Abstract
Introduction
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.
Methods
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.
Results
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.
Conclusions
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.
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References
Baskin SI, Fricke RF. The pharmacology of p-aminopropio-phenone in the detoxification of cyanide.Drug Reviews 1992; 10: 358–375.
Baskin SI, Rockwood GA. Neurotoxicological and behavioral effects of cyanide and its potential therapies.Mil Psychol 2002; 14: 159–177.
Chen KK, Rose CL. Nitrite and thiosulfate therapy in cyanide poisoning.JAMA 1952; 149: 113–119.
Rockwood GA, Baskin SI, Romano JA Jr, Murrow ML, Preville JA, Lee RB, et al. Comparison of hematologic conse-quences and efficacy of p-aminophenones in mice.Environ Toxicol Pharmacol 1999; 7: 237–252.
Marino MT, Peggins JO, Brown LD, Urquart MR, Brewer TG. Pharmacokinetics and kinetic-dynamic modeling of an 8-aminoquinoline candidate anticyanide and antimalarial drug (WR242511).Drug Metab Dispos 1994; 22: 358–366.
Bright JE, Marrs TC. Kinetics of methaemoglobin production (2). Kinetics of the cyanide antidote p-aminopropiophe-none during oral administration.Hum Toxicol 1986; 5: 303–307.
Marrs TC, Bright JE. Kinetics of methaemoglobin production (1). Kinetics of methaemoglobinemia induced by the cyanide antidotes p-aminopropiophenone,p-hydroxyaminopro-piophenone or p-dimethylaminophenol after intravenous administration.Hum Toxicol 1986; 5: 295–301.
Levine BS, Wheeler CW, Tomlinson MJ. Acute and sub-chronic oral toxicity of the anticyanide drug WR242511 tartrate.Toxicologist 1996; 30: 106–107.
Bright JE, Woodman AC, Marrs TC, Wood SG. Sex differences in the production of methemoglobinemia by 4-amino-propiophenone.Xenobiotica 1987; 17: 79–83.
Bright JE, Marrs TC. A model for the induction of moderate levels of methaemoglobinemia in man using 4-dimethyl-aminophenol.Arch Toxicol 1982; 50: 57–64.
Transition Information Paper. WR242511 and WR269410—methemoglobin-formers as cyanide prophylactics for the soldier. Walter Reed Army Institute of Research, Washington, DC, U.S. Army Medical Research Institute of Chemical Defense, APG, MD, and U.S. Army Medical Research and Materiel Command Research Area V, Medical Chemical Defense Research Program, Frederick, MD, 1994.
Smith CC. Predicting drug metabolism pathways in man. In: Vagrborg, H, ed. Use of nonhuman primates in drug evaluation. Austin: University of Texas Press; 1968. pp. 470–479.
Blanchard KC, Schmidt LH. Chemical series of potential interest. In: Wiselogle FY, ed. A Survey of Antimalarial Drugs, Ann Arbor: JW Edwards, Vol 1; 1946. pp. 73–175.
Schmidt LH. Relationships between chemical structures of 8-aminoquinolines and their capacities for radical cure of infections withplasmodium cynomolgi in rhesus monkeys.Antimicrob Agents Chemother 1983; 24: 615–652.
Schmidt LH, Fradkin R, Vaughn D, Rasco J. Radical cure of infections with plasmodium cynomolgi: a function of total 8-aminoquinoline dose.Am J Trop Med Hyg 1977; 26: 1116–1128.
Schmidt IG, Schmidt LH. Neurotoxicity of the 8-amino-quinolines.J Comp Neurol 1949; 91: 337–368.
Moe GK, Peralta V, Seevers MH. Central impairment of sympathetic reflexes by 8-aminoquinolines.J Pharmacol Exp Ther 1949; 95: 407–414.
Wiselogle FY. A survey of antimalarial drugs, Vol 1, Ann Arbor: J.W. Edwards; 1949.
Martin DG, Watson CE, Gold MB, Woodard CL, Baskin SI. Topical anesthetic-induced methemoglobinemia and sulfhemo-globinemia in macaques: a comparison of benzocaine and lido-caine.J Appl Toxicol 1995; 15: 153–158.
Rockwood GA, Duniho SI, Briscoe CM, Gold MB, Armstrong KR, Shih ML, et al. The effects of WR242511 in rhesus monkeys. USAMRICD-TR-00-10. U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD. A385196; 2000.
Rockwood GA, Gold MB, Finger AV, Baskin SI. The effects of sodium nitrite on methemoglobin formation in nonhuman primates.Toxicologist 1999; 48: 373–374.
National Research Council. Guide for the care and use of laboratory animals. Washington: National Academy Press, 1996.
National Research Council. Nutrient requirements of nonhuman primates. Washington: National Academy of Sciences, 1978.
Noker PE. Single dose iv and oral pharmacokinetics, bioavailability and metabolism study of WR242511 in dogs. Final Report, Contract: DAMD 17-93-C-3004, 1994.
Vick, JA, Froehlich H. Treatment of cyanide poisoning.Mil Med 1991; 156: 330–339.
Johnson, WD. Effects of methemoglobin versus potassium cyanide intoxication. Final Report, Contract: DAMD17-83-C-3083. AD-B122 370, 1987.
Eng L-IL. Glucose-6-phosphate dehydrogenase activity in the red blood cells of monkeys.Nature 1962; 195: 1110.
Rockwood GA, Armstrong KR, Baskin SI. Species comparison of methemoglobin reductase.Exp Biol Med 2003; 228: 79–83.
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Funding for this study was provided by the United States Department of Defense.
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Rockwood, G.A., Duniho, S.M., Briscoe, C.M. et al. Toxicity in rhesus monkeys following administration of the 8-aminoquinoline 8-[(4-amino-l-methylbutyl)amino]-5-(l-hexyloxy)-6-methoxy-4-methylquinoline (WR242511). J. Med. Toxicol. 4, 157–166 (2008). https://doi.org/10.1007/BF03161194
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DOI: https://doi.org/10.1007/BF03161194