Acute Coronary Syndrome animal model

描述（由申请人提供）：大多数保护实验动物梗死面积的新治疗措施在临床上都失败了，很大程度上是因为它们仅在冠状动脉闭塞前给药时有效。我们的初步数据表明，腺苷酸环化酶5型（AC 5）抑制剂阿糖腺苷（也称为Ara-A，AraAde和Vira-A）在冠状动脉再灌注后给药时似乎可以减少梗死面积（见初步数据）。这种药物已经被FDA批准作为一种抗病毒化合物，将对接受再灌注治疗的心肌梗死（MI）患者有潜在的用处。更重要的是，这种药物将在急性冠状动脉综合征的情况下是有用的，急性冠状动脉综合征正变得越来越普遍1，尽管目前的进展，急性冠状动脉综合征的死亡率仍然很高2。急性冠状动脉综合征包括与急性心肌梗死（AMI）或心绞痛一致的广泛的临床病症，每年有136万人住院。急性冠状动脉综合征的关键特征是患者发生缺血性发作，给予医生即将发生MI的警告，使得在MI后使用减少梗死面积的药物非常有用，特别是在先前的缺血性事件后有效的药物。在阶段I中，我们将集中于确定AC 5抑制剂在以下两种情况下保护梗死面积的程度：在未发生缺血的心脏中，在冠状动脉闭塞后的冠状动脉再灌注后，在缺血后环境中，在15分钟后，（前哨）冠状动脉闭塞，其诱导小梗塞，随后在初始缺血损伤后8小时进行较长时间的测试缺血，在第一和第二窗口缺血预处理均不活跃时，以及在延长的30分钟缺血事件后施用AC 5抑制剂。一旦目标1和2完成，在第二阶段，我们建议在猪模型中测试AC 5抑制急性冠状动脉综合征的有效性和安全性，如果结果是积极的，我们将进入临床试验，因为drg已经被FDA批准。 公共卫生相关性：根据2009年AHA心脏病和中风统计数据，估计美国每5例死亡中就有1例是由冠心病和心肌梗死引起的。目前的提案将开发一种药物，已经FDA批准，可以给急性心肌梗死患者以及急性冠状动脉综合征患者。急性冠状动脉综合征包括与急性心肌梗死一致的广泛的临床病症，每年有136万人住院。

DESCRIPTION (provided by applicant): Most new therapeutic measures that protect infarct size in experimental animals have failed in the clinics, to a large extent because they are only effective when administered prior to coronary artery occlusion. Our preliminary data indicate that an adenylyl cyclase type 5 (AC5) inhibitor, vidarabine (also known as Ara-A, AraAde, and Vira-A) appears to reduce infarct size when administered after coronary artery reperfusion (see preliminary data). This drug, which is already FDA approved, as an antiviral compound, will be potentially useful for patients with myocardial infarction (MI), who undergo reperfusion therapy. Even more important, this drug will be useful in the setting of acute coronary syndrome, which is becoming increasingly prevalent1 and despite current advances, the mortality of acute coronary syndrome remains high2. Acute coronary syndrome encompasses a broad spectrum of clinical conditions consistent with acute myocardial infarction (AMI) or angina and accounts for 1.36 million hospitalizations a year. The key feature of acute coronary syndrome is that the patients develop ischemic episodes giving the physician warning of an impending MI, making the use of an agent that reduces infarct size after MI extremely useful, particularly one that is effective following a preceding ischemic event. In phase I we will focus on determining the extent to which AC5 inhibitor protects infarct size when administered either after coronary artery reperfusion following coronary occlusion in a heart virgin to ischemia, in the post ischemic setting after a 15 minute (sentinel) coronary occlusion which induces a small infarct followed by a longer period of test ischemia at 8 hours after the initial ischemic insult, at a time when neithr first nor second window ischemic preconditioning is active, and AC5 inhibitor administration after the prolonged 30 minute ischemic event. Once Aims 1and 2 have been completed, in phase II we propose to test AC5 inhibition for acute coronary syndrome in a pig model for efficacy and safety, and if the results are positive we will move to a clinical trial, since the drg is already FDA approved. PUBLIC HEALTH RELEVANCE: According to the 2009 AHA heart disease and stroke statistics it has been estimated that 1 out of every 5 deaths in the United States is caused by coronary heart disease and myocardial infarction. The current proposal will develop a drug, already FDA approved, that can be given to patients with acute myocardial infarction as well as to those with acute coronary syndrome. Acute coronary syndrome encompasses a broad spectrum of clinical conditions consistent with acute myocardial infarction and accounts for 1.36 million hospitalizations a year.