In Vivo Efficacy of Novel Uncharged Bis-Oximes in OP Poisoning Treatment

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In vivo efficacy of novel uncharged bis-oximes in OP poisoning treatment. Project Summary. Nucleophilic oxime reactivators of organophosphate (OP) inhibited acetylcholinesterase (AChE) are the only true antidotes against OP intoxication in nerve agent or OP pesticide exposure. One significant way of improving current antidotal treatment of OP intoxication is by creation of reactivating antidotes that will reach inhibited AChE in peripheral tissue but also in the CNS, where currently approved antidotes cannot enter. Using X-ray structural analysis of RS194B uncharged acetamido aldoxime that has been shown to reactivate inhibited AChE in vivo, both centrally and in periphery, albeit at high dose, we have designed and characterized in vitro (Gorecki et al.,2020) seven improved uncharged LG bis-oxime antidotes with better reactivation of sarin, cyclosarin, VX and paraoxon inhibited hAChE than RS194B. Preliminary toxicity and pharmacokinetic studies in mice for the three most promising LG- oximes by the CPDF of the CounterAct program are ongoing (SRI Project P24997) indicating no toxicity up to 160 mg/kg i.m. which is better than 2PAM, and is approaching low toxicity of RS194B. Initial in vivo therapy of LG-703 done at IMROH, tested in mice superior to RS194B. We propose for this study to evaluate in vivo in mice, therapeutic efficacy of three best LG- oximes upon animal exposure to representative nerve agent OPs and to selected OP pesticides and evaluate pharmacokinetic profile and neuroprotection for the most efficacious LG bis-oxime. Promising outcomes, of the ongoing preliminary in vivo experiments in mice and of completed in vitro characterizations, provide substantial hope for good antidotal potential of this novel class of centrally active, uncharged bis-oximes, and good prospects for their future therapeutic use.