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（由申请人提供）：在美国，失血性休克继发的缺血和再灌注（I/R）损伤后的炎症是造成严重死亡和发病的原因，在事故现场用于治疗低血容量休克的可用静脉输液并不能完全预防。缺血和再灌注损伤的重新启动导致细胞因子类型的几种炎症介质、选择素和其他分子的激活，从而迅速动员随后的全身器官的炎症反应。该项目的目标是通过优化高渗盐水 (HS) (7.5%) 复苏溶液的抗炎特性来预防或减少复苏后缺血性损伤的有害影响。本实验室开发的抗缺血、抗炎抗选择素化合物OC-229，可阻断P-、L-、E-选择素等粘附分子， 1, ¿ 2- 和 a4 整合素、血管粘附分子-1 (VCAM-1) 和细胞间粘附分子-1 (ICAM-1) 以及充当一氧化氮供体的亚硝基嘧啶物质 (EC-234) 我们的假设是。这种组合液体将通过调节不良分子信号传导途径有效调节白细胞募集并克服炎症和缺血反应。在这方面，我们已经清楚地证明了。在几项研究中，与对照组相比，用抗选择素治疗后，HS动物受损的生理循环参数得到显着改善，并且治疗动物的存活率显着增加。大鼠受控-非受控失血性休克复苏，这是研究低血容量休克的公认模型，即小体积 4 ml/kg HS 与抗缺血化合物 OC-229 和/或EC-234，将：1) 通过改善平均动脉压、动脉血气和肝功能反应的终点，对出血/低血容量产生有意义的保护性生理病理反应，2) 改善根据 3-3 时动物存活率确定的保护作用失血性休克后 7 天，该研究还将评估与出血相关的分子途径的反应，并改进治疗，进一步表征与失血性休克的作用相关的抗炎信号机制。解决方案，并在猪军事相关模型中研究复苏液最佳组合剂量的组织分布、细胞毒性和生理反应评估。美国每年有超过 20 万人死于感染性休克和失血性休克。车祸、枪伤、刀伤和跌倒造成的外伤是失血性休克发生的主要原因，也是 45 岁以下人群死亡的主要原因。当今美国，可挽救的战场伤亡和平民事故的唯一主要原因是出血和低血容量休克，液体复苏是几乎所有形式休克的初始治疗的基石，也是重伤患者治疗的重要组成部分。为了防止出血或缺血后细胞、生化和分子的有害变化，人们已经做出了重大努力来改善复苏液体，但迄今为止，死亡率尚未得到显着改善。该疗法，特别是关于失血性休克的炎症后果，提出了控制和/或减轻复苏期间和之后的缺血/再灌注损伤的新治疗应用。通过优化高渗盐水 (HS) (7.5%) 复苏液的抗炎特性。