Pharmacotherapy to counterACT parathion-induced NMJ dysfunction

描述(申请人提供)：有机磷农药的急性毒性主要是由于对乙酰胆碱酯酶(AChE)的抑制。目前对OP中毒的治疗需要使用阿托品进行复苏，然后使用肟类药物重新激活AChE，并使用苯二氮卓类药物来减轻神经系统并发症。然而，这些解毒剂的效果有限，根据负责的OP，10%至40%的患者即使在重症监护支持下仍会死亡。此外，神经肌肉传递的急性故障会导致呼吸衰竭和严重的虚弱。这种神经肌肉接头(NMJ)的失效最近被证明发生在严重中毒后的几个小时内。这项资助的目的是确定烟碱受体拮抗剂潘库溴铵在保护新的对硫磷中毒大鼠模型的NMJ功能和NMJ构筑方面的生理学和免疫组织化学效果。该模型将模拟中间综合征，由重症监护治疗和综合药物治疗组成，包括机械通气、阿托品、2-PAM、苯二氮卓类药物和血管增压剂。我们的中心假设是，在急性对硫磷中毒的大鼠模型中，以潘库溴铵为靶点的NMJ将改善肌肉力量和NMJ结构。最后，虽然这些研究非常适用于化学战和大规模伤亡情况，但它们也适用于美国和国外每天发生的严重OP中毒的个别案例。

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 profound weakness. This failure of the neuromuscular junction (NMJ) has recently been shown to occur within hours after severe poisoning. The purpose of this grant is to determine the physiologic and immunohistochemical efficacy of the nicotinic receptor antagonist pancuronium in preserving NMJ function and NMJ architecture in a novel rat model of parathion poisoning. This model will mimic the Intermediate Syndrome and consist of intensive care treatment with comprehensive medical therapy, including mechanical ventilation, atropine, 2-PAM, benzodiazepines, and vasopressors. Our central hypothesis is that pharmacologic targeting of the NMJ with pancuronium will improve muscle strength and NMJ structure in a rat model of acute parathion poisoning. 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.