New methods to deliver therapeutic drugs in myocardial ischemia/reperfusion injur

心肌缺血/再灌注损伤递送治疗药物的新方法

• 批准号: 7773180
• 负责人: Richard Vander Heide
• 金额: $ 18.92万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7773180
• 关键词: Accident and Emergency department; Acidity; Adenosine; Adverse effects; Animal Model; Antioxidants; Area; Arts; Biochemical; Biological Models; Cardiac Myocytes; Cell Death; Cessation of life; Clinical Trials; Cytoskeleton; Development; Dose; Drug Delivery Systems; Drug Formulations; Event; Free Radical Scavengers; Free Radicals; Healthcare Systems; Heart; Human; Hydrogen; In Vitro; Infarction; Injury; Kinetics; Laboratories; Life; Methods; Mitochondria; Modeling; Morbidity - disease rate; Muscle Cells; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; Nanotechnology; Necrosis; Outcome; Oxygen; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Play; Polymers; Preparation; Proteins; Pump; Reperfusion Injury; Reperfusion Therapy; Research Personnel; Role; Side; Sodium; Techniques; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Toxic effect; United States; United States Public Health Service; Ventricular; base; catalase; cost; design; heart function; improved; in vivo Model; inhibitor/antagonist; inorganic phosphate; mortality; nanoparticle; novel therapeutics; oxidative damage; particle; prevent; public health relevance; trafficking

DESCRIPTION (provided by applicant):: Protecting myocytes from death is the best way to lower the mortality associated with myocardial infarction (MI). MI results from ischemia/reperfusion injury (IR). IR causes many detrimental changes in the biochemical and structural composition of myocytes including a rapid decrease in high-energy phosphate (ATP), destabilization and/or damage to the myocyte cytoskeleton, and progressive mitochondrial damage. It has been established that oxygen-derived free radicals (ODFR) play an important role in the overall injury associated with IR especially during the reperfusion phase. Reperfusion results in additional myocyte necrosis, which further increases the morbidity and mortality associated with MI. Over the past 20 years many drugs, including free radical scavengers, adenosine, and sodium-hydrogen exchange inhibitors, which have showed promise in animal models in reducing or inhibiting necrosis have been tried in human trials but have not proven to be beneficial in improving morbidity or mortality. Among the reasons that clinical trials of anti-ischemic compounds may have failed include: 1) the inability of potent drugs to reach effective concentrations without causing systemic side effects/toxicity; and/or 2) the inability to achieve effective concentrations of the drug at the myocyte. To truly know whether anti-ischemic drugs have a significant benefit in reducing infarct size requires delivery at an effective concentration at the correct time; at the start of reperfusion. The rapid development of nanotechnology has allowed the design of new delivery vehicles capable of trafficking drugs to specific areas where the action is most effective. In this highly interactive and integrated application, we propose to design and develop a new and unique delivery vehicle using state of the art pharmaceutical techniques capable of delivering therapeutic drugs to acidotic tissue. Delivering the drug to the acidotic tissue will allow rapid and sustained delivery of catalase to the myocardium throughout the reperfusion period. In these initial studies, we will use the endogenous anti-oxidant protein catalase. In addition to characterizing and optimizing the delivery of catalase-particles to ventricular myocytes, we will test the ability of delivered catalase to inhibit myocyte cell death using both in vitro and in vivo model systems of IR. If we are successful, this new vehicle would provide renewed opportunities for antioxidant drugs as well as stimulate the development of new therapeutic agents selectively designed to target many areas of IR injury as well as other aspects of myocardial infarction. PUBLIC HEALTH RELEVANCE: If achievable, this drug delivery vehicle could be given to a patient with a developing heart attack (i.e. a developing myocardial infarct) in the field or in the emergency department and directly reduce the cell death resulting from the event. The best predictor of morbidity and mortality subsequent to myocardial infarction is the amount of heart tissue that dies. Therefore, if the drug reduces the amount of cell death, it will directly reduce morbidity, mortality, and the cost to the patient and the overall health care system. Furthermore, our delivery vehicle is not restricted to the use of a single drug. In these initial studies we will use the readily available, well-characterized antioxidant catalase. However, the delivery vehicle would be adaptable to many other free radical scavengers as well other drugs that could be designed to directly reduce or prevent myocyte cell death. The ultimate outcome of such a drug delivery vehicle could have a large impact on the health care system in the United States.

描述（申请人提供）::保护心肌免受死亡的保护是降低与心肌梗塞（MI）相关的死亡率的最佳方法。 MI由缺血/再灌注损伤（IR）产生。 IR在肌细胞的生化和结构组成中引起许多有害的变化，包括高能磷酸盐（ATP）的快速降低，对肌细胞细胞骨架的不稳定和/或损害，以及进行性线粒体损伤。已经确定，氧衍生的自由基（ODFR）在与IR相关的总损伤中起着重要作用，尤其是在再灌注阶段。再灌注会导致额外的肌细胞坏死，从而进一步增加了与MI相关的发病率和死亡率。在过去的20年中，许多药物，包括自由基清除剂，腺苷和氢交换抑制剂，这些药物在动物模型中在减少或抑制坏死方面表现出了希望，但在人类试验中已经尝试过，但尚未证明对提高发病率或死亡率有益。在抗缺血化合物的临床试验可能失败的原因之一包括：1）有效药物无法达到有效浓度而不会引起全身副作用/毒性；和/或2）无法在肌细胞上实现有效浓度的药物浓度。真正知道抗缺血药物是否在减少梗塞大小的情况下是否有重大益处，需要在正确的时间以有效的浓度输送；在再灌注开始时。纳米技术的快速发展使设计新的运输车辆可以将药物运输到最有效的特定领域。在这种高度互动和综合的应用中，我们建议使用能够将治疗药物运送到酸性组织的最先进的药物技术设计和开发新的独特的输送车。在整个再灌注期间，将药物递送到酸性组织将允许过氧化氢酶的快速递送到心肌。在这些最初的研究中，我们将使用内源性抗氧化剂蛋白过氧化氢酶。除了表征和优化过氧化氢酶粒子向心室肌细胞的递送外，我们还将测试使用IR的体外和体内模型系统抑制递氧化氢酶抑制肌细胞细胞死亡的能力。如果我们取得成功，这款新车将为抗氧化剂提供新的机会，并刺激新的治疗剂的开发，以选择性地旨在针对许多IR损伤区域以及心肌梗死的其他方面。 公共卫生相关性：如果可以实现的话，可以将这种药物交付给患有心脏病发作的患者（即，在野外或急诊室中发育中的心肌梗死），并直接减少事件导致的细胞死亡。心肌梗死后发病率和死亡率的最佳预测指标是死亡的心脏组织量。因此，如果该药物减少了细胞死亡的量，它将直接降低患者和整体医疗保健系统的发病率，死亡率和成本。此外，我们的输送车不限于使用一种药物。在这些最初的研究中，我们将使用易于使用的良好特征抗氧化剂过氧化氢酶。但是，送货车将适用于许多其他自由基清除剂以及其他可以直接减少或预防心肌细胞死亡的药物。这种药物输送工具的最终结果可能会对美国的医疗保健系统产生重大影响。