Department of Pharmacology and Pharmacotherapy, Semmelweis University, 1089 Budapest, Hungary.
Pharmahungary Group, 6722 Szeged, Hungary.
Cells. 2020 Feb 26;9(3):551. doi: 10.3390/cells9030551.
Cardiac adverse effects are among the leading causes of the discontinuation of clinical trials and the withdrawal of drugs from the market. The novel concept of 'hidden cardiotoxicity' is defined as cardiotoxicity of a drug that manifests in the diseased (e.g. ischemic/reperfused), but not in the healthy heart or as a drug-induced deterioration of cardiac stress adaptation (e.g. ischemic conditioning). Here, we aimed to test if the cardiotoxicity of a selective COX-2 inhibitor rofecoxib that was revealed during its clinical use, i.e., increased occurrence of proarrhythmic and thrombotic events, could have been revealed in early phases of drug development by using preclinical models of ischemia/reperfusion (I/R) injury. Rats that were treated with rofecoxib or vehicle for four weeks were subjected to 30 min. coronary artery occlusion and 120 min. reperfusion with or without cardioprotection that is induced by ischemic preconditioning (IPC). Rofecoxib increased overall the arrhythmias including ventricular fibrillation (VF) during I/R. The proarrhythmic effect of rofecoxib during I/R was not observed in the IPC group. Rofecoxib prolonged the action potential duration (APD) in isolated papillary muscles, which was not seen in the simulated IPC group. Interestingly, while showing hidden cardiotoxicity manifested as a proarrhythmic effect during I/R, rofecoxib decreased the infarct size and increased the survival of adult rat cardiac myocytes that were subjected to simulated I/R injury. This is the first demonstration that rofecoxib increased acute mortality due to its proarrhythmic effect via increased APD during I/R. Rofecoxib did not interfere with the cardiprotective effect of IPC; moreover, IPC was able to protect against rofecoxib-induced hidden cardiotoxicity. These results show that cardiac safety testing with simple preclinical models of I/R injury uncovers hidden cardiotoxicity of rofecoxib and might reveal the hidden cardiotoxicity of other drugs.
心脏不良事件是导致临床试验中止和药物从市场撤出的主要原因之一。“隐匿性心脏毒性”的新概念被定义为一种药物的心脏毒性，表现在患病（如缺血/再灌注）心脏中，而不在健康心脏中，或者表现为药物引起的心脏应激适应恶化（如缺血预处理）。在这里，我们旨在测试一种选择性 COX-2 抑制剂罗非昔布的心脏毒性，这种毒性在其临床应用中被揭示，即增加了心律失常和血栓形成事件的发生，是否可以通过使用缺血/再灌注 (I/R) 损伤的临床前模型在药物开发的早期阶段被揭示。用罗非昔布或载体处理四周的大鼠接受 30 分钟冠状动脉闭塞和 120 分钟再灌注，或在缺血预处理 (IPC) 诱导的心脏保护下进行。罗非昔布增加了 I/R 期间的心律失常，包括室颤 (VF)。IPC 组未观察到 I/R 期间罗非昔布的致心律失常作用。罗非昔布延长了分离乳头肌的动作电位持续时间 (APD)，而在模拟 IPC 组中未见。有趣的是，虽然罗非昔布在 I/R 期间表现出隐匿性心脏毒性，表现为致心律失常作用，但罗非昔布减少了模拟 I/R 损伤的成年大鼠心肌细胞的梗死面积并增加了其存活率。这是首次证明罗非昔布通过增加 I/R 期间的 APD 增加致心律失常作用而导致急性死亡率增加。罗非昔布不干扰 IPC 的心脏保护作用；此外，IPC 能够保护免受罗非昔布引起的隐匿性心脏毒性。这些结果表明，使用简单的 I/R 损伤临床前模型进行心脏安全性测试可以揭示罗非昔布的隐匿性心脏毒性，并可能揭示其他药物的隐匿性心脏毒性。
