ICA-17043, a novel Gardos channel blocker, prevents sickled red blood cell dehydration in vitro and in vivo in SAD mice

Stocker, Jonathan W.; Franceschi, Lucia De; McNaughton‐Smith, Grant; Corrocher, Roberto; Beuzard, Yves; Brugnara, Carlo

doi:10.1182/blood-2002-05-1433

Cited by 181 publications

(145 citation statements)

References 59 publications

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“…Two more-selective KCa3.1 blockers, which lack cytochrome P450 inhibitory activity, are the triarylmethanes TRAM-34 and ICA-17043 (15)(16)(17)(18). KCa3.1 blockers inhibit VSMC proliferation and migration (6,14), macrophage function (8,19), T cell activation (15), and EC proliferation (9).…”

Section: Introductionmentioning

confidence: 99%

The intermediate-conductance calcium-activated potassium channel KCa3.1 contributes to atherogenesis in mice and humans

et al. 2008

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Atherosclerosis remains a major cause of death in the developed world despite the success of therapies that lower cholesterol and BP. The intermediate-conductance calcium-activated potassium channel KCa3.1 is expressed in multiple cell types implicated in atherogenesis, and pharmacological blockade of this channel inhibits VSMC and lymphocyte activation in rats and mice. We found that coronary vessels from patients with coronary artery disease expressed elevated levels of KCa3.1. In Apoe -/-mice, a genetic model of atherosclerosis, KCa3.1 expression was elevated in the VSMCs, macrophages, and T lymphocytes that infiltrated atherosclerotic lesions. Selective pharmacological blockade and gene silencing of KCa3.1 suppressed proliferation, migration, and oxidative stress of human VSMCs. Furthermore, VSMC proliferation and macrophage activation were reduced in KCa3.1 -/-mice. In vivo therapy with 2 KCa3.1 blockers, TRAM-34 and clotrimazole, significantly reduced the development of atherosclerosis in aortas of Apoe -/-mice by suppressing VSMC proliferation and migration into plaques, decreasing infiltration of plaques by macrophages and T lymphocytes, and reducing oxidative stress. Therapeutic concentrations of TRAM-34 in mice caused no discernible toxicity after repeated dosing and did not compromise the immune response to influenza virus. These data suggest that KCa3.1 blockers represent a promising therapeutic strategy for atherosclerosis.

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Section: Introductionmentioning

confidence: 99%

The intermediate-conductance calcium-activated potassium channel KCa3.1 contributes to atherogenesis in mice and humans

et al. 2008

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“…6,7 Senicapoc is well tolerated by both healthy volunteers and patients with SCD and has favorable pharmacokinetics, with a long half-life permitting once-daily dosing. 7 The study goals in this 12-week phase 2 study were to assess the effect of senicapoc on total hemoglobin levels and markers of RBC destruction, to obtain additional safety data, and to identify the most appropriate dose for a pivotal phase 3 study.…”

Section: Introductionmentioning

confidence: 99%

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

Ataga¹,

Smith

Castro

et al. 2008

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“…10,11 In normal RBCs, Piezo1 appears to be a major factor in cell response to mechanical stress (by controlling calcium influx), 12,13 and there is a functional connection between Piezo1 and KCNN4 through the modification of intracellular calcium concentration. Our present study was designed to evaluate in HX the functional link between mutated Piezo1 and KCNN4 and to assess the efficiency of a KCNN4 blocker, Senicapoc, 14 to treat HX whatever the molecular cause.…”

mentioning

confidence: 99%

Red blood cell Gardos channel (KCNN4): the essential determinant of erythrocyte dehydration in hereditary xerocytosis

et al. 2017

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ICA-17043, a novel Gardos channel blocker, prevents sickled red blood cell dehydration in vitro and in vivo in SAD mice

Cited by 181 publications

References 59 publications

The intermediate-conductance calcium-activated potassium channel KCa3.1 contributes to atherogenesis in mice and humans

The intermediate-conductance calcium-activated potassium channel KCa3.1 contributes to atherogenesis in mice and humans

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

Red blood cell Gardos channel (KCNN4): the essential determinant of erythrocyte dehydration in hereditary xerocytosis

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