Blinded validation of the isolated arterially perfused rabbit ventricular wedge in preclinical assessment of drug-induced proarrhythmias
Blinded validation of the isolated arterially perfused rabbit ventricular wedge in preclinical assessment of drug-induced proarrhythmias
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DOI：
10.1016/j.hrthm.2006.04.021
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发表时间：
2006-08-01
期刊：
影响因子：
5.5
通讯作者：
Yan, Gan-Xin
中科院分区：
文献类型：
--
作者：
Liu, Tengxian;Brown, Barry S.;Yan, Gan-Xin
开发具有高预测价值的临床前模型，用于鉴定在临床中具有诱导尖端扭转型室性心动过速（TdP）倾向的药物，长期以来一直是学术界、工业界和监管机构的迫切目标。本研究提供了一个盲法评价的药物，在一个孤立的动脉灌注兔心室楔制备，有和没有潜在的生产TdP.METHODS和结果13化合物进行了测试，其潜在的TdP使用兔左心室楔。所有研究者对药物的名称、浓度和分子量均不知情。化合物由研究申办方制备，并作为4组13份贮备液发送给研究者，每组中的顺序由随机数发生器指定。基于对心室复极（测量为QT间期）、复极离散度（测量为Tp-e/QT比值）和早期后除极的影响，对每种化合物的TdP相对潜力进行半定量评分。在研究完成后披露名称和浓度显示，所有已知无TdP风险的化合物的评分均小于或等于0.25，而那些已知TdP风险的患者在浓度低于其游离治疗血浆C-max的100倍时得到的评分范围为1.00至7.25。灌注兔楔形制备证明了在评估13种具有不同倾向的药物引起TdP时的高灵敏度和特异性。
BACKGROUND The development of preclinical models with high predictive value for the identification of drugs with a proclivity to induce Torsade de Pointes (TdP) in the clinic has Long been a pressing goal of academia, industry and regulatory agencies alike. The present study provides a blinded appraisal of drugs, in an isolated arterially-perfused rabbit ventricular wedge preparation, with and without the potential to produce TdP.METHODS AND RESULTS Thirteen compounds were tested for their potential for TdP using the rabbit left ventricular wedges. All investigators were blinded to the names, concentrations and molecular weights of the drugs. The compounds were prepared by the study sponsor and sent to the investigator as 4 sets of 13 stock solutions with the order within each set being assigned by a random number generator. Each compound was scored semi-quantitatively for its relative potential for TdP based on its effect on ventricular repolarization measured as QT interval, dispersion of repolarization measured as Tp-e/QT ratio and early afterdepolarizations. Disclosure of the names and concentrations after completion of the study revealed that all compounds known to be free of TdP risk received a score of Less or equal to 0.25, whereas those with known TdP risk received a score ranging from 1.00 to 7.25 at concentrations less than 100X their free therapeutic plasma C-max.CONCLUSIONS Our study provides a blinded evaluation of the isolated arterially-perfused rabbit wedge preparation demonstrating both a high sensitivity and specificity in the assessment of 13 agents with varying propensity for causing TdP.