Phase I study of magnesium pidolate in combination with hydroxyurea for children with sickle cell anemia

ArticleinBritish Journal of Haematology 140(1):80-5 · February 2008with17 Reads
DOI: 10.1111/j.1365-2141.2007.06884.x · Source: PubMed
Abstract
In sickle cell anaemia, red cell dehydration increases intracellular HbS concentration and promotes sickling. Higher erythrocyte magnesium reduces water loss through negative regulation of membrane transporters. Hydroxycarbamide (also known as hydroxyurea) reduces sickling partly by increasing intracellular HbF. Combining drugs with distinct mechanisms could offer additive effects. A phase I trial combining oral magnesium pidolate and hydroxycarbamide was performed to estimate the maximum tolerated dose (MTD) and toxicity of magnesium. Cohorts of three children with HbSS, who were on a stable dose of hydroxycarbamide (median 28.5 mg/kg/d), received magnesium pidolate for 6 months beginning at 83 mg/kg/d. The dose was escalated by 50% for subsequent cohorts. Laboratory evaluations were performed at 0, 3, 6 and 9 months. Sixteen children (aged 4-12 years) participated. All four dose-limiting toxicities (grade III diarrhoea and abdominal pain) occurred within the first month of starting magnesium. Additionally, diarrhoea grades I (n = 1) and II (n = 3), and abdominal pain grade II (n = 3) occurred. Hydroxycarbamide dose reduction or interruption was not required. The MTD for magnesium pidolate used in combination with hydroxycarbamide was 125 mg/kg/d. KCl co-transporter activity declined after 3 months of magnesium pidolate (P = 0.02). A phase II study is needed to investigate the efficacy of this drug combination.
    • "In contrast with previously published literature in Hb SS disease (De Franceschi et al, 1997), we did not find significant effects of Mg pidolate on HbSC red cell properties, nor did we see an increase in the Mg content of erythrocytes, suggesting that permeability to Mg may differ in HbSS and HbSC cells. In our study Mg was given at a lower than maximally tolerated dose (Hankins et al, 2007), perhaps limiting our ability to find expected biological effects on RBC density. In summary, HC had significant effects on HbSC red cells, including increased HbF and MCV. "
    [Show abstract] [Hide abstract] ABSTRACT: In a phase-II multi-centre double-blinded trial, we evaluated haematological effects of oral hydroxycarbamide (HC) and magnesium (Mg) in patients with HbSC, aged 5-53 years old. Subjects were randomized to HC + placebo, Mg + placebo, HC + Mg, or placebo + placebo. The primary endpoint was the proportion of hyperdense red blood cells after 8 weeks. Thirty-six subjects were evaluable, but the study was terminated early because of slow enrollment. In the combined HC groups, mean cell volume and HbF were increased, but differences were not seen in hyperdense red cells or vaso-occlusive events. Mg had no effects. Further investigation of hydroxycarbamide as monotherapy in HbSC disease is warranted.
    Full-text · Article · Mar 2011
    • "Preliminary research on dietary habits shows that food and nutrient intake by patients with SCD in general meets or exceeds recommendations and is not significantly different from healthy controls [20]. In a study, administration of 540mg magnesium pidolate orally has been shown to reverse some of the characteristic RBC abnormalities and to reduce the number of painful days for sickle cell patients [21] [22]. This means that higher levels of magnesium intake from foods such as beans, nuts, green leafy vegetables etc., can possibly 2+ ameliorate the effects of red cell dehydration. "
    [Show abstract] [Hide abstract] ABSTRACT: Low concentrations of magnesium (Mg2+) in red blood cells (RBC) have been implicated in the pathogenesis of dehydration in RBCs known to be a precipitating factor in sickle cell crisis. The present study is aimed at estimating the activities of ATPases localized on the red cell membrane, protein and intracellular red blood cell Mg2+ concentrations of normal and sickle cell patients. Intracellular magnesium (Mg2+), protein and membrane ATPases were estimated in a total of 60 subjects (30 males and 30 females) in Enugu metropolis, aged between 18 and 40 years. Twenty (20) of them (10 males and 10 females) were patients with sickle cell disease (SCD) attending the Sickle Cell Clinic at the University of Nigeria Teaching Hospital (UNTH), Ituku-Ozalla, Enugu, Nigeria whereas 40 of them were volunteers (20 males and 20 females) with homozygous (AA) and heterozygous (AS) haemoglobin phenotypes. A significant low mean value (P<0.05) was noted for the intracellular RBC Mg2+ concentration in the SCD subjects relative to the AA and AS subject groups, where high levels were recorded. The mean value of Ca2+-ATPase in the SCD group of patients was 0.2499 ± 0.02 , which indicated a high specific activity (P<0.05) relative to the AA and AS groups, whereas low enzyme activities were observed for the Mg2+ and Ca2+/Mg2+-ATPases compared to those of the control groups. Mg2+-ATPase and Ca2+/Mg2+-ATPase activities were generally decreased whereas Ca2+-ATPase activity increased in SCD patients. There were significantly low levels of RBC Mg2+ in SCD patients compared to the controls.
    Full-text · Article · Nov 2010 · PLoS ONE
    • "Therapeutic prolongation of the deoxy-HbSS delay time is the goal of pharmacological inhibition of sickle erythrocyte solute leak and dehydration [4,9]. A study of inhibition of erythroid K-Cl cotransporters with magnesium pidolate is emerging from Phase I [10]. The KCa3.1 inhibitor ICA-17043 (senicapoc) completed Phase II clinical trial with promising results [11] and progressed through much of Phase III with continued, convincing hematological efficacy, although without improvement in clinical pain symptoms [12]. "
    [Show abstract] [Hide abstract] ABSTRACT: Deoxygenation of sickle erythrocytes activates a cation permeability of unknown molecular identity (Psickle), leading to elevated intracellular [Ca(2+)] ([Ca(2+)](i)) and subsequent activation of K(Ca) 3.1. The resulting erythrocyte volume decrease elevates intracellular hemoglobin S (HbSS) concentration, accelerates deoxygenation-induced HbSS polymerization, and increases the likelihood of cell sickling. Deoxygenation-induced currents sharing some properties of Psickle have been recorded from sickle erythrocytes in whole cell configuration. We now show by cell-attached and nystatin-permeabilized patch clamp recording from sickle erythrocytes of mouse and human that deoxygenation reversibly activates a Ca(2+)- and cation-permeable conductance sensitive to inhibition by Grammastola spatulata mechanotoxin-4 (GsMTx-4; 1 microM), dipyridamole (100 microM), DIDS (100 microM), and carbon monoxide (25 ppm pretreatment). Deoxygenation also elevates sickle erythrocyte [Ca(2+)](i), in a manner similarly inhibited by GsMTx-4 and by carbon monoxide. Normal human and mouse erythrocytes do not exhibit these responses to deoxygenation. Deoxygenation-induced elevation of [Ca(2+)](i) in mouse sickle erythrocytes did not require KCa3.1 activity. The electrophysiological and fluorimetric data provide compelling evidence in sickle erythrocytes of mouse and human for a deoxygenation-induced, reversible, Ca(2+)-permeable cation conductance blocked by inhibition of HbSS polymerization and by an inhibitor of strctch-activated cation channels. This cation permeability pathway is likely an important source of intracellular Ca(2+) for pathologic activation of KCa3.1 in sickle erythrocytes. Blockade of this pathway represents a novel therapeutic approach for treatment of sickle disease.
    Full-text · Article · Jan 2010
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