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

Medical College of Wisconsin, Milwaukee, Wisconsin, United States
British Journal of Haematology (Impact Factor: 4.71). 02/2008; 140(1):80-5. 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.

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    • "In contrast with previously published literature in Hb SS disease ( De Franceschi et al , 1997 , 2000 ) , 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 . "
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    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.
    British Journal of Haematology 03/2011; 152(6):771-6. DOI:10.1111/j.1365-2141.2010.08523.x · 4.71 Impact Factor
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    • "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]. "
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    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.
    PLoS ONE 01/2010; 5(1):e8732. DOI:10.1371/journal.pone.0008732 · 3.23 Impact Factor
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    • "A double-blind, placebo controlled crossover study with Mg pidolate supplementation in children with sickle cell disease did not demonstrate any significant changes in the haematological parameters studied; however, the Mg-pidolate dosage used was markedly lower than that proposed in the previous studies. In a phase I study, the therapeutic association of Mg-pidolate with hydroxyurea have been evaluated in patients with HbSC disease, showing a significant reduction in the activity of the K-Cl cotransport after 3 months of supplementation34. "
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    ABSTRACT: A homozygous mutation in the gene for β globin, a subunit of adult hemoglobin A (HbA), is the proximate cause of sickle cell disease (SCD). Sickle hemoglobin (HbS) shows peculiar biochemical properties, which lead to polymerizing when deoxygenated. HbS polymerization is associated with a reduction in cell ion and water content (cell dehydration), increased red cell density which further accelerate HbS polymerization. Dense, dehydrated erythrocytes are likely to undergo instant polymerization in conditions of mild hypoxia due to their high HbS concentration, and HbS polymers may be formed under normal oxygen pressure. Pathophysiological studies have shown that the dense, dehydrated red cells may play a central role in acute and chronic clinical manifestations of sickle cell disease, in which intravascular sickling in capillaries and small vessels leads to vaso-occlusion and impaired blood flow in a variety of organs and tissue. The persistent membrane damage associated with HbS polymerization also favors the generation of distorted rigid cells and further contributes to vaso-occlusive crisis (VOCs) and cell destruction in the peripheral circulation. These damaged, dense sickle red cells also show a loss of phospholipid asymmetry with externalization of phosphatidylserine (PS), which is believed to play a significant role in promoting macrophage recognition with removal of erythrocytes (erythrophagocytosis). Vaso-occlusive events in the microcirculation result from a complex scenario involving the interactions between different cell types, including dense, dehydrated sickle cells, reticulocytes, abnormally activated endothelial cells, leukocytes, platelets and plasma factors such as cytokine and oxidized pro-inflammatory lipids. Hydroxycarbamide (hydroxyurea) is currently the only drug approved for chronic administration in adult patients with sickle cell disease to prevent acute painful crises and reduce the incidence of transfusion and acute chest crises. Here, we will focus on consolidated and experimental therapeutic strategies for the treatment of sickle cell disease, including: agents which reduce or prevent sickle cell dehydrationagents which reduce sickle cell-endothelial adhesive eventsnitric oxide (NO) or NO-related compoundsanti-oxidant agentsCorrection of the abnormalities ranging from membrane cation transport pathways to red cell-endothelial adhesive events, might constitute new pharmacological targets for treating sickle cell disease.
    Mediterranean Journal of Hematology and Infectious Diseases 12/2009; 1(1):e2009024. DOI:10.4084/MJHID.2009.024
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