In vivo analysis of torsadogenic potential of an antipsychotic drug paliperidone using the acute atrioventricular block rabbit as a proarrhythmia model

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• 作者：Mihoko Hagiwara ; Ryuichi Kambayashi ; Megumi Aimoto ; Yoshinobu Nagasawa ; Akira Takahara ; ^{akirat@phar.toho-u.ac.jp" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Paliperidone ; QT prolongation ; Torsades de pointes ; Atrioventricular block
• 刊名：Journal of Pharmacological Sciences
• 出版年：2016
• 出版时间：September 2016
• 年：2016
• 卷：132
• 期：1
• 页码：48-54
• 全文大小：1040 K

文摘

We assessed electrophysiological effects of an atypical antipsychotic drug paliperidone in acute atrioventricular block rabbits. Intravenous administration of paliperidone at a clinically relevant dose (0.06 mg/kg) hardly affected the QT interval or monophasic action potential (MAP) duration, and the higher doses (0.6 and 6 mg/kg) prolonged the QT interval and MAP duration. Meanwhile, premature ventricular contractions with R on T phenomenon were observed in 3 out of 6 animals at the middle dose, and torsades de pointes (TdP) episodes were detected in 2 out of 6 animals at the high dose. Intravenous administration of its chemically related compound risperidone at a clinically relevant dose (0.03 mg/kg) hardly affected the electrophysiological parameters, and the higher doses (0.3 and 3 mg/kg) prolonged the QT interval and MAP duration. Meanwhile, the premature ventricular contractions with R on T were observed in 2 out of 6 animals at the middle dose, and TdP episodes were detected in 4 out of 6 animals at the high dose. These results suggest that paliperidone showed torsadogenic potential at supra-therapeutic doses, whose potency can be estimated to be equal or slightly subordinate in comparison with that of risperidone.