Toxicity in rhesus monkeys following administration of the 8-aminoquinoline 8-[(4-amino-l-methylbutyl)amino]- 5-(l-hexyloxy)-6-methoxy-4-methylquinoline (WR242511).

Gary Rockwood, Steven Duniho, Crystal Briscoe, Mark Gold, Kevin Armstrong, David Kahler, Anita Moran, Steven Baskin

Analytical Toxicology Division, United States Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5400, USA. gary.a.rockwood@us.army.mil

Journal of medical toxicology : official journal of the American College of Medical Toxicology 2008 Sep

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Many substances that form methemoglobin (MHb) effectively counter cyanide (CN) toxicity. Although MHb formers are generally applied as treatments for CN poisoning, it has been proposed that a stable, long-acting MHb former could serve as a CN pretreatment. Using this rationale, the 8-aminoquinoline WR242511, a potent long-lasting MHb former in rodents and beagle dogs, was studied in the rhesus monkey for advanced development as a potential CN pretreatment. In this study, WR242511 was administered intravenously (IV) in 2 female and 4 male rhesus monkeys in doses of 3.5 and/or 7.0 mg/kg; a single male also received WR242511 orally (PO) at 7.0 mg/kg. Health status and MHb levels were monitored following exposure. The selected doses of WR242511, which produced significant methemoglobinemia in beagle dogs in earlier studies conducted elsewhere, produced very little MHb (mean < 2.0%) in the rhesus monkey. Furthermore, transient hemoglobinuria was noted approximately 60 minutes postinjection of WR242511 (3.5 or 7.0 mg/kg), and 2 lethalities occurred (one IV and one PO) following the 7.0 mg/kg dose. Myoglobinuria was also observed following the 7.0 mg/kg dose. Histopathology analyses in the 2 animals that died revealed liver and kidney toxicity, with greater severity in the orally-treated animal. These data demonstrate direct and/or indirect drug-induced toxicity. It is concluded that WR242511 should not be pursued as a pretreatment for CN poisoning unless the anti-CN characteristics of this compound can be successfully dissociated from those producing undesirable toxicity.

Citation

Gary Rockwood, Steven Duniho, Crystal Briscoe, Mark Gold, Kevin Armstrong, David Kahler, Anita Moran, Steven Baskin. Toxicity in rhesus monkeys following administration of the 8-aminoquinoline 8-[(4-amino-l-methylbutyl)amino]- 5-(l-hexyloxy)-6-methoxy-4-methylquinoline (WR242511). Journal of medical toxicology : official journal of the American College of Medical Toxicology. 2008 Sep;4(3):157-66