Extended Therapy with Intravenous Arginine Butyrate in Patients with β-Hemoglobinopathies

Sher, Graham D.; Ginder, Gordon D.; Little, Jane A.; Yang, Sungchil; Dover, George J.; Olivieri, Nancy F.

doi:10.1056/nejm199506153322404

Cited by 161 publications

(93 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However this increase in HbF levels was not sustained with continuous therapy. 26,27 The decrease in HbF levels after prolonged exposure to arginine butyrate, considered in the context of the well-known growth-inhibitory activity of butyrate, suggested that an intermittent dosing schedule may prevent toxicity and allow proliferation of the erythroid cells in which HbF is induced. Thus, when arginine butyrate was given intermittently for 4 days every 4 weeks, it led to sustained induction of HbF production in a majority of patients with SCD.…”

Section: Butyratementioning

confidence: 99%

Induction of Fetal Hemoglobin in the Treatment of Sickle Cell Disease

Fathallah

Atweh

2006

Hematology

View full text Add to dashboard Cite

Reactivation of fetal hemoglobin (HbF) expression is an important therapeutic option in patients with hemoglobin disorders. In sickle cell disease (SCD), an increase in HbF inhibits the polymerization of sickle hemoglobin and the resulting pathophysiology. Hydroxyurea, an inducer of HbF, has already been approved for the treatment of patients with moderate and/or severe SCD. Recent clinical trials with other pharmacological inducers of HbF, such as butyrate and decitabine, have shown considerable promise. In this chapter, we highlight the important clinical trials with pharmacological inducers of HbF, discuss their mechanisms of action and speculate about the future of this therapeutic approach in the treatment of patients with SCD.

show abstract

Section: Butyratementioning

confidence: 99%

Induction of Fetal Hemoglobin in the Treatment of Sickle Cell Disease

Fathallah

Atweh

2006

Hematology

View full text Add to dashboard Cite

show abstract

“…Recent multicenter studies with hydroxyurea (HU) have shown that administration of this drug to patients with sickle cell anemia significantly increases Hb F production and improves clinical symptoms by reducing the frequency of pain crisis (9,10). Butyrate compounds have been administered to patients with ␤-thalassemia (11,12) or sickle cell anemia (13), and further large-scale studies seem to be necessary to evaluate the clinical efficacy of the compounds. Despite a number of clinical trials with Hb F-inducing agents, little is known about the molecular and cellular basis of their mode of action.…”

mentioning

confidence: 99%

Mechanism for fetal globin gene expression: Role of the soluble guanylate cyclase-cGMP-dependent protein kinase pathway

Ikuta¹

2001

Proceedings of the National Academy of Sciences

134

View full text Add to dashboard Cite

Despite considerable concerns with pharmacological stimulation of fetal hemoglobin (Hb F) as a therapeutic option for the ␤-globin disorders, the molecular basis of action of Hb F-inducing agents remains unclear. Here we show that an intracellular pathway including soluble guanylate cyclase (sGC) and cGMP-dependent protein kinase (PKG) plays a role in induced expression of the ␥-globin gene. sGC, an obligate heterodimer of ␣-and ␤-subunits, participates in a variety of physiological processes by converting GTP to cGMP. Northern blot analyses with erythroid cell lines expressing different ␤-like globin genes showed that, whereas the ␤-subunit is expressed at similar levels, high-level expression of the ␣-subunit is preferentially observed in erythroid cells expressing ␥-globin but not those expressing ␤-globin. Also, the levels of expression of the ␥-globin gene correlate to those of the ␣-subunit. sGC activators or cGMP analogs increased expression of the ␥-globin gene in erythroleukemic cells as well as in primary erythroblasts from normal subjects and patients with ␤-thalassemia. Nuclear run-off assays showed that the sGC activator protoporphyrin IX stimulates transcription of the ␥-globin gene. Furthermore, increased expression of the ␥-globin gene by well known Hb F-inducers such as hemin and butyrate was abolished by inhibiting sGC or PKG activity. Taken together, these results strongly suggest that the sGC-PKG pathway constitutes a mechanism that regulates expression of the ␥-globin gene. Further characterization of this pathway should permit us to develop new therapeutics for the ␤-globin disorders.

show abstract

“…However, a subsequent study showed that the continuous infusion of Arginine Butyrate did not result in a sustained HbF production and did not improve the hematologic condition of both sickle cell disease and β-thalassemic patients [141].…”

Section: Butyratementioning

confidence: 96%