Pharmacotherapy to counterACT parathion-induced NMJ dysfunction

对抗 ACT 对硫磷引起的 NMJ 功能障碍的药物治疗

• 批准号: 8735218
• 负责人: STEVEN B BIRD
• 金额: $ 8.31万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8735218
• 关键词: Acetylcholinesterase; Acute; Affect; Animal Model; Animals; Antidotes; Appearance; Architecture; Area; Atropine; Benzodiazepines; Chemical Warfare; Clinical effectiveness; Complication; Cranial Nerves; Critical Care; Effectiveness; Electromyography; Environmental air flow; Exercise; Failure; Functional disorder; Goals; Grant; Hour; Human; Imaging Techniques; Intensive Care; Interdisciplinary Study; Intervention; Intratracheal Intubation; Investigation; Laboratories; Limb structure; Measures; Mechanical ventilation; Medical; Methods; Modeling; Morbidity - disease rate; Muscarinics; Muscle; NIH Program Announcements; Neurologic; Neuromuscular Junction; Neuropathy; Nicotinic Receptors; Norepinephrine; Oximes; Paralysed; Parathion; Patients; Pesticides; Pharmacotherapy; Physiological; Physiology; Poisoning; Procedures; Public Health; Rattus; Recovery; Research; Resolution; Respiratory Failure; Respiratory Muscles; Resuscitation; Rotarod Performance Test; Structure; Syndrome; Toxic effect; Vasoconstrictor Agents; Work; cholinergic; clinical application; clinically relevant; conventional therapy; evidence base; experience; grasp; improved; in vivo; innovation; molecular imaging; mortality; muscle strength; neuromuscular transmission; neurophysiology; novel; pesticide poisoning; public health relevance

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.

描述（由申请人提供）：OP 的急性毒性主要是由于抑制乙酰胆碱酯酶（AChE）。目前OP中毒的治疗方法需要使用阿托品进行复苏，然后使用肟来重新激活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，即使有重症监护支持，仍有 10% 至 40% 的患者死亡，具体取决于负责的 OP。此外，神经肌肉传输的急性衰竭会导致呼吸衰竭和严重虚弱。最近的研究表明，这种神经肌肉接头（NMJ）故障会在严重中毒后数小时内发生。 该资助的目的是确定烟碱受体拮抗剂泮库溴铵在新型对硫磷中毒大鼠模型中保留 NMJ 功能和 NMJ 结构的生理学和免疫组织化学功效。该模型将模仿中间综合征，包括重症监护治疗和综合药物治疗，包括机械通气、阿托品、2-PAM、苯二氮卓类药物和血管加压药。我们的中心假设是，在急性对硫磷中毒大鼠模型中，用泮库溴铵靶向 NMJ 的药理作用将改善肌肉力量和 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有机磷中毒的孤立病例。