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: 7605307
• 负责人: GEORGE ATWEH
• 金额: $ 5.05万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7605307
• 关键词: Accident and Emergency department; Acute; Arginine Butyrate; Butyrates; Cells; Clinical; Combined Modality Therapy; Computer Retrieval of Information on Scientific Projects Database; Erythrocytes; Event; Fetal Hemoglobin; Funding; Grant; Hospitalization; Incidence; Institution; Investigation; Molecular; Multicenter Studies; Numbers; Organ; Patients; Physiologic pulse; Potassium; Pulse taking; Research; Research Personnel; Research Project Grants; Resources; Sickle Cell; Sickle Cell Anemia; Source; Standards of Weights and Measures; Therapeutic Agents; United States National Institutes of Health; Visit; acute chest syndrome; base; butyrate; density; hydroxyurea; novel; prevent; treatment effect

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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 尽管已经进行了大量尝试来开发针对镰状细胞病的新型分子疗法，但唯一批准用于临床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）的多中心研究证明羟基脲治疗可显着降低血管闭塞危象和急性胸部综合征的发生率，这是镰状细胞病的两种最重要的并发症，我们之前已经证明精氨酸的间歇或脉冲治疗。丁酸盐 (AB) 可导致大多数接受治疗的患者持续诱导 Hb F 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已成为深入研究的主题，但它们的影响。包括终末器官损伤在内的长期并发症的影响仍然很大程度上未知。有理由相信，可能需要非常高的 Hb F 水平来预防和/或逆转镰状细胞病的器官损伤。为此，我们开始研究由羟基脲和精氨酸丁酸盐组成的联合疗法对镰状细胞病患者 Hb F 水平的影响。我们的初步研究表明，在接受羟基脲治疗期间接受精氨酸丁酸盐的患者中，该组合至少对 Hb F 水平具有相加作用，有时甚至是协同作用。这些研究需要扩大，以更好地确定此类联合疗法的活性范围和适应症。 因此，我们研究项目的具体目标是： 1) 确定 HU + 脉冲 AB 联合治疗将导致 Hb F 水平增加至少 5% 的镰状细胞病患者比例仅使用 HU 即可达到的水平； 2) 确定镰状细胞病患者的比例，其中 HU + 脉冲 AB 联合治疗将导致 F 细胞比例比单独使用 HU 所达到的 F 细胞数量增加至少 10%； 3) 确定HU+脉冲AB治疗对其他红细胞参数的影响，包括红细胞密度、变形能力和钾渗漏； 4) 确定与单独使用 HU 治疗相比，使用 HU + 脉冲 AB 治疗是否可以减少需要急诊室就诊或住院治疗的镰状细胞相关临床事件。 假设：羟基脲和丁酸盐的联合治疗可以比羟基脲标准治疗获得更高的 Hb F 水平。