arginine-butyrate and isobutyramide

The inherited beta-hemoglobinopathies (sickle cell disease and beta thalassemia) are the result of a mutation in the adult (beta) globin gene. The fetal globin chain, encoded by the gamma globin genes, can substitute for the mutated or defective beta globin chain, but expression of the gamma globin gene is developmentally inactivated prior to birth. Re-inducing expression of the normal fetal globin genes is a preferred method of ameliorating sickle cell disease and the beta thalassemias. Stimulation of as little as 4-8% fetal globin synthesis in the bone marrow can produce > 20% fetal hemoglobin in the peripheral circulation, due to enhanced survival of red blood cells containing both sickle and fetal hemoglobin, compared to those containing sickle hemoglobin alone. Butyric acid and butyrate derivatives are generally safe compounds which induce fetal hemoglobin production by stimulating the promoter of the fetal globin genes. An initial trial with the parent compound, delivered as Arginine Butyrate, has demonstrated rapid stimulation of fetal globin expression to levels that have been shown to ameliorate these conditions. Phase 1 trials of an oral butyrate derivative with a long plasma half-life have just begun. These agents now provide a specific new approach for ameliorating these classic molecular disorders and merit further investigation in larger patient populations.

Topics: Amides; Animals; Arginine; Butyrates; Fetal Hemoglobin; Genes; Globins; Hemoglobinopathies; Humans

Stimulating expression of the normal fetal globin genes is a preferred method of ameliorating sickle cell disease and beta-thalassemia for the majority of patients in North America who do not have appropriate bone marrow donors.. Due to increased survival of red blood cells that contain both hemoglobin S and hemoglobin F, as little as 4-8% fetal globin synthesis in the bone marrow can produce levels of hemoglobin F of approximately 20% in the peripheral circulation. Some success has been achieved in stimulating hemoglobin F using chemotherapeutic agents (such as hydroxyurea and 5-azacytidine) and growth factors (erythropoietin) that alter erythroid growth kinetics. However, there is reluctance to treat children with chemotherapeutic agents because of possible undesirable long-term side effects.. Butyric acid and butyrate derivatives are generally safe compounds that stimulate the promoters of individual fetal and embryonic globin genes and thus provide a more specific therapy. An initial trial with the parent compound, given as arginine butyrate, has demonstrated rapid stimulation of fetal globin expression to levels that can ameliorate these conditions. Phase I trials of an oral butyrate derivative with a long plasma half-life have begun.. These agents may provide a new and specific approach for ameliorating the clinical manifestations of sickle cell disease and beta-thalassemia.

Topics: Adolescent; Adult; Amides; Anemia, Sickle Cell; Animals; Arginine; beta-Thalassemia; Butyrates; Child; Child, Preschool; Fetal Hemoglobin; Globins; Humans; Promoter Regions, Genetic

Topics: Adult; Amides; Arginine; Butyrates; Epilepsy; Fetal Hemoglobin; Humans; Phenylacetates; Phenylbutyrates; Reference Values; Valproic Acid