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。 以及由急性接触对硫磷引起的发病率，对硫磷是一种被认为是有机磷(OP)的杀虫剂 高度优先的化学威胁。对硫磷的毒性依赖于其细胞色素的代谢。 P450系统转化为活性代谢物对氧磷。通过抑制P450介导的对氧磷的产生， 进行性毒性是可以减少的。我们实验室在氧化还原化学领域正在进行的研究 以确定一种候选治疗药物，该药物是P450系统的高效抑制剂。这种药物， 毒性非常低，目前正在进行其他疾病的高级临床试验，并已 被FDA批准用于其他适应症。在“概念验证”研究中，我们产生了强有力的数据 表明我们的药物在降低对硫磷毒性方面非常有效。我们与一家公司合作， 有一种药物产品，含有我们的候选治疗药物，正在进行1期/2期临床试验。我们的目标是 评价该药抑制对硫磷的生物活性和降低对硫磷毒性的能力 模型，对用于OP中毒的药物产品进行临床前IND使能研究，并确定是否 该药物产品可以增强目前使用的药物的治疗作用，这些药物是 OP中毒的治疗。这一提议的成功可能会导致一种新的代理的快速发展，以 治疗人类暴露在高度优先的化学威胁中。使用FDA批准的药物将大大减少 监管审批所需的时间。

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.