Advanced Development of Drugs to Mitigate Parathion Intoxication

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 监管批准所需的时间。

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.