Use of an Organophosphorus (OP) Hydrolase for Acute OP Poisoning

使用有机磷 (OP) 水解酶治疗急性 OP 中毒

• 批准号: 7489907
• 负责人: STEVEN B BIRD
• 金额: $ 19.91万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7489907
• 关键词: Accidents; Acetylcholinesterase; Acute; Adverse effects; Animal Model; Antidotes; Asia; Atropine; Australia; Bacteria; Benzodiazepines; Biomedical Engineering; Cercopithecus pygerythrus; Cessation of life; Clinical; Clinical Trials; Collaborations; Conduct Clinical Trials; Crowding; Developed Countries; Developing Countries; Development; Dichlorvos; Dose; Drug Kinetics; Effectiveness; Entomology; Environment; Enzymes; Europe; Grant; Hour; Human; Human Development; Hydrolysis; Impairment; In Vitro; Intensive Care; Intravenous; Investigation; Kinetics; Lead; Lethal Dose 50; Military Personnel; Modeling; Natural Disasters; Neurologic; North America; Numbers; Oral; Organophosphorus Compounds; Outcome; Oximes; Oxygen; Parathion; Patients; Pesticides; Poisoning; Population; Procedures; Production; Property; Purpose; Rattus; Recombinants; Research; Research Personnel; Research Project Grants; Resuscitation; Risk; Safety; Site; Sri Lanka; Step Tests; System; Testing; Therapeutic Intervention; Therapeutic Uses; Toxic effect; Venous blood sampling; Water Supply; aryldialkylphosphatase; concept; cost; drug development; emergency service responder; improved; killings; nerve gas; nonhuman primate; pesticide poisoning; prevent; therapeutic protein

Organophosphorus (OP) pesticide poisoning is a leading cause of premature death in many developing countries, killing an estimated 200,000 people every year in the Asia-Pacific region alone. In North America and Europe, the situation is quite different. While pesticide poisoning does occur, the main risk of OP poisoning is from terrorist attacks on civilian populations ¿ through the release of OP nerve gases in crowded spaces or perhaps introduction of highly toxic pesticides into water supplies. The acute toxicity of OPs is primarily due to inhibition of acetylcholinesterase (AChE). Current therapy for OP poisoning requires resuscitation and use of atropine, followed by administration of oximes to reactivate AChE. 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. Although OP pesticides have been a clinical problem for 50 years, no new therapies have been introduced since the 1960s. Because early therapeutic interventions lead to improved outcomes after OP poisoning, a treatment that is safe and highly effective, and that can be given by first responders at the site of poisoning, should markedly improve outcome. Both bacteria and humans make enzymes that hydrolyze OP compounds. Recombinant bacterial OP hydrolases have the potential to provide an affordable, widely available, and safe treatment that is rapidly effective against a wide variety of OPs. CSIRO, Entomology, in Australia has developed a bacterial enzyme, called OpdA, with excellent in vitro catalytic activity against many currently used OPs. In proof-of-concept studies, we have shown that OpdA has excellent efficacy when used alone or with 2- PAM in rat models of parathion and dichlorvos poisoning. However, a number of further steps, including the proposed non-human primate studies, are required before clinical trials in humans with OP poisoning. The purposes of this grant are to develop a new non-human primate (NHP) model of parathion poisoning and to test the safety and efficacy of OpdA in this NHP model. Proof that the enzyme is safe and effective against parathion should provide the necessary impetus for further development for human use. Our central hypothesis is that OpdA is safe and improves survival after poisoning with parathion.

有机磷（OP）农药中毒是早产儿的主要原因之一。 在许多发展中国家，估计每年有20万人死亡， 仅亚太地区。在北美和欧洲， 不同.虽然农药中毒确实发生，但OP中毒的主要风险来自 通过释放OP神经毒气对平民进行恐怖袭击， 拥挤的空间或可能将剧毒农药引入供水系统。 有机磷农药的急性毒性主要是由于抑制乙酰胆碱酯酶 （乙酰胆碱酯酶）。目前OP中毒的治疗需要复苏和使用阿托品， 随后给予肟以重新激活AChE。然而，这些解毒剂具有 有效性有限，10%至40%的患者，具体取决于负责人 OP，即使在重症监护支持下仍然死亡。虽然OP杀虫剂一直是一种 临床问题50年来，自20世纪60年代以来没有引入新的治疗方法。 由于早期治疗干预可改善OP中毒后的结局， 一种安全高效的治疗方法，可以由第一反应者在 中毒部位，应能明显改善预后。 细菌和人类都产生水解OP化合物的酶。 重组细菌OP水解酶具有提供负担得起的、广泛应用的生物技术的潜力。 可用的、安全的治疗方法，对各种OP迅速有效。 澳大利亚的CSIRO昆虫学研究所开发了一种细菌酶，称为OpdA， 对许多目前使用的OP具有优异的体外催化活性。在概念验证中 研究，我们已经表明，OpdA具有优异的疗效时，单独使用或与2- PAM在敌敌畏和敌敌畏中毒大鼠模型中的应用。然而，一些进一步 在临床试验之前，需要采取步骤，包括拟议的非人灵长类动物研究。 OP中毒的人体试验 这项资助的目的是开发一种新的非人类灵长类动物（NHP） 目的：观察OpdA在NHP中的安全性和有效性 模型证明这种酶是安全有效的， 为人类的进一步发展提供了必要的动力。我们的核心假设是， OpdA是安全的，并提高了中毒后的生存与氟氯磷。

项目成果

Non-muscarinic therapeutic targets for acute organophosphorus poisoning.

急性有机磷中毒的非毒蕈碱治疗靶点。

• DOI: 10.1007/s13181-010-0093-7
• 发表时间: 2010
• 期刊: Journal of medical toxicology : official journal of the American College of Medical Toxicology
• 作者: Rosenbaum,Christopher;Bird,StevenB
• 通讯作者: Bird,StevenB