XO INHIBITOR FOR THERAPY OF ACETAMINOPHEN INTOXICATION

用于治疗对乙酰氨基酚中毒的 XO 抑制剂

• 批准号: 6143505
• 负责人: ANDREW Lurie SALZMAN
• 金额: $ 62.84万
• 依托单位: INOTEK PHARMACEUTICALS CORPORATION
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6143505
• 关键词: acetaminophen; antiinflammatory agents; cytoprotection; detoxification; dogs; drug adverse effect; drug screening /evaluation; hepatotoxin; histopathology; laboratory mouse; laboratory rat; peroxidation; pharmacokinetics; pyrazolopyrimidine; xanthine oxidase inhibitor

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.

对乙酰氨基酚中毒的治疗是肝损伤的主要原因，在美国每年有2.5亿美元的市场。现有的独家市场进入者N-乙酰半胱氨酸的益处有限。在一项I期NIH SBIR中，我们已经证明，在对乙酰氨基酚严重小鼠中毒的实验模型中，给予黄嘌呤氧化酶抑制剂4-氨基-6-羟基吡唑[3，4-d]嘧啶（AHPP）可显著预防肝毒性。在II期SBIR中，我们现在建议：1）开发一种有效的放大合成工艺，以生产GMP级、千克级、批量的AHPP; 2）测定AHPP的体外和体内遗传毒性; 3）测定AHPP在大鼠和犬中的体内药代动力学、分布、代谢和排泄; 4）在大型动物模型中，按照灌胃给药途径测定AHPP的生物化学和组织病理学毒理学;和5）建立AHPP和当前市场进入者N-乙酰半胱氨酸的协同功效。剂量范围探索毒性研究将首先确定耐受性和安全性的大致水平。将进行连续一周的毒性研究，并获得完整的行为、生化和组织病理学特征。在此II期SBIR工作范围内的拟议研究将为1）向FDA提交IND申请以研究I期临床试验的安全性和耐受性以及2）通过私募筹集资金以支持AHPP的进一步商业开发提供基础。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：大量的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治疗;第二阶段SBIR工作范围的资金将允许在4年内进入市场。