Developing Drugs to Mitigate Parathion Intoxication

开发减轻对硫磷中毒的药物

基本信息

批准号：
8545998
负责人：
JEFFREY D LASKIN
金额：
$ 78.53万
依托单位：
RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
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：
2013-09-16 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8545998
关键词：
Accidents Acetylcholinesterase Acetylcholinesterase Inhibitors Acute Affect Aftercare Agrochemicals Animal Model Atropine Binding Biochemical Brain Carboxylic Ester Hydrolases Chemicals Chemistry Cholinergic Antagonists Clinical Trials Combined Modality Therapy Cytochrome P450 Data Development Disease Dose Drug Targeting Electron Transport Electrons Emergency Situation Enzymes Exposure to FDA approved Generations Goals Hepatocyte Insecticides Intoxication Isoenzymes Laboratories Lead Lethal Dose 50 Liver Microsomes Mediating Metabolism Modeling Morbidity - disease rate NADP NADPH-Ferrihemoprotein Reductase Natural Disasters Natural regeneration Neurons New Agents Organophosphates Oxidation-Reduction Oxidoreductase Oximes Paraoxon Parathion Pharmaceutical Preparations Poison Poisoning Process Protein Isoforms Rattus Research Risk Rodent Model Role Serum Signs and Symptoms Site System Testing Therapeutic Therapeutic Effect Therapeutic Uses Time Tissues Toxic effect Toxin Vitamin K 3 base carboxylesterase cytotoxicity drug metabolism exposed human population improved inhibitor/antagonist inorganic phosphate mortality nerve agent neurotoxicity novel novel strategies organophosphate poisoning prevent programs protective effect public health relevance research study success

项目摘要

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 reduced. 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 P40 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. In 'proof-of-principle' studies, we have developed strong evidence to show that our drug is highly effective in reducing parathion toxicity in a rat model. We have further demonstrated that our drug is effective in reducing parathion-induced inhibition of brain acetylcholinesterase activity. Our specific aims are to investigate the precise site of action of our drug in the cytochrome P450 system, to characterize its efficacy in mitigating parathion toxicity in a rodent model, and explor its potential to improve efficacy of currently used therapeutic drugs for organophosphate toxicity. Success of this proposal may lead to the rapid development of a new agent to treat human exposure to a high priority chemical threat. Use of an FDA approved drug will greatly reduce the time required for regulatory approval.

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，可以降低进行性毒性。在我们在氧化还原化学领域的实验室中正在进行的研究导致鉴定了候选治疗方法，该治疗方法是P40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。在“原理证明”研究中，我们开发了有力的证据，以表明我们的药物在降低大鼠模型中的Parathion毒性方面非常有效。我们进一步证明，我们的药物可有效减少对大脑乙酰胆碱酯酶活性的抑制作用。我们的具体目的是研究我们药物在细胞色素P450系统中的精确作用部位，以表征其在啮齿动物模型中降低Parathion毒性方面的功效，并探索其提高当前使用的有机磷酸盐毒性治疗药物疗效的潜力。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。使用FDA批准的药物将大大减少监管批准所需的时间。