In vivo canine model comparison of cardiohemodynamic and electrophysiological effects of a new antipsychotic drug aripiprazole (OPC-14597) to haloperidol.
The cardiovascular effects of aripiprazole were assessed in comparison with those of haloperidol using a halothane-anesthetized canine model with monophasic action potential monitoring. Aripiprazole (n = 6) or haloperidol (n = 6) was infused over 10 min at escalating doses of 0.03, 0.3, and 3.0 mg/kg with intervals of 20 min between doses. Clinically relevant plasma concentrations were obtained after 0.03-0.3 mg/kg of aripiprazole as well as haloperidol. After 0.03-0.3 mg/kg of aripiprazole, positive chronotropic, inotropic, and dromotropic effects, shortening of the ventricular effective refractory period (ERP) and repolarization phase, and decrease of total peripheral resistance were observed in a dose-related manner. However, in the presence of a beta-blocking dose of esmolol (0.1 mg/kg/min), these changes were not induced. After 3.0 mg/kg of aripiprazole administration, cardiac effects induced by the lower doses were attenuated or disappeared, while the negative chronotropic, dromotropic, and hypotensive actions and prolongation of ERP and repolarization phase were induced. After 0.03 mg/kg of haloperidol, no significant change was observed, except for the decrease of the peripheral resistance. After 0.3-3.0 mg/kg of haloperidol, negative chronotropic, inotropic, and hypotensive actions, intraventricular conduction delay, and prolongation of ventricular ERP and repolarization phase were observed in a dose-related manner accompanied by further decrease of the peripheral resistance. The inhibitory effects of aripiprazole on cardiovascular parameters in dogs were less potent than those of haloperidol at clinically relevant exposures, moreover, aripiprazole, unlike haloperidol, neither induced early afterdepolarization nor prolonged the ventricular electrical vulnerable period. Therefore, aripiprazole can be considered safer to use than haloperidol.
Sugiyama
A
A
Department of Pharmacology, Yamanashi Medical University, Tamaho-cho, Nakakoma-gun, Yamanashi, 409-3898, Japan. atsushis@res.yamanashi-med.ac.jp
Satoh
Y
Y
Hashimoto
K
K
D000818:Animals; D014150:Antipsychotic Agents / Q000097:blood / Q000494:pharmacology*; D000068180:Aripiprazole; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects; D006220:Haloperidol / Q000097:blood / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D010879:Piperazines / Q000097:blood / Q000494:pharmacology*; D015363:Quinolones / Q000097:blood / Q000494:pharmacology*; D014655:Vascular Resistance / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects; D017725:Ventricular Pressure / Q000187:drug effects
D014150:Antipsychotic Agents; D010879:Piperazines; D015363:Quinolones; D000068180:Aripiprazole; D006220:Haloperidol