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

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: Evaluation of Potential Synergy of Combining Hydroxyurea With Nitric Oxide Donors on Fetal Hemoglobin Synthesis in Patients With Sickle Cell Anemia

Brief Summary:

Patients with sickle cell disease have abnormal hemoglobin (the protein in red blood cells that carries oxygen to the body). This abnormality causes red blood cells to take on a sickle shape, producing disease symptoms. Fetal hemoglobin, a type of hemoglobin present in fetuses and babies, can prevent red cells from sickling. The drug hydroxyurea increases fetal hemoglobin production in patients with sickle cell disease by making a molecule called nitric oxide. The drugs L-arginine and Sildenafil (Viagra) increase the amount or the effect of nitric oxide. This study will evaluate:

  • The safety of giving L-arginine or Sildenafil together with hydroxyurea in patients with sickle cell disease;
  • The effectiveness of L-arginine plus hydroxyurea or Sildenafil plus hydroxyurea in increasing fetal hemoglobin in patients with sickle cell disease; and
  • The effectiveness of L-arginine plus hydroxyurea or Sildenafil and hydroxyurea in lowering blood pressure in the lungs of patients with sickle cell disease. (Pulmonary blood pressure is elevated in about one-third of patients with sickle cell disease, and this condition increases the risk of dying from the disease.)

Patients with hemoglobin S-only, S-beta-thalassemia, or other sickle cell disease genotype may be eligible for this study.

Before starting treatment, patients will have a complete medical history and physical examination. All patients will take hydroxyurea once a day every day by mouth for at least 2 months. They will be admitted to the NIH Clinical Center to take their first dose of hydroxyurea, and will have blood drawn through a catheter (plastic tube placed in a vein) every hour for 6 hours for tests to determine nitr

Detailed Summary: 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.
Sponsor: National Institutes of Health Clinical Center (CC)

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Information By: National Institutes of Health Clinical Center (CC)

Dates:
Date Received: March 12, 2003
Date Started: March 10, 2003
Date Completion:
Last Updated: April 19, 2017
Last Verified: December 7, 2015