The nonclinical Evaluation of the Potential for delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals Step 5 NOTE FOR GUIDANCE ON THE NONCLINICAL EVALUATION OF THE POTENTIAL FOR DELAYED VENTRICULAR REPOLARIZATION (QT INTERVAL PROLONGATION) BY HUMAN PHARMACEUTICALS (C
The nonclinical Evaluation of the Potential for delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals Step 5 NOTE FOR GUIDANCE ON THE NONCLINICAL EVALUATION OF THE POTENTIAL FOR DELAYED VENTRICULAR REPOLARIZATION (QT INTERVAL PROLONGATION) BY HUMAN PHARMACEUTICALS (C
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人类药物延迟心室复极（QT 间期延长）潜力的非临床评估步骤 5 人类药物延迟心室复极（QT 间期延长）潜力非临床评估指导说明（C）
DOI：
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发表时间：
2004
期刊：
影响因子：
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通讯作者：
Jen Sheen (phase‐extraction)
中科院分区：
文献类型：
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作者：
R. Kingston;Jen Sheen (phase‐extraction)
引言药物对心室复极和预防风险的影响的评估是积极调查的主题。当将来积累更多数据（非临床和临床）时，将对其进行评价，并可能修订本指南。1.1本指导原则的目的本指导原则描述了用于评估供试品延迟心室复极的潜力的非临床试验策略。本指南包括非临床试验和综合风险评估的相关信息。1.2背景心电图（ECG）的QT间期（从QRS波群开始到T波结束的时间）是心室去极化和复极持续时间的量度。QT间期延长可以是先天性的或获得性的（例如，药物诱导的）。当心室复极延迟和QT间期延长时，室性快速性心律失常（包括尖端扭转型室性心动过速）的风险增加，特别是与其他风险因素（例如，低钾血症、结构性心脏病、心动过缓）。因此，许多重点已经放在与QT间期延长相关的药物的潜在促心律失常作用上。心室复极是一个复杂的生理过程，由心脏动作电位的持续时间决定。它是许多膜离子通道和转运蛋白活动的净结果。在生理条件下，这些离子通道和转运蛋白的功能高度相互依赖。每个离子通道或转运蛋白的活性受多种因素影响，包括但不限于细胞内和细胞外离子浓度、膜电位、细胞间电耦合、心率和自主神经系统活性。代谢状态（例如，酸碱平衡）以及心肌细胞的位置和类型也很重要。人心室动作电位由五个连续的阶段组成：·阶段0：动作电位的上升主要是Na +（I Na）通过Na +通道快速瞬时流入的结果。·第一阶段：动作电位上升的终止和复极早期是由于Na +通道失活和K +通过K +通道的瞬时外排所致。·第二阶段：动作电位的平台反映了L型钙通道的钙内流（ICa）与外向复极钾电流之间的平衡。·阶段3：动作电位的持续向下行程和复极晚期阶段是由...
INTRODUCTION The assessment of the effects of pharmaceuticals on ventricular repolarization and proarrhythmic risk is the subject of active investigation. When additional data (non-clinical and clinical) are accumulated in the future, they will be evaluated and this guideline might be revised. 1.1 Objective of the Guideline This guideline describes a non-clinical testing strategy for assessing the potential of a test substance to delay ventricular repolarization. This guideline includes information concerning non-clinical assays and integrated risk assessments. 1.2 Background The QT interval (time from the beginning of the QRS complex to the end of the T wave) of the electrocardiogram (ECG) is a measure of the duration of ventricular depolarization and repolarization. QT interval prolongation can be congenital or acquired (e.g., pharmaceutical-induced). When ventricular repolarization is delayed and the QT interval is prolonged, there is an increased risk of ventricular tachyarrhythmia, including torsade de pointes, particularly when combined with other risk factors (e.g., hypokalemia, structural heart disease, bradycardia). Thus, much emphasis has been placed on the potential proarrhythmic effects of pharmaceuticals that are associated with QT interval prolongation. Ventricular repolarization, determined by the duration of the cardiac action potential, is a complex physiological process. It is the net result of the activities of many membrane ion channels and transporters. Under physiological conditions, the functions of these ion channels and transporters are highly interdependent. The activity of each ion channel or transporter is affected by multiple factors including, but not limited to, intracellular and extracellular ion concentrations, membrane potential, cell-to-cell electrical coupling, heart rate, and autonomic nervous system activity. The metabolic state (e.g., acid-base balance) and location and type of cardiac cell are also important. The human ventricular action potential consists of five sequential phases: • phase 0: The upstroke of the action potential is primarily a consequence of a rapid, transient influx of Na + (I Na) through Na + channels. • phase 1: The termination of the upstroke of the action potential and early repolarization phase result from the inactivation of Na + channels and the transient efflux of K + (I to) through K + channels. • phase 2: The plateau of the action potential is a reflection of a balance between the influx of Ca 2+ (I Ca) through L-type Ca 2+ channels and outward repolarizing K + currents. • phase 3: The sustained downward stroke of the action potential and the late repolarization phase result from the …