losartan-potassium and 4-phenylbutyric-acid

Patients with hemoglobin E (Hb E)-beta 0-thalassemia, one of the most common hemoglobinopathies worldwide, could benefit from drugs that increase fetal and total hemoglobin levels and thereby decrease the need for transfusions. The long-term clinical outcome of such therapy, its hematologic effects, and which patients are likely to benefit from treatment are unknown. Consequently, the use of such drugs for Hb E-beta 0-thalassemia is limited, and countries where resources for safe and regular transfusion are scarce cannot benefit from them. In a multicenter trial of 42 patients treated with hydroxyurea for two years, almost half the patients demonstrated a significant increase in steady-state hemoglobin level. Drug toxicity was minimal. Combined treatment of hydroxyurea with erythropoietin benefited selected patients, but the addition of sodium phenyl butyrate was ineffective. After 5 years of follow-up, a subset of patients remained off transfusions. Hydroxyurea should be considered for a subset of Hb E-beta 0-thalassemia patients.

Topics: beta-Thalassemia; Blood Transfusion; Combined Modality Therapy; Drug Therapy, Combination; Erythropoiesis; Erythropoietin; Facial Bones; Fetal Hemoglobin; Gene Expression; Genotype; Globins; Hematopoiesis, Extramedullary; Hemoglobin E; Humans; Hydroxyurea; Phenylbutyrates; Radiography; Recombinant Proteins; Splenectomy; Splenomegaly; Treatment Outcome

Butyrate analogues have been shown to increase fetal hemoglobin (HbF) production in vitro and in vivo. Sodium phenylbutyrate (SPB), an oral agent used to treat individuals with urea-cycle disorders, has been shown to increase HbF in nonanemic individuals and in individuals with sickle cell disease. We have treated eleven patients with homozygous beta thalassemia (three transfusion dependent) and one sickle-beta-thalassemia patient with 20 g/d (forty 500-mg tablets) of SPB for 41 to 460 days. All patients showed an increase in the percent of F reticulocytes associated with treatment, but only four patients responded by increasing their Hb levels by greater than 1 g/dL (mean increase, 2.1 g/dL; range, 1.2 to 2.8 g/dL). None of the transfusion-dependent thalassemia subjects responded. Increase in Hb was associated with an increase in red blood cell number (mean increase, 0.62 x 10(12)/L), and mean corpuscular volume (mean increase, 6 fL). Changes in percent HbF, absolute HbF levels, or alpha- to non-alpha-globin ratios as measured by levels of mRNA and globin protein in peripheral blood did not correlate with response to treatment. Response to treatment was not associated with the type of beta-globin mutation, but baseline erythropoietin levels of greater than 120 mU/mL was seen in all responders and only two of eight nonresponders to SPB. Compliance with treatment was greater than 90% as measured by pill counts. Side effects of the drug included weight gain and/or edema caused by increase salt load in 2/12, transient epigastric discomfort in 7/12, and abnormal body odor in 3/12 subjects. Two splenectomized patients who were not on prophylactic antibiotics developed sepsis while on treatment. We conclude that SPB increases Hb in some patients with thalassemia, but the precise mechanism of action is unknown.

Topics: Adult; Anemia, Sickle Cell; beta-Thalassemia; Blood Transfusion; Erythropoietin; Female; Fetal Hemoglobin; Globins; Hemoglobins; Hemolysis; Homozygote; Humans; Male; Mutation; Patient Compliance; Phenylbutyrates; Reticulocytes