Evaluation of Hydroxyurea Plus L-arginine or Sildenafil to Treat Sickle Cell Anemia

Hydroxyurea is a cell-cycle specific agent that blocks DNA synthesis by inhibiting ribonucleotide reductase, the enzyme that converts ribonucleotides to deoxyribonucleotides. Hydroxyurea has been shown to induce the production of fetal hemoglobin (HbF), initially in non-human primates, and now in patients with sickle cell anemia. The majority of patients with sickle cell disease respond to the drug with a more than two-fold increase in HbF levels; in some patients the percent of HbF exceeds 10 or 15 percent. It is estimated that levels of 20 percent are required to substantially reduce the sickling propensity of red cells and to modulate disease severity. We have recently found that hydroxyurea therapy is associated with the intravascular and intraerythrocytic generation of nitric oxide (NO), and that NO accounts for HbF induction via the guanylyl cyclase/cGMP dependent pathways. In fact, NO donors such as S-nitroso-cysteine and NONOates similarly induce HbF expression in human erythropoietin treated human CD 34+ stem cells. Possible synergy between NO donor therapy and classic cytostatic and differentiating medications should be explored. We propose to treat several patients chronically with hydroxyurea to determine hematological changes Iongitudinally. Once a maximal Hb-F raising effect of hydroxyurea has been established, oral L-arginine (the substrate for NO synthase) and sildenafil (Viagra, a phosphodiesterase inhibitor that potentates cGMP dependent signaling) will be added to determine the ability of other agents to enhance HbF synthesis, especially in hydroxyurea non-responders or partial-responders. Additionally, we have found that up to 33% of patients with sickle cell disease also have secondary pulmonary hypertension, measured by echocardiogram. A secondary endpoint of this study will be to evaluate if chronic hydroxyurea therapy and the addition of L-arginine or sildenafil will improve the pulmonary hypertension in this subgroup.