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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. [ABSTRACT FROM AUTHOR]

Prevention of erythrocyte dehydration by specific blockade of the transport pathways promoting loss of potassium (K) is a potential therapeutic strategy for sickle cell (SS) disease. Dietary magnesium (Mg) pidolate supplementation over a 4-week period has been shown to inhibit K–Cl co-transport and reduce dehydration. We report here the results in 17 of 20 patients with SS disease treated in an open-label unblinded study of the effects of long-term (6 months) oral Mg pidolate administration (540 mg Mg/d). A significant decrease (P < 0.0025) was observed with Mg therapy in the distribution widths for red cell mean cell haemoglobin concentration (MCHC) (haemoglobin distribution width; HDW), reticulocyte mean cell volume (red cell distribution width of reticulocytes; RDWr) and MCHC (reticulocyte HDW; HDWr), activity of red cell K–Cl co-transport, Na/Mg exchanger and Ca2+-activated (Gardos) K+ channel, whereas red cell K and Mg contents were significantly increased. Hb levels and absolute reticulocyte counts did not change with Mg therapy. Two patients did not complete the trial because of diarrhoea and one did not complete the trial for unrelated reasons. Although the median number of painful days in a 6-month period decreased from 15 (range 0–60) in the year before the trial to 1 (range 0–18; P < 0.0005) during the period of Mg therapy, no firm conclusion on therapeutic efficacy could be drawn from this unblinded open-label trial. [ABSTRACT FROM AUTHOR]