PND (POLYNITROXYL-DEXTRAN): GUT PROTECTION AFTER SHOCK

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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.