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 5...

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Bibliographic Details
Published in:Toxicologic pathology 2016-12, Vol.44 (8), p.1128-1136
Main Authors: Galarneau, Jean-Rene, Meseck, Emily K., Hall, Robert L., Li, Wenkui, Weaver, Margaret L.
Format: Article
Language:English
Subjects:
1-Naphthylamine - analogs & derivatives
1-Naphthylamine - toxicity
Aminoquinolines - blood
Aminoquinolines - toxicity
Animals
Antimalarials - blood
Antimalarials - toxicity
Central Nervous System - blood supply
Central Nervous System - drug effects
Central Nervous System - pathology
Dogs
Dose-Response Relationship, Drug
Female
Immunohistochemistry
Liver - blood supply
Liver - drug effects
Liver - pathology
Male
Toxicokinetics
Vasculitis - chemically induced
Vasculitis - pathology
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Summary: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.
ISSN:0192-6233
1533-1601
DOI:10.1177/0192623316676422