PULSE ARGININE BUTYRATE WITH STANDARD HYDROXYUREA THERAPY IN SICKLE CELL

这个子项目是众多研究子项目之一

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. Although numerous attempts have been made to develop novel molecular-based therapies for sickle cell disease, the only specific therapy approved for clinical use is one that is aimed at raising the levels of fetal hemoglobin (Hb F. The multicenter study of hydroxyurea (HU) demonstrated that treatment with hydroxyurea results in a significant reduction in the incidence of vaso-occlusive crises and acute chest syndrome, two of the most important complications of sickle cell disease. We had previously shown that intermittent or pulse therapy with arginine butyrate (AB) can result in sustained induction of Hb F in the majority of treated patients. Although the effects of this group of therapeutic agents on Hb F levels and on acute complications of sickle cell disease have been the subject of intense investigation, their effects on long-term complications, including end organ damage, remain largely unknown. There are reasons to believe that very high Hb F levels may be necessary to prevent and/or reverse organ damage in sickle cell disease. To that end, we have started investigating the effects of combination therapy consisting of hydroxyurea and arginine butyrate on the Hb F levels in patients with sickle cell disease. Our preliminary studies demonstrate at least an additive and sometimes a synergistic effect of this combination on Hb F levels in patients who receive arginine butyrate while on hydroxyurea therapy. These studies need to be expanded to better define the spectrum of activity and the indications for this type of combination therapy. Thus, he specific aims of our research project are: 1) To determine the proportion of patients with sickle cell disease in whom combined treatment with HU + pulse AB will result in an increase in Hb F levels by at least 5% above the Hb F levels achieved with HU alone; 2) To determine the proportion of patients with sickle cell disease in whom combined treatment with HU + pulse AB will result in an increase in the proportion of F-cells by at least 10% above the number of F-cells achieved with HU alone; 3) To determine the effects of treatment with HU + pulse AB on other red blood cell parameters, including red cell density, deformability, and potassium leak; and 4) To determine if treatment with HU + pulse AB decreases sickle cell-related clinical events requiring emergency room visits or hospitalization compared to treatment with HU alone. Hypothesis: Higher levels of Hb F can be achieved with combination therapy consisting of hydroxyurea and butyrate than can be achieved with standard treatment with hydroxyurea.