Prevention of ischemia reperfusion injury associated with acute myocardial infarc

描述（由申请人提供）：Hope Pharmaceuticals是一家经销亚硝酸钠注射液的小型企业，并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缺血一段时间后，血液供应恢复到组织中所引起的组织损伤。一个部位缺乏氧气和其他重要的营养物质会造成这样一种情况，即该部位的循环恢复会导致炎症和氧化损伤，而不是正常功能的恢复。新回流的血液将免疫细胞带到该区域，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。急性心肌梗死动物模型研究表明，致死性缺血再灌注损伤约占心肌梗死最终面积的50%。亚硝酸钠的细胞保护作用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%。在犬的延长缺血模型中，缺血2小时后5分钟的亚硝酸钠治疗也导致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治疗标准侧重于快速恢复血液流动的治疗。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。如果一种治疗方法被证明是安全有效的，可以预防缺血再灌注损伤，梗死面积可以缩小，心功能得以保留，生活质量得以维持。最近完成了一项关于健康志愿者48小时静脉输注亚硝酸盐的安全性和药代动力学的一期临床研究。这项拨款申请旨在支持临床开发计划中的下一项研究：一项涉及急性心肌梗死患者的2期(a)研究。这项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。该研究的信息将用于设计后续的2期(B)和3期临床试验。

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.