Anti-ischemic Resuscitation Fluid

抗缺血复苏液

• 批准号: 7325501
• 负责人: Martin H Bluth
• 金额: $ 10.42万
• 依托单位: BIOMEDICA MANAGEMENT CORPORATION
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-05 至 2008-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7325501
• 关键词: Accidents; Acidosis; Address; Advocate; Age; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Biochemical; Blood Vessels; Blood Volume; Blood flow; Blood gas; Caring; Cause of Death; Cell Adhesion Molecules; Characteristics; Clinical; Data; Development; Dose; Down-Regulation; Drug effect disorder; Drug or chemical Tissue Distribution; E-Selectin; End Point; Evaluation; Experimental Designs; Experimental Models; Family suidae; Goals; Guidelines; Hemorrhage; Hemorrhagic Shock; Hour; Hybrids; Hypertonic Saline Solution; Hypotension; Hypovolemia; Hypovolemic Shock; IV Fluid; Individual; Inflammation; Inflammatory; Inflammatory Response; Infusion procedures; Injury; Integrins; Intercellular adhesion molecule 1; Ischemia; Laboratories; Length; Leukocytes; Liquid substance; Liver Function Tests; MAP Kinase Gene; Measures; Mediator of activation protein; Metabolic; Metabolism; Military Personnel; Modeling; Molecular; Morbidity - disease rate; NF-kappa B; Neutrophil Infiltration; Nitric Oxide Donors; Organ; Outcome; Oxygen; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Physiological; Physiological reperfusion; Play; Property; Pyrimidine; Pyrimidines; Rate; Rattus; Reperfusion Injury; Reperfusion Therapy; Resuscitation; Role; Saline; Secondary to; Selectins; Septic Shock; Shock; Signal Pathway; Signal Transduction; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Solutions; Staging; Standards of Weights and Measures; Study Section; Sus scrofa; TP53 gene; Thrombosis; Time; Tissues; Today; Trauma; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; United States; Universities; Up-Regulation; Venous; automobile accident; base; chemokine; concept; cytokine; cytotoxicity; day; design; experience; falls; human TNF protein; improved; inhibitor/antagonist; injured; ischemic lesion; liver function; mortality; novel therapeutics; preclinical study; pressure; prevent; response; restoration; small molecule

DESCRIPTION (provided by applicant): Inflammation after ischemia and reperfusion (I/R) injury secondary to hemorrhagic shock is responsible for significant mortality and morbidity in the United States. Available intravenous fluids administered at the incident scene to treat hypovolemic shock do not completely prevent ischemia and reperfusion injury. Re- initiation of blood flow causes activation of several inflammatory mediators of the cytokine type, selectins and other molecules that rapidly mobilize the inflammatory response with subsequent global organ damage. The goal of the proposed project is to prevent or reduce the deleterious effects of ischemic damage following resuscitation by optimizing the anti-inflammatory properties of the hypertonic saline (HS) (7.5%) resuscitation solution. The approach is based on the utilization of the anti-ischemic and anti-inflammatory anti-selectin compound OC-229 developed by our laboratory, which blocks adhesion molecules such as P-, L-, and E-selectins, ¿1, ¿2-, and a4 integrins, vascular adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) and of a nitroso pyrimidyl substance (EC-234) that acts as a nitric oxide donor. Our hypothesis is that this combination fluid will effectively regulate leukocyte recruitment and overcome the inflammatory and ischemic response by modulating undesirable molecular signaling pathways. In this regard, we have clearly demonstrated in several studies that following treatment with anti- selectins, the impaired physiological circulatory parameters of animals with HS were significantly improved and the survival was significantly increased in treated animals as compared to control. We propose to demonstrate, in a non-heparinized hybrid model of controlled-uncontrolled hemorrhagic shock resuscitation in the rat, an accepted model to study hypovolemic shock, that a small volume of 4 ml/kg of HS combined with anti-ischemic compounds OC-229 and/or EC-234, will: 1) have a meaningful protective physiopathologic response to hemorrhage/hypovolemia by improving the end points of mean arterial pressure, arterial blood gases and liver function response, and 2) improve protection as determined by animal survival seen at 3-7 days after hemorrhagic shock. The study will also assess the response of the molecular pathways associated with hemorrhage and improved treatment. A phase II study will further characterize the anti-inflammatory signaling mechanisms associated with the effect of the solution, and study tissue distribution, cytotoxicity, and evaluation of the physiological response to the optimal combination dose of the resuscitation fluid in a pig military-relevant model. More than 200,000 people in the U.S. die from septic shock and hemorrhagic shock each year. Trauma injury resulting from automobile accidents, bullet or knife wounds and falls is the primary reason for development of hemorrhagic shock, and is the leading cause of death for individuals under the age of 45 in the U.S. today. The single major cause of death in potentially salvageable battlefield casualties and in civilian accidents is hemorrhage and hypovolemic shock. Fluid resuscitation is the cornerstone of initial therapy for nearly all forms of shock, and a critical component of therapy for the critically injured patient. Significant efforts have been made to improve resuscitation fluids in order to protect from the cellular, biochemical and molecular deleterious changes following hemorrhage or ischemia, but to date no significant improvement in mortality has been demonstrated by this therapy, particularly in regard to the inflammatory consequences of hemorrhagic shock. This proposal advances new therapeutic applications to control and/or alleviate ischemia/reperfusion injury during and following resuscitation. The goal is to prevent or reduce the deleterious effects of ischemic damage following resuscitation by optimizing the anti-inflammatory properties of the hypertonic saline (HS) (7.5%) resuscitation solution.

