XO INHIBITOR FOR THERAPY OF ACETAMINOPHEN INTOXICATION

对乙酰氨基酚中毒是肝损伤的主要原因，其治疗在美国每年有2.5亿美元的市场。目前市场上唯一的进入者n -乙酰半胱氨酸的效益有限。在一项I期NIH SBIR研究中，我们证明了黄嘌呤氧化酶抑制剂4-氨基-6-羟吡唑[3,4-d]嘧啶（AHPP）在对乙酰氨基酚严重中毒的小鼠实验模型中提供了显著的肝毒性保护。在二期SBIR中，我们现在建议：1)开发一种高效的规模化合成工艺，以生产gmp级、公斤级、批量的AHPP；2)测定AHPP的体内外遗传毒性；3)测定AHPP在大鼠和狗体内的药动学、分布、代谢和排泄；4)测定AHPP在大动物模型中按灌胃给药途径的生化和组织病理学毒理学；5)建立AHPP与当前市场进入者N-乙酰半胱氨酸的协同效应。范围毒性研究将首先确定耐受性和安全性的大致水平。将进行为期一周的最终毒性研究，并获得完整的行为、生化和组织病理学资料。该II期SBIR工作范围的拟议研究将为以下工作提供基础：1)向FDA申请IND，以研究I期临床试验中的安全性和耐受性；2)通过私募筹集资金，以支持AHPP的进一步商业开发。拟议的商业应用：对乙酰氨基酚中毒的新型有效疗法的国内市场估计为每年2.5亿美元。全球市场估计为8亿美元。目前的市场进入者是边际有效的：大量对乙酰氨基酚中毒经常导致暴发性肝衰竭，需要原位肝移植。AHPP可能是目前治疗方案的第一个高效和成功的辅助手段；第二期SBIR工作范围的资金将允许在4年内进入市场。

Treatment of acetaminophen intoxication, a leading cause of hepatic injury, represents a $250 million annual US market. The exclusive existing market entrant, N-acetylcysteine, is of limited benefit. In a Phase I NIH SBIR, we have demonstrated that administration of the xanthine oxidase inhibiter, 4- Amino-6-hydroxypyrazole[3,4-d]pyrimidine (AHPP), provided dramatic protection against hepatotoxicity in an experimental model of severe murine intoxication by acetaminophen. In a Phase II SBIR, we now propose to: 1) Develop an efficient scaled-up synthetic process to produce GMP-grade, kilogram-level, batch quantities of AHPP; 2) Determine the in vitro and in vivo genotoxicity of AHPP; 3) Determine the in vivo pharmacokinetics, distribution, metabolism, and excretion of AHPP in rats and dogs; 4) Determine the biochemical and histopathologic toxicology of AHPP in a large animal model per a gavage route of administration; and 5) Establish the synergistic efficacy of AHPP and the current market entrant, N- acetylcysteine. Range-finding toxicity studies will first establish the approximate level of tolerance and safety. Definitive one-week toxicity studies will be performed and a full behavioral, biochemical, and histopathologic profile obtained. The proposed studies in this Phase II SBIR scope of work will provide the foundation for 1) an IND application to the FDA to study safety and tolerance in a Phase I clinical trial, and 2) fund raising via private placement to support further commercial development of AHPP. 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 the Phase II SBIR scope of work will allow for market entry in 4 years.