"Development of Drugs to Mitigate Parathion Intoxication"

“开发减轻对硫磷中毒的药物”

• 批准号: 8153112
• 负责人: JEFFREY D LASKIN
• 金额: $ 39万
• 依托单位: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8153112
• 关键词: Accidents; Acetylcholinesterase; Acetylcholinesterase Inhibitors; Acute; Aftercare; Agrochemicals; Atropine; Binding; Biochemical; Carboxylic Ester Hydrolases; Chemicals; Chemistry; Cholinergic Antagonists; Clinical Trials; Cytochrome P450; Data; Development; Disease; Dose; Drug Delivery Systems; Electron Transport; Electrons; Enzymes; Exposure to; FDA approved; Generations; Goals; Health; Hepatocyte; Insecticides; Intoxication; Isoenzymes; Laboratories; Lead; Lethal Dose 50; Liver Microsomes; Mediating; Metabolic Pathway; Metabolism; Morbidity - disease rate; NADP; NADPH-Ferrihemoprotein Reductase; Natural Disasters; Natural regeneration; Neurons; New Agents; Organophosphates; Oxidation-Reduction; Oxidoreductase; Paraoxon; Parathion; Pharmaceutical Preparations; Poison; Poisoning; Process; Protein Isoforms; Rattus; Research; Risk; Rodent Model; Role; Serum; Site; System; Testing; Therapeutic; Time; Tissues; Toxic effect; Toxin; Vitamin K 3; carboxylesterase; cytotoxicity; design; drug development; drug metabolism; exposed human population; in vivo; inhibitor/antagonist; inorganic phosphate; mortality; nerve agent; neurotoxicity; novel; organophosphate poisoning; prevent; programs; protective effect; success; vitamin analog

DESCRIPTION (provided by applicant): The overall goal of the current research is to develop a novel class of therapeutics that will mitigate mortality and morbidity caused by acute exposure to parathion, an organophosphate insecticide that is considered a high priority chemical threat. The toxicity of parathion is dependent on its metabolism by the cytochrome P450 system to an active metabolite, paraoxon. By inhibiting P450-mediated generation of paraoxon, progressive toxicity can be prevented or reversed. Ongoing research in our laboratory in the field of redox chemistry has led to the identification of a candidate therapeutic that is a highly effective inhibitor of the P450 system. This drug, which has very low toxicity, is currently undergoing advanced clinical trials for other diseases and has been approved by the FDA for other indications. Use of an FDA approved drug will greatly reduce the time required for regulatory approval should the proposed studies demonstrate that our candidate therapeutic is effective in counteracting parathion toxicity. Our studies represent a 'proof-of-principle' proposal designed to generate Preliminary Data on the efficacy of our drug; results from these studies will enable the development of a competitive application for more extensive support from the CounterACT program. Our specific aims are to identify the precise site of action of our drug in the cytochrome P450 system and to test its efficacy in mitigating parathion toxicity in a rodent model. Success of this proposal may lead to the rapid development of a new agent to treat human exposure to a high priority chemical threat. PUBLIC HEALTH RELEVANCE: There is increasing concern that toxic chemicals could be released by a deliberate terrorist attack, or by accident or natural disaster. One readily obtainable toxic chemical that is considered of particular risk is parathion, an organophosphate insecticide. Parathion is a widely used agricultural chemical that becomes a toxic nerve agent once absorbed into the body where it is metabolized to a reactive metabolite called paraoxon. A major site of action for paraoxon is the enzyme acetylcholinesterase; proper functioning of this enzyme is crucial for normal nerve cell activity and its inhibition can be fatal. There are several treatments for organophosphate poisoning including atropine, a competitive antagonist of acetylcholine, and pralidoxime which binds to organophosphate-inactivated acetylcholinesterase and regenerates the enzyme. Both of these agents have limitations and there remains a pressing need to develop new more efficacious therapies for parathion poisoning. Success of this proposal will lead to the rapid development of a new agent to treat human exposure to a high priority chemical threat.

描述（由申请人提供）：当前研究的总体目标是开发一类新型治疗药物，以减轻急性暴露于对硫磷（一种被认为是高度优先化学威胁的有机磷杀虫剂）引起的死亡率和发病率。对硫磷的毒性依赖于细胞色素P450系统对活性代谢物对硫磷的代谢。通过抑制p450介导的对氧磷的产生，可以防止或逆转进行性毒性。我们实验室在氧化还原化学领域正在进行的研究已经确定了一种候选治疗药物，它是P450系统的高效抑制剂。这种药物毒性非常低，目前正在进行其他疾病的高级临床试验，并已获得FDA批准用于其他适应症。使用FDA批准的药物将大大减少监管机构批准所需的时间，如果拟议的研究表明我们的候选治疗方法有效地抵消对硫磷毒性。我们的研究代表了一个“原理证明”提案，旨在生成我们药物疗效的初步数据；这些研究的结果将有助于开发具有竞争力的应用程序，以获得抵消计划更广泛的支持。我们的具体目标是确定我们的药物在细胞色素P450系统中的确切作用位点，并在啮齿动物模型中测试其减轻对硫磷毒性的功效。这一建议的成功可能会导致一种新的药剂的快速发展，以治疗人类暴露于高度优先的化学威胁。