Sugiyama A
Department of Pharmacology, Yamanashi Research Center of Clinical Pharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.
Br J Pharmacol. 2008 Aug;154(7):1528-37. doi: 10.1038/bjp.2008.240. Epub 2008 Jun 16.
As an increasing number of non-cardiac drugs have been reported to cause QT interval prolongation and torsades de pointes (TdP), we extensively studied the utility of atrioventricular (AV) block animals as a model to predict their torsadogenic action in human. The present review highlights such in vivo proarrhythmia models. In the case of the canine model, test substances were administered p.o. at conscious state >4 weeks after the induction of AV block, with subsequent Holter ECG monitoring to evaluate drug effects. Control AV block dogs (no pharmacological treatment) survive for several years without TdP attack. For pharmacologically treated dogs, drugs were identified as high, low or no risk. High-risk drugs induced TdP at 1-3 times the therapeutic dose. Low-risk drugs did not induce TdP at this dose range, but induced it at higher doses. No-risk drugs never induced TdP at any dose tested. Electrophysiological, anatomical histological and biochemical adaptations against persistent bradycardia-induced chronic heart failure were observed in AV block dogs. Recently, we have developed another highly sensitive proarrhythmia model using a chronic AV block cynomolgus monkey, which possesses essentially the same pathophysiological adaptations and drug responses as those demonstrated in the canine model. As a common remodelling process leading to a diminished repolarization reserve may present in patients who experience drug-induced TdP and in the AV block animals, the in vivo proarrhythmia models described in this review may be useful for predicting the risk of pharmacologically induced TdP in humans.
由于越来越多的非心脏药物被报道可导致QT间期延长和尖端扭转型室性心动过速（TdP），我们广泛研究了房室（AV）传导阻滞动物作为预测其在人类中致TdP作用模型的实用性。本综述重点介绍了此类体内致心律失常模型。在犬类模型中，在诱导AV传导阻滞4周后，于清醒状态下口服给予受试物质，随后进行动态心电图监测以评估药物作用。对照AV传导阻滞犬（未进行药物治疗）可存活数年且无TdP发作。对于接受药物治疗的犬，药物被确定为高风险、低风险或无风险。高风险药物在治疗剂量的1 - 3倍时诱导TdP。低风险药物在此剂量范围内不诱导TdP，但在更高剂量时诱导。无风险药物在任何测试剂量下均未诱导TdP。在AV传导阻滞犬中观察到了针对持续性心动过缓诱导的慢性心力衰竭的电生理、解剖组织学和生化适应性变化。最近，我们利用慢性AV传导阻滞食蟹猴开发了另一种高度敏感的致心律失常模型，其具有与犬类模型中所展示的基本相同的病理生理适应性和药物反应。由于经历药物诱导TdP的患者和AV传导阻滞动物中可能存在导致复极储备减少的共同重塑过程，本综述中描述的体内致心律失常模型可能有助于预测人类药物诱导TdP的风险。
