ANIMAL TRIAL OF SEPTIC SHOCK WITH A NOVEL PARS INHIBITOR

使用新型 PARS 抑制剂进行感染性休克的动物试验

• 批准号: 2793632
• 负责人: ANITA MARTON
• 金额: $ 10万
• 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: 1999-05-01 至 2000-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2793632
• 关键词: adenine phosphoribosyltransferase; adenosine diphosphate; cardiovascular agents; cytotoxicity; drug design /synthesis /production; drug screening /evaluation; enzyme inhibitors; hemodynamics; multiple organ failure; nitric oxide; peroxynitrites; septic shock; sheep

Nitric oxide (NO) and peroxynitrite are reactive, short-lived species that are important mediators of cellular injury in shock and ischemia-reperfusion. In particular, peroxynitrite, a short-lived potent oxidant, produced from superoxide and NO, can initiate a range of cytotoxic processes. Agents which scavenge NO or peroxynitrite, or agents that prevent NO-or peroxynitrite induced vascular and cytotoxic processes can be useful tools in treating shock, when applied alone, or in combination with other agents. Inotek Corporation is developing a unique tool, 5-amino-6-iodo-1,2-benzopyrone (INH2BP), a potent, cell-permeable inhibitor of the nuclear enzyme poly (ADP-ribose) synthetase (PARS). Studies in cell culture and in rodent models of shock demonstrate that endotoxin induces peroxynitrite generation, DNA injury, and subsequent PARS activation. These processes can lead to acute cellular dysfunction and cell death. Accordingly, in rodent models of endotoxic shock, pharmacological inhibition of PARS improves survival and vascular function. The specific aim of the present proposal is to synthesize large quantities of INH2BP, and perform studies in a large animal model of septic shock in order to obtain definitive proof of principle that this agent can reduce the tissue injury and improve hemodynamics and survival in septic shock. The applicants' intention is to test the INH2BP for its potential against shock. The results of the present application will provide ultimate proof of principle and permit application for Phase 2 SBIR funding to support: pre-clinical pharmaceutical testing (advanced toxicity determinations, pathology, stability, pharmacokinetics, in vivo efficacy), investigational drug application to the FDA and Phase 1 clinical trial. PROPOSED COMMERCIAL APPLICATION: Worldwide the market for an effective, safe anti-shock pharmaceutical is estimated to be $20 billion per year, based upon 2 million patients @ $10,000 per treatment course. The demand for effective treatment of shock is expected to increase steadily over the next 15 years. Funding of SBIR Phase I and II will allow for market entry in 3.5 years.

一氧化氮 (NO) 和过氧亚硝酸盐是活性短暂的物质，是休克和缺血再灌注中细胞损伤的重要介质。特别是过氧亚硝酸盐，一种由超氧化物和 NO 产生的短效强氧化剂，可以引发一系列细胞毒性过程。 清除NO或过氧亚硝酸盐的药剂，或预防NO-或过氧亚硝酸盐诱导的血管和细胞毒性过程的药剂，当单独施用或与其他药剂组合施用时，可以是治疗休克的有用工具。 Inotek Corporation 正在开发一种独特的工具，5-氨基-6-碘-1,2-苯并吡喃酮 (INH2BP)，它是核酶聚 (ADP-核糖) 合成酶 (PARS) 的有效、细胞渗透性抑制剂。细胞培养和休克啮齿动物模型研究表明，内毒素会诱导过氧亚硝酸盐生成、DNA 损伤以及随后的 PARS 激活。这些过程可导致急性细胞功能障碍和细胞死亡。因此，在内毒素休克的啮齿动物模型中，PARS 的药理学抑制可改善存活率和血管功能。本提案的具体目的是合成大量INH2BP，并在大型动物感染性休克模型中进行研究，以获得该药物可以减少组织损伤、改善感染性休克中的血流动力学和生存的明确原理证明。申请人的目的是测试 INH2BP 的抗冲击潜力。本申请的结果将提供最终的原理证明，并允许申请 2 期 SBIR 资金，以支持：临床前药物测试（高级毒性测定、病理学、稳定性、药代动力学、体内功效）、向 FDA 的研究药物申请和 1 期临床试验。拟议的商业应用：全球有效、安全的抗休克药物市场估计每年达 200 亿美元，基于 200 万患者，每个疗程费用为 10,000 美元。预计未来 15 年对有效治疗休克的需求将稳步增长。 SBIR 第一期和第二期的资金将允许在 3.5 年内进入市场。