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

基本信息

批准号：
9136875
负责人：
ROMOLO J GASPARI
金额：
$ 67.05万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9136875
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 Failure Functional disorder Goals Grant Hand Strength Health 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 acute toxicity cholinergic clinical application clinically relevant conventional therapy endurance exercise evidence base experience improved in vivo innovation mass casualty molecular imaging mortality muscle strength neuromuscular transmission neurophysiology novel pesticide poisoning treadmill

项目摘要

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。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The toxicology investigators consortium case registry-the 2013 experience.

毒理学调查员联盟病例登记——2013 年的经验。

DOI：
10.1007/s13181-014-0417-0
发表时间：
2014
期刊：
Journal of medical toxicology : official journal of the American College of Medical Toxicology
影响因子：
0
作者：
Rhyee,SeanH;Farrugia,Lynn;Wiegand,Timothy;Smith,EricA;Wax,PaulM;Brent,Jeffrey;ToxicologyInvestigatorsConsortium
通讯作者：
ToxicologyInvestigatorsConsortium