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。摘要有机磷酸盐（OP）抗胆碱酯酶，例如神经剂和某些杀虫剂，对通过恐怖活动或事故通过恐怖活动或事故的平民。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）的持续抑制剂。高剂量OP 暴露会导致癫痫发作，呼吸衰竭和死亡。幸存者可能会遭受脑损伤和行为不足。这些OP杀虫剂之一Phorate是非常急剧的毒性，这可能是一种潜在的威胁。与神经剂不同，phorate需要对其抗胆碱酯酶代谢产物（牛）生物活化导致有毒体征（震颤，唾液和癫痫发作行为）的延迟（4-5 h）。当前疗法（美国）对于严重的OP中毒，包括阿托品加上2-PAM的甲梅酸痛反抗器。 2-的主要限制 PAM是其相对较短的血浆半衰期，无法穿越血脑屏障（BBB）并保护脑。我们的实验室已经发明并申请了一系列牛，这些牛肉表现出了生存功效和大鼠暴露于高水平的神经剂后，类似癫痫的行为和神经病理学的衰减替代物和一种OP杀虫剂代谢产物（副代谢物）。 phorate挑战后有毒迹象的延迟使摄影剂的时间和Oxime血浆半衰期在建立有效的时间治疗方案。与2-PAM相比这应该是有益的对抗OP，在胆碱能危机开始时具有延迟。我们的一些新颖的氧气也可以有效激活丁乙酸酯酶（BCHE），抗胆碱酯酶抑制 OP的代谢物在内，包括Phate。 Bche在血清中很突出，并被循环牛群抑制。一个可以有效重新激活BCHE的氧电机，形成循环牛的伪催化的生物安全，可以预防或衰减毒性毒性。该项目的目的是：1）特征暂时性 CHE抑制与肥胖毒品之间的关系，以及3提供的生存功效新颖的Oximes； 2）表现出体外（大鼠和人）和体内（雄性和雌性大鼠）选定的新型氧电氧电能使重新激活phorate抑制的BCHE并增强存活能力。这挑战剂量的剂量将是致命的（LD99），仅接受阿托品的大鼠。新颖的氧电或2-PAM将会在启动癫痫发作行为的启动下，并在开始之前的一个早期时间点进行管理胆碱能危机。此外，Oxime介导的OP抑制BCHE的重新激活将允许证明伪催化的BCHE介导的OP破坏会减轻毒性。选择性BCHE抑制剂将是用于确认BCHE重新激活的显着性，这是通过减少ACHE抑制和具有功能性BCHE（大鼠未接受BCHE抑制剂的大鼠）的甲电处理大鼠的致死性。来自此的数据转化项目将用于进一步发展氧电，以使其在更有效的治疗中用于中毒杀虫剂（如Phate），由于需要生物活化而显示出延迟的毒品。