PND (POLYNITROXYL-DEXTRAN): GUT PROTECTION AFTER SHOCK

胶体是休克复苏的主要手段，但最近的证据表明，由于缺血/再灌注（I/R）对血管内皮的损伤，目前的胶体治疗在一些危重患者中可能存在问题；治疗策略应考虑到微血管的健康以及容量的补充。在肠黏膜中，I/R可导致屏障功能丧失，导致细菌易位和败血症，这可在休克患者复苏后发生。活性氧是I/R病理生理的核心，该建议的假设是具有强抗氧化活性的复苏液可以减轻肠道I/R损伤的严重程度。本项目将测试新的化合物PND（多硝基化右旋糖酐）加上小分子量的4-羟基-2,2,6,6-四甲基管道基氧基（Tempol），称为PND/Tempol。PND是通过标记葡聚糖与高摩尔比的氮氧化物，一种抗氧化酶模拟物。第一阶段的目标是：优化PND/Tempol剂量，亚硝化或氧化应激程度的生化测量，以及使用体内EPR光谱法对大鼠肠上皮高通透性失血性休克模型进行药代动力学分析。如果成功，该研究将导致PND作为一种具有强抗氧化活性的治疗胶体产品的进一步发展。一种成功的产品的医疗和商业效益将是极其显著的。拟议的商业应用：本研究的预期结果是具有强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展。胶体疗法是一个重要的市场，因此，这种改进产品的保健和经济影响将极为重要。

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.