In vivo analysis of torsadogenic potential of an antipsychotic drug paliperidone using the acute atrioventricular block rabbit as a proarrhythmia model.
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.
Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Toho University, Funabashi, Chiba 274-8510, Japan.
Mihoko
M
Hagiwara
Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Toho University, Funabashi, Chiba 274-8510, Japan.
Ryuichi
R
Kambayashi
Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Toho University, Funabashi, Chiba 274-8510, Japan.
Megumi
M
Aimoto
Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Toho University, Funabashi, Chiba 274-8510, Japan.
Yoshinobu
Y
Nagasawa
Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Toho University, Funabashi, Chiba 274-8510, Japan. Electronic address: akirat@phar.toho-u.ac.jp.
Akira
A
Takahara
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects*; D054537:Atrioventricular Block; D004305:Dose-Response Relationship, Drug; D008297:Male; D000068882:Paliperidone Palmitate / Q000009:adverse effects*; D011817:Rabbits; D018967:Risperidone / Q000009:adverse effects; D016171:Torsades de Pointes / Q000139:chemically induced*
D014150:Antipsychotic Agents; D018967:Risperidone; D000068882:Paliperidone Palmitate
Atrioventricular block; Paliperidone; QT prolongation; Torsades de pointes