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

新型不带电双肟治疗 OP 中毒的体内疗效

基本信息

批准号：
10598635
负责人：
Zoran Radic
金额：
$ 15.58万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10598635
关键词：
Acetylcholinesterase Address Animals Antidotes Brain Chemical Weapons Communities Development Dose Drug Kinetics Evaluation Exposure to Future Generations In Vitro Individual Intoxication Lethal Dose 50 Libraries Mus Organophosphates Outcome Oximes Paraoxon Peripheral Pesticides Phosphorus Recovery Roentgen Rays Sarin Security Serine Testing Therapeutic Therapeutic Uses Tissues Toxic effect Treatment Efficacy animal tissue blood-brain barrier crossing blood-brain barrier penetration cyclosarin design experimental study improved in vivo in vivo evaluation indexing nerve agent neuroinflammation neuroprotection novel organophosphate poisoning pesticide exposure programs tabun toxic organophosphate insecticide exposure

Acetylcholinesterase Address Animals Antidotes Brain Chemical Weapons Communities Development Dose Drug Kinetics Evaluation Exposure to Future Generations In Vitro Individual Intoxication Lethal Dose 50 Libraries Mus Organophosphates Outcome Oximes Paraoxon Peripheral Pesticides Phosphorus Recovery Roentgen Rays Sarin Security Serine Testing Therapeutic Therapeutic Uses Tissues Toxic effect Treatment Efficacy animal tissue blood-brain barrier crossing blood-brain barrier penetration cyclosarin design experimental study improved in vivo in vivo evaluation indexing nerve agent neuroinflammation neuroprotection novel organophosphate poisoning pesticide exposure programs tabun toxic organophosphate insecticide exposure

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项目摘要

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.

新型未充电双子在OP中毒治疗中的体内功效。项目摘要。有机磷酸盐（OP）的亲核氧电抗激活剂抑制乙酰胆碱酯酶（ACHE）是神经剂或 OP农药暴露。改善当前对OP中毒的解毒疗法的一种重要方法是创建重新激活的解毒剂将在周围组织中抑制ACHE，但也会在中枢神经系统中抑制ACHE 目前批准的解毒剂无法输入。使用RS194B的X射线结构分析未充电的乙酰氨基醛氧ime已被证明在体内重新激活抑制的ACHE，两者都中心和外围，尽管在高剂量下，我们已经在体外设计和表征了（Gorecki等，2020）七个改善了未充电的LG Bis-Oxime解毒剂，具有更好的再活化 Sarin，Cyclosarin，VX和paraoxon抑制Hache的Hache比RS194B。小鼠的初步毒性和药代动力学研究最有希望的LG- 反对计划的CPDF的OXIMES正在进行中（SRI Project P24997）表示没有毒性高达160 mg/kg I.M.它比2 ppam好，并且接近低毒性 RS194B。在IMROH进行的LG-703的初始体内治疗，在高于194b的小鼠中进行了测试。我们建议这项研究评估小鼠体内的体内，三个最佳LG-的治疗功效动物暴露于代表性神经剂OP和选定的OP农药时的含氧并评估最有效的LG BIS-OXIME的药代动力学谱和神经保护作用。有希望的结果，在小鼠中正在进行的初步体内实验和已完成的实验体外表征，为这个新阶级的良好解毒剂提供了巨大的希望在中心活跃，无负荷的双子症和未来治疗用途的良好前景。