Prevention of ischemia reperfusion injury associated with acute myocardial infarc

急性心肌梗死相关缺血再灌注损伤的预防

• 批准号: 7909560
• 负责人: Craig Sherman
• 金额: $ 23.69万
• 依托单位: HOPE PHARMACEUTICALS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-19 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7909560
• 关键词: Accounting; Acute; Acute myocardial infarction; Aftercare; Animal Model; Applications Grants; Area; Behavior Therapy; Blood; Blood Circulation; Blood flow; Businesses; Canis familiaris; Cardiac; Cell membrane; Cells; Cessation of life; Clinical; Clinical Research; Complication; Continuous Intravenous Infusion; Development Plans; Dose; Drug Kinetics; Evaluation; Free Radicals; Goals; Government; Heart failure; Hour; Immune; Infarction; Inflammation; Inflammatory; Infusion procedures; Injection of therapeutic agent; Intravenous; Ischemia; Legal patent; Medical center; Modeling; Morbidity - disease rate; Mus; Myocardial; Myocardial Infarction; Nitrites; Nutrient; Oxygen; Patients; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase III Clinical Trials; Prevention; Property; Proteins; Quality of life; Reperfusion Injury; Request for Applications; Research Ethics Committees; Rights; Risk; Safety; Sodium Nitrite; Tissues; United States; United States Food and Drug Administration; Vascular blood supply; design; experience; healthy volunteer; intravenous administration; mortality; myocardial infarct sizing; oxidative damage; prevent; public health relevance; response; restoration; standard of care

DESCRIPTION (provided by applicant): Hope Pharmaceuticals is a small business that distributes Sodium Nitrite Injection and owns patent rights to a recently discovered use for sodium nitrite as a means to prevent ischemia-reperfusion injury. Ischemia-reperfusion injury refers to tissue damage caused when blood supply returns to the tissue after a period of ischemia. The absence of oxygen and other vital nutrients to an area creates a condition in which the restoration of circulation to the area can result in inflammation and oxidative damage rather than restoration of normal function. Immune cells carried to the area by the newly returning blood release a host of inflammatory factors in response to tissue damage. These inflammatory factors include free radicals that can damage cellular proteins and disrupt cell membranes. Studies in animal models of acute myocardial infarction suggest that lethal ischemia-reperfusion injury can account for approximately 50% of the final size of a myocardial infarct. The cytoprotective properties of sodium nitrite have been demonstrated in several animal models of myocardial infarction. In a murine model of myocardial infarction, intravenous administration of sodium nitrite significantly reduced cardiac infarct size by 67%. In a canine model of extended ischemia, five minutes of sodium nitrite treatment after two hours of ischemia also resulted in approximately 50% reduction in myocardial infarct size. In 2006, over 600,000 people in the United States were hospitalized with an acute myocardial infarction. The current standard of care for an acute myocardial infarction focuses on therapies to restore blood flow quickly. At present, no therapy has been approved by the Food and Drug Administration (FDA) to prevent ischemia-reperfusion injury in these patients. The morbidity and mortality associated with an acute myocardial infarction correlates inversely with infarct size. The goal is to minimize infarct size. If a therapy is proven safe and effective for the prevention of ischemia-reperfusion injury, infarct sizes may be reduced, cardiac function preserved, and quality of life maintained. A Phase 1 clinical study of the safety and pharmacokinetics of a 48-hour intravenous nitrite infusion in healthy volunteers was recently completed. This grant application is intended to support the next study in a clinical development plan: a Phase 2(A) study involving patients with acute myocardial infarction. This study is being conducted at Johns Hopkins Medical Center and has been approved to proceed by both the FDA and the Johns Hopkins' Institutional Review Board. Information from this study will be used to design subsequent Phase 2(B) and Phase 3 clinical trials. PUBLIC HEALTH RELEVANCE: Ischemia-reperfusion injury is a serious complication associated with acute myocardial infarction that is characterized by inflammation and oxidative damage to tissues caused when blood flow is restored after a period of ischemia. Ischemia-reperfusion injury can cause irreversible tissue damage. At present, there is no FDA-approved therapy for this condition. This grant application requests support for a Phase 2A clinical study that is part of a development plan to evaluatesodium nitrite injection as a therapy to prevent ischemia-reperfusion injury and thereby maintain the quality of life of patients who experience an acute myocardial infarction.

描述（由申请人提供）：希望制药公司是一家分销亚硝酸钠注射液的小企业，拥有最近发现的亚硝酸钠用于预防缺血再灌注损伤的专利权。缺血-再灌注损伤是指在缺血一段时间后血液供应返回组织时引起的组织损伤。一个区域缺乏氧气和其他重要营养物质会造成一种情况，在这种情况下，该区域的循环恢复可能导致炎症和氧化损伤，而不是恢复正常功能。免疫细胞被新回流的血液带到该区域，释放大量炎症因子以应对组织损伤。这些炎症因子包括自由基，可以破坏细胞蛋白质和破坏细胞膜。在急性心肌梗死动物模型中的研究表明，致死性缺血-再灌注损伤可占心肌梗死最终大小的约50%。亚硝酸钠的细胞保护特性已在几种心肌梗死动物模型中得到证实。在小鼠心肌梗死模型中，静脉注射亚硝酸钠可使心肌梗死面积显著减少67%。在犬的长期缺血模型中，在缺血两小时后给予亚硝酸钠治疗五分钟也可使心肌梗死面积减少约50%。2006年，美国有超过60万人因急性心肌梗死住院。目前急性心肌梗死的护理标准侧重于快速恢复血流的治疗。目前，美国食品和药物管理局（FDA）尚未批准任何治疗方法来预防这些患者的缺血再灌注损伤。急性心肌梗死的发病率和死亡率与梗死面积呈负相关。目标是使梗死面积最小化。如果一种治疗被证明是安全和有效的预防缺血再灌注损伤，梗死面积可能会减少，心脏功能的保护，生活质量的维持。最近完成了一项在健康志愿者中进行48小时静脉输注亚硝酸盐的安全性和药代动力学的I期临床研究。本基金申请旨在支持临床开发计划中的下一项研究：涉及急性心肌梗死患者的2期（A）研究。本研究正在约翰霍普金斯医学中心进行，并已获得FDA和约翰霍普金斯机构审查委员会的批准。本研究的信息将用于设计后续的II期（B）和III期临床试验。 公共卫生关系： 缺血-再灌注损伤是与急性心肌梗死相关的严重并发症，其特征在于缺血一段时间后血流恢复时引起的组织炎症和氧化损伤。缺血再灌注损伤可引起不可逆的组织损伤。目前，FDA还没有批准针对这种疾病的治疗方法。该资助申请要求支持2A期临床研究，该研究是开发计划的一部分，旨在评估亚硝酸钠注射液作为预防缺血再灌注损伤的治疗方法，从而维持急性心肌梗死患者的生活质量。