Novel Neuromuscular Protection to CounterACT Organophosphorus (OP) Poisoning

描述（由申请人提供）：OPs的急性毒性主要是由于乙酰胆碱酯酶（AChE）的抑制。目前对OP中毒的治疗需要使用阿托品进行复苏，随后给予肟类药物以重新激活乙酰胆碱酯酶，并使用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，根据负责的OP，即使在重症监护支持下仍有10%至40%的患者死亡。此外，神经肌肉传递的急性衰竭会导致呼吸衰竭和长期虚弱。这种神经肌肉连接处（NMJ）的衰竭最近被证明在严重中毒后数小时内发生。本应用的目的是确定烟碱受体拮抗剂罗库溴铵在维持乐果和对硫磷中毒的新型迷你猪NMJ功能和NMJ结构方面的生理和肌电图功效。我们的中心假设是，罗库溴铵的药物靶向NMJ将改善迷你猪OP中毒模型NMJ功能和NMJ结构。从这些研究中产生的数据将有助于进一步开展针对NMJ治疗靶点的研究活动。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

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.