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.

当前研究的总体目标是开发一种新型的治疗剂，以减轻死亡率急性暴露于Parathion（一种有机磷酸盐（OP）杀虫剂）引起的发病率高优先级化学威胁。 Parathion的毒性取决于其新陈代谢的细胞色素 P450系统到活性代谢产物，paraoxon。通过抑制p450介导的二氧氧气的产生，可以降低进行性毒性。我们在氧化还原化学领域实验室正在进行的研究已导致鉴定是P450系统的高效抑制剂的候选治疗方法。这种药物，毒性非常低，目前正在接受其他疾病的晚期临床试验，并且已经是经FDA批准其他适应症。在“概念证明”研究中，我们产生了强大的数据表明我们的药物在降低Parathion毒性方面非常有效。我们已经与一家公司合作在第1阶段/第2阶段临床试验中，有一个含有我们候选治疗的药物。我们的目标是评估该药物抑制Parathion生物活化并降低大鼠毒性的能力模型，为药物中毒中使用的药物进行临床前研究研究，并确定是否是否该药物可以增强目前使用的药物的治疗作用，这些药物是护理的标准 OP毒性的治疗。该提议的成功可能会导致新代理的快速发展治疗人类暴露于高优先级化学威胁。使用FDA批准的药物将大大减少监管批准所需的时间。