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

基本信息

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
项目类别：
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

项目摘要

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) 抗胆碱酯酶药物，例如神经毒剂和一些杀虫剂，对人体构成威胁。恐怖活动或事故造成的平民。这些 OP 化合物或代谢物是有效的并且中枢和周围神经系统乙酰胆碱酯酶（AChE）的持久抑制剂。高剂量OP 接触可能导致癫痫发作、呼吸衰竭和死亡。幸存者可能会遭受脑损伤行为缺陷。其中一种 OP 杀虫剂甲拌磷具有剧毒，使其成为潜在威胁。与神经毒剂不同，甲拌磷需要对其抗胆碱酯酶代谢物（oxons）进行生物激活，这导致中毒症状（震颤、流涎和癫痫样行为）延迟（4-5小时）。目前的治疗方法（美国）对于严重 OP 中毒，包括阿托品加肟乙酰胆碱酯酶 (AChE) 重激活剂 2-PAM。 2-的主要限制 PAM 的缺点是其血浆半衰期相对较短，并且无法穿过血脑屏障 (BBB) 并保护脑。我们的实验室发明了一系列肟并获得了专利，这些肟已显示出生存功效和大鼠暴露于高浓度神经毒剂后癫痫样行为和神经病理学减弱替代物和一种 OP 杀虫代谢物（对氧磷）。甲拌磷挑战后毒性症状的延迟使得肟给药的时机和肟血浆半衰期对于建立有效的治疗方案。与 2-PAM 相比，我们的主要新型肟具有更长的血浆半衰期这应该有利于对抗延迟引发胆碱能危机的OP。我们的一些新型肟还可以有效地重新激活被抗胆碱酯酶抑制的丁酰胆碱酯酶（BChE） OP 的代谢物包括甲拌磷。 BChE 在血清中含量很高，并被循环的oxon 抑制。一个肟可以有效地重新激活BChE，创造出循环氧子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）表征时间 ChE 抑制与甲拌磷氧化反应之间的关系，以及 3 提供的生存功效新型肟； 2) 演示体外（大鼠和人类）和体内（雄性和雌性大鼠）的下调选定的先导新型肟能够重新激活甲拌磷抑制的 BChE 并提高存活率。这甲拌磷的攻击剂量对于仅接受阿托品的大鼠来说是致命的（LD99）。新型肟或 2-PAM 将在癫痫发作样行为开始时以及在癫痫发作开始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 重新激活将证明伪催化 BChE 介导的 OP 破坏可以减轻毒性。选择性 BChE 抑制剂将是用于确认 BChE 重新激活的重要性，如 AChE 抑制的减少和肟处理的具有功能性 BChE 的大鼠（未接受 BChE 抑制剂的大鼠）的致死率。数据来自于此转化项目将用于进一步将肟开发为更有效的中毒治疗方法杀虫有机磷农药，如甲拌磷，由于需要生物活化而表现出延迟的氧化反应。