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 nitric oxide levels. After discharge, they will
return to the clinic once every 2 weeks to check for treatment side effects and for blood
tests to monitor hemoglobin and fetal hemoglobin levels. After fetal hemoglobin levels have
been stable for 2 months, patients will be admitted to the Clinical Center for their first
dose of L-arginine (for men) or Sildenafil (for women). Again, blood samples will be
collected through a catheter once an hour for 6 hours. If there are no complications,
patients will be discharged and will continue taking hydroxyurea once a day and L-arginine or
Sildenafil three times a day for at least 3 months until fetal hemoglobin levels have been
stable for at least 2 months. Patients will return to the clinic for blood tests every week
for 2 weeks and then every 2 weeks to monitor hemoglobin and fetal hemoglobin levels and to
check for treatment side effects.
Patients will have eye examinations before and during treatment. Some patients with sickle
cell disease develop abnormalities in the blood vessels of the eye. Also, Sildenafil can
cause temporary changes in color vision. Rarely, more serious eye problems can occur, such as
bleeding from the eye blood vessels or damage to the retina a layer of tissue that lines the
back of the eye. Patients will also have an echocardiogram (ultrasound of the heart) before
beginning treatment, after hydroxyurea treatment, and after 1 and 3 months of combined
treatment with hydroxyurea and L-arginine or Sildenafil to help measure blood pressure in the
Patients who develop complications from L-arginine or Sildenafil may continue in the study on
hydroxyurea alone. Patients whose fetal hemoglobin levels increase with the combination
therapy of hydroxyurea and L-arginine or Sildenafil may continue to take them.
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.
- INCLUSION CRITERIA:
1. Patients must have documented hemoglobin S-only, S-beta-thalassemia, or other
sickle cell disease genotype. Only patients with hemoglobin S-only will be
considered in the primary analysis.
2. Patients must have relatively well preserved renal and hepatic function
(creatinine less than 1.6 mg/dl and normal liver function test less than 5 X
3. Evidence of severe sickle cell anemia will include one or more of the following:
recurrent pain crisis (greater than or equal to 2 ER visits per year), recurrent
acute chest syndrome (a lung problem like pneumonia), hospitalizations, leg
ulceration, priapism, aseptic necrosis of the hip, and/or pulmonary hypertension.
4. Patients must be able to provide informed consent.
1. Patients who have hemoglobin S and A (trait) or hemoglobin A-only (non-sickle cell).
2. Patients must not be on a chronic transfusion program, defined as regular transfusions
every 2-8 weeks.
3. Patients must not be pregnant or breast feeding.
4. Patients on chronic nitrates, such as nitroglycerin.
John F Tisdale, M.D.
National Heart, Lung, and Blood Institute (NHLBI)