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Novel substituted phenoxyalkyl pyridinium oximes enhance survival and attenuate seizure-like behavior of rats receiving lethal levels of nerve agent surrogates.

Abstract：

:Novel substituted phenoxyalkyl pyridinium oximes, previously shown to reactivate brain cholinesterase in rats treated with high sublethal dosages of surrogates of sarin and VX, were tested for their ability to prevent mortality from lethal doses of these two surrogates. Rats were treated subcutaneously with 0.6mg/kg nitrophenyl isopropyl methylphosphonate (NIMP; sarin surrogate) or 0.65mg/kg nitrophenyl ethyl methylphosphonate (NEMP; VX surrogate), dosages that were lethal within 24h to all tested rats when they received only 0.65mg/kg atropine at the time of initiation of seizure-like behavior (about 30min). If 146mmol/kg 2-PAM (human equivalent dosage) was also administered, 40% and 33% survival was obtained with NIMP and NEMP, respectively, while the novel Oximes 1 and 20 provided 65% and 55% survival for NIMP and 75 and 65% for NEMP, respectively. In addition, both novel oximes resulted in a highly significant decrease in time to cessation of seizure-like behavior compared to 2-PAM during the first 8h of observation. Brain cholinesterase inhibition was slightly less in novel oxime treated rats compared to 2-PAM in the 24h survivors. The lethality data indicate that 24h survival is improved by two of the novel oximes compared to 2-PAM. The cessation of seizure-like behavior data strongly suggest that these novel oximes are able to penetrate the blood-brain barrier and can combat the hypercholinergic activity that results in seizures. Therefore this oxime platform has exceptional promise as therapy that could both prevent nerve agent-induced lethality and attenuate nerve agent-induced seizures.

journal_name

Toxicology

journal_title

Toxicology

authors

Chambers JE,Meek EC,Bennett JP,Bennett WS,Chambers HW,Leach CA,Pringle RB,Wills RW

doi

10.1016/j.tox.2015.12.001

subject

Has Abstract

pub_date

2016-01-02 00:00:00

pages

51-57

eissn

0300-483X

issn

1879-3185

pii

S0300-483X(15)30058-5

journal_volume

339

pub_type

杂志文章

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