Novel oxime antidotes for an organophosphate insecticide requiring bioactivation

用于需要生物活化的有机磷杀虫剂的新型肟解毒剂

• 批准号: 10629574
• 负责人: Edward C Meek
• 金额: $ 21.98万
• 依托单位: MISSISSIPPI STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10629574
• 关键词: Accidents; Acetylcholinesterase; Acute; Antidotes; Aryl Hydrocarbon Hydroxylases; Atropine; Attenuated; Behavior; Behavioral; Brain; Brain Injuries; Bronchoconstriction; Butyrylcholinesterase; Central Nervous System; Cessation of life; Chemicals; Cholinesterase Inhibitors; Circulation; Cytochrome P450; Data; Data Set; Dose; Female; Flavins; Goals; Half-Life; Hour; Human; In Vitro; Insecticides; Laboratories; Lead; Legal patent; Libraries; Life; Literature; Mediating; Metabolism; Mixed Function Oxygenases; Modeling; Muscarinic Acetylcholine Receptor; Neurons; Organophosphates; Oximes; Paraoxon; Parathion; Parents; Pattern; Peripheral; Peripheral Nervous System; Phorate; Plasma; Poisoning; Population; Rattus; Regimen; Reporting; Respiratory Failure; Respiratory Muscles; Sarin; Seizures; Series; Serum; Sex Differences; Spasm; Survivors; Testing; Therapeutic; Time; Toxic effect; Toxicity Attenuation; Tremor; Violence; antagonist; attenuation; bioscavenger; blood-brain barrier crossing; blood-brain barrier penetration; cholinergic; detoxication; dosage; enzyme activity; improved; in vivo; inhibitor; invention; male; nerve agent; neuropathology; novel; organophosphate poisoning; prevent; respiratory; saliva secretion; sex; therapeutically effective; toxic organophosphate insecticide exposure

7. Abstract Organophosphate (OP) anticholinesterases, e.g., nerve agents and some insecticides, present a threat to the civilian population via terrorist activity or accidents. These OP compounds or metabolites are potent and persistent inhibitors of central and peripheral nervous system acetylcholinesterase (AChE). High dose OP exposures can lead to seizures, respiratory failure and death. Survivors may suffer from brain damage and behavioral deficits. One of these OP insecticides, phorate, is very acutely toxic making it a potential threat. Unlike the nerve agents, phorate requires bioactivation to its anticholinesterase metabolites (oxons) which results in a delay (4-5 h) in toxic signs (tremors, salivation, and seizure-like behavior). The current therapy (US) for severe OP poisoning includes atropine plus the oxime AChE reactivator 2-PAM. A major limitation of 2- PAM is its relatively short plasma half-life and inability to cross the blood-brain barrier (BBB) and protect the brain. Our laboratories have invented and patented a series of oximes that have shown survival efficacy and attenuation of seizure-like behavior and neuropathology following exposure of rats to high levels of nerve agent surrogates and one OP insecticidal metabolite (paraoxon). The delay in toxic signs following phorate challenge makes the timing of oxime administration and oxime plasma half-life important in establishing an effective therapeutic regimen. Our lead novel oximes have demonstrated longer plasma half-lives compared to 2-PAM which should be beneficial combating OPs that have delays in initiation of the cholinergic crisis. Some of our novel oximes can also effectively reactivate butyrylcholinesterase (BChE) inhibited by the anticholinesterase metabolites of OPs including phorate. BChE is prominent in serum and is inhibited by circulating oxons. An oxime that can effectively reactivate BChE, creating a pseudo-catalytic bio-scavenger of circulating oxons, could prevent or attenuate OP-induced toxicity. The Aims of this project are: 1) Characterize the temporal relationship between ChE inhibition and the phorate toxidrome, and the survival efficacy provided by 3 novel oximes; 2) Demonstrate in vitro (rat and human) and in vivo (male and female rats) with a down- selected lead novel oxime the ability to reactivate phorate inhibited BChE and enhance survival. The challenge dosage of phorate will be lethal (LD99) to rats receiving atropine only. A novel oxime or 2-PAM will be administered at the initiation of seizure-like behavior and at one earlier time point prior to initiation of cholinergic crisis. In addition, oxime-mediated reactivation of OP-inhibited BChE will allow a demonstration that pseudo-catalytic BChE-mediated destruction of OP can attenuate toxicity. A selective BChE inhibitor will be used to confirm the significance of BChE reactivation, as evidenced by a reduction of AChE inhibition and lethality in oxime-treated rats having functional BChE (rats not receiving the BChE inhibitor). The data from this translational project will be used to further develop an oxime into a more effective therapeutic for poisoning by insecticidal OPs, like phorate, that display a delayed toxidrome because they require bioactivation.

7.摘要 有机磷(OP)抗胆碱酯酶，如神经毒剂和一些杀虫剂，对 通过恐怖主义活动或事故造成的平民人口。这些OP化合物或代谢物是有效的 中枢和外周神经系统乙酰胆碱酯酶(AChE)的持久抑制剂。大剂量OP 接触可导致癫痫发作、呼吸衰竭和死亡。幸存者可能会遭受脑损伤和 行为缺陷。其中一种有机磷杀虫剂甲拌磷具有剧毒，是一种潜在的威胁。 与神经毒剂不同的是，甲拌磷需要对其抗胆碱酯酶代谢产物(氧离子)进行生物激活。 导致中毒症状延迟(4-5小时)(震颤、流口水和癫痫样行为)。目前的治疗方法(美国) 严重的OP中毒包括阿托品加乙酰胆碱酯酶复活剂2-PAM。两个人的主要限制是- PAM的血浆半衰期相对较短，不能通过血脑屏障(BBB)保护 大脑。我们的实验室已经发明并申请了一系列已经显示出生存功效和 大鼠暴露于高水平神经毒剂后癫痫样行为和神经病理的减轻 代用品和一种OP杀虫代谢物(对氧磷)。甲胺磷挑战后中毒症状的延迟 使给药时间和血药半衰期对建立有效的 治疗方案。与2-PAM相比，我们的新型先导化合物具有更长的血浆半衰期 这对打击延迟启动胆碱能危机的行动应该是有益的。我们的一些人 新的肟类还能有效地重新激活被抗胆碱酯酶抑制的丁酰胆碱酯酶(BChE) 有机磷农药的代谢物，包括甲拌磷。BChE在血清中显著存在，并被循环中的氧离子抑制。一个 可以有效地重新激活BChE的肟类，创造了一种循环氧的伪催化生物清除剂， 可以预防或减轻OP引起的毒性。该项目的目标是：1)刻画时间 甲胺磷毒素对胆碱酯酶抑制作用的影响及3-甲胺磷的生存效应 2)在体外(大鼠和人)和体内(雄性和雌性大鼠)证明有一种下 精选的新型先导肟能重新激活甲胺磷，抑制BChE，提高存活率。这个 甲拌磷的激发剂量将对只接受阿托品的大鼠致死(LD99)。一种新型的肟或2-PAM将 在癫痫样行为开始时和在开始发作前的一个较早时间点给药 胆碱能危象。此外，肟介导的OP抑制的BChE的重新激活将允许证明 假催化BChE介导的OP破坏可以减轻毒性。一种选择性的BChE抑制剂将是 用于确认BChE重新激活的意义，如AChE抑制和AChE抑制的减少和 具有功能性BChE的肟类处理大鼠(未接受BChE抑制剂的大鼠)的致死性。来自这里的数据 翻译项目将被用来进一步将一种肟开发成一种更有效的治疗中毒的方法 杀虫有机磷，如甲拌磷，表现出延迟的毒力，因为它们需要生物激活。