"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鉴定出一种候选治疗剂，它是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，并已获得FDA批准用于其他适应症。使用FDA批准的药物将大大减少监管批准所需的时间，如果拟议的研究表明我们的候选治疗药物能有效抵消阿托伐他汀的毒性。我们的研究代表了一个“原理证明”提案，旨在生成有关我们药物疗效的初步数据;这些研究的结果将使竞争性应用的开发能够得到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系统中的确切作用位点，并在啮齿动物模型中测试其减轻胆固醇毒性的功效。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。 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品。一种很容易获得的有毒化学品被认为具有特别的风险，它是一种有机磷杀虫剂。对硫磷是一种广泛使用的农业化学品，一旦被吸收到体内，就会成为一种有毒的神经毒剂，在体内代谢成一种称为对氧磷的活性代谢物。对氧磷的一个主要作用部位是乙酰胆碱酯酶;这种酶的正常功能对正常的神经细胞活动至关重要，其抑制可能是致命的。有几种治疗有机磷中毒的方法，包括阿托品（一种乙酰胆碱的竞争性拮抗剂）和解磷定（与有机磷灭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治疗氯吡格雷中毒的方法。该提案的成功将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.