Novel Neuromuscular Protection to CounterACT Organophosphorus (OP) Poisoning

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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.