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Advanced Development of Drugs to Mitigate Parathion Intoxication

减轻对硫磷中毒药物的先进开发

基本信息

批准号：
10227007
负责人：
JEFFREY D LASKIN
金额：
$ 75.92万
依托单位：
RBHS-SCHOOL OF PUBLIC HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2022-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10227007
关键词：
Accidents Acetylcholine Acetylcholinesterase Acetylcholinesterase Inhibitors Acute Advanced Development Adverse event Aftercare Agrochemicals Antidotes Antioxidants Ascorbic Acid Atropine Binding Blood - brain barrier anatomy Blood Coagulation Disorders Chemistry Cholinergic Antagonists Clinical Trials Cytochrome P450 Data Development Disease Dose Drug usage Effectiveness Electron Transport Emergency Situation Enzymes Exposure to FDA approved Generations Goals Human In Vitro Inflammatory Insecticides Intoxication Isoenzymes Laboratories Lead Lethal Dose 50 Malignant Neoplasms Mediating Metabolic Activation Metabolism Modeling Morbidity - disease rate Muscarinic Acetylcholine Receptor Muscarinic Antagonists NADP NADPH-Ferrihemoprotein Reductase Natural Disasters Natural regeneration Neurons New Agents Occupational Exposure Oral Administration Organophosphates Oxidation-Reduction Oximes Paraoxon Parathion Pesticides Pharmaceutical Preparations Phase Phase I/II Clinical Trial Poison Poisoning Publications Rattus Recording of previous events Research Risk Serum Site Symptoms System Terrorism Therapeutic Time Tissues Toxic effect Toxicology Translations Vitamin K 3 base carboxylesterase chemical threat drug development efficacious treatment enzyme activity experimental study exposed human population improved outcome in vivo inhibitor/antagonist inorganic phosphate mass casualty mortality nerve agent neurotoxicity novel novel strategies organophosphate poisoning pharmacokinetics and pharmacodynamics pre-clinical preclinical study prevent programs safety assessment standard of care success therapeutic candidate toxicant

项目摘要

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 (OP) 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 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. In 'proof-of-concept' studies, we have generated strong data showing that our drug is highly effective in reducing parathion toxicity. We have partnered with a company that has a drug product containing our candidate therapeutic in phase 1/phase 2 clinical trials. Our aims are to assess the ability of this drug product to inhibit bioactivation of parathion and reduce parathion toxicity in the rat model, conduct preclinical IND-enabling studies for the drug product for use in OP poisoning, and determine if the drug product can enhance the therapeutic actions of currently used drugs that are the standard of care in the treatment of OP 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.

目前研究的总体目标是开发一种新的治疗方法，以降低死亡率和急性暴露于敌百虫（一种有机磷杀虫剂，高度优先的化学威胁敌百虫的毒性依赖于细胞色素的代谢 P450系统的活性代谢物，对氧磷。通过抑制P450介导的对氧磷的产生，可以降低进行性毒性。我们实验室在氧化还原化学领域正在进行的研究已经导致涉及作为P450系统的高效抑制剂的候选治疗剂的鉴定。这种药这种药物毒性很低，目前正在进行其他疾病的高级临床试验， FDA批准用于其他适应症。在“概念验证”研究中，我们获得了强有力的数据，表明我们的药物能有效降低氯吡格雷的毒性我们与一家公司合作，在1期/2期临床试验中有一种含有我们候选治疗药物的药物产品。我们的目标是评估该制剂抑制大鼠中氯吡格雷生物活化和降低氯吡格雷毒性的能力模型，对用于OP中毒的制剂进行临床前IND使能研究，并确定该药物产品可以增强目前使用的药物的治疗作用， OP毒性的治疗。该提案的成功可能会导致一种新的代理人的快速发展，处理人类暴露于高度优先的化学威胁。使用FDA批准的药物将大大减少监管机构批准所需的时间。