Adult Human Primary Cardiomyocyte-Based Model for the Simultaneous Prediction of Drug-Induced Inotropic and Pro-arrhythmia Risk.
Adult Human Primary Cardiomyocyte-Based Model for the Simultaneous Prediction of Drug-Induced Inotropic and Pro-arrhythmia Risk.
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DOI：
10.3389/fphys.2017.01073
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发表时间：
2017
影响因子：
4
通讯作者：
Abi-Gerges N
中科院分区：
文献类型：
--
作者：
Nguyen N;Nguyen W;Nguyenton B;Ratchada P;Page G;Miller PE;Ghetti A;Abi-Gerges N
心脏安全仍然是药物开发停止的主要原因。我们开发了一种基于人类心肌细胞的模型，该模型有可能提供一种预测性临床前方法，用于同时预测药物引起的正性肌力和促心律失常风险。方法：使用来自伦理同意的器官捐献者的成人原代心肌细胞来测量收缩性瞬态。我们使用收缩性参数变化的测量作为标记来推断药物引起的正性肌力作用（肌节缩短）和促心律失常（后收缩，AC）；收缩逃逸（CE）；达到 90% 松弛的时间 (TR90)。我们通过评估 23 种致扭转性药物和 10 种非扭转性药物的效果来探讨该方法的临床相关性。每种药物均以游离有效治疗血浆浓度 (fETPC) 的四倍数单独进行测试。结果：基于人类心肌细胞的模型区分了致扭转和非致扭转药物。例如，多非利特（一种扭转性药物）会引起 AC，并在 fETPC 的 10 倍时增加 TR90，而在 fETPC 的最高倍数（100 倍）时观察到 CE 事件。维拉帕米是一种非扭转性药物，不会改变 TR90，并且在本研究中测试的 fETPC 最高倍数（222 倍）内不会诱导 AC 或 CE。当药物促心律失常活性以 fETPC 的 10 倍进行评估时，AC 参数具有出色的检测灵敏度和特异性，分别为 96% 和 100%。这种高预测性支持了该制剂和所选标记物的转化安全潜力。数据表明，人类心肌细胞还可以识别与正性肌力作用相关的药物。 hERG 通道阻滞剂（如多非利特）对肌节缩短没有影响，而多离子通道阻滞剂（如维拉帕米）则抑制肌节缩短。结论：分离的成人原代心肌细胞可以同时预测与正性肌力活性和促心律失常相关的风险，并且可以生成可靠的预测数据，用于在药物发现的早期阶段评估人类心脏毒性。
Cardiac safety remains the leading cause of drug development discontinuation. We developed a human cardiomyocyte-based model that has the potential to provide a predictive preclinical approach for simultaneously predicting drug-induced inotropic and pro-arrhythmia risk. Methods: Adult human primary cardiomyocytes from ethically consented organ donors were used to measure contractility transients. We used measures of changes in contractility parameters as markers to infer both drug-induced inotropic effect (sarcomere shortening) and pro-arrhythmia (aftercontraction, AC); contractility escape (CE); time to 90% relaxation (TR90). We addressed the clinical relevance of this approach by evaluating the effects of 23 torsadogenic and 10 non-torsadogenic drugs. Each drug was tested separately at four multiples of the free effective therapeutic plasma concentration (fETPC). Results: Human cardiomyocyte-based model differentiated between torsadogenic and non-torsadogenic drugs. For example, dofetilide, a torsadogenic drug, caused ACs and increased TR90 starting at 10-fold the fETPC, while CE events were observed at the highest multiple of fETPC (100-fold). Verapamil, a non-torsadogenic drug, did not change TR90 and induced no AC or CE up to the highest multiple of fETPCs tested in this study (222-fold). When drug pro-arrhythmic activity was evaluated at 10-fold of the fETPC, AC parameter had excellent assay sensitivity and specificity values of 96 and 100%, respectively. This high predictivity supports the translational safety potential of this preparation and of the selected marker. The data demonstrate that human cardiomyocytes could also identify drugs associated with inotropic effects. hERG channel blockers, like dofetilide, had no effects on sarcomere shortening, while multi-ion channel blockers, like verapamil, inhibited sarcomere shortening. Conclusions: Isolated adult human primary cardiomyocytes can simultaneously predict risks associated with inotropic activity and pro-arrhythmia and may enable the generation of reliable and predictive data for assessing human cardiotoxicity at an early stage in drug discovery.
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影响因子：
7.3
作者：
Abi-Gerges, Najah;Valentin, Jean-Pierre;Pollard, Chris E.
通讯作者：
Pollard, Chris E.
影响因子：
10.8
作者：
DELMONTE, F;OGARA, P;HARDING, SE
通讯作者：
HARDING, SE
DOI：
10.1177/107424840400900105
发表时间：
2004-09-01
影响因子：
2.6
作者：
Chaitman, Bernard R.
通讯作者：
Chaitman, Bernard R.
影响因子：
10.8
作者：
Brandenburger, Matthias;Wenzel, Jan;Dendorfer, Andreas
通讯作者：
Dendorfer, Andreas
影响因子：
37.8
作者：
DEFERRARI, GM;NADOR, F;SCHWARTZ, PJ
通讯作者：
SCHWARTZ, PJ