Novel antioxidant catalyst for transplant rejection

用于移植排斥的新型抗氧化催化剂

• 批准号: 6582431
• 负责人: PRAKASH G JAGTAP
• 金额: $ 22.7万
• 依托单位: INOTEK PHARMACEUTICALS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-01 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6582431
• 关键词: antioxidants; catalyst; combination chemotherapy; cyclosporines; cytoprotection; drug design /synthesis /production; drug screening /evaluation; heart transplantation; laboratory rat; peroxynitrites; transplant rejection

DESCRIPTION (provided by the applicant): Immune-mediated rejection is the principal obstacle to the use of heart transplantation for the treatment of end-stage cardiac failure. Current immunosuppressive regimens have limited efficacy and are associated with substantial toxicity. A key final common pathway of allograft injury is mediated by the free radical nitric oxide and the potent oxidant, peroxynitrite, which is formed from the reaction of nitric oxide and superoxide anion. Inotek is developing a novel class of peroxynitrite decomposition catalysts that are dramatically protective in experimental models of oxidant-mediated inflammatory diseases, including autoimmune arthritis, diabetes, and colitis. These agents are fundamentally superior to conventional anti-oxidants: First, they act as catalysts, rather than scavengers, and are therefore not consumed in the decomposition of oxidant species. Second, their reaction rate is in excess of 100 million, more than I million fold faster than classic anti-oxidants such as Vitamin C and E. Third, they have profound activity against both peroxynitrite and hydrogen peroxide, and thus provide broad-spectrum protection against oxidative and nitrosative stress. In vivo studies confirm their dramatic potency, as evidenced by protection in various models of inflammation at oral doses in the microgram per kg range. In experimental disease models, they have been shown to eliminate colitis, increase survival in endotoxic shock, and profundly reduce tissue damage during ischemia-reperfusion. The specific aim of the present proposal is to determine the benefit of our lead peroxynitrite decomposition catalyst, INO-1080, in the prevention of organ dysfunction and cellular injury in an experimental rodent model of heterotopic cardiac allograft rejection. We will establish the synergy of INO-1080, alone and with sub-therapeutic dosing of cyclosporine A. Demonstration that INO-1080 prevents tissue injury and prolongs allograft survival would represent a breakthrough in the design of novel anti-inflammatory regimens to prolong allograft survival. Phase II funding would support pharamcokinetic, toxicology, and pharmacodynamic studies required for IND submission and FDA-sanctioned clinical Phase I trials.

描述（由申请人提供）：免疫介导的排斥反应是使用心脏移植治疗终阶段心脏衰竭的主​​要障碍。当前的免疫抑制方案的功效有限，并且与实质性毒性有关。同种异体移植损伤的关键最终公共途径是由自由基一氧化氮和有效的氧化剂，过氧亚硝酸盐介导的，这是由一氧化氮和超氧化物阴离子的反应形成的。 Inotek正在开发一类新型的过氧亚硝酸盐分解催化剂，这些催化剂在氧化剂介导的炎性疾病的实验模型中具有显着保护性，包括自身免疫性关节炎，糖尿病和结肠炎。这些药物从根本上优于常规抗氧化剂：首先，它们充当催化剂，而不是清除剂，因此在氧化物种的分解中没有消耗。其次，它们的反应速率超过1亿倍，比经典的抗氧化剂（如维生素C和E）快的速度超过I百万倍，第三，它们具有对过氧亚硝酸盐和过氧化氢具有深刻的活性，因此提供了针对氧化和硝化应力的广谱保护。体内研究证实了它们的戏剧性效能，这是通过在每千克微克范围内的各种口服剂量的炎症模型中的保护证明的。在实验疾病模型中，已显示它们可以消除结肠炎，增加内毒性休克的存活率，并在缺血 - 再灌注期间大大减少组织损伤。本提案的具体目的是确定我们铅过氧亚硝酸盐分解催化剂INO-1080在预防器官功能障碍和细胞损伤中的益处，这是异性同种异体移植抑制的实验啮齿动物模型。我们将单独建立INO-1080的协同作用，并与环孢素A的亚治疗剂量进行。第二阶段的资金将支持IND提交和FDA批准的I期I期试验所需的毒干性，毒理学和药效学研究。