PULSE ARGININE BUTYRATE IN SICKLE CELL DISEASE

脉冲精氨酸丁酸盐治疗镰状细胞病

• 批准号: 7379483
• 负责人: SUSAN Park PERRINE
• 金额: $ 1.54万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7379483
• 关键词: PULSE; ARGININE; BUTYRATE; SICKLE; CELL

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. It has been well-established that inducing fetal hemoglobin (Hb F) by any increment can ameliorate the clinical complications of sickle cell disease, but that high levels, 20% or higher, are required to prevent organ damage. The chemotherapeutic drug Hydroxyurea (HU) induces Hb F to a mean level of 8.6% in 50% of adult patients. Many patients still have crises and serious complications on HU, but it is the only FDA-approved treatment for sickle cell disease. In pilot studies, a Pulsed regimen of Arginine Butyrate (AB) induced Hb F to a mean level of 21% in 9/11 adult patients when used alone, (4 days, once per month). When added to HU treatment, a mean increase in Hb F of 12% over levels on HU alone resulted in 6 patients. HU and AB induce Hb F through different mechanisms; HU acts through cytostatic effects, while AB induces transcription from the fetal globin gene promoter and may increase gene expression in general through HDAC inhibition. Evidence from clinical and basic studies suggests that both agents are more effective in patients with active erythropoiesis. This open-label Phase II cross-over study will test hypotheses that 1) Pulsed AB will induce higher levels of Hb F than HU alone, and 2) assessment of factors influencing erythropoietic rates may identify patient subsets who are more likely to respond to HU + AB. The study is open only to patients who have not had resolution of their symptoms with HU alone, and have a baseline Hb F of at least 2%. Patients will serve as their own controls. Clinical events and hematologic factors will be assessed in patients on HU alone for 6 months. AB therapy will then be added, (4 days, once/ month), and Hb F parameters and clinical events will be assessed on combined therapy. If additive effects are found with the two agents, the trial may provide a basis for selecting patients most likely to benefit from AB (in addition to HU therapy) and for design of Phase III trials. (This small trial will not serve as a pivotal trial for FDA approval of AB for treatment of sickle cell disease

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。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。所列机构为中心，不一定是研究者所在机构。已经确定，通过任何增量诱导胎儿血红蛋白（Hb F）可以改善镰状细胞病的临床并发症，但是需要20%或更高的高水平以防止器官损伤。化疗药物羟基脲（HU）在50%的成人患者中诱导Hb F平均水平为8.6%。许多患者在HU上仍然有危机和严重并发症，但它是FDA批准的唯一镰状细胞病治疗方法。 在初步研究中，单独使用精氨酸丁酸盐（AB）脉冲方案（4天，每月一次）时，9/11例成人患者的Hb F平均水平为21%。当加入HU治疗时，6名患者的Hb F平均增加12%，超过单独HU治疗的水平。HU和AB通过不同的机制诱导Hb F; HU通过细胞生长抑制作用起作用，而AB诱导从胎儿珠蛋白基因启动子的转录，并且通常可以通过HDAC抑制来增加基因表达。来自临床和基础研究的证据表明，这两种药物在红细胞生成活跃的患者中更有效。 这项开放标签II期交叉研究将检验以下假设：1）脉冲式AB将诱导比HU单药治疗更高水平的Hb F，2）评估影响红细胞生成率的因素可能会识别出更有可能对HU + AB产生应答的患者亚组。该研究仅对单独使用HU未缓解症状且基线Hb F至少为2%的患者开放。患者将作为自己的对照。将在接受6个月HU单药治疗的患者中评估临床事件和血液学因素。然后添加AB治疗（4天，每月一次），并评估联合治疗的Hb F参数和临床事件。如果发现两种药物的叠加效应，则试验可为选择最有可能从AB（除HU治疗外）获益的患者和III期试验的设计提供基础。(This小规模试验不能作为FDA批准AB治疗镰状细胞病的关键试验