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: 7313289
• 负责人: STEVEN B BIRD
• 金额: $ 23.41万
• 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/7313289
• 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; Gas Poisoning; 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; Public Health; 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; suicidal; therapeutic protein

DESCRIPTION (provided by applicant): 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. If successful, the proposed research promises to improve public health by mitigating the acute toxic effects of pesticides after accidental, intentional, or suicidal poisoning. The research also has implications for the treatment of military personnel and civilians after nerve gas poisoning.

描述（由申请人提供）：有机磷（OP）农药中毒是许多发展中国家过早死亡的主要原因，仅在亚太地区每年就有20万人死亡。在北美和欧洲，情况则大不相同。虽然农药中毒确实会发生，但OP中毒的主要风险来自对平民的恐怖袭击-通过在拥挤的空间释放OP神经毒气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。目前OP中毒的治疗需要复苏和使用阿托品，然后给予肟重新激活AChE。然而，这些解毒剂的有效性有限，10%至40%的患者（取决于负责的OP）即使在重症监护支持下仍然死亡。尽管OP杀虫剂已经成为临床问题50年了，但自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以改善OP中毒后的结果，因此安全且高效且可由中毒现场急救人员提供的治疗应该会显着改善结果。细菌和人类都产生水解OP化合物的酶。重组细菌OP水解酶有可能提供一种经济实惠、广泛可用且安全的治疗方法，对多种OP快速有效。澳大利亚昆虫科学与工业研究组织开发了一种细菌酶，称为OpdA，对许多目前使用的OP具有优异的体外催化活性。在概念验证研究中，我们已经表明，OpdA单独使用或与2- PAM在敌敌畏和敌敌畏中毒大鼠模型中具有优异的疗效。然而，在对OP中毒的人类进行临床试验之前，还需要采取一些进一步的步骤，包括拟议的非人类灵长类动物研究。该资助的目的是开发一种新的非人灵长类动物（NHP）模型，并在该NHP模型中测试OpdA的安全性和有效性。证明这种酶对草甘膦是安全有效的，应该为人类使用的进一步发展提供必要的动力。我们的中心假设是，OpdA是安全的，并提高了中毒后的生存率。如果成功，拟议的研究有望通过减轻意外，故意或自杀性中毒后农药的急性毒性作用来改善公众健康。这项研究也对神经毒气中毒后军事人员和平民的治疗有影响。