title: Effects of 4-pyridine aldoxime on nerve agent-inhibited acetylcholinesterase activity in guinea pigs.
abstract: Methoxime (MMB-4) is a leading candidate oxime acetylcholinesterase (AChE) reactivator to replace pralidoxime (2-PAM) for therapeutic treatment of nerve agent intoxication. 4-Pyridine aldoxime (4-PA) is a synthetic starting material, a breakdown product, and a probable metabolite of MMB-4. There is a possibility that 4-PA may adversely interact with the nerve agent, thereby affecting nerve agent toxicity and biological AChE activity. This study evaluated the effects of 4-PA on sarin (GB)-, cyclosarin (GF)-, and VX-induced toxicity and AChE activity in blood, brain, and peripheral tissues of guinea pigs. Animals were pretreated with atropine methyl nitrate (1.0 mg/kg, im) 15 min prior to subcutaneous administration with 1.0 x LD(50) of GB, GF, or VX and then treated 15 min after the administration of nerve agents with 4-PA (3.5, 7.0, or 14.0 mg/kg, im). The dose-response effects of 4-PA alone were also examined. Toxic signs and lethality were monitored, blood and tissues were collected, and AChE activities were determined at 60 min after nerve agent administration. Under the condition of this study, all animals exposed to nerve agents exhibited some degree of toxic signs such as salivation, lacrimation, rhinorrhea, and convulsions. 4-PA at the three doses tested neither induced toxic signs nor altered the toxicity of GB, GF, or VX at the 1.0 x LD(50) exposure dose. Additionally, it did not modify the AChE activity in blood, brain, and peripheral tissues by itself or affect the AChE activity inhibited by a 1.0 x LD(50) dose of these three nerve agents in guinea pigs.
authors.affiliation: Pharmacology Branch, Research Division, US Army Medical Research Institute of Chemical Defense, ATTN: MCMR-CDR-P, 3100 Ricketts Point Road, Aberdeen Proving Ground, Aberdeen, MD 21010-5400, USA. tsungming.a.shih@us.army.mil
authors.forename: Tsung-Ming
authors.initials: TM
authors.lastname: Shih
authors.forename: Jacob W
authors.initials: JW
authors.lastname: Skovira
authors.forename: John H
authors.initials: JH
authors.lastname: McDonough
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D002619:Chemical Warfare Agents / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D002801:Cholinesterase Reactivators / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006168:Guinea Pigs; D008136:Longevity / Q000187:drug effects; D008297:Male; D020258:Neurotoxicity Syndromes / Q000201:enzymology* / Q000209:etiology; D009943:Organophosphorus Compounds / Q000633:toxicity; D009946:Organothiophosphorus Compounds / Q000633:toxicity; D010091:Oximes / Q000494:pharmacology*; D012472:Salivation / Q000187:drug effects; D012524:Sarin / Q000633:toxicity; D012640:Seizures / Q000139:chemically induced; D013666:Tears / Q000378:metabolism
chemical_list: D000110:Acetylcholinesterase; D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D009943:Organophosphorus Compounds; D009946:Organothiophosphorus Compounds; D010091:Oximes; D012524:Sarin; C050580:pyridine-4-aldoxime; C009680:VX-agent; C053914:cyclohexyl methylphosphonofluoridate