"Development of Drugs to Mitigate Parathion Intoxication"

“开发减轻对硫磷中毒的药物”

• 批准号: 8548459
• 负责人: JEFFREY D LASKIN
• 金额: $ 7.74万
• 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/8548459
• 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种新型的治疗剂，该治疗剂将减轻急性暴露于Parathion引起的死亡率和发病率，急性暴露于Parathion（一种有机磷酸盐杀虫剂），这是一种被认为是高优先级化学威胁。 Parathion的毒性取决于其对活性代谢产物Paraoxon的代谢。通过抑制P450介导的二极管产生，可以预防或反转进行性毒性。我们在氧化还原化学领域实验室正在进行的研究导致鉴定了候选治疗，该治疗是P450系统的高效抑制剂。这种药物的毒性非常低，目前正在针对其他疾病进行晚期临床试验，并已获得FDA批准其他适应症。如果拟议的研究表明我们的候选治疗方法有效抵消Parathion毒性，则使用FDA批准的药物将大大减少监管批准所需的时间。我们的研究代表了旨在生成有关我们药物有效性的初步数据的“原则”提案；这些研究的结果将使竞争应用程序能够从反对计划中获得更广泛的支持。我们的具体目的是确定我们药物在细胞色素P450系统中的精确作用部位，并测试其在啮齿动物模型中降低Parathion毒性方面的功效。该提案的成功可能会导致一种新代理的快速发展，以治疗人类对高优先级化学威胁的暴露。 公共卫生相关性：越来越担心有毒化学物质可以通过故意的恐怖袭击，偶然或自然灾害释放。一种容易被认为具有特殊风险的有毒化学物质是Parathion，一种有机磷酸盐杀虫剂。 Parathion是一种广泛使用的农业化学化学物质，它是一种被吸收到体内的有毒神经剂，在该体体中被代谢为一种称为副氧气的反应性代谢产物。二氧氧气的主要作用部位是乙酰胆碱酯酶酶。该酶的正确功能对于正常的神经细胞活性至关重要，其抑制作用可能是致命的。有几种用于有机磷酸盐中毒的治疗方法，包括阿托品，乙酰胆碱的竞争性拮抗剂和用于与有机磷酸盐灭菌的乙酰胆碱酯酶结合并再生酶的pralidoxime。这两个代理都有局限性，并且仍然需要开发新的更有效的疗法来使Parathion中毒。该提案的成功将导致新的代理人快速发展，以治疗人类对高优先级化学威胁的暴露。