Naphthoquine-induced Central Nervous System and Hepatic Vasculocentric Toxicity in the Beagle Dog

摘要

Naphthoquine phosphate (NP) was considered as a partner drug with a promising antimalarial drug candidate. Here we report unexpected adverse clinical signs and microscopic findings in a canine pilot toxicology study with NP. Male and female dogs were dosed daily by oral gavage with NP at 2, 10, or 50 mg/kg/day for a maximum of 14 days. NP was not tolerated at >= 10 mg/kg/day; several animals were sacrificed in moribund condition and marked neurological clinical signs were noted at 50 mg/kg/day. The main microscopic observation was central nervous system vasculocentric inflammation (mainly lymphocytes and macrophages) in the white and gray matter of various regions of the brain at >= 2 mg/kg/day and at lower incidence in the spinal cord at >= 10 mg/kg/day. Vasculocentricmicroscopic changes predominantly centered on the centrilobular vein were also observed in the liver at >= 2 mg/kg/day. Females were more sensitive thanmaleswith comparable NP plasma exposure. In conclusion, under the conditions of this study, the administration of NP to dogs via daily oral gavage for up to 2 weeks was not tolerated causing moribundity, marked neurological clinical signs, and vasculocentric microscopic changes in the central nervous system and the liver.