Akman Tulay, Erbas Oytun, Akman Levent, Yilmaz Ahmet U
Department of Medical Oncology, Tepecik Education and Research Hospital.
Department of Physiology, Medical School, Ege University.
Arq Bras Cardiol. 2014 Nov;103(5):403-409. doi: 10.5935/abc.20140138. Epub 2014 Sep 12.
Background: Pazopanib (PZP) may induce prolonged cardiac repolarization and proarrhythmic effects, similarly to other tyrosine kinase inhibitors. Objectives: To demonstrate PZP-induced prolonged cardiac repolarization and proarrhythmic electrophysiological effects and to investigate possible preventive effects of metoprolol and diltiazem on ECG changes (prolonged QT) in an experimental rat model. Methods: Twenty-four Sprague-Dawley adult male rats were randomly assigned to 4 groups (n = 6). The first group (normal group) received 4 mL of tap water and the other groups received 100 mg/kg of PZP (Votrient® tablet) perorally, via orogastric tubes. After 3 hours, the following solutions were intraperitoneally administered to the animals: physiological saline solution (SP), to the normal group and to the second group (control-PZP+SP group); 1 mg/kg metoprolol (Beloc, Ampule, AstraZeneca), to the third group (PZP+metoprolol group); and 1mg/kg diltiazem (Diltiazem, Mustafa Nevzat), to the fourth group (PZP+diltiazem group). One hour after, and under anesthesia, QTc was calculated by recording ECG on lead I. Results: The mean QTc interval values were as follows: normal group, 99.93 ± 3.62 ms; control-PZP+SP group, 131.23 ± 12.21 ms; PZP+metoprolol group, 89.36 ± 3.61 ms; and PZP+diltiazem group, 88.86 ± 4.04 ms. Both PZP+metoprolol and PZP+diltiazem groups had significantly shorter QTc intervals compared to the control-PZP+SP group (p < 0.001). Conclusion: Both metoprolol and diltiazem prevented PZP-induced QT interval prolongation. These drugs may provide a promising prophylactic strategy for the prolonged QTc interval associated with tyrosine kinase inhibitor use.
与其他酪氨酸激酶抑制剂类似，帕唑帕尼（PZP）可能会导致心脏复极延长和促心律失常作用。目的：在实验大鼠模型中证实PZP诱导的心脏复极延长和促心律失常电生理效应，并研究美托洛尔和地尔硫䓬对心电图变化（QT延长）的可能预防作用。方法：将24只成年雄性Sprague-Dawley大鼠随机分为4组（n = 6）。第一组（正常组）给予4 mL自来水，其他组经口胃管口服100 mg/kg的PZP（Votrient®片剂）。3小时后，向动物腹腔注射以下溶液：生理盐水（SP），给予正常组和第二组（对照-PZP+SP组）；1 mg/kg美托洛尔（倍他乐克，安瓿剂，阿斯利康），给予第三组（PZP+美托洛尔组）；1 mg/kg地尔硫䓬（地尔硫䓬，穆斯塔法·内夫扎特），给予第四组（PZP+地尔硫䓬组）。1小时后，在麻醉状态下，通过记录I导联心电图计算QTc。结果：平均QTc间期值如下：正常组，99.93±3.62 ms；对照-PZP+SP组，131.23±12.21 ms；PZP+美托洛尔组，89.36±3.61 ms；PZP+地尔硫䓬组，88.86±4.04 ms。与对照-PZP+SP组相比，PZP+美托洛尔组和PZP+地尔硫䓬组的QTc间期均显著缩短（p < 0.001）。结论：美托洛尔和地尔硫䓬均可预防PZP诱导的QT间期延长。这些药物可能为与酪氨酸激酶抑制剂使用相关的QTc间期延长提供一种有前景的预防策略。
