In Vitro Cardiovascular Effects of Dihydroartemisin-Piperaquine Combination Compared with Other Antimalarials
In Vitro Cardiovascular Effects of Dihydroartemisin-Piperaquine Combination Compared with Other Antimalarials
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DOI：
10.1128/aac.05688-11
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发表时间：
2012-06-01
影响因子：
4.9
通讯作者：
Funck-Brentano, Christian
中科院分区：
文献类型：
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作者：
Borsini, Franco;Crumb, William;Funck-Brentano, Christian
比较了双氢青蒿素(DHA)和磷酸哌喹(PQP)与其他抗疟药的体外心脏特性。结果抗疟疾药物，根据其在血浆中的自由治疗最大浓度(C-max)选择，表示为该特定效果相对于其C-max的倍数。以下测试在37摄氏度下使用：HERG(人类乙醚-a-GO-GO相关基因)阻断和运输，兔心脏心室准备，以及钠和慢钾离子电流干扰(分别为I-Na和I-Ks)。在HERG研究中测试了氯喹、氟喹啉、甲氟喹和鲁米芬三种药物，但只有氯喹、多非利特、鲁米芬三种药物和蒿甲醚联合应用于兔的心室准备、HERG转运研究以及I-Na和I-Ks分析。在每次测试中都使用了适当的参照物。在HERG研究中，证实了氟喹啉较高的50%抑制浓度(IC50)，低于其C-max。在HERG转运研究中，氯喹的促进作用被证实为其C(Max)的约30倍，而DHA的阻断浓度约为其C(Max)的300倍。在兔心室制剂中，作为阳性对照的多非利特显示出发生尖端扭曲症的高风险，而氯喹显示出中等风险。DHA-PQP和蒿甲醚-鲁米芬在体外均未显示明显的心律失常风险。只有氯喹能阻断I-Na离子电流，其作用速度约为C-max的30倍。对I(Ks)无明显影响。总之，尽管存在显著的HERG阻断作用，DHA-PQP和蒿甲醚-鲁米芬似乎不能在体外诱导潜在的催泪作用，也不影响HERG的转运，也不能阻断钠离子和慢钾离子电流。
The in vitro cardiac properties of dihydroartemisinin (DHA) plus piperaquine phosphate (PQP) were compared with those of other antimalarial compounds. Results with antimalarial drugs, chosen on the basis of their free therapeutic maximum concentration in plasma (C-max), were expressed as the fold of that particular effect with respect to their C-max. The following tests were used at 37 degrees C: hERG (human ether-a-go-go-related gene) blockade and trafficking, rabbit heart ventricular preparations, and sodium and slow potassium ion current interference (I-Na and I-Ks, respectively). Chloroquine, halofantrine, mefloquine, and lumefantrine were tested in the hERG studies, but only chloroquine, dofetilide, lumefantrine, and the combination of artemetherlumefantrine were used in the rabbit heart ventricular preparations, hERG trafficking studies, and I-Na and I-Ks analyses. A proper reference was used in each test. In hERG studies, the high 50% inhibitory concentration (IC50) of halofantrine, which was lower than its C-max, was confirmed. All the other compounds blocked hERG, with IC(50)s ranging from 3- to 30-fold their C(max)s. In hERG trafficking studies, the facilitative effects of chloroquine at about 30-fold its C-max were confirmed and DHA blocked it at a concentration about 300-fold its C-max. In rabbit heart ventricular preparations, dofetilide, used as a positive control, revealed a high risk of torsades de pointes, whereas chloroquine showed a medium risk. Neither DHA-PQP nor artemether-lumefantrine displayed an in vitro signal for a significant proarrhythmic risk. Only chloroquine blocked the I-Na ion current and did so at about 30-fold its C-max. No effect on I(Ks)was detected. In conclusion, despite significant hERG blockade, DHA-PQP and artemether-lumefantrine do not appear to induce potential torsadogenic effects in vitro, affect hERG trafficking, or block sodium and slow potassium ion currents.