THE EFFECT OF HMG COA REDUCTASE INHIBITORS ON CBF

描述：(逐字摘自申请人的摘要) 3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂(他汀类)增加 上调血管内皮细胞对小鼠基础脑血流量的影响 一氧化氮合酶(ENOS)。血液流量的增加为大脑提供了 对缺血的保护。这一机制可能是造成这种减少的原因 在他汀类药物的临床试验中观察到的缺血性中风风险 有动脉粥样硬化危险因素的患者。这项工作的主要目标是 翻译研究旨在检验以下假设：(1)他汀类药物治疗将 增加动脉粥样硬化性冠心病患者的脑血流量(特定目标 1)，已有中风风险降低的报告，以及(2)他汀类药物 不会增加动脉粥样硬化性脑血管病患者的脑血流量 和预先存在的自动调节性血管扩张(特定目标2)。 动脉粥样硬化性冠状动脉疾病患者(n=30)或 单侧颈动脉闭塞(n=40)将进入随机、 辛伐他汀治疗(每天40毫克)对照双盲研究 安慰剂30天。将对CBF进行定量的区域测量 在基线和30d时进行正电子发射断层扫描。次要的 目的是确定：(1)他汀类药物是否会增加脑血流量。 闭塞颈动脉对侧大脑半球；(2) 辛伐他汀对一氧化氮介导的外周血管扩张的影响 反应；以及(3)如果治疗导致血清中 一氧化氮代谢物。 拟议中的研究将确定他汀类药物是否能增加人类的脑血流 中风的风险，并将提供对这些疾病的机制的洞察 药物为冠心病患者提供中风保护。如果没有 对DBF的影响还发现了其他机制，如抗血栓或 他汀类药物的抗动脉粥样硬化作用，可能是更重要和进一步的药物 开发可以进行适当的调整。此外，来自这些网站的数据 研究将确定他汀类药物是否可以增加患有高血压的人的脑血流 动脉粥样硬化性脑血管疾病，有无血流灌注减少 压力。这些实验的积极结果将进一步支持 一种潜在的重要卒中保护机制的研究 适用于所有动脉粥样硬化性心脑血管疾病患者 疾病。

DESCRIPTION: (Verbatim from the Applicant's Abstract) 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) increase basal cerebral blood flow (CBF) in mice through upregulation end endothelial nitric oxide synthase (eNOS). The increase in blood flow provides cerebral protection from ischemia. This mechanism may be responsible for the reduction in the risk of ischemic stroke observed in clinical trials of statins in patietns with atherosclerotic risk factors. The primary objectives of this translational study are to test the hypotheses that (1) statin therapy will increase CBF in patients with atherosclerotic coronary disease (Specific Aim 1), in whom the stroke risk reduction has been reported, and (2) that statins will not increase CBF in patients with atherosclerotic cerebrovascular disease and pre-existing auto regulatory vasodilatation (Specific Aim 2). Patients with either atherosclerotic coronary artery disease (n=30) or unilateral carotid artery occlusion (n=40) will be entered in a randomized, controlled , double-blinded study of simvastatin therapy (40 mg per day) versus placebo for 30 days. Quantitative regional measurements of CBF will be made with positron emission tomography at baseline and at 30 days. Secondary objectives are to determine: (1) if statin therapy will increase CBF in the hemisphere contralateral to the occluded carotid artery; (2) the magnitude of the effect of simvastatin on peripheral nitric oxide mediated vasodilatory responses; and (3) if treatment results in an increase in serum levels of nitric oxide metabolites. The proposed studies will determine whether statins can increase CBF in humans at risk for stroke and will provide insight into the mechanism by which these drugs provide stroke protection in patients with coronary artery disease. If no effect on DBF is found other mechanism such as antithrombotic or antiatherosclerotic effects of statins, may be more important and further drug development can be tailored appropriately. In addition, the data from these studies will determine if statins can increase CBF in humans with atherosclerotic cerebrovascular disease, with and without reduced perfusion pressure. Positive results from these experiments would support further investigation of a potentially important mechanism of stroke protection applicable to all patients with atherosclerotic coronary and cerebrovascular disease.