Characterization and treatment of the toxicity of O-isobutyl S-[2-(diethylamino)ethyl]methylphosphonothioate, a structural isomer of VX, in guinea pigs

O-isobutyl S-[2-(diethylamino)ethyl]methyIphosphonothioate (VR), a structural isomer of the chemical warfare agent O-ethyl S-[2(diisopropylamino)ethyl] methylphosphonothioate (VX) was characterized with respect to its toxicity, acetylcholinesterase (AChE) inhibition, oxime reactivation, and antidotal treatment. VR was highly toxic in guinea pigs, with an s.c. LD(50) of 11.3 mu g/g. The bimolecular rate constant for inhibition of AChE by VR was 1.4 x 10(8) M(-1) min(-1), which is similar to the AChE inhibition rate constants of VX and of other chemical warfare agents whose toxicity is attributed to their inhibition of AChE. Complete in vitro reactivation of VR-inhibited AChE was produced by oximes, but reactivation with the bispyridinium oximes 1-(((4-(aminocarbonyl)pyridino)methoxy methyl)-2-((hydroximino)methyl)pyridinium dichloride (HI-6), 1-(((4-(aminocarbonyl)pyridino)methoxy)methyl)-2,4-bis(hydroxyimino)methyl)pyridinium dimethanesulfonate (HL delta 7), and toxogonin dichloride (TOXO) occurred at a much higher rate than with the monopyridinium oxime 2-pyridine aldoxime methylchloride (2-PAM). The reactivation rates with HL delta 7, HI-6, and TOXO were, respectively, 21-, 5-, and 3-fold greater than with 2-PAM. The aging of VR-inhibited AChE to an oxime-resistant state occurred slowly with a half-life of 43 h. Treatment of guinea pigs with equimolar (145 mu mol/kg) amounts of HI-6 (55 mg/kg) or 2-PAM (25 mg/kg) in combination with atropine (16 mg/kg) i.m. 1 min after VR exposure produced protective ratios of 43.9 for HI-6 and 6.5 for 2-PAM. Carbamate pretreatment prior to these oxime/atropine treatments caused no increase in their protective ratios against VR. These observations suggest that VR is a highly toxic anticholinesterase agent that can be effectively treated with an appropriate oxime/atropine regimen.