临床体外心脏电生理学:抗组胺药的方法预测arrhythmogenic潜在的人类?
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Cavero我城区M Guillon JM, Heuillet E,罗奇AG)
临床体外心脏电生理学:抗组胺药的方法预测arrhythmogenic潜在的人类?
药物Saf。1999; 21增刊1:19-31;讨论81 - 7。
- PubMed ID
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10597865 (在PubMed]
- 文摘
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心脏动作电位的结果之间的动态平衡内心动摇Na +和Ca2 +外水流和K + repolarising电流。在心动周期中,从所有心室细胞repolarisation阶段的合成是由表面心电图QT间隔的。先天性长QT综合征(LQTS)的特点是多态室性心动过速有时扭QRS形态(带条de同构),尽管通常是自限性的,可以导致心脏性猝死。获得LQTS可以诱导多种药物,包括一些nonsedative组胺H1受体拮抗剂(阿司咪唑、terfenadine)。欧盟的专利药品委员会最近提出研究体外心脏动作电位可作为临床前测试预测noncardiovascular药物诱导的倾向在人类恶性QT延长。几组胺H1受体拮抗剂的影响电诱发动作电位一直在评估兔浦肯野纤维。在这个准备,阿司咪唑(0.3 - 10 micromol / L)延长动作电位持续时间以repolarisation的水平90%完成(APD90)。这种效果是依赖药物浓度、培养时间、节奏频率和K +浓度或Mg2 +。阿司咪唑的增长速度也明显降低了动作电位(Vmax)。Terfenadine显示定性相似,但定量小,在这个模型的影响。 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.