Journal
BLOOD
Volume 111, Issue 8, Pages 3991-3997Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2007-08-110098
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Senicapoc, a novel Gardos channel inhibitor, limits solute and water loss, thereby preserving sickle red blood cell (RBC) hydration. Because hemoglobin S polymerization is profoundly influenced by intracellular hemoglobin concentration, senicapoc could improve sickle FIBC survival. In a 12-week, multicenter, phase 2, randomized, double-blind, dose-finding study, we evaluated senicapoc's safety and its effect on hemoglobin level and markers of RBC hemolysis in sickle cell anemia patients. The patients were randomized into 3 treatment arms: placebo; low-dose (6 mg/day) senicapoc; and high-dose (10 mg/day) senicapoc. For the primary efficacy end point (change in hemoglobin level from baseline), the mean response to high-dose senicapoc treatment exceeded placebo (6.8 g/L [0.68 g/ dL] vs 0.1 g/L [0.01 g/dL], P <.001). Treatment with high-dose senicapoc also produced significant decreases in such secondary end points as percentage of dense RBCs (-2.41 vs -0.08, P <.001); reticulocytes (-4.12 vs -0.46, P <.001); lactate dehydrogenase (-121 U/L vs - 15 U/L, P =.002); and indirect bilirubin (-1.18 mg/dL vs 0.12 mg/dL, P <.001). Finally, senicapoc was safe and well tolerated. The increased hemoglobin concentration and concomitant decrease in the total number of reticulocytes and various markers of RBC destruction following senicapoc administration suggests a possible increase in the survival of sickle RBCs. This study is registered at http:// clinicaltrials.gov as NCT00040677.
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