Evaluation of several oximes as reactivators of unaged soman-inhibited whole blood acetylcholinesterase in rabbits.
The antidotal benefit of oximes against organophosphorus (OP) anticholinesterase intoxication is thought to be due to reactivation of the OP-inhibited acetylcholinesterase (AChE). This study was conducted to determine whether the antidotal efficacy against soman by the oximes 2-hydroxyiminomethyl-3-methyl-1-[2-(3-methyl-3-nitrobutyl oxymethyl)]-imidazolium Cl (ICD 467) and 1,1'-methylenebis[4-(hydroxyiminomethyl) pyridinium] di-Cl (MMB-4) resulted, in part, from reactivation of the inhibited AChE. These oximes were tested in parallel with pralidoxime Cl (2-PAM) and 1-(2-hydroxyiminomethyl-1-pyridinio-3-(4-carbamoyl-1-pyridinio+ ++)-2-oxapropane di-Cl (HI-6). Rabbits were atropinized (8 mg/kg, i.m.) and intoxicated with soman (13 micrograms/kg, i.v.; 1.2 x LD50) 5 min later. Three minutes after soman, animals were treated with oxime (50, 100 or 150 mumol/kg, i.m.). Whole blood was collected from a catheter in the central artery of the ear just before soman, at 2 min after soman and at 2, 5, 10, 15, 30, and 60 min after oxime or vehicle for determination of AChE activity. Shortly thereafter, animals were anesthetized and exsanguinated with immediate flushing using heparinized saline. AChE activity was also determined on the cortex, medulla-pons and diaphragm to assess central and peripheral reactivation. Treatment with HI-6 or MMB-4 (50 mumol/kg, i.m.) resulted in significant (P less than 0.05) reactivation of soman-inhibited whole blood AChE and diaphragm cholinesterase (ChE), but not brain AChE. In contrast, 2-PAM was completely ineffective in reactivating soman-inhibited AChE. HI-6 was significantly better than MMB-4 in reactivating blood AChE; they were essentially equal against soman-inhibited diaphragm ChE. Three animals exposed to soman and treated with ICD 467 died within 15 min. When animals not exposed to soman were treated with ICD 467 (25 mumol/kg, i.m.), whole blood AChE activity was depressed by 60% within 5-10 min after treatment. Furthermore, ICD 467 failed to reactivate significantly unaged soman-inhibited erythrocyte AChE, in vitro. These observations indicate that ICD 467 would be contraindicated as a therapy for anti-ChE intoxication and that the efficacy of HI-6 or MMB-4 can be explained, in part, by reactivation of soman-inhibited AChE.
Harris
L W
LW
Applied Pharmacology Branch, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5425.
Anderson
D R
DR
Lennox
W J
WJ
Woodard
C L
CL
Pastelak
A M
AM
Vanderpool
B A
BA
D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D002540:Cerebral Cortex / Q000201:enzymology; D002800:Cholinesterase Inhibitors / Q000378:metabolism*; D003964:Diaphragm / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D007093:Imidazoles / Q000494:pharmacology*; D008526:Medulla Oblongata / Q000201:enzymology; D010091:Oximes / Q000494:pharmacology*; D011220:Pralidoxime Compounds / Q000494:pharmacology; D011726:Pyridinium Compounds / Q000494:pharmacology; D011817:Rabbits; D012999:Soman / Q000494:pharmacology*; D013997:Time Factors
D002800:Cholinesterase Inhibitors; D007093:Imidazoles; D010091:Oximes; D011220:Pralidoxime Compounds; D011726:Pyridinium Compounds; C065160:WR 255737; C005514:N,N'-monomethylenebis(pyridiniumaldoxime); D012999:Soman; D000110:Acetylcholinesterase; C022870:asoxime chloride; C028797:pralidoxime