Novel Neuromuscular Protection to CounterACT Organophosphorus (OP) Poisoning

对抗有机磷 (OP) 中毒的新型神经肌肉保护

• 批准号: 8337703
• 负责人: STEVEN B BIRD
• 金额: $ 40.89万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8337703
• 关键词: Acetylcholinesterase; Acute; Address; Animal Model; Antidotes; Architecture; Atropine; Benzodiazepines; Chemical Warfare; Data; Development; Dimethoate; Effectiveness; Failure; Hour; Human; Intensive Care; Investigation; Laboratories; Mechanical ventilation; Methods; Military Personnel; Miniature Swine; Modeling; Morbidity - disease rate; Muscarinics; Muscle Weakness; NIH Program Announcements; Neurologic; Neuromuscular Junction; Nicotinic Receptors; Oximes; Parathion; Patients; Pesticides; Physiological; Physiology; Poisoning; Population; Public Health; Receptor Activation; Research; Research Activity; Respiratory Failure; Resuscitation; Seizures; Toxic effect; Toxin; United States National Institutes of Health; cholinergic; clinical application; clinically relevant; evidence base; hemodynamics; improved; innovation; mortality; nerve agent; neuromuscular; neuromuscular transmission; novel; pesticide poisoning; respiratory; therapeutic target

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.

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长期虚弱。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。本研究旨在探讨烟碱受体拮抗剂罗库溴铵在氧乐果和对硫磷中毒小型猪模型中保留NMJ功能和NMJ构筑的生理学和肌电效应。我们的中心假设是，在小型猪OP中毒模型中，以罗库溴铵为靶点的NMJ将改善NMJ功能和NMJ结构。这些研究产生的数据将使针对NMJ治疗靶点的进一步研究活动得以开展。最后，虽然这些研究关键地适用于化学战和大规模伤亡情况，但它们也适用于 在美国和国外每天都会发生严重的OP中毒的孤立案例。