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Torsadogenic potential of a novel remyelinating drug clemastine for multiple sclerosis assessed in the rabbit proarrhythmia model.
Kawakami, Satoshi; Nagasawa, Yoshinobu; Hagiwara-Nagasawa, Mihoko; Omura, Kensuke; Aimoto, Megumi; Takahara, Akira.
Afiliação
  • Kawakami S; Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Toho University, Funabashi, Chiba 274-8510, Japan.
  • Nagasawa Y; Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Toho University, Funabashi, Chiba 274-8510, Japan.
  • Hagiwara-Nagasawa M; Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Toho University, Funabashi, Chiba 274-8510, Japan; Department of Pharmacology, Faculty of Medicine, Toho University, Ota-ku, Tokyo 143-8540, Japan.
  • Omura K; Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Toho University, Funabashi, Chiba 274-8510, Japan.
  • Aimoto M; Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Toho University, Funabashi, Chiba 274-8510, Japan.
  • Takahara A; Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Toho University, Funabashi, Chiba 274-8510, Japan. Electronic address: akirat@phar.toho-u.ac.jp.
J Pharmacol Sci ; 144(3): 123-128, 2020 Nov.
Article em En | MEDLINE | ID: mdl-32921393
We assessed the torsadogenic effects of a novel remyelinating drug clemastine for multiple sclerosis using an in vivo proarrhythmia model of acute atrioventricular block rabbit, since the drug has been demonstrated to suppress the human ether-á-go-go related gene (hERG) K+ channels. Bradycardia was induced by atrioventricular node ablation in isoflurane-anesthetized New Zealand White rabbits (n = 5), and the ventricle was electrically driven at 60 beats/min throughout the experiment, except when extrasystoles appeared. Intravenous administration of clinically relevant dose of 0.03 mg/kg of clemastine and 10-times higher dose of 0.3 mg/kg hardly affected the QT interval or duration of the monophasic action potential (MAP) of the ventricle. Additional administration of clemastine at 3 mg/kg significantly increased the QT interval, MAP duration and the short-term variability of repolarization. Meanwhile, the premature ventricular contractions with R on T phenomenon were observed in 3 out of 5 animals, and torsades de pointes arrhythmias were detected in 1 out of 5 animals. These results suggest that the torsadogenic potential of clemastine is obviously observed in the acute atrioventricular block rabbit, which will not appear within the prescribed dose for multiple sclerosis.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Síndrome do QT Longo / Torsades de Pointes / Clemastina / Esclerose Múltipla Limite: Animals Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Síndrome do QT Longo / Torsades de Pointes / Clemastina / Esclerose Múltipla Limite: Animals Idioma: En Ano de publicação: 2020 Tipo de documento: Article