DEFERIPRONE THERAPY FOR SICKLE CELL DISEASE

描述 (摘自申请者的摘要)本研究旨在 确定口服活性铁络合剂去铁酮 能改善镰状细胞病的慢性溶血性贫血 抑制铁对镰状红细胞膜的氧化损伤 减少对红细胞的破坏。镰刀菌的细胞质表面 细胞已被证明携带异常的游离铁沉积，能够 产生自由基，诱导蛋白质硫醇氧化，并 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。删除 红细胞膜中的铁有望减少新陈代谢。 它代表了一种治疗糖尿病的新方法。 镰状细胞病。口服活性铁的初步研究 螯合剂去铁酮(L1)已经证明了该试剂的用途 在清除红细胞膜上的游离铁沉淀物方面 体外和体内。在拟议的研究中，剂量、时间表 去铁酮的给药和药动学特征将是最 有效清除红细胞膜游离铁 实现去铁酮的最大持续血药浓度将是 建立和改善生物素红细胞存活率，铁动力学 红细胞转铁蛋白摄取及相关异常的测量 在红色中有血红蛋白的氧化变性和脂质过氧化 长期治疗的镰状细胞病患者的细胞 然后将检查最佳给药方案下的去铁酮。这个 生物素化测定红细胞存活率的组合方法 红细胞和红细胞转移率的铁动力学测量 摄取将提供对红细胞产生和 镰状细胞病患者延长治疗前后的破坏情况 用去铁酮治疗。

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.