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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来降低死亡率