ANIMAL TRIAL OF SEPTIC SHOCK WITH A NOVEL PARS INHIBITOR

一氧化氮（NO）和过氧亚硝酸盐是反应性的，短暂的物种，是休克和缺血再灌注细胞损伤的重要介质。特别是，过氧亚硝酸盐，一个短暂的有效的氧化剂，产生的超氧化物和NO，可以启动一系列的细胞毒性过程。 抑制NO或过氧亚硝酸盐的试剂，或防止NO或过氧亚硝酸盐诱导的血管和细胞毒性过程的试剂，当单独应用或与其它试剂组合应用时，可以是治疗休克的有用工具。Inotek公司正在开发一种独特的工具，5-氨基-6-碘-1，2-苯并吡喃酮（INH 2BP），这是一种有效的细胞可渗透的核酶聚（ADP-核糖）合成酶（PARS）抑制剂。在细胞培养和啮齿动物休克模型中的研究表明，内毒素诱导过氧亚硝酸盐的产生、DNA损伤和随后的PARS活化。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的药理学抑制改善了存活率和血管功能。本提案的具体目的是合成大量INH 2BP，并在感染性休克的大型动物模型中进行研究，以获得明确的原理证明，该试剂可以减少组织损伤并改善感染性休克中的血流动力学和存活率。申请人的意图是测试INH 2BP的抗冲击潜力。本申请的结果将提供最终的原则证明，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、体内疗效）、向FDA申请研究药物和1期临床试验。拟定商业应用：根据200万名患者每疗程10，000美元计算，全球有效、安全的抗休克药物市场估计为每年200亿美元。在今后15年中，对有效治疗休克的需求预计将稳步增加。SBIR第一和第二阶段的资金将允许在3.5年内进入市场。

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.