描述（由适用提供）：缺血和再灌注后的炎症（I/R）继发于出血性休克的损伤是美国的重大死亡率和发病率。在事件现场进行的可用静脉输液以治疗低血容量休克不会完全预防缺血和再灌注损伤。血流的重新生产会导致细胞因子类型的几种炎症介质，Selectins和其他分子迅速动员炎症反应并随后的全球器官损伤。拟议项目的目的是通过优化高渗盐水（HS）（7.5％）复苏解决方案的抗炎特性来预防或减少复苏后缺血损伤的有害作用。 The approach is based on the utilization of the anti-ischemic and anti-inflammatory anti-selectin compound OC-229 developed by our laboratory, which blocks Adhesion molecules such as P-, L-, and E-selectins, ¿ 1, ¿ 2-, and a4 integrins, vascular adhesive molecule-1 (VCAM-1) and intercellular adhesive molecule-1 (ICAM-1) and of a用作一氧化氮供体的硝基嘧啶基物质（EC-234）。我们的假设是，这种组合流体将有效地调节白细胞募集，并通过调节不明显的分子信号通路来克服炎症和缺血反应。在这方面，我们在几项研究中清楚地证明了在用抗选择素治疗后，与对照相比，治疗的动物中，具有HS动物的动物的物理电路参数受损显着提高。我们建议在大鼠中受控无控制的出血性休克复苏的非热养杂交模型中证明，这是一种研究低血液性休克的公认模型，较小体积的4 ml/kg HS结合了抗渗透性化合物OC-229和/或EC-234的抗渗透性响应：1）具有强度的保护性。通过改善含义动脉压的终点，动脉血液和肝功能反应，以及2）改善通过出血性休克后3-7天的动物存活确定的保护。该研究还将评估与出血和改善治疗相关的分子途径的响应。 II期研究将进一步表征与溶液的作用相关的抗炎信号传导机制，并研究组织分布，细胞毒性，并评估对猪军事相关模型中复苏液的最佳组合剂量的物理反应。每年，美国有超过20万人死于败血性冲击和出血性休克。汽车事故，子弹或尼特菲赢家造成的创伤是出血性休克发展的主要原因，这是当今美国45岁以下个人死亡的主要原因。潜在可挽救的战场伤亡和平民事故中的单一主要死亡原因是出血和低血压冲击。流体复苏是几乎所有形式的休克的初始治疗的基石，也是重伤患者治疗的关键成分。为了保护出血或缺血后的细胞，生化和分子有害变化，已经采取了重大努力来改善复苏液，但迄今为止，这种疗法尚未证明死亡率的显着改善，尤其是在出血性休克的炎症后果方面。该提案推进了新的治疗应用，以控制和/或在复苏期间和之后减轻缺血/再灌注损伤。目的是通过优化高渗盐水（HS）（7.5％）复苏解决方案的抗炎特性来预防或减少复苏后缺血损伤的有害影响。