D0870,an Antifungal Agent, Induces Reverse Use-dependent QT Prolongation in Dogs

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  • MATSUNAGA Toshiyuki
    Toxicology Laboratory, Research Center, Mochida Pharmaceutical Co., Ltd., 342 Gensuke, Fujieda, Shizuoka 426-8640, Japan
  • HARADA Takuma
    Toxicology Laboratory, Research Center, Mochida Pharmaceutical Co., Ltd., 342 Gensuke, Fujieda, Shizuoka 426-8640, Japan
  • HIRATA Zenzou
    Toxicology Laboratory, Research Center, Mochida Pharmaceutical Co., Ltd., 342 Gensuke, Fujieda, Shizuoka 426-8640, Japan
  • MITSUI Takeshi
    Toxicology Laboratory, Research Center, Mochida Pharmaceutical Co., Ltd., 342 Gensuke, Fujieda, Shizuoka 426-8640, Japan
  • MURANO Hiroyuki
    Toxicology Laboratory, Research Center, Mochida Pharmaceutical Co., Ltd., 342 Gensuke, Fujieda, Shizuoka 426-8640, Japan
  • SHIBUTANI Yasunori
    Toxicology Laboratory, Research Center, Mochida Pharmaceutical Co., Ltd., 342 Gensuke, Fujieda, Shizuoka 426-8640, Japan

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  • D0870, an Antifungal Agent, Induces Reverse Use-dependent QQT Prolongation in Dogs.

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We previously reported that D0870 induced QT prolongation and sudden death due to torsades de pointes (TdP) in dogs and that catecholamines played an important part in the development of the sudden death. In the present study, we analyzed in detail the ambulatory electrocardiographic recordings obtained from the just-mentioned study to elucidate the mechanism of the onset of TdPs and conducted an in vitro study using isolated canine Purkinje fibers to assess the effect of D0870 on repolarization. The hearts with TdPs observed before the sudden death showed a higher sinus rate for 5 and 10 sec before the onset, a shorter coupling interval, and a higher ventricular tachycardia rate compared with those having the non-sustained TdPs. These findings suggest that D0870-induced fatal TdPs may be provoked by a triggered activity developed from delayed after depolarizations. In contrast, as the pause-dependent, non-sustained TdPs in bradycardia showed a typical “short-long-short” sequence, they may be developed from early afterdepolarization . Moreover, the results of the in vitro study supported our contention that D0870 induced QT prolongation in a reverse use-dependent manner in vivo and suggested that it may inhibit not only rapidly activating delayed rectifier potassium current (Ikr) but also L-type Ca current (ICa-L).

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