QT prolongation and torsades de pointes induced by an antifungal agent, D0870, in conscious dogs.
D0870 ((R)-2-(2,4-difluoro-phenyl)-1-[3-[(E)-4-(2,2,3,3-tetrafluoropropoxy+ ++)-styryl]-1H-1,2,4-triazol-1-yl]-3-(1H-1,2,4-triazole-1-yl) propan-2-ol), a novel bis-triazole antifungal agent, induced sudden deaths at a high dose of 5 mg/kg/day in a 6-month toxicity study in dogs. In the present study, we intended to elucidate the cause of the sudden death in dogs. When used in a single dose, D0870 induced prolongation of QTc intervals in proportion to its plasma concentration, and the threshold plasma concentration of the drug causing 10% QTc prolongation was estimated to be 3.8 microg/ml. Then, we conducted a study to induce sudden death in dogs using loading (50 mg/kg) and maintenance (5 mg/kg/day) doses with long-term ambulatory electrocardiographic monitoring. Marked QTc prolongation (52-96%), ventricular premature contractions, and T-wave alternans were observed in all 10 animals treated with the drug, and seven out 10 animals died of ventricular fibrillation (VF) associated with torsades de pointes (TdP) when the dogs were treated with D0870 for 14 or 16 days. The TdPs were elicited in both tachycardia and bradycardia, and some of them in the former proceeded to VF. Consequently, we clarified that D0870-induced sudden death is primarily attributable to the development of TdP preceding VF and may be enhanced by sympathetic nervous tone produced by emotional or physical stress.
Matsunaga
T
T
Toxicology Division, Fuji Central Research Laboratory, Mochida Pharmaceutical, Fujieda, Shizuoka, Japan.
Harada
T
T
Harada
T
T
Inokuma
M
M
Mitsui
T
T
Duffy
P A
PA
Aldridge
A
A
Shibutani
Y
Y
D000818:Animals; D000935:Antifungal Agents / Q000633:toxicity*; D004285:Dogs; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D008297:Male; D016171:Torsades de Pointes / Q000139:chemically induced*; D014230:Triazoles / Q000097:blood / Q000633:toxicity*
D000935:Antifungal Agents; D014230:Triazoles; C058219:ICI 195739