Efficacy and safety of the Gardos channel blocker, senicapoc (ICA-17043), in patients with sickle cell anemia.

Division of Hematology/Oncology, University of North Carolina at Chapel Hill, CB no. 7305, 3009 Old Clinic Bldg, Chapel Hill, NC 27599-7305, USA.
Blood (Impact Factor: 9.78). 04/2008; 111(8):3991-7. DOI: 10.1182/blood-2007-08-110098
Source: PubMed

ABSTRACT 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 RBC 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 as NCT00040677.

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    ABSTRACT: Sickle cell disease (SCD) is a very devastating condition caused by an autosomal recessive inherited haemoglobinopathy. This disease affects millions of peoples globally which results in serious complications due to vasoocclusive phenomenon and haemolysis. This genetic abnormality is due to substitution of amino acid valine for the glutamic acid at the sixth position of beta chain of haemoglobin. This disease was described about one hundred year ago. The haemoglobin S (hbS) produced as result of this defect is poorly soluble and polymerized when deoxygenated. Symptoms of sickle cell disease are due to chronic anaemia, pain full crises, acute chest syndrome, stroke and susceptibility to bacterial infection. In recent years measures like prenatal screening, better medical care, parent education, immunization and penicillin prophylaxis have successfully reduced morbidity and mortality and have increased tremendously life expectancy of affected individuals. Three principal current therapeutics modalities available for childhood SCD are blood transfusion, Hydroxy urea and bone marrow transplantation. Genetic counseling, continued medical education for health professionals about sickle cell disease, its complications and management is necessary. World health organization has actively promoted several national screening programms with dual goals of informing reproductive choice and thereby reducing the number of severely affected children.
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    ABSTRACT: The molecular mechanisms by which nitric oxide (NO) bioavailability modulates the clinical expression of sickle cell disease (SCD) remain elusive. We investigated the effect of hypoxia and NO bioavailability on sickle red blood cell (sRBC) adhesion using mice deficient for endothelial nitric oxide synthase (eNOS) because their NO metabolite levels are similar to those of SCD mice but without hypoxemia. Whereas sRBC adhesion to endothelial cells in eNOS-deficient mice was synergistically upregulated at the onset of hypoxia, leukocyte adhesion was unaffected. Restoring NO metabolite levels to physiological levels markedly reduced sRBC adhesion to levels seen under normoxia. These results indicate that sRBC adherence to endothelial cells increases in response to hypoxia prior to leukocyte adherence, and that low NO bioavailability synergistically upregulates sRBC adhesion under hypoxia. While multiple adhesion molecules mediate sRBC adhesion, we found a central role for P-selectin in sRBC adhesion. Hypoxia and low NO bioavailability upregulated P-selectin expression in endothelial cells in an additive manner through p38 kinase pathways. These results demonstrate novel cellular and signaling mechanisms that regulate sRBC adhesion under hypoxia and low NO bioavailability. Importantly, these findings point us toward new molecular targets to inhibit cell adhesion in SCD.
    Blood 01/2014; · 9.78 Impact Factor
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    ABSTRACT: Background Idiopathic pulmonary fibrosis is a common and invariably fatal disease with limited therapeutic options. Ca2+-activated KCa3.1 potassium channels play a key role in promoting TGFß1 and bFGF-dependent profibrotic responses in human lung myofibroblasts (HLMFs). We hypothesised that KCa3.1 channel-dependent cell processes regulate HLMF ¿SMA expression via Smad2/3 signalling pathways.Methods In this study we have compared the phenotype of HLMFs derived from non-fibrotic healthy control lungs (NFC) with cells derived from IPF lungs. HLMFs grown in vitro were examined for ¿SMA expression by immunofluorescence (IF), RT-PCR and flow cytommetry. Basal Smad2/3 signalling was examined by RT-PCR, western blot and immunofluorescence. Two specific and distinct KCa3.1 blockers (TRAM-34 200 nM and ICA-17043 [Senicapoc] 100nM) were used to determine their effects on HLMF differentiation and the Smad2/3 signalling pathways.ResultsIPF-derived HLMFs demonstrated increased constitutive expression of both ¿-smooth muscle actin (¿SMA) and actin stress fibres, indicative of greater myofibroblast differentiation. This was associated with increased constitutive Smad2/3 mRNA and protein expression, and increased Smad2/3 nuclear localisation. The increased Smad2/3 nuclear localisation was inhibited by removing extracellular Ca2+ or blocking KCa3.1 ion channels with selective KCa3.1 blockers (TRAM-34, ICA-17043). This was accompanied by de-differentiation of IPF-derived HLMFs towards a quiescent fibroblast phenotype as demonstrated by reduced ¿SMA expression and reduced actin stress fibre formation.Conclusions Taken together, these data suggest that Ca2+- and KCa3.1-dependent processes facilitate ¿constitutive¿ Smad2/3 signalling in IPF-derived fibroblasts, and thus promote fibroblast to myofibroblast differentiation. Importantly, inhibiting KCa3.1 channels reverses this process. Targeting KCa3.1 may therefore provide a novel and effective approach for the treatment of IPF and there is the potential for the rapid translation of KCa3.1-directed therapy to the clinic.
    Respiratory Research 12/2014; 15(1):155. · 3.13 Impact Factor

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