Effects of terfenadine, astemizole and epinastine on electrocardiogram in conscious cynomolgus monkeys.
We examined the effects of non-sedative histamine H1 receptor antagonists on the electrocardiogram (ECG) in conscious cynomolgus monkeys. Terfenadine (3 mg kg(-1) h(-1), i.v.) and astemizole (0.3 and 1 mg kg(-1) h(-1), i.v.) caused significant time-dependent increases in the QT interval and QTc Bazett (QTc). However, normal ECG forms were found during a 60-min infusion of epinastine (3 mg kg(-1) h(-1) i.v.). A higher dose of epinastine (10 mg kg(-1) h(-1), i.v.) increased the QTc and PR interval only 5 min after the start of the infusion. The minimum plasma concentrations of terfenadine, astemizole and epinastine which caused QTc prolongation were 85, 35 and over than 3600 ng/ml, respectively. These drugs did not alter the PQ and QRS intervals and did not cause arrhythmia or atrioventricular block. Our results are consistent with the clinical observation that prolongation of QTc is caused by terfenadine and astemizole but not by epinastine. Thus, measurement of QTc in cynomolgus monkey appears to be a useful approach for evaluating the potential cardiotoxicity of histamine H1 receptor antagonists.
Ohmura
T
T
Department of Pharmacology, Kawanishi Pharma Research Institute, Nippon Boehringer Ingelheim, Japan. ohmura@boehringer-ingelheim.co.jp
Chachin
M
M
Tarui
S
S
Nagakura
A
A
Igarashi
T
T
Ikeda
H
H
Ikegami
K
K
Kitagawa
H
H
Uchida
S
S
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D016589:Astemizole / Q000097:blood / Q000494:pharmacology; D003984:Dibenzazepines / Q000097:blood / Q000494:pharmacology; D004562:Electrocardiography / Q000187:drug effects*; D006327:Heart Block / Q000139:chemically induced*; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D007093:Imidazoles / Q000097:blood / Q000494:pharmacology; D008252:Macaca fascicularis; D008297:Male; D016593:Terfenadine / Q000097:blood / Q000494:pharmacology; D013997:Time Factors
D003984:Dibenzazepines; D006634:Histamine H1 Antagonists; D007093:Imidazoles; D016593:Terfenadine; D016589:Astemizole; C053090:epinastine