Abstract
Red blood cell (RBC) sickling is promoted by increased intracellular deoxygenated Hb S concentration and via cell dehydration. Magnesium (Mg) can reduce RBC water loss through its negative regulation of K-Cl cotransport, a pathway which mediates cell dehydration. Hydroxyurea (HU) reduces sickling in part by increasing intracellular fetal hemoglobin (Hb F). The combination of HU and Mg pidolate, two drugs with distinct mechanisms of action, could offer additive or synergistic effects. We performed a phase I study of treatment with HU and Mg pidolate in children with sickle cell anemia (SCA), to estimate the maximum tolerated dose (MTD) and toxicity of this drug combination, and obtained preliminary data regarding cellular effects of this treatment. Children with SCA who had been treated with HU on a stable dose for a minimum of 6 months, received 6 months of treatment with Mg pidolate in addition to HU. The Mg dose was 0.6 mEq/kg/day for the first cohort of patients and was escalated by 50 % in each subsequent cohort to a maximum of 1.9 mEq/kg/d. HU was continued at the patients’ pre-study dose. Compliance was measured using returned bottles and pills counts for both HU and Mg pidolate. Hematologic studies were performed at baseline, 3, and 6 months, and 3 months after Mg pidolate discontinuation (9 months). In vitro RBC adhesion to immobilized thrombospondin was measured under low shear flow conditions. Sixteen patients participated in the study; 9 were boys, and the median age was 7 years (range 4 – 12 years). All were African American and had Hb SS. The median HU dose was 28.5 mg/kg/day (range 25 to 30 mg/kg/d) and the median pre-study HU treatment duration was 1.9 years (range 0.7 – 8.4 years). The MTD for Mg pidolate used in combination with HU was 0.9 mEq/kg/day. The dose limiting toxicity (DLT) of Mg pidolate was diarrhea. There were 4 cases of grade III toxicity (all in the first 4 weeks of the study), 2 cases of grade II and one case of grade I diarrhea. There also were grade III (2), and grade II (3) abdominal pain events. There were no cases of hematologic toxicity, and no patients required HU dose reduction or interruption. Compliance was above 85 % for both drugs in 95 % of the visits. At baseline, high density RBC and KCl co-transport activity were much lower, and intracellular K was much higher than in untreated Hb SS RBC; these values remained relatively stable on Mg pidolate therapy. Mean RBC adhesion to thrombospondin at baseline was low (323 ± 286 RBCs/mm2) and decreased even further to 245 ± 161 RBCs/mm2 during Mg pidolate use. No significant changes in Hb, WBC, platelets, reticulocytes, Hb F, and MCV occurred. We conclude:
The MTD for Mg pidolate when used in combination with HU for children with SCA is 0.9 mEq/kg/d, The most common dose-limiting toxicities from Mg pidolate are diarrhea and abdominal pain, There is no additional hematologic toxicity from HU therapy when Mg pidolate is added, RBC adhesion to endothelium may be further decreased in SCA patients treated with HU when Mg pidolate is added, HU therapy when used at 30 mg/kg/day in fully compliant patients may promote decreased RBC adhesion, higher intracellular K, and lower KCl co-transport activity.
Phase I study of eptifibatide in patients with sickle cell anaemia