Liu Tengxian, Brown Barry S, Wu Ying, Antzelevitch Charles, Kowey Peter R, Yan Gan-Xin
Main Line Health Heart Center, Wynnewood, PA 19096, USA.
Heart Rhythm. 2006 Aug;3(8):948-56. doi: 10.1016/j.hrthm.2006.04.021. Epub 2006 Apr 22.
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.
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 T(p-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).
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.
开发对识别临床上有诱发尖端扭转型室性心动过速（TdP）倾向的药物具有高预测价值的临床前模型，长期以来一直是学术界、产业界和监管机构的紧迫目标。本研究在离体动脉灌注兔心室楔形标本中，对有无产生TdP可能性的药物进行了盲法评估。
使用兔左心室楔形标本测试了13种化合物诱发TdP的可能性。所有研究人员均对药物的名称、浓度和分子量不知情。化合物由研究主办方制备，并作为4组每组13种储备溶液发送给研究人员，每组内的顺序由随机数生成器指定。根据每种化合物对心室复极的影响（以QT间期衡量）、复极离散度（以T(p-e)/QT比值衡量）和早期后除极，对其诱发TdP的相对可能性进行半定量评分。研究完成后公布名称和浓度显示，所有已知无TdP风险的化合物得分均小于或等于0.25，而那些已知有TdP风险的化合物在浓度低于其游离治疗血浆C(max)的100倍时，得分范围为1.00至7.25。
我们的研究对离体动脉灌注兔楔形标本进行了盲法评估，结果表明在评估13种具有不同TdP诱发倾向的药物时，该模型具有高敏感性和特异性。
