PARS INHIBITOR FOR THE THERAPY OF CIRCULATORY SHOCK

描述（来自申请人的摘要的逐字）：基于在 根据体外和体内数据，申请人正在开发新型的 具有抗休克作用和显著治疗潜力的化合物。 在这项提案中，我们提出的证据表明，选择新的抑制剂， 聚（DP-核糖）合成酶（PARS）是（1）细胞保护剂和抑制剂 体外氧化剂诱导的细胞坏死，（2）抑制剂的生产， 体外巨噬细胞源性促炎介质，（3）强效抗休克 大鼠和小鼠的全身炎症，最后（4），一种选择性的，有效的 这类新型PARS抑制剂的成员（例如PJ 34）提供了显著的 在严重的血流动力学崩溃和休克的猪模型中的保护。这些 观察结果，加上申请人实验室和几个实验室的数据， 其他研究小组，证明PARS敲除小鼠是大规模的， 保护免受各种形式的冲击，共同支持申请人的 建议，这是有效的药理学抑制剂的PARS可以是 作为一种新型的抗休克剂。申请人打算 开发PJ 34作为抗休克药物。目前的第一个具体目标 建议在啮齿动物和猪系统中进行额外的研究， 确定PJ 34干预的窗口期，最合适的剂量 管理，并确定最佳的策略，停止 那个特工该提案的另一个具体目标是， GMP-量的PJ 34化合物，并配制成静脉内给药制剂。 可注射的这些研究将在第二年进行，随后 正式的临床前毒性研究，以及在正常人中进行的I期a研究 志愿者目前的项目将使申请人能够在以下方面取得进展： 两年，接近II期疗效试验开始时的水平， 败血症患者 拟定商业应用： 不可用

DESCRIPTION (Verbatim from the Applicant's Abstract): Bases on promising in vitro and in vivo data, the applicants are developing novel classes of compounds with anti-shock effects, and with significant therapeutic potential. In this proposal, we present evidence that selected novel inhibitors of poly(DP-ribose) synthetase (PARS) are (1) cytoprotective agents and inhibitors of oxidant-induced cell necrosis in vitro, (2) inhibitors of the production of macrophage-derived pro-inflammatory mediators in vitro, (3) potent anti-shock systemic inflammation in rats and mice and, finally (4), a selected, potent member of this novel class of PARS inhibitors (e.g. PJ34) provides dramatic protection in a porcine model of severe homodynamic collapse and shock . These observations, coupled with data from the applicant's laboratories and several other research groups, demonstrating that PARS knockout mice are massively protected against various forms of shock, collectively support the applicant's proposal, which is that potent pharmacological inhibitors of PARS can be developed as a novel class of anti-shock agents. The applicant's intend to develop PJ34 as an anti-shock drug. The first specific aims of the present proposal is to perform additional studies in the rodent and porcine system with PJ34 to determine the window of intervention, the most appropriate dose of administration, and to determine the optimal strategy for discontinuation of the agent. An additional specific aim of the proposal is to synthesize large GMP-quantities of the PJ34 compound, and to formulate as an intravenous injectable. These studies will be performed in the second year, followed by formal preclinical toxicity studies, and Phase I a study in normal human volunteers. The current project will enable the applicants to move forward in two years, near to the level of the beginning of Phase II efficacy trial in septic patients. PROPOSED COMMERCIAL APPLICATION: Not Available