PULSE ARGININE BUTYRATE WITH STANDARD HYDROXYUREA THERAPY IN SICKLE CELL

镰状细胞中脉冲精氨酸丁酸与标准羟基脲疗法

• 批准号: 7380569
• 负责人: GEORGE ATWEH
• 金额: $ 0.32万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-17 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7380569
• 关键词: arginine; butyrates; combination therapy; sickle cell anemia

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.

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。尽管针对镰状细胞疾病的新型分子疗法已经做了很多尝试，但唯一被批准用于临床的特异性疗法是一种旨在提高胎儿血红蛋白(HbF)水平的疗法。羟基尿素(HU)的多中心研究表明，羟基尿素治疗可显著降低血管闭塞危象和急性胸腔综合征的发生率，这是镰状细胞病的两个最重要的并发症。我们之前已经证明，在大多数接受治疗的患者中，精氨酸丁酸盐(AB)的间歇或脉冲治疗可以导致持续的Hb F诱导。尽管这组治疗药物对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，但它们对包括终末器官损害在内的长期并发症的影响仍然很大程度上是未知的。有理由相信，非常高的Hb F水平对于预防和/或逆转镰状细胞病的器官损害可能是必要的。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，在接受羟基尿素治疗的同时接受精氨酸丁酸盐治疗的患者中，这种组合至少是一种相加的、有时是协同作用的效果。这些研究需要扩大，以更好地定义这种类型的联合治疗的活动范围和适应症。因此，我们研究项目的具体目标是：1)确定HU+PULSE AB联合治疗将导致Hb F水平比HU单独治疗至少增加5%的镰状细胞病患者的比例；2)确定HU+PULSE AB联合治疗将导致F细胞比例比HU单独治疗F细胞增加至少10%的镰状细胞疾病患者的比例；3)确定HU+PULSE AB治疗对其他红细胞参数的影响，包括红细胞密度、变形性和钾泄漏；以及4)确定与HU单独治疗相比，HU+PULSE 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：羟基尿素和丁酸盐组成的联合治疗可以达到比标准羟基尿素治疗更高的Hb F水平。