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.
