Novel Neuromuscular Protection to CounterACT Organophosphorus (OP) Poisoning

说明（由申请方提供）：有机磷农药的急性毒性主要是由于抑制乙酰胆碱酯酶。目前OP中毒的治疗需要使用阿托品复苏，然后给予肟以重新激活AChE，并给予苯二氮卓类药物以减轻神经系统并发症。然而，这些解毒剂的有效性有限，10%至40%的患者（取决于负责的OP）即使在重症监护支持下仍然死亡。此外，神经肌肉传递的急性衰竭导致呼吸衰竭和长期虚弱。这种神经肌肉接头（NMJ）的失效最近被证明在严重中毒后数小时内发生。本申请的目的是确定烟碱受体拮抗剂罗库溴铵在乐果和敌百虫中毒的新型小型猪模型中保护NMJ功能和NMJ结构的生理和肌电图功效。我们的中心假设是，罗库溴铵的药理学靶向NMJ将改善小型猪模型OP中毒的NMJ功能和NMJ结构。从这些研究中产生的数据将使针对NMJ治疗靶向的进一步研究活动的发展成为可能。最后，虽然这些研究非常适用于化学战和大规模伤亡情况，但它们也适用于 严重OP中毒的孤立病例每天都在美国和国外发生。 公共卫生相关性：如果成功的话，拟议的研究有望通过减轻有机磷农药的急性和亚急性毒性效应来改善公众健康。 或是意外中毒

DESCRIPTION (provided by applicant): The acute toxicity of OPs is primarily due to inhibition of acetylcholinesterase (AChE). Current therapy for OP poisoning requires resuscitation with the use of atropine, followed by administration of oximes to reactivate AChE, and benzodiazepines to mitigate neurological complications. However, these antidotes have limited effectiveness and between 10 and 40% of patients, depending on the responsible OP, still die even with intensive care support. Furthermore, acute failure of neuromuscular transmission leads to respiratory failure and prolonged weakness. This failure of the neuromuscular junction (NMJ) has recently been shown to occur within hours after severe poisoning. The purpose of this application is to determine the physiologic and electromyographic efficacy of the nicotinic receptor antagonist rocuronium in preserving NMJ function and NMJ architecture in novel minipig models of dimethoate and parathion poisoning. Our central hypothesis is that pharmacologic targeting of the NMJ with rocuronium will improve NMJ function and NMJ architecture in minipig models OP poisoning. Data generated from these studies will enable the development of further research activities directed towards therapeutic targeting of the NMJ. Lastly, while these studies are critically applicable to chemical warfare and mass casualty situations, they are also applicable to isolated cases of severe OP poisoning that occur every day in the U.S. and abroad. PUBLIC HEALTH RELEVANCE: If successful, the proposed research promises to improve public health by mitigating the acute and subacute toxic effects of OP pesticides after intentional or accidental poisoning.