurement of Heart Dimensions in Anesthetized Dogs . . . . . . . . . . . . . . Baroreceptor Reflexes . . . . . . . . . . . . . Influence on Orthostatic Hypotension . . . . . . . . . . . . . . . . . . . . . . Bezold–Jarisch Reflex . . . . . . . . . . . . . Measurement of Cardiac Output and Regional Blood Flow with Microspheres . . . . . . . . . . . . . . . . . . . . .
84 85 86 87
87 89 89 90 91 91 92
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I.D.1 Background The inclusion of pharmacological studies in the safety evaluation of new drugs is a well established practice (Zbinden 1966; Alder and Zbinden 1973). These studies contribute to the pharmacological profiles of possib
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