Khobragade Shailaja B, Gupta Pankaj, Gurav Prashant, Chaudhari Girish, Gatne Madhumanjiri M, Shingatgeri Vyas M
Department of Drug Safety Evaluation, Ranbaxy Research Laboratories, Gurgaon, Haryana, India.
J Pharmacol Pharmacother. 2013 Apr;4(2):116-24. doi: 10.4103/0976-500X.110892.
To evaluate the prolongation of ventricular repolarization and proarrhythmic activity of antimalarial drug chloroquine in two rabbit proarrhythmia models viz., in vivo α1 adrenoceptor-stimulated anesthetized rabbit and ex vivo isolated Langendorff rabbit heart using clofilium as standard proarrhythmic agent.
In the in vivo model, three groups of rabbits, anesthetized by pentobarbitone sodium and α-chloralose, sensitized with α1 agonist methoxamine followed by either continuous infusion of saline (control) or clofilium (3 mg/kg) or chloroquine (21 mg/kg) for 30 min. In ex vivo model, rabbit hearts were perfused with clofilium (10 μM) or chloroquine (300 μM) continuously after priming along with methoxamine, acetylcholine chloride and propranolol hydrochloride.
In these models, prolongation of repolarization during α1-adrenoceptor stimulation produced early after depolarization (EAD) and Torsade de pointes (TdP). Saline infusion did not induce any abnormality in the animals. Clofilium caused expected changes in the electrocardiogram in both the models including TdP (50.0% in in vivo and 66.67% in ex vivo). Chloroquine caused decrease in heart rate and increase in the corrected QT (QTc) interval in both the models. Further, apart from different stages of arrhythmia, TdP was evident in 33.33% in ex vivo model, whereas no TdP was observed in in vivo model.
The results indicated that proarrhythmic potential of chloroquine and clofilium was well evaluated in both the models; moreover, both the models can be used to assess the proarrhythmic potential of the new drug candidates.
在两种兔心律失常模型中，即体内α1肾上腺素能受体刺激的麻醉兔和体外分离的Langendorff兔心脏，以氯非铵作为标准致心律失常药物，评估抗疟药氯喹对心室复极的延长作用和致心律失常活性。
在体内模型中，三组兔子用戊巴比妥钠和α-氯醛糖麻醉，用α1激动剂甲氧明致敏，随后连续输注生理盐水（对照）或氯非铵（3mg/kg）或氯喹（21mg/kg）30分钟。在体外模型中，兔心脏在灌注起始时与甲氧明、氯化乙酰胆碱和盐酸普萘洛尔一起连续灌注氯非铵（10μM）或氯喹（300μM）。
在这些模型中，α1肾上腺素能受体刺激期间复极延长产生了早期后除极（EAD）和尖端扭转型室速（TdP）。输注生理盐水未在动物中诱发任何异常。氯非铵在两种模型中均引起了预期的心电图变化，包括TdP（体内为50.0%，体外为66.67%）。氯喹在两种模型中均导致心率降低和校正QT（QTc）间期延长。此外，除了心律失常的不同阶段外，TdP在体外模型中为33.33%，而在体内模型中未观察到TdP。
结果表明，在两种模型中均很好地评估了氯喹和氯非铵的致心律失常潜力；此外，两种模型均可用于评估新候选药物的致心律失常潜力。
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