Oral Isobutyramide Therapy in Patients with Thalassemia Intermedia: Results of a Phase II Open Study

Erythroid differentiation ability of butyric acid analogues: Identification of basal chemical structures of new inducers of foetal haemoglobin

“…As far as clinical trials, several examples are present in the literature including those based on sodium butyrate and sodium phenylbutyrate (Dover et al, 1994, Collins et al, 1995, Sher et al, 1995, arginine butyrate (McMahon et al, 2010) and isobutyramide (Domenica Cappellini et al, 2000). While all these molecules deserve attention in further clinical studies, the identification of novel foetal haemoglobin inducers, including butyric acid analogues, might help in defining mechanism of action on one hand and structure-related efficacy on the other, including tailored combinations of therapeutics .…”

“…The compounds 4174 (7 mM), 4174 A (10 mM), 4174B (5.6 mM), 4174 C (7 mM), 4174D (2 mM), 4174E (2 mM) and butyric acid (1.5 mM), a known stimulator of foetal haemoglobin production in vitro and in vivo (Domenica Cappellini et al, 2000;BerkovitchLuria et al, 2012;Perrine et al, 2011;Gabbianelli et al, 2000 andJohnson et al, 2005), were added on day 5 of phase two (when cells started to synthesize haemoglobin), and the cells were harvested on day 12. After treatment, the effects on α-globin, β-globin and γ-globin mRNAs were analysed by quantitative RT-PCR.…”

“…A large number of compounds stimulating foetal haemoglobin production, such as chemotherapeutic agents, 5-azacytidine and hydroxyurea (Bunn, 1997, Ferster et al, 1996, Ballas et al, 2006and Italia et al, 2013, was considered; however, citotoxicity, potential carcinogenicity and the moderate effects obtained have limited their clinical use (Domenica Cappellini et al, 2000).…”

Fetal globin gene inducers: novel agents and new potential

“…Proof‐of‐principle has been demonstrated in clinical trials in which pharmacological reactivation of γ‐globin expression has reduced anemia and eliminated transfusion requirements in patients with thalassemia. Fetal globin reinduction was accomplished with chemotherapeutic agents, particularly 5‐azacytidine, and 5‐aza‐2‐deoxy‐cytidine (decitabine), 14–20 and with short‐chain fatty acids (SCFAs), such as arginine butyrate (AB) and sodium phenylbutyrate 2,9,10,12,13,21 . SCFAs would be preferable for a long‐term therapy compared to chemotherapeutics, which typically are cytotoxic and have carcinogenicity risks long‐term.…”

“…Many patients with higher γ‐globin levels than their counterparts with the same mutations often do not require regular transfusions, or do not require transfusions on a regular basis as early in life as do others with lower γ‐globin levels. These observations, and clinical trials of fetal globin inducers, have clearly established that patients with β‐thalassemia benefit from persistence of, or pharmacologic induction of, γ‐globin 1–20 . Inducing γ‐globin expression by even small increments is an established therapeutic approach that is most likely to be feasible to apply worldwide, as the γ‐globin genes are universally present and normally integrated in hematopoietic stem cells 1,2 …”