title: Comparison of several oximes on reactivation of soman-inhibited blood, brain and tissue cholinesterase activity in rats.
abstract: The ability of three oximes, HI-6, MMB-4 and ICD-467, to reactivate cholinesterase (ChE) inhibited by the organophosphorus compound soman was compared in blood (plasma and erythrocytes), brain regions (including spinal cord) and peripheral tissues of rats. Animals were intoxicated with soman (100 micrograms/kg, SC; equivalent to 0.9 x LD50 dose) and treated 1 min later with one of these oximes (100 or 200 mumol/kg, IM). Toxic sign scores and total tissue ChE activities were determined 30 min later. Soman markedly inhibited ChE activity in blood (93-96%), brain regions (ranging from 78% to 95%), and all peripheral tissues (ranging from 48.9% to 99.8%) except liver (11.9%). In blood, treatment with HI-6 or ICD-467 resulted in significant reactivation of soman-inhibited ChE. In contrast, MMB-4 was completely ineffective. HI-6 and ICD-467 were equally effective at the high dose. At the low dose ICD-467 treatment resulted in significantly higher plasma ChE than HI-6 treatment, whereas HI-6 treatment resulted in higher erythrocyte ChE than ICD-467 treatment. However, none of these three oximes reactivated or protected soman-inhibited ChE in the brain. In all peripheral tissues (except liver) studied, MMB-4 was not effective. HI-6 reactivated soman-inhibited ChE in all tissues except lung, heart, and skeletal muscle. ICD-467 was highly effective in reactivating ChE in all tissues and afforded a complete recovery of ChE to control levels in intercostal muscle and salivary gland. Oxime treatments did not modify the toxic scores produced by soman. However, treatment with the high dose (200 mumol/kg) of ICD-467 depressed respiration and two of the six rats died in 10 min. These observations indicate that MMB-4 is completely ineffective in protecting and/or reactivating soman-inhibited ChE, HI-6 is an effective ChE reactivator as reported earlier in rats and other species, and the imidazolium oxime ICD-467 is a powerful reactivator of soman-inhibited ChE; however, its toxic interactions with soman may not be related to tissue ChE levels.
authors.affiliation: Biochemical Pharmacology Branch, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5425.
authors.forename: T M
authors.initials: TM
authors.lastname: Shih
mesh_terms: D000818:Animals; D000931:Antidotes / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D002801:Cholinesterase Reactivators / Q000494:pharmacology*; D002802:Cholinesterases / Q000097:blood* / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006321:Heart / Q000187:drug effects; D010091:Oximes / Q000494:pharmacology*; D011726:Pyridinium Compounds / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012999:Soman / Q000633:toxicity*; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: D000931:Antidotes; D002801:Cholinesterase Reactivators; D010091:Oximes; D011726:Pyridinium Compounds; D012999:Soman; D002802:Cholinesterases; C022870:asoxime chloride