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. We have found in our laboratories that hydroxyurea exerts many of its effects via the production of nitric oxide gas. In this study we treat patients chronically with hydroxyurea to determine hematological changes longitudinally. 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) is added to determine the ability of other agents to enhance HbF synthesis, especially in hydroxyurea non-responders or partial-responders. We began enrolling patients in May 2003 and have treated 37, 13 with hydroxyurea and L-arginine (12 subjects have completed this arm of the study), 14 with hydroxyurea and sildenafil (11 subjects completed this arm of the study) , 11 with hydroxyurea alone and 2 with sildenafil alone. The results are now published in the British Journal of Haematology, indicating that sildenafil therapy decreased the estimated pulmonary artery systolic pressure by 9 mmHg (p=0.04) and increased 6-minute walk distance by 78 m (p=0.001). We have found that in patients with sickle cell disease, 1) pulmonary hypertension, though relatively mild, is associated with severe impairments in cardiopulmonary function, 2) traditional markers of functional capacity such as six-minute walk test can be utilized in this population as a therapeutic endpoint for clinical trials, 3) and therapy with sildenafil seems to have a favorable impact on pulmonary pressures and functional capacity. Our last patient recently completed the sildenfil arm of the study. We are no longer enrolling patients and are beginning our formal data analysis.

National Institute of Health (NIH)
Clinical Center (CLC)
Intramural Research (Z01)
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