α-Lipoic acid protects against arsenic trioxide-induced acute QT prolongation in anesthetized guinea pigs.
α-Lipoic acid protects against arsenic trioxide-induced acute QT prolongation in anesthetized guinea pigs.
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α-硫辛酸可防止麻醉豚鼠因三氧化二砷引起的急性 QT 间期延长。
DOI：
10.1016/j.ejphar.2013.02.027
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发表时间：
2013
期刊：
影响因子：
5
通讯作者：
Kumazaki M
中科院分区：
文献类型：
--
作者：
Tomoyo Oguri;Ayako Mitsuma;Megumi Inada-Inoue;Sachi Morita;Takashi Shibata;Tomoya Shimokata;Mihoko Sugishita;Goro Nakayama;Keisuke Uehara;Yoshinori Hasegawa;Yuichi Ando;Kumazaki M
三氧化二砷（As_2O_3）可诱导复发或难治性急性早幼粒细胞白血病缓解，但由于其心脏毒性而限制了其临床应用。心脏毒性的症状包括急性心脏传导障碍，如QT间期延长。本实验观察了α-硫辛酸（LA）对As_2O_3诱发的豚鼠急性心电图异常（QTc间期延长）的影响。静脉注射As_2O_3可引起豚鼠QTc间期延长，与LA（0.35、3.5和35 mg/kg）合用可明显减轻As_2O_3引起的QTc间期延长，并呈剂量依赖性。在离体豚鼠心肌细胞中，加入LA（10μM）可使As_2O_3（1μM）引起的IK电流下降迅速恢复到基础水平。与这一发现相一致的是，在豚鼠中用LA后处理也迅速改善了As 2 O3诱导的QTc间期延长。电喷雾电离飞行时间质谱分析检测到一个预期的峰的砷-LA复合物在体外，表明LA和As 2 O3形成一个新的化合物在体内。此外，预先给予螯合剂英国抗路易氏剂（BAL，3.5或35 mg/kg）也可减轻As_2O_3引起的QTc间期延长。在这项研究中，共同和后处理与LA和预处理与BAL改善As 2 O3诱导的急性QT间期延长麻醉豚鼠。由于LA和BAL可能与As 2 O3结合，因此这些药物可能通过其螯合活性发挥保护作用。需要进一步的研究，以确定是否LA是有益的预防或救援剂的急性早幼粒细胞白血病患者与As 2 O3治疗。
Clinical use of arsenic trioxide (As2O3), which can induce the remission of relapsed or refractory acute promyelocytic leukemia, is often limited because of its cardiotoxicity. Symptoms of cardiotoxicity include acute cardiac conduction disturbances, such as QT prolongation. The present study was undertaken to evaluate the effects of α-lipoic acid (LA) on acute As2O3-induced ECG abnormalities (QTc interval prolongation) in anesthetized guinea pigs. Intravenous injection of As2O3in guinea pigs caused QTc interval prolongation, which was significantly attenuated by co-treatment with LA (0.35, 3.5 and 35mg/kg) in a dose-dependent manner. In isolated guinea pig cardiomyocytes, the decrease in IKscurrent induced by As2O3(1μM) was rapidly restored to the basal level by the addition of LA (10μM). Consistent with this finding, the As2O3-induced QTc interval prolongation was also improved rapidly by post-treatment with LA in guinea pigs. Electrospray ionization time-of-flight mass spectrometry analysis detected an expected peak of arsenic-LA complex in vitro, indicating that LA and As2O3form a new compound in vivo. In addition, pre-treatment with a chelating agent, British anti-Lewisite (BAL, 3.5 or 35mg/kg), also attenuated the As2O3-induced QTc interval prolongation. In this study, co- and post-treatments with LA and pre-treatment with BAL ameliorated As2O3-induced acute QT prolongation in anesthetized guinea pigs. Because LA and probably BAL may bind to As2O3, these agents may exert protective effects through their chelating activity. Further studies are needed to determine whether LA is beneficial as a prophylactic or rescue agent for acute promyelocytic leukemia patients treated with As2O3.