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

• 批准号: 10412696
• 负责人: Zoran Radic
• 金额: $ 20.98万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10412696
• 关键词: Acetylcholinesterase; Address; Animals; Antidotes; Blood - brain barrier anatomy; 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; base; 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

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.

新型不带电双肟治疗 OP 中毒的体内疗效。 项目摘要。有机磷酸酯 (OP) 的亲核肟再激活剂受到抑制 乙酰胆碱酯酶 (AChE) 是神经毒剂或 OP 中毒唯一真正的解毒剂。 OP 农药暴露。 改善目前 OP 中毒解毒治疗的一种重要方法是创造 重新激活解毒剂，这些解毒剂将到达外周组织以及中枢神经系统中被抑制的乙酰胆碱酯酶， 目前批准的解毒剂无法进入的地方。使用RS194B的X射线结构分析 不带电荷的乙酰胺醛肟，已被证明可以在体内重新激活受抑制的 AChE， 尽管剂量较高，但我们已经在体外设计并表征了中央和外周 （Gorecki 等人，2020）七种改进的不带电 LG 双肟解毒剂，具有更好的再激活能力 沙林、环沙林、VX 和对氧磷对 hAChE 的抑制作用强于 RS194B。 三种最有前途的 LG-在小鼠中的初步毒性和药代动力学研究 CounterAct 计划的 CPDF 正在进行肟化（SRI 项目 P24997），表明没有 肌内毒性高达 160 mg/kg优于2PAM，接近低毒 RS194B。 LG-703 的初始体内治疗在 IMROH 进行，在小鼠中进行测试，效果优于 RS194B。 我们建议这项研究在小鼠体内评估三种最佳 LG-的治疗效果 动物接触代表性神经毒剂 OP 和选定的 OP 农药后产生的肟 并评估最有效的 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实验结果有希望 体外表征，为此类新型药物的良好抗毒潜力提供了巨大的希望 具有中心活性、不带电的双肟，其未来的治疗用途具有良好的前景。