Niacin therapy to improve endothelial function in Sickle Cell Disease

在过去的几年里，包括我们自己在内的几个组织发表的数据表明， 镰状细胞病患者的血管平滑肌功能障碍。这种血管的病因 功能障碍无疑是多因素的，尽管我们的研究小组已经证明了相当多的证据， 机制涉及消耗一氧化氮的无细胞血浆血红蛋白释放过程中 血管内溶血我们最近完成的研究直接证明了内皮 镰状细胞病患者的功能障碍，其特征是ACh依赖性降低 血管舒张在前臂血流研究，这是不同的一氧化氮抵抗机制 上面提到的。此外，我们在镰状细胞病患者中发现了低水平的 apoA-I、肺动脉高压和内皮功能障碍。提高高密度脂蛋白水平，从而提高载脂蛋白A-1水平， 具有改善镰状细胞病的内皮功能障碍特征的作用， 影响内皮依赖性血管舒张。针对这些患者恢复HDL的治疗可能 是有益的。我们建议用Niaspan进行前臂血流生理学研究，Niaspan是一种缓释形式的 烟酸，先前报道增加高密度脂蛋白（HDL）和载脂蛋白A-1水平。具体目标 本研究的目的是：（1）确定口服Niaspan是否显著增加HDL水平， 镰状细胞病患者（主要终点）。(2)为了确定口服Niaspan是否 显著增加镰状细胞病患者的乙酰胆碱刺激血流量（继发性 终点），以及（3）确定内皮功能障碍的血浆标志物是否显著改变 通过口服Niaspan。将入组35例Hb SS或SbO-地中海贫血成人患者。到 增加受试者在研究入组时发生内皮功能障碍的可能性，我们将尝试招募 先前研究发现受试者的apoA-l水平低于平均水平< 89 mg/dL或HDL < 39 mg/dL。在基线前臂血流测量后，患者将开始3个月的疗程， 烟酸治疗，并安排了病史和体格检查的临床访视，剂量滴定（最大 1500毫克烟酸-ER每日），药丸计数和实验室检查。治疗3个月后， 以确定主要终点（HDL升高），并重复前臂血流检测。

Over the last few years, data has been published by several groups, including our own, indicating that vascular smooth muscle is dysfunctional in patients with sickle cell disease. The etiology of this vascular dysfunction is undoubtedly multifactorial, though our group has demonstrated considerable evidence for a mechanism involving consumption of nitric oxide by cell-free plasma hemoglobin released during intravascular hemolysis. We recently have completed studies that directly demonstrate endothelial dysfunction in patients with sickle cell disease, a dysfunction characterized by decreased ACh dependent vasorelaxation in forearm blood flow studies, and that is distinct from the nitric oxide resistance mechanism mentioned above. Further, we have found in sickle cell patients a new association between low levels of apoA-l, pulmonary hypertension and endothelial dysfunction. Raising levels of HDL and therefore apoA-l, could have the effect of ameliorating the endothelial dysfunction characteristic of sickle cell disease by affecting endothelium dependent vasorelaxation. Therapies directed at restoring HDL in these patients may be beneficial. We propose a forearm blood flow physiology study with Niaspan, a slow release form of niacin, previously reported to increase high density lipoprotein (HDL) and apo A-l levels. The specific aims of this study are: (1) To determine whether orally administered Niaspan significantly increases HDL levels in patients with sickle cell disease (primary endpoint). (2) To determine whether orally administered Niaspan significantly increases acetylcholine-stimulated blood flow in patients with sickle cell disease (secondary endpoint), and (3) To determine whether plasma markers of endothelial dysfunction are significantly changed by orally administered Niaspan. Thirty-five adult patients with Hb SS or SbO-thalassemia will be enrolled. To increase the likelihood that subjects will have endothelial dysfunction at study entry, we will try to recruit subjects found by previous studies to have a lower than average apoA-l level of < 89 mg/dL or HDL < 39 mg/dL. After baseline forearm blood flow measurements patients will be started on a 3 month course of niacin therapy, and have scheduled clinic visits for history and physicals, dose titration (to a maximum of 1500 mg Niacin-ER daily), pill counts, and laboratory tests. After 3 months of this treatment, blood sampling to determine the primary endpoint (increased HDL), and forearm blood flow testing will be repeated.