This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The experimental design is to administer different doses of Butyrate on an intra-patient, dose escalation schedule and to analyze Hb F production (through measurement of F-cells, F-reticulocytes, globin chain synthesis ratios, Hb F, globin mRNA), and hematologic tests, to determine an effective regimen for the individual patient. The latter tests include CBCs, differentials, reticulocyte counts, plasma free hemoglobin, proportions of irreversibly sickled cells, and globin chain electrophoresis. Chemistry panels and urinalyses will be followed to monitor for side effects. Drug levels are measured in plasma and urine. Optimal globin chain ratios are expected at 24-48 hours after dose, but have persisted for 7-10 days in some thalassemia patients. After a correction or a significant improvement in globin chain ratio or fetal globin synthesis is detected, that dose will be continued and blood drawings will be decreased in frequency. If biochemical responses are not detected, hematologic improvement can not be expected to follow. Accordingly, patients will not be continued on study, if stimulation of Hb F by at least one parameter is not detected after a maximal administered dose of 2000 mg/kg. Infusion rates will be adjusted to deliver the desired total dose at a rate tailored to avoid side effects such as nausea and headache and suppression of hemoglobin synthesis thought to be induced by excessively high plasma levels of the drug. Doses will be infused over 4 to 18 hours, at a rate not to exceed 85 mg/kg/hour. Drug will be given from 1 to 4 days per week, followed by at least 5-14 days without drug, while the patient's blood is sampled and tested. Intervals between drug treatments may be extended beyond 14 days, in order to determine how long the drug effect lasts and how often therapy is really needed once Hb F inverses. After an effective dose for a given patient is identified at the biochemical level, and a rise in total hemoglobin or a decrease in post-transfusion hemoglobin nadir is observed, the frequency of blood testing will be decreased to 4 times/ month.
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