Naphthoquine-induced Central Nervous System and Hepatic Vasculocentric Toxicity in the Beagle Dog.
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. Vasculocentric microscopic changes predominantly centered on the centrilobular vein were also observed in the liver at ≥2 mg/kg/day. Females were more sensitive than males with 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.
1 Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Jean-Rene
JR
Galarneau
2 Covance Laboratories, Madison, Wisconsin, USA.|3 Novartis Institutes for BioMedical Research, East Hanover, New Jersey, USA.
Emily K
EK
Meseck
2 Covance Laboratories, Madison, Wisconsin, USA.
Robert L
RL
Hall
3 Novartis Institutes for BioMedical Research, East Hanover, New Jersey, USA.
Wenkui
W
Li
1 Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Margaret L
ML
Weaver
D015057:1-Naphthylamine / Q000031:analogs & derivatives* / Q000633:toxicity; D000634:Aminoquinolines / Q000097:blood / Q000633:toxicity*; D000818:Animals; D000962:Antimalarials / Q000097:blood / Q000633:toxicity*; D002490:Central Nervous System / Q000098:blood supply / Q000187:drug effects* / Q000473:pathology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D007150:Immunohistochemistry; D008099:Liver / Q000098:blood supply / Q000187:drug effects* / Q000473:pathology; D008297:Male; D066007:Toxicokinetics; D014657:Vasculitis / Q000139:chemically induced* / Q000473:pathology
D000634:Aminoquinolines; D000962:Antimalarials; C000625384:naphthoquine; D015057:1-Naphthylamine
Plasmodium falciparum; hepatotoxicity; malaria; naphthoquine; neurotoxicity; toxicity; vasculocentric inflammation