Developing Drugs to Mitigate Parathion Intoxication

描述（由申请人提供）：当前研究的总体目标是开发一类新型治疗药物，该药物将减轻急性暴露于敌百虫（一种被认为是高优先级化学威胁的有机磷杀虫剂）引起的死亡率和发病率。氯磷的毒性取决于其通过细胞色素P450系统代谢为活性代谢物对氧磷。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鉴定出一种候选治疗剂，它是P40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，并已获得FDA批准用于其他适应症。在“原理验证”研究中，我们已经开发出强有力的证据，表明我们的药物在降低大鼠模型中的氯吡格雷毒性方面非常有效。我们已经进一步证明，我们的药物是有效的减少对硫磷诱导的抑制脑乙酰胆碱酯酶活性。我们的具体目标是研究我们的药物在细胞色素P450系统中的确切作用位点，以表征其在啮齿动物模型中减轻磷中毒的功效，并探索其改善目前使用的有机磷毒性治疗药物功效的潜力。 该提案的成功可能会导致快速开发一种新的药剂，用于治疗人类接触高度优先的化学品威胁。使用FDA批准的药物将大大减少监管批准所需的时间。

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.