Influences of catecholamines on the sudden death induced in dogs by an antifungal agent, D0870.
We previously reported the occurrence of QT prolongation and sudden death owing to torsades de pointes (TdP) in dogs treated with D0870, an antifungal agent. In the present study, we evaluated the influences of epinephrine and isoproterenol on the onset of TdP each time D0870 was given to 6 anesthetized open-chest dogs at a dosage of 20 mg/kg, 5 times every 40 minutes, by the simultaneous measurements of surface electrocardiogram and epicardial monophasic action potential (MAP). D0870 alone induced noticeable prolongation of the QT interval and action potential duration (APD), but neither ventricular premature contraction (VPC) nor sudden death. In contrast, the additional administration of the catecholamines induced a greater shortening of APD during the later phase of repolarization than during its earlier one and VPCs in all dogs tested, and sudden deaths owing to TdPs in 4 of the 6 dogs treated with D0870. These results suggest that D0870 alone does not induce TdP but that catecholamines play an important part in the development of sudden death induced by D0870 in dogs.
Matsunaga
T
T
Toxicology Laboratory, Research Center, Mochida Pharmaceutical, Co., Ltd., Fujieda, Shizuoka, Japan.
Harada
T
T
Mitsui
T
T
Murano
H
H
Duffy
P A
PA
Aldridge
A
A
Shibutani
Y
Y
D000200:Action Potentials; D000818:Animals; D000935:Antifungal Agents / Q000633:toxicity*; D002395:Catecholamines / Q000633:toxicity*; D016757:Death, Sudden, Cardiac; D004285:Dogs; D004562:Electrocardiography; D004837:Epinephrine / Q000633:toxicity; D006352:Heart Ventricles / Q000503:physiopathology; D007545:Isoproterenol / Q000633:toxicity; D016171:Torsades de Pointes / Q000139:chemically induced / Q000175:diagnosis; D014230:Triazoles / Q000633:toxicity*
D000935:Antifungal Agents; D002395:Catecholamines; D014230:Triazoles; C058219:ICI 195739; D007545:Isoproterenol; D004837:Epinephrine