PND (POLYNITROXYL-DEXTRAN): GUT PROTECTION AFTER SHOCK

PND（聚硝基右旋糖酐）：休克后的肠道保护

• 批准号: 6015646
• 负责人: Carleton Hsia
• 金额: $ 10万
• 依托单位: SYNZYME TECHNOLOGY, INC.
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-15 至 2001-05-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6015646
• 关键词: antioxidants; dextrans; disease /disorder model; disease /disorder prevention /control; drug screening /evaluation; electron spin resonance spectroscopy; gastrointestinal epithelium; hemorrhagic shock; laboratory rat; nitrogen oxides; oxidative stress; pharmacokinetics; polymers; vascular endothelium permeability

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.

胶体是休克复苏的主要支柱，但最近的证据表明，由于缺血/再灌注（I/R）对血管内皮的损害，因此目前的胶体治疗在某些重症患者中可能会出现问题。治疗策略应解决微脉管系统的健康以及体积的补充。在肠道粘膜中，I/R会导致屏障功能的丧失，导致细菌易位和败血症，这可能会在休克患者复苏后发生。活性氧对I/R病理生理学是核心，该提议的假设是具有有效抗氧化活性的复苏液可以减少肠损伤的严重程度。该项目将测试新的化合物PND（多硝基化右右右旋体）加上小分子量4-羟基-2,2,6,6-四甲基吡啶基 - 氧基（tempol），称为PND/Tempol。 PND是通过标记具有高摩尔比硝基氧化物（抗氧化酶模拟物）的右旋烷的标记而产生的。第一阶段的目标是：优化PND/Tempol剂量，硝化应力程度的生化测量方法，以及使用体内EPR光谱法在大鼠肠道上皮上皮过度透明度的出血性休克模型中使用体内EPR光谱法进行了药代动力学分析。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物的进一步发展。成功产品的医疗和商业利益将非常重要。拟议的商业应用：这项研究的预期结果是具有有效抗氧化剂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的影响，同时有助于体积的补充，从而代表了当前胶体治疗产品的重大进步。胶体疗法是一个重要的市场，因此，改进产品的医疗保健和经济影响将非常重要。