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

新型不带电的双肟在OP中毒治疗中的体内功效。 项目摘要。有机磷酸酯（OP）亲核肟类再活化剂 乙酰胆碱酯酶（AChE）是唯一真正的解毒剂对OP中毒的神经毒剂或 OP农药暴露。 改善目前OP中毒解毒治疗的一个重要方法是创造 重新激活解毒剂，将达到抑制乙酰胆碱酯酶在外周组织，但也在中枢神经系统， 目前批准的解毒剂不能进入RS 194 B的X射线结构分析 不带电荷的乙酰氨基醛肟已被证明能在体内重新激活受抑制的乙酰胆碱酯酶， 尽管剂量很高，但我们在体外设计并表征了 （Gorecki等人，2020）七种改进的不带电LG双肟解毒剂，具有更好的再活化作用 沙林、环沙林、VX和对氧磷对hAChE的抑制作用强于RS 194 B。 小鼠中三种最有前途的LG的初步毒性和药代动力学研究- CPDF的CounterAct计划正在进行肟（SRI项目P24997），表明没有 高达160 mg/kg i.m.的毒性其性能优于2 PAM，接近低毒， RS194B。LG-703的初始体内治疗在IMROH进行，在小鼠中测试优于RS 194 B上级。 我们建议这项研究，以评估在小鼠体内，治疗效果的三个最好的LG- 动物暴露于代表性神经性毒剂OP和选定OP农药后， 并评价最有效的LG双肟的药代动力学特征和神经保护作用。 正在进行的小鼠体内初步实验和已完成的 体外表征为这一新类别的良好解毒潜力提供了实质性希望 具有中枢活性的不带电的双肟，以及它们未来治疗用途的良好前景。

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.