Division of Drug Informatics, Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, 7-2-1 Kamiono, Himeji, Hyogo, 670-8524 Japan.
Malar J. 2010 Nov 10;9:318. doi: 10.1186/1475-2875-9-318.
Concern over the potential cardiotoxicity of anti-malarial drugs inducing a prolonged electrocardiographic QT interval has resulted in the almost complete withdrawal from the market of one anti-malarial drug - halofantrine. The effects on the QT interval of four anti-malarial drugs were examined, using the guinea pig heart.
The guinea pig heart was isolated, mounted on a Langendorff apparatus, and was then perfused with pyruvate-added Klebs-Henseleit solutions containing graded concentrations of the four agents such as quinidine (0.15 - 1.2 μM), quinine (0.3 - 2.4 μM), halofantrine (0.1 - 2.0 μM) and mefloquine (0.1 - 2.0 μM). The heart rate-corrected QaTc intervals were measured to evaluate drug-induced QT prolongation effects.
Quinidine, quinine, and halofantrine prolonged the QaTc interval in a dose-dependent manner, whereas no such effect was found with mefloquine. The EC50 values for the QaTc prolongation effects, the concentration that gives a half-maximum effect, were quinidine < quinine ≈ halofantrine.
In this study, an isolated, perfused guinea pig heart system was constructed to assess the cardiotoxic potential of anti-malarial drugs. This isolated perfused guinea pig heart system could be used to test newly developed anti-malarial drugs for their inherent QT lengthening potential. More information is required on the potential variation in unbound drug concentrations in humans, and their role in cardiotoxicity.
抗疟药物导致心电图 QT 间期延长的潜在心脏毒性问题引起了关注，这导致一种抗疟药物——卤泛群几乎完全退出市场。本研究使用豚鼠心脏模型，检测了四种抗疟药物对 QT 间期的影响。
将豚鼠心脏分离出来，安装在 Langendorff 仪器上，然后用含有不同浓度四种药物（如奎尼丁[0.15-1.2 μM]、奎宁[0.3-2.4 μM]、卤泛群[0.1-2.0 μM]和甲氟喹[0.1-2.0 μM]）的改良 Krebs-Henseleit 溶液进行灌流。测量心率校正的 QaTc 间期，以评估药物引起的 QT 延长效应。
奎尼丁、奎宁和卤泛群均呈浓度依赖性地延长 QaTc 间期，而甲氟喹则无此作用。引起 QaTc 间期延长 50%的药物浓度（EC50 值），奎尼丁<奎宁≈卤泛群。
本研究构建了一个分离的、灌流的豚鼠心脏系统，用于评估抗疟药物的心脏毒性潜力。该分离的灌流豚鼠心脏系统可用于测试新开发的抗疟药物是否具有固有 QT 延长的潜力。需要更多关于人类游离药物浓度的潜在变化及其在心脏毒性中的作用的信息。
