PND (POLYNITROXYL-DEXTRAN): GUT PROTECTION AFTER SHOCK

胶体是休克复苏的支柱，但最近的证据表明，由于缺血/再灌注（I/R）损伤血管内皮，目前的胶体治疗可能是有问题的，在一些危重患者;治疗策略应解决微血管系统的健康以及容量充盈。在肠粘膜中，I/R可引起屏障功能丧失，导致细菌移位和败血症，这可在休克患者复苏后发生。活性氧是I/R病理生理学的核心，该提议的假设是具有有效抗氧化活性的复苏液可以降低肠道I/R损伤的严重程度。该项目将测试新化合物PND（多硝基葡聚糖）加上小分子量4-lydroxyl-2，2，6，6-tetramethylpipidyl-oxyl（Tempol），称为PND/Tempol。PND是通过用高摩尔比的氮氧化物（一种抗氧化酶模拟物）标记葡聚糖而产生的。第一阶段的目标是：PND/Tempol剂量的优化、亚硝化或氧化应激程度的生物化学测量以及在大鼠肠上皮通透性过高的出血性休克模型中使用体内EPR光谱法的药代动力学分析。如果成功，该研究将导致PND作为具有有效抗氧化活性的治疗性胶体产品的进一步开发。一个成功的产品的医疗和商业利益将是非常重要的。拟议的商业应用：本研究的预期成果是具有强效抗氧化活性的治疗性胶体产品的商业开发。这将保护血管内皮免受缺血性损伤，同时有助于容量补充，从而代表了当前胶体治疗产品的重大进步。胶体治疗是一个重要的市场，因此这种改进产品的医疗保健和经济意义将非常重要。

Colloids are a mainstay of shock resuscitation, but recent evidence suggests that because of ischemia/reperfusion (I/R) damage to the vascular endothelium, current colloid therapy may be problematic in some critically ill patients; treatment strategy should address the health of the microvasculature as well as volume repletion. In the gut mucosa, I/R can cause a loss of barrier function, leading to bacterial translocation and the septicemia which can occur following resuscitation of shock patients. Reactive oxygen species are central to I/R pathophysiology, and the hypothesis of this proposal is that a resuscitation fluid with potent antioxidant activity can reduce the severity of gut I/R injury. This project will test the new compound PND (polynitroxylated dextran) plus small molecular weight 4-lydroxyl-2,2,6,6-tetramethylpipedyl-oxyl (Tempol) called PND/Tempol. PND is created by labeling dextran with a high molar ratio of nitroxide, an antioxidant enzyme mimic. Phase I goals are: optimization of a PND/Tempol dosage, biochemical measures of the degree of nitrosative or oxidative stress, and pharmacokinetic analysis using in vivo EPR spectrometry in a hemorrhagic shock model of intestinal epithelial hyperpermeability in the rat. If successful, the study will lead to further development of PND as a therapeutic colloid product with potent antioxidant activity. The medical and commercial benefits of a successful product would be extremely significant. PROPOSED COMMERCIAL APPLICATIONS: The expected outcome of this research is the commercial development of therapeutic colloid product with potent antioxidant activity. This would protect the vascular endothelium from ischemic injury while aiding in volume repletion, thereby representing a major advance on current colloid therapy products. Colloid therapy is an important market, and the health care and economic implications of this improved product would therefore be extremely significant.