期刊
JOURNAL OF PHARMACOLOGICAL AND TOXICOLOGICAL METHODS
卷 72, 期 -, 页码 72-84出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.vascn.2014.10.006
关键词
Arrhythmia; Cardiac conduction; Cardiovascular safety; Dofetilide; Dog; Flecainide; Ischemia; Methods; Pacing
资金
- Janssen Research and Development, Division of Janssen Pharmaceutica NV
- Janssen Research and Development, LLC
Introduction: Preclinical proarrhythmic risk assessment of drug candidates is focused predominantly on arrhythmias arising from repolarization abnormalities. However, drug-induced cardiac conduction slowing is associated with significant risk of life-threatening ventricular arrhythmias, particularly in a setting of cardiac ischemia. Therefore, we optimized and characterized an anesthetized dog model to evaluate the potential proarrhythmic risk of drug candidates in ischemic heart disease patients. Methods: Anesthetized dogs were instrumented with atrial and ventricular epicardial electrodes for pacing and measurement of conduction times, and a balloon occluder and flow probe placed around the left anterior descending coronary artery (LAD) distal to the first branch. Conduction times, ECG intervals and incidence of arrhythmias were assessed serially at the end of each dose infusion (flecainide: 0.32, 0.63, 1.25, 2.5 and 5 mg/kg, i.v.; dofetilide: 1.25, 2.5, 5, 10 and 20 mu g/kg, i.v.; or vehicle; n = 6/group) both during normal flow (with and without rapid pacing) and during 5-min LAD occlusion (with and without rapid pacing). Compound X, a development candidate with mild conduction slowing activity, was also evaluated. Results: Flecainide produced pronounced, dose-dependent slowing of conduction that was exacerbated during ischemia and rapid pacing. In addition, ventricular tachycardia (VT) and fibrillation (VF) occurred in 4 of 6 dogs (3 VF @ 0.63 mg/kg; 1VT @ 2.5 mg/kg). In contrast, no animals in the vehicle group developed arrhythmias. Dofetilide, a potent I-Kr blocker that does not slow conduction, prolonged QT interval but did not cause further conduction slowing during ischemia with or without pacing and there were no arrhythmias. Compound X, like flecainide, produced marked conduction slowing and arrhythmias (VT, VF) during ischemia and pacing. Discussion: This model may be useful to more accurately define shifts in safety margins in a setting of ischemia and increased cardiac demand for drugs that slow conduction. (C) 2014 Elsevier Inc. All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据