"Development of 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疗法，以减轻急性接触对硫磷（一种被认为是高度优先化学威胁的有机磷杀虫剂）引起的死亡率和发病率。对硫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，可以预防或逆转进行性毒性。我们实验室在氧化还原化学领域正在进行的研究已经确定了一种候选疗法，它是 P450 系统的高效抑制剂。这种药物毒性极低，目前正在进行针对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。如果拟议的研究证明我们的候选疗法能够有效对抗对硫磷毒性，那么使用 FDA 批准的药物将大大减少监管批准所需的时间。我们的研究代表了一项“原理验证”提案，旨在生成有关我们药物功效的初步数据；这些研究的结果将有助于开发具有竞争力的应用程序，以获得 CounterACT 计划更广泛的支持。我们的具体目标是确定我们的药物在细胞色素 P450 系统中的精确作用位点，并在啮齿动物模型中测试其减轻对硫磷毒性的功效。该提案的成功可能会导致一种新药物的快速开发，以治疗人类暴露于高度优先的化学威胁。 公共卫生相关性：人们越来越担心蓄意的恐怖袭击、事故或自然灾害可能会释放有毒化学物质。对硫磷是一种容易获得且被认为具有特殊风险的有毒化学物质，它是一种有机磷杀虫剂。对硫磷是一种广泛使用的农用化学品，一旦被吸收到体内，就会成为一种有毒的神经毒剂，并代谢成一种称为对氧磷的反应性代谢物。对氧磷的主要作用位点是乙酰胆碱酯酶；这种酶的正常运作对于正常的神经细胞活动至关重要，其抑制可能是致命的。有多种治疗有机磷中毒的方法，包括阿托品（乙酰胆碱的竞争性拮抗剂）和解磷定（与有机磷失活的乙酰胆碱酯酶结合并再生该酶）。这两种药物都有局限性，仍然迫切需要开发新的更有效的对硫磷中毒疗法。该提案的成功将导致一种新药剂的快速开发，以治疗人类暴露于高度优先的化学威胁。

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 prevented or reversed. 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. Use of an FDA approved drug will greatly reduce the time required for regulatory approval should the proposed studies demonstrate that our candidate therapeutic is effective in counteracting parathion toxicity. Our studies represent a 'proof-of-principle' proposal designed to generate Preliminary Data on the efficacy of our drug; results from these studies will enable the development of a competitive application for more extensive support from the CounterACT program. Our specific aims are to identify the precise site of action of our drug in the cytochrome P450 system and to test its efficacy in mitigating parathion toxicity in a rodent model. Success of this proposal may lead to the rapid development of a new agent to treat human exposure to a high priority chemical threat. PUBLIC HEALTH RELEVANCE: There is increasing concern that toxic chemicals could be released by a deliberate terrorist attack, or by accident or natural disaster. One readily obtainable toxic chemical that is considered of particular risk is parathion, an organophosphate insecticide. Parathion is a widely used agricultural chemical that becomes a toxic nerve agent once absorbed into the body where it is metabolized to a reactive metabolite called paraoxon. A major site of action for paraoxon is the enzyme acetylcholinesterase; proper functioning of this enzyme is crucial for normal nerve cell activity and its inhibition can be fatal. There are several treatments for organophosphate poisoning including atropine, a competitive antagonist of acetylcholine, and pralidoxime which binds to organophosphate-inactivated acetylcholinesterase and regenerates the enzyme. Both of these agents have limitations and there remains a pressing need to develop new more efficacious therapies for parathion poisoning. Success of this proposal will lead to the rapid development of a new agent to treat human exposure to a high priority chemical threat.