DEFERIPRONE THERAPY FOR SICKLE CELL DISEASE

镰状细胞病的去铁酮治疗

• 批准号: 2030831
• 负责人: NANCY F OLIVIERI
• 金额: $ 17.38万
• 依托单位: HOSPITAL FOR SICK CHLDRN (TORONTO)
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-30 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2030831
• 关键词: biotin; blood disorder chemotherapy; cell death; chelating agents; chelation therapy; clinical research; erythrocytes; erythropoiesis; free radicals; human subject; human therapy evaluation; iron; oxidative stress; peroxidation; sickle cell anemia; sickling inhibitor; transferrin

DESCRIPTION (Adapted from applicant's abstract) This research study is designed to determine if administration of the orally active iron chelator deferiprone can ameliorate the chronic hemolytic anemia of sickle cell disease by inhibiting iron-induced oxidative damage to the sickle erythrocyte membrane and decreasing red cell destruction. The cytoplasmic surface of sickled cells has been shown to carry abnormal deposits of free iron, capable of generating free hydroxyl radicals that induce protein thiol oxidation and lipid peroxidation leading to cation leak, cell dehydration, reduced erythrocyte deformability, and premature red cell destruction. Removal of iron from the red cell membrane would be expected to reduce the generation of hydroxyl radical, and represents a novel approach to the therapy of sickle cell disease. Preliminary studies with the orally active iron chelating agent deferiprone (L1) have demonstrated the utility of this agent in the removal of free iron deposits from membranes of red blood cells in vitro and in vivo. In the proposed studies the dose, schedule of administration, and pharmacokinetic profile of deferiprone that will be most effective in the removal of erythrocyte membrane free iron and that which achieves maximal sustained plasma drug concentrations of deferiprone will be established, and improvement in biotin red cell survival, ferrokinetic measurements of erythron transferrin uptake, and abnormalities associated with oxidative denaturation of hemoglobin and lipid peroxidation within red cells in patients with sickle cell disease treated with an extended period of deferiprone under the optimal dosing regimen will then be examined. The combination of determinations of red cell survival using biotinylated erythrocytes and of ferrokinetic measurements of erythron transferring uptake will provide a comprehensive assessment of red cell production and destruction in patients with sickle cell disease, before and after extended therapy with deferiprone.

描述 （根据申请人的摘要改编）该研究旨在 确定口服活性铁螯合剂的施用是否 可以通过 抑制铁诱导的镰状红细胞膜的氧化损伤 并减少红细胞破坏。 镰状的细胞质表面 细胞已被证明携带异常的自由铁的沉积物，能够 产生诱导蛋白质硫醇氧化和的游离羟基自由基 脂质过氧化导致阳离子泄漏，细胞脱水，减少 红细胞的可变形性和过早的红细胞破坏。 去除 从红细胞膜上的铁将减少产生 羟基自由基，代表了一种新颖的治疗方法 镰状细胞性贫血症。 口服活性铁的初步研究 螯合剂脱脂酮（L1）已证明了该代理的实用性 在去除红细胞膜中的游离铁沉积物中 体内和体内。 在拟议的研究中 脱佛酮的管理和药代动力学特征将是最多的 有效去除红细胞膜无铁和 达到最大持续等离子体药物的脱磷脂将是 生物素红细胞存活的生存和改善 赤龙转铁蛋白摄取的测量和相关的异常 与红红色和脂质过氧化的氧化变性 长时间治疗的镰状细胞疾病患者的细胞 然后将检查最佳给药方案下的脱发。 这 使用生物素化确定红细胞存活的结合 红细胞和铁肌转移的超金属测量值 吸收将对红细胞生产和 镰状细胞疾病患者的破坏，延长之前和之后 脱脂酮治疗。