ABSTRACT
The butyrate derivative isobutyramide (IBT) increases fetal hemoglobin (HbF) in patients with beta-hemoglobinopathies, but little is known about its usefulness for prolonged therapeutic use. We treated 8 patients with transfusion-dependent beta-thalassemia with 350 mg/kg of body weight per day of oral IBT for 126 to 384 days. During the trial period, the hemoglobin level was maintained between 85 g/L (range 82-87 g/L) (pretransfusion) and 115 g/L (range 110-119 g/L) (post-transfusion) (median, interquartile range), corresponding to 4-week transfusion intervals in all patients during the pretreatment phase. Adverse effects (bitter taste, epigastric discomfort) did not cause discontinuation of IBT. HbF increased in all patients from 3.1% (range 1.9%-4.8%) to 6.0% (range 3.3%-8.7) (P =.0017), while free Hb dropped from 0.48 g/L (range 0.39-0.81 g/L) to 0.19 g/L (range 0.16-0.24 g/L) (P <.0001). Transfusion intervals were consistently extended to 8 or 9 weeks in 1 patient, resulting in a decrease of daily iron load from 455 microgram/kg per day (range 451-459 microgram/kg per day) before therapy to 211 microgram/kg per day (range 203-286 microgram/kg per day) during the 12-month treatment period. Prolongation of transfusion intervals achieved by IBT was less consistent in another patient, whose parenteral iron load nevertheless decreased from 683 microgram/kg per day (range 618-748 microgram/kg per day) to 542 microgram/kg per day (340-596 microgram/kg per day). In the other 6 patients, no prolongation of transfusion intervals was achieved. Response to treatment was associated with high pretreatment HbF (> 4.5%), high parental HbF, and increased erythropoietin levels (> 150 IU/L). We conclude that IBT prolongs transfusion intervals and reduces parenteral iron burden in some patients with transfusion-dependent beta-thalassemia.
Subject(s)
Amides/pharmacology , Blood Transfusion , beta-Thalassemia/drug therapy , Administration, Oral , Adolescent , Adult , Amides/administration & dosage , Amides/adverse effects , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacology , Blood/drug effects , Child , Child, Preschool , Drug Evaluation , Erythrocyte Indices/drug effects , Erythropoietin/blood , Female , Fetal Hemoglobin/drug effects , Fetal Hemoglobin/metabolism , Genotype , Hemoglobins/drug effects , Hemoglobins/metabolism , Hemolysis/drug effects , Homozygote , Humans , Iron/blood , Longitudinal Studies , Male , Patient Compliance , Time Factors , beta-Thalassemia/genetics , beta-Thalassemia/therapyABSTRACT
The branched-chain amino acid leucine plays an important role in the protein metabolism of human beings. It not only inhibits protein degradation but also stimulates protein synthesis. The oxidation rate of leucine and the influence which nutritional conditions have on this amino acid can be measured with the intravenous 13C-leucine breath test. In order the apply the breath test on newborn infants, the required dosage of L-(1-13C)-leucine and the reproducibility of the test had, firstly, to be determined. Following this, the extent to which the leucine oxidation rate was influenced by a simultaneous carbohydrate intake was investigated. An evident discrimination between the 13CO2-exhalation and the 13CO2-baseline exhalation is demonstrated after a bolus injection of 1 mg L-(1-13C)-leucine/kg B.W. We were able to measure reproducible values of the leucine oxidation rate in newborn infants with a tracer dosage of 4 mg L-(1-13C)-leucine/kg B.W. We found that a higher intake of carbohydrate given at the same time produced a lower rate of leucine oxidation, which indicates increased utilization of leucine for the benefit of protein synthesis.
