PULSE ARGININE BUTYRATE WITH STANDARD HYDROXYUREA THERAPY IN SICKLE CELL

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 尽管已经进行了许多尝试来开发用于镰状细胞病的新的基于分子的疗法，但唯一被批准用于临床使用的特定疗法是旨在提高胎儿血红蛋白（Hb F）水平的疗法。 羟基脲（HU）的多中心研究表明，使用羟基脲治疗可显著降低血管闭塞性危象和急性胸部综合征（镰状细胞病的两种最重要并发症）的发生率。我们以前曾表明，间歇或脉冲治疗与精氨酸丁酸（AB）可以导致持续诱导Hb F在大多数治疗的患者。虽然这组治疗药物对Hb F水平和镰状细胞病急性并发症的影响一直是深入研究的主题，但其对长期并发症（包括终末器官损伤）的影响仍在很大程度上未知。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/或扭转器官损害镰状细胞病。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，该组合对Hb F水平至少具有相加作用，有时具有协同作用。这些研究需要扩大，以更好地确定活性谱和这种类型的联合治疗的适应症。 因此，我们的研究项目的具体目标是：1）确定联合使用HU +脉冲AB治疗的镰状细胞病患者的比例，这些患者的Hb F水平将比单独使用HU获得的Hb F水平至少增加5%; 2）确定HU +脉冲AB联合治疗将导致F-比例增加的镰状细胞病患者比例。3）确定用HU +脉冲AB处理对其他红细胞参数的影响，包括红细胞密度、变形性和钾渗漏;和4）为了确定用HU +脉冲AB治疗是否减少镰状细胞-与HU单独治疗相比，需要急诊室就诊或住院的相关临床事件。 假设：与使用羟基脲的标准治疗相比，使用由羟基脲和丁酸盐组成的联合治疗可以实现更高水平的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, he 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.