临床前体外心脏电生理学:一种预测抗组胺药在人体内致心律失常潜力的方法?
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Cavero I, Mestre M, Guillon JM, Heuillet E, Roach AG
临床前体外心脏电生理学:一种预测抗组胺药在人体内致心律失常潜力的方法?
1999;21增刊1:19-31;讨论81 - 7。
- PubMed ID
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10597865 (PubMed视图］
- 摘要
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心脏动作电位是由向内去极化的Na+和Ca2+电流和向外再极化的K+电流之间的动态平衡产生的。在一个心脏周期中，所有心室细胞的复极化相的结果由体表心电图的QT间期表示。先天性长QT综合征(LQTS)以多形性室性心动过速为特征，有时QRS形态扭曲(尖扭转)，虽然通常自限性，但可导致心源性猝死。获得性LQTS可由多种药物诱导，包括一些非镇静组胺H1受体拮抗剂(阿司咪唑，特非那定)。欧盟专利药品委员会最近建议研究体外心脏制剂的作用潜力，作为预测非心血管药物诱发人类恶性QT延长倾向的临床前试验。在兔浦肯野纤维中评价了几种组胺H1受体拮抗剂对电诱发动作电位的影响。在该制剂中，阿斯咪唑(0.3至10微mol/L)延长了在复极完成90% (APD90)时测量的动作电位的持续时间。这种效应与药物浓度、培养时间、起搏频率和K+或Mg2+浓度有关。阿司咪唑还能显著降低动作电位(Vmax)的上升速率。特非那定在该模型中表现出质的相似，但在数量上较小的影响。 The histamine H1 receptor antagonists cetirizine, ebastine, carebastine, loratadine and fexofenadine do not significantly affect APD90 at 1 micromol/L, but cetirizine and carebastine prolong it slightly at 10 micromol/L. In conclusion, in rabbit Purkinje fibres, astemizole and terfenadine produce adverse electrophysiological effects at concentrations which may be achieved in the human myocardium in certain clinical situations. APD90 lengthening induced by carebastine and cetirizine is minor and occurs at concentrations that are very unlikely to be encountered clinically, since these drugs, in contrast to astemizole and terfenadine, do not accumulate in the myocardium. Direct extrapolation of preclinical results to humans requires great caution, since malignant QT prolongations by terfenadine and astemizole are extremely rare clinical events. However, since prolongation of the QT interval often precedes the development of torsade de pointes, any significant delay in cardiac repolarisation produced by noncardiovascular drugs in preclinical, and particularly in clinical, studies should, in general, be considered to indicate a potential cardiac risk in humans. Its significance should subsequently be evaluated in appropriate studies in patients with conditions known to predispose to arrhythmias.