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（由申请方提供）：免疫介导的排斥反应是心脏移植治疗终末期心力衰竭的主要障碍。目前的免疫抑制方案具有有限的功效并且与实质性毒性相关。同种异体移植物损伤的一个关键的最终共同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，过氧亚硝酸盐是由一氧化氮和超氧阴离子反应形成的。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症性疾病的实验模型中具有显着的保护作用，包括自身免疫性关节炎，糖尿病和结肠炎。这些试剂从根本上上级于常规抗氧化剂：首先，它们充当催化剂，而不是清除剂，因此在氧化剂物质的分解中不会被消耗。其次，它们的反应速率超过1亿，比经典的抗氧化剂如维生素C和E快100万倍以上。第三，它们对过氧亚硝酸盐和过氧化氢都有很强的活性，因此可以提供广谱保护，防止氧化和亚硝化应激。体内研究证实了其显著的效力，如在微克/千克范围内的口服剂量下在各种炎症模型中的保护作用所证明的。在实验性疾病模型中，它们已被证明可以消除结肠炎，增加内毒素休克的存活率，并大大减少缺血再灌注期间的组织损伤。本提案的具体目的是确定我们的过氧亚硝酸铅分解催化剂INO-1080在异位心脏同种异体移植排斥的实验啮齿动物模型中预防器官功能障碍和细胞损伤的益处。我们将确定INO-1080单独使用和与亚治疗剂量的环孢霉素A的协同作用。INO-1080预防组织损伤和同种异体移植物存活的证明将代表在设计新的抗炎方案以延长同种异体移植物存活方面的突破。II期资金将支持IND提交和FDA批准的I期临床试验所需的药代动力学、毒理学和药效学研究。