PULSE ARGININE BUTYRATE WITH STANDARD HYDROXYUREA THERAPY IN SICKLE CELL

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。尽管已经进行了许多尝试来开发新的基于分子的镰状细胞病治疗方法，但唯一被批准用于临床的特异性治疗是一种旨在提高胎儿血红蛋白（Hb F）水平的治疗方法。羟基脲（HU）的多中心研究表明，羟基脲治疗可显著降低血管闭塞危像和急性胸综合征的发生率，这是镰状细胞病最重要的两种并发症。我们之前的研究表明，用精氨酸丁酸盐（AB）间歇或脉冲治疗可导致大多数治疗患者持续诱导Hb F。尽管这组治疗药物对血红蛋白F水平和镰状细胞病急性并发症的影响已被深入研究，但它们对长期并发症（包括终末器官损伤）的影响在很大程度上仍然未知。有理由相信，非常高的血红蛋白F水平可能是必要的，以防止和/或逆转镰状细胞病的器官损害。为此，我们已经开始研究由羟基脲和精氨酸丁酸盐组成的联合治疗对镰状细胞病患者Hb F水平的影响。我们的初步研究表明，在接受精氨酸丁酸盐同时接受羟基脲治疗的患者中，这种组合对Hb F水平至少有一种附加效应，有时也有协同效应。这些研究需要扩大，以更好地定义这种联合治疗的活性谱和适应症。因此，我们的研究项目的具体目的是：1)确定在镰状细胞病患者中，HU +脉冲AB联合治疗使Hb F水平比单独使用HU至少提高5%的比例；2)确定在镰状细胞病患者中，HU +脉冲AB联合治疗使f细胞比单独使用HU增加至少10%的比例；3)确定HU + AB脉冲治疗对其他红细胞参数的影响，包括红细胞密度、变形性、钾泄漏；4)确定与单独使用HU治疗相比，HU +脉冲AB治疗是否减少了需要急诊室就诊或住院的镰状细胞相关临床事件。假设：与羟基脲标准治疗相比，羟基脲和丁酸盐联合治疗可达到更高水平的Hb F。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Although numerous attempts have been made to develop novel molecular-based therapies for sickle cell disease, the only specific therapy approved for clinical use is one that is aimed at raising the levels of fetal hemoglobin (Hb F). The multicenter study of hydroxyurea (HU) demonstrated that treatment with hydroxyurea results in a significant reduction in the incidence of vaso-occlusive crises and acute chest syndrome, two of the most important complications of sickle cell disease. We had previously shown that intermittent or pulse therapy with arginine butyrate (AB) can result in sustained induction of Hb F in the majority of treated patients. Although the effects of this group of therapeutic agents on Hb F levels and on acute complications of sickle cell disease have been the subject of intense investigation, their effects on long-term complications, including end organ damage, remain largely unknown. There are reasons to believe that very high Hb F levels may be necessary to prevent and/or reverse organ damage in sickle cell disease. To that end, we have started investigating the effects of combination therapy consisting of hydroxyurea and arginine butyrate on the Hb F levels in patients with sickle cell disease. Our preliminary studies demonstrate at least an additive and sometimes a synergistic effect of this combination on Hb F levels in patients who receive arginine butyrate while on hydroxyurea therapy. These studies need to be expanded to better define the spectrum of activity and the indications for this type of combination therapy. Thus, the specific aims of our research project are: 1) To determine the proportion of patients with sickle cell disease in whom combined treatment with HU + pulse AB will result in an increase in Hb F levels by at least 5% above the Hb F levels achieved with HU alone; 2) To determine the proportion of patients with sickle cell disease in whom combined treatment with HU + pulse AB will result in an increase in the proportion of F-cells by at least 10% above the number of F-cells achieved with HU alone; 3) To determine the effects of treatment with HU + pulse AB on other red blood cell parameters, including red cell density, deformability, and potassium leak; and 4) To determine if treatment with HU + pulse AB decreases sickle cell-related clinical events requiring emergency room visits or hospitalization compared to treatment with HU alone. Hypothesis: Higher levels of Hb F can be achieved with combination therapy consisting of hydroxyurea and butyrate than can be achieved with standard treatment with hydroxyurea.