XO INHIBITOR FOR THERAPY OF ACETAMINOPHEN INTOXICATION

扑热息痛的急性肝毒性是一个主要的健康问题，因为这种止痛药是故意过量使用的最常用药物之一。扑热息痛中毒的临床表现是快速和进行性的肝损伤，可能导致死亡。对乙酰氨基酚中毒发病机制的一个关键方面是激活炎症细胞产生一氧化氮和超氧阴离子自由基，以及它们的反应产物--强大的氧化剂过氧亚硝酸盐。目前对乙酰氨基酚所致肝毒性的抗炎治疗方案疗效有限。INovk公司正在开发一种独特的抗炎吡唑并[3，4-d]嘧啶衍生物4-氨基-6-羟基吡唑并[3，4-d]嘧啶(AHPP)，它可以选择性地抑制黄嘌呤氧化酶(XO)的活性。鉴于超氧阴离子自由基的产生和XO激活在肝脏炎症损伤的发生中所起的关键作用，我们假设AHPP代表着一种具有巨大商业潜力的创新治疗候选方案。AHPP需要在临床相关和严格的对乙酰氨基酚中毒实验模型中证明其有效性，才能证明其作为一种预防肝功能衰竭的新型抗炎药的商业化。在特定的目标#1中，我们将在一个公认的扑热息痛中毒的啮齿动物模型中测试这一假设。在具体目标#2中，我们将确定AHPP没有遗传毒性。证明AHPP无致突变性并有效预防组织学损伤、组织脂质过氧化和血清转氨酶升高，将代表着设计治疗对乙酰氨基酚中毒的新方案的突破，并证明其进一步商业化开发是合理的。拟议的商业应用：对乙酰氨基酚中毒的一种新的、有效的治疗方法在国内市场每年估计为2.5亿美元。据估计，全球市场规模为8亿美元。目前的市场进入者略微有效：大量对乙酰氨基酚中毒经常导致暴发性肝功能衰竭，需要进行原位肝移植。AHPP可能是当前治疗方案的第一个高度有效和成功的辅助方案；SBIR第一和第二阶段的资金将允许在4年内进入市场。

The acute hepatotoxicity of acetaminophen is a major health concern since this analgesic is one of the most commonly used drugs in intentional overdose. The clinical presentation of acetaminophen toxicity is characterized by rapid and progressive liver injury that may result in death. A critical aspect of the pathogenesis of acetaminophen toxicity is the activation of inflammatory cells to produce nitric oxide and superoxide radical, and their reaction product, the potent oxidant peroxynitrite. Current anti-inflammatory treatment regimens for acetaminophen-induced hepatotoxicity have limited efficacy. Inotek Corporation is developing a unique anti-inflammatory pyrazolopyrimidine derivative, 4- Amino.6.hydroxypyrazolo[3,4-d] pyrimidine (AHPP), which selectively inhibits xanthine oxidase (XO) activity. Given the critical role that superoxide radical production and XO activation play in the generation of hepatic inflammatory injury, we hypothesize that AHPP represents an innovative therapeutic candidate with significant commercial potential. AHPP requires demonstration of efficacy in a clinically relevant and stringent experimental model of acetaminophen intoxication in order to justify its commercialization as a novel anti-inflammatory agent for the prevention of liver failure. In Specific Aim #1, we will test this hypothesis in a well-established rodent model of acetaminophen intoxication. In Specific Aim #2, we will establish that AHPP is not genotoxic. The demonstration that AHPP is not mutagenic and effectively prevents histologic injury, tissue lipid peroxidation, and serum transaminasemia would represent a breakthrough in the design of novel regimens for the treatment of acetaminophen intoxication and would justify its further commercial development. PROPOSED COMMERCIAL APPLICATIONS: The domestic market for a novel, effective therapy for acetaminophen intoxication is estimated at $250 million per annum. Global markets are estimated at $800 million. Current market entrants are marginally effective: massive acetaminophen intoxication frequently results in fulminant liver failure necessitating orthotopic liver transplantation. AHPP may represent the first highly potent and successful adjunct to the current therapeutic regimen; funding of SBIR Phases I and II will allow for market entry in 4 years.