POLYNITROXYL HEMOGLOBIN:NEUROPROTECTIVE OXYGEN CARRIER

描述：(研究人员摘要)多氮氧血红蛋白(PNH)将被 被开发为神经保护性氧气载体。PNH与%1不同 一代基于血红蛋白的氧气载体(HBOC)，因为它已经添加了 抗炎活性除氧载体功能外。PNH是 由共价连接的氮氧化物产生，是一氧化氮(NO)的类似物 一个胡椒“笼子”，HBOC。我们已经证明了PNH是一种氧载体，具有 抗炎超氧化物歧化酶和过氧化氢酶模拟活性。在 在本申请的第一阶段，我们建议将PNH开发为 抗炎氧载体，并证明其对 体外氧化损伤和体内神经保护。在此SBIR的第二阶段 应用，我们建议阐明PNH的机制和疗效 临床相关脑损伤模型的血液稀释方案。在一个 伴随阶段I/Il SBIR，题为“多氮氧基血红蛋白：临床前 我们建议对PNH进行毒理学研究，以供IND提交 给食品和药物管理局。 建议的商业应用： 一种具有抗炎活性的携氧复苏液，如PNH 非常可取。HBOC产品在高级临床开发中，仅提供氧气 送货。不幸的是，在严重出血或创伤期间，会有明显的炎症 (缺血和再灌流)损伤。炎症性损伤常导致多器官功能衰竭 (财政部)。因此，使用PNH是为了更好地预防创伤中的多器官功能衰竭 复苏可作为脑缺血、出血患者的神经保护性氧载体 和创伤性头部损伤。第二代HBOC的市场潜力被确定为 30亿美元/年。

DESCRIPTION: (Investigator's abstract) Polynitroxyl hemoglobin (PNH) will be developed as a neuroprotective oxygen carrier. PNH is different from 1st generation hemoglobin-based oxygen carriers (HBOCs) in that it has added anti-inflammatory activity in addition to oxygen carrier function. PNH is created by covalently attached nitroxides, an analogue of nitric oxide (NO) in a piperdine "cage," to HBOC. We have shown that PNH is an oxygen carrier with anti-inflammatory superoxide dismutase and catalase mimetic activities. In the Phase I of the present application, we propose to develop PNH as an anti-inflammatory oxygen carrier and demonstrate that it is resistant to oxidative damage in vitro and neuroprotective in vivo. In Phase II of this SBIR application, we propose to elucidate the mechanisms and efficacy of PNH with a hemodilution protocol in clinically relevant brain injury models. In a companion Phase I/Il SBIR entitled "Polynitroxyl Hemoglobin (PNH) : Preclinical Safety," we propose to conduct toxicology studies of PNH for an IND submission to FDA. PROPOSED COMMERCIAL APPLICATION: An oxygen carrying resuscitative fluid with anit-inflammatory activities such as PNH is highly desirable. HBOC products in advanced clinical development, provide only oxygen delivery. Unfortunately, during severe hemorrhage, or trauma, there is significant inflammatory (ischemia and reperfusion) injury. The inflammatory injury often lead to multiple organ failure (MOF). Therefore the use of PNH is to provide better protection against MOF in trauma resuscitation and can be used as a neuroprotective oxygen carrier in ischemic, hemorrhagic and traumatic head injury. The market potential for a 2nd generation HBOC is established to be 3 billion/year.