DEFERIPRONE THERAPY FOR SICKLE CELL DISEASE

描述 （改编自申请人摘要）本研究旨在 确定口服活性铁螯合剂去铁酮 可改善镰状细胞病的慢性溶血性贫血， 抑制铁诱导的镰状红细胞膜氧化损伤 减少红细胞破坏。 镰状细胞的细胞质表面 细胞已被证明携带游离铁的异常沉积，能够 产生诱导蛋白质硫醇氧化的自由羟基， 脂质过氧化导致阳离子泄漏，细胞脱水，减少 红细胞变形性和过早的红细胞破坏。 去除 来自红细胞膜的铁预计会减少 的羟基自由基，并代表了一种新的方法来治疗 镰状细胞病 口服活性铁的初步研究 螯合剂去铁酮（L1）已经证明了这种试剂的实用性 在从红细胞膜中去除游离铁沉积物中， 体外和体内。 在拟定的研究中， 给药，和去铁酮的药代动力学特征，这将是最 有效去除红细胞膜游离铁， 达到去铁酮的最大持续血浆药物浓度将是 建立和改善生物素红细胞存活，铁动力学 测量转铁蛋白摄取和相关异常 血红蛋白氧化变性和红细胞内脂质过氧化 长期治疗镰状细胞病患者的红细胞 然后将检查最佳给药方案下的去铁酮。 的 使用生物素标记的红细胞存活测定的组合 红细胞和铁动力学的测量， 摄取将提供对红细胞生成的全面评估， 镰状细胞病患者的死亡率， 去铁酮治疗

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.