Pyruvate-enhanced cardiopulmonary resuscitation

描述(由申请人提供)： 心脏骤停几乎总是致命的。尽管美国的紧急医疗护理有了显著的改善，心脏骤停患者的预后仍然黯淡。心脏骤停会中断心脏和大脑的营养灌流，导致组织能量耗竭，细胞内钙积聚，并在再灌注时大量产生以氧为中心的细胞毒性自由基，最终导致这些重要器官的衰竭。同时提供代谢能量和中和氧自由基的干预措施在减轻细胞损伤和保护心脏骤停和复苏后心肌和大脑皮层的生理功能方面尤其有效。我们实验室最近的工作表明，天然碳水化合物丙酮酸可能是第一个被发现的多功能治疗药物。在缺血后心肌中，外源性丙酮酸在增强收缩性能的同时，显著增加能量储备和增强抗氧化氧化还原潜力。丙酮酸是无毒的，很容易穿过质膜和血脑屏障，因此它也可能是保护大脑免受缺血损伤的有效手段。这项应用的总体目标是确定丙酮酸在心脏骤停和关闭胸腔心肺复苏(CPR)期间保护心肌和大脑皮层的治疗效果。实验将在长期使用仪器测量左心室收缩功能和大脑皮层电生理活动的狗身上进行。心脏骤停5min后，经胸按压心肺复苏20min，心脏除颤恢复自主循环，同时监测心脑功能。在心肺复苏术和/或除颤后，丙酮酸将按规定的间隔和剂量静脉输注。能量和抗氧化剂储备、区域灌注和组织损伤将在心肌和大脑皮层的活组织检查中确定。丙酮酸盐对心脏和脑功能的长期影响将在停搏后3d进行研究。通过系统地确定丙酮酸的有效剂量、治疗窗口和细胞机制，本研究将为丙酮酸治疗心脏骤停的临床开发奠定基础。

DESCRIPTION (provided by applicant): Cardiac arrest is almost always fatal. Despite marked improvements in emergency medical care in the United States, the prognosis for victims of cardiac arrest remains bleak. Cardiac arrest interrupts nutritive perfusion of the heart and brain, leading to tissue energy depletion, intracellular calcium accumulation, and massive production of cytotoxic oxygen-centered free radicals upon reperfusion, culminating in failure of these vital organs. Interventions that both supply metabolic energy and neutralize oxyradicals would be particularly effective at mitigating cellular injury and preserving physiological function of myocardium and cerebral cortex following cardiac arrest and resuscitation. Recent work in our laboratory indicates that the natural carbohydrate pyruvate may be the first such pluripotent treatment identified. In post-ischemic myocardium, exogenous pyruvate markedly increases energy reserves and bolsters antioxidant redox potential in parallel with its enhancement of contractile performance. Pyruvate is nontoxic and readily traverses plasma membranes and the blood-brain barrier, so it could be an effective means of protecting the brain from ischemic injury, too. The overall objective of this application is to determine the therapeutic efficacy of pyruvate to protect myocardium and cerebral cortex during cardiac arrest and closed chest cardiopulmonary resuscitation (CPR). Experiments will be conducted in dogs chronically instrumented to measure left ventricular contractile function and cerebrocortical electrophysiological activity. After 5 min cardiac arrest, CPR will be administered by precordial chest compressions for 20 min, then hearts will be defibrillated to restore spontaneous circulation, while cardiac and cerebral function are monitored. Pyruvate will be infused intravenously at defined intervals and dosages during CPR and/or after defibrillation. Energy and antioxidant reserves, regional perfusion and tissue injury will be determined in biopsies of myocardium and cerebral cortex. Pyruvate's long-term impact on cardiac and cerebral function will be studied for 3 d post-arrest. By systematically determining the effective dosages, therapeutic window and cellular mechanisms of pyruvate's salutary effects, this investigation will establish the foundation for clinical development of pyruvate to treat cardiac arrest.