PROSPECTIVE COMPARISON OF TWO REGIMENS OF DEFEROXAMINE

两种去铁胺方案的前瞻性比较

• 批准号: 6952416
• 负责人: NANCY F OLIVIERI
• 金额: $ 37.14万
• 依托单位: UNIVERSITY HEALTH NETWORK
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-16 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6952416
• 关键词: blood chemistry; blood disorder chemotherapy; chelating agents; clinical research; clinical trials; cytotoxicity; deferoxamine; drug administration rate /duration; drug administration routes; drug screening /evaluation; excretion; health care cost /financing; human subject; human therapy evaluation; injection /infusion; iron metabolism; iron storage disorder; lipid peroxides; liver metabolism; longitudinal human study; peroxidation; thalassemia; therapy compliance; urinalysis

Since the discovery of fetal hemoglobin, augmentation of its synthesis has been proposed as a therapeutic goal in patients with beta thalassemia. Unfortunately, clinical trials of most pharmacologic agents have demonstrated modest clinical responses only. Guided by previous work, the primary hypotheses of this research proposal is that augmentation of fetal hemoglobin, sufficient to increase steady-state total hemoglobin concentration and reduce transfusion requirements, will be most effective during sequential administration of selected agents to patients with specific mutations within the beta globin cluster and that responses will also be influenced by the degree of erythroid marrow expansion, with the most marked responses observed in patients in whom marrow expansion is maximized before therapy. The specific aim is to determine increases in steady-state total and fetal hemoglobin concentrations, reduction in globin chain imbalance, toxicity, and patient compliance associated with selected pharmacologic regimens with patients with genotypes selected to test the above hypotheses. To achieve this aim, 30 patients with three groups of mutations, including specific deletions or rearrangements of putatively important regulatory elements within the beta globin cluster, will be recruited. In the first study phase, patients will be treated with sodium phenylbutyrate, hydroxyurea and recombinant erythropoietin alone and in combination. In the second study phase, low-dose subcutaneous cytosine arabinoside will be offered to adult patients. The key study comparison will be made with respect to the total hemoglobin concentration; we estimate that the minimal clinically important difference between the hemoglobin concentration at baseline and after treatment will be 3 grams/deciliter. Compliance with oral therapy will be monitored using computerized pill containers, and with subcutaneous therapy using counts for syringes returned each visit. This study represents an attempt to provide definitive therapy for the primary abnormally in severe beta thalassemia, severe imbalance of globin chains, and to reduce or eliminate transfusions in selected patients.

自从胎儿血红蛋白被发现以来，增强其合成一直被认为是β地中海贫血患者的治疗目标。不幸的是，大多数药物的临床试验只显示了适度的临床反应。在前人工作的指导下，这项研究建议的主要假设是，增加胎儿血红蛋白，足以增加稳态总血红蛋白浓度并减少输血需求，在连续给药期间，对具有β珠蛋白簇中特定突变的患者将是最有效的，反应也将受到红系骨髓扩张程度的影响，在治疗前骨髓扩张最大化的患者中观察到最显著的反应。其具体目的是确定与选定的药物方案相关的稳态总血红蛋白浓度和胎儿血红蛋白浓度的增加、球蛋白链失衡的减少、毒性和患者的依从性。为了实现这一目标，将招募30名具有三组突变的患者，包括β珠蛋白簇中可能重要的调控元件的特定缺失或重排。在第一个研究阶段，患者将接受苯丁酸钠、羟基尿素和重组促红细胞生成素单独和联合治疗。在第二个研究阶段，小剂量的阿糖胞苷皮下注射给成年患者。关键研究将针对总的血红蛋白浓度进行比较；我们估计，基线和治疗后的血红蛋白浓度之间最小的临床重要差异将是3克/分升。口服治疗的依从性将使用计算机化的药片容器进行监测，皮下治疗的依从性将使用每次就诊时返回的注射器的计数进行监测。这项研究试图为重症β地中海贫血的原发异常、严重的珠蛋白链失衡提供明确的治疗方法，并减少或取消选定患者的输血。