n vivo reactivation by oximes of inhibited blood, brain and peripheral tissue holinesterase activity following exposure to nerve agents in guinea pigs

This study compared the ability of nine oximes (HI-6, HLö7, MMB-4, TMB-4, carboxime, ICD585, ICD692, ICD3805, and 2-PAM) to reactivate in vivo cholinesterase (ChE) in blood, brain, and peripheral tissues in guinea pigs intoxicated by one of four organophosphorus nerve agents. Two bis-pyridinium compounds without an oxime group, SAD128 and ICD4157, served as non-oxime controls. Animals were injected subcutaneouslywith 1.0× LD50 of the nerve agents sarin, cyclosarin, VRorVXand treated intramuscularly 5min later with one of these oximes. Toxic signs and lethality weremonitored; tissue ChE activities were determinedat60minafternerveagent. Someanimals exposed to sarinor cyclosarin,withorwithoutnonoxime treatment, died within 60min; however, no animal treated with an oxime died. For VR or VX, all animals survived the 60min after exposure, with orwithout non-oxime or oxime therapy. The four nerve agents caused differential degrees of inhibition in blood, brain regions and peripheral tissues. The tested oximes exhibited differential potency in reactivating nerve agent-inhibited ChE in various peripheral tissues, but did not affect ChE activity in the brain regions. There was no direct relation between blood and peripheral tissues in the reactivating efficacy of oxime treatments. ChE inhibited by sarin was the most susceptible to oxime reactivation while cyclosarin the least susceptible. There was no difference in the ChE reactivating potency between the dimethanesulfonate and dichloride salts of HI-6. MMB-4 significantly reactivated the ChE inhibited by these four nerve agents in blood and all three peripheral tissues of the guinea pig, and among all the oximes tested it was themost effective in vivo ChE reactivator against all four nerve agents.