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

新型无电荷二肟类药物治疗OP中毒的体内疗效。 项目摘要。抑制有机磷(OP)的亲核肟类复活剂 乙酰胆碱酯酶(AChE)是治疗神经性毒剂中OP中毒的唯一真正解毒剂 有机磷农药暴露。 改善目前OP中毒解毒治疗的一个重要途径是通过创造 在外周组织和中枢神经系统中，重新激活的解毒剂将达到被抑制的AChE， 目前批准的解毒剂不能进入的地方。RS194B的X射线结构分析 已被证明可在体内重新激活抑制的AChE的未带电的乙酰胺缩醛肟，两者 在中心和外围，尽管在高剂量下，我们已经在体外设计和表征了 (Gorecki等人，2020)七种改进的无电荷LG双肟解毒剂，具有更好的再激活 沙林、环沙林、VX和对氧磷对HAChE的抑制作用强于RS194B。 三种最有希望的LG-2在小鼠体内的毒性和药代动力学初步研究 反腐败方案的合作伙伴关系正在进行中(SRI项目P24997)，表明没有 毒性高达160毫克/公斤I.M.它比2PAM更好，接近2PAM的低毒 RS194B。LG-703的初始体内治疗在IMROH进行，在小鼠身上测试优于RS194B。 我们建议本研究在小鼠体内评价三种最好的LG-2的治疗效果。 动物暴露于典型的神经毒剂OP和选定的OP杀虫剂时的肟类 并评价最有效的LG双肟的药代动力学和神经保护作用。 正在进行的小鼠体内初步实验和已完成的有希望的结果 体外表征，为这类新化合物良好的解毒潜力提供了很大的希望 具有中枢活性的、不带电荷的二-肟，以及它们未来治疗应用的良好前景。

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.