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 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中出现。列出的机构是中心的机构，不一定是研究者的机构。众所周知，以任何增量诱导胎儿血红蛋白 (Hb F) 都可以改善镰状细胞病的临床并发症，但需要高水平（20% 或更高）才能防止器官损伤。化疗药物羟基脲 (HU) 可使 50% 的成年患者的 Hb F 平均水平达到 8.6%。许多患者在接受 HU 治疗后仍然出现危机和严重并发症，但它是 FDA 批准的唯一治疗镰状细胞病的方法。 在试点研究中，单独使用精氨酸丁酸 (AB) 脉冲疗法（4 天，每月一次）时，可使 9/11 成年患者的 Hb F 平均水平达到 21%。当加入 HU 治疗时，6 名患者的 Hb F 比单独使用 HU 的水平平均增加了 12%。 HU和AB通过不同的机制诱导Hb F； HU 通过细胞抑制作用发挥作用，而 AB 诱导胎儿珠蛋白基因启动子的转录，并可能通过 HDAC 抑制总体上增加基因表达。临床和基础研究的证据表明，这两种药物对红细胞生成活跃的患者更有效。 这项开放标签 II 期交叉研究将测试以下假设：1) 脉冲 AB 会比单独使用 HU 诱导更高水平的 Hb F，2) 对影响红细胞生成率的因素进行评估可能会识别出更有可能对 HU 做出反应的患者亚群+AB。该研究仅对仅使用 HU 治疗后症状未得到缓解且基线 Hb F 至少为 2% 的患者开放。患者将作为自己的对照。将评估仅接受 HU 治疗 6 个月的患者的临床事件和血液学因素。然后添加 AB 疗法（4 天，每月一次），并且将评估联合疗法的 Hb F 参数和临床事件。如果发现两种药物具有累加效应，则该试验可为选择最有可能从 AB（除 HU 治疗外）中受益的患者以及设计 III 期试验提供基础。 （这项小型试验不会作为 FDA 批准 AB 治疗镰状细胞病的关键试验