Developing Drugs to Mitigate Parathion Intoxication

描述(申请人提供)：目前研究的总体目标是开发一类新的治疗方法，以减少急性接触对硫磷造成的死亡率和发病率，对硫磷是一种被认为是高度优先的化学威胁的有机磷杀虫剂。对硫磷的毒性依赖于细胞色素P450系统对活性代谢物对氧磷的代谢。通过抑制P450介导的对氧磷的生成，可以减少渐进毒性。我们实验室在氧化还原化学领域正在进行的研究已经确定了一种候选疗法，它是一种高效的P40系统抑制剂。这种毒性很低的药物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“原则证明”研究中，我们已经找到了强有力的证据，表明我们的药物在降低大鼠模型中的对硫磷毒性方面非常有效。我们进一步证明，我们的药物在减轻对硫磷对脑乙酰胆碱酯酶活性的抑制方面是有效的。我们的具体目标是研究我们的药物在细胞色素P450系统中的准确作用部位，在啮齿动物模型中表征其减轻对硫磷毒性的有效性，并发掘其提高目前使用的治疗有机磷中毒药物的疗效的潜力。 这一提议的成功可能会导致一种治疗人类暴露于高度优先的化学威胁的新试剂的快速开发。使用FDA批准的药物将大大缩短监管部门批准所需的时间。

DESCRIPTION (provided by applicant): 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 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 P40 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-principle' studies, we have developed strong evidence to show that our drug is highly effective in reducing parathion toxicity in a rat model. We have further demonstrated that our drug is effective in reducing parathion-induced inhibition of brain acetylcholinesterase activity. Our specific aims are to investigate the precise site of action of our drug in the cytochrome P450 system, to characterize its efficacy in mitigating parathion toxicity in a rodent model, and explor its potential to improve efficacy of currently used therapeutic drugs for organophosphate 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.