Clotrimazole in rheumatoid arthritis.

Wojtulewski, J A; Gow, Peter; Walter, Jennifer; Grahame, Rodney; Gibson, T.; Panayi, G. S.; Mason, Jolene

doi:10.1136/ard.39.5.469

Cited by 41 publications

(22 citation statements)

References 8 publications

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“…In particular, KCa3.1 blockade therapy with clotrimazole or TRAM-34 did not change BP or cause left-ventricular hypertrophy in Apoe +/+ and Apoe -/-C57BL/J mice or Lewis rats, unlike KCa3.1 KO in mice, which produces a 7-mmHg increase in BP and mild cardiac hypertrophy (45). Our results are consistent with reports that ICA-17043 and clotrimazole do not cause cardiovascular changes in humans, rats, and mice (17,18,(46)(47)(48). In KCa3.1 -/-mice, the gene was deleted, which may have caused compensatory changes during development, and the functional effect of such a deletion will be substantially different from that of pharmacological blockade, which varies during the day, depending on the pharmacokinetic properties of the blocker.…”

Section: Discussionsupporting

confidence: 91%

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: Discussionsupporting

confidence: 91%

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

et al. 2008

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“…Because IKCa1 is the functionally dominant K ϩ channel in naive and early memory B and T cells, IKCa1 blockers might have use in suppressing acute immune reactions, for example, during graft rejection and during the acute phases of autoimmune diseases. Clotrimazole, an IKCa1 blocker, was reported to ameliorate rheumatoid arthritis in patients, but was abandoned due to adverse effects resulting from blockade of cytochrome P450 enzymes (64,65). The newer IKCa1-specific blockers TRAM-34, ICA-17043, and 4-phenyl-4H-pyran (66 -68), which lack this activity, should be evaluated for therapeutic use in autoimmune disorders.…”

Section: Cd27mentioning

confidence: 99%

K+ Channel Expression during B Cell Differentiation: Implications for Immunomodulation and Autoimmunity

Wulff

Knaus

Pennington

et al. 2004

The Journal of Immunology

177

189

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Using whole-cell patch-clamp, fluorescence microscopy and flow cytometry, we demonstrate a switch in potassium channel expression during differentiation of human B cells from naive to memory cells. Naive and IgD+CD27+ memory B cells express small numbers of the voltage-gated Kv1.3 and the Ca2+-activated intermediate-conductance IKCa1 channel when quiescent, and increase IKCa1 expression 45-fold upon activation with no change in Kv1.3 levels. In contrast, quiescent class-switched memory B cells express high levels of Kv1.3 (∼2000 channels/cell) and maintain their Kv1.3high expression after activation. Consistent with their channel phenotypes, proliferation of naive and IgD+CD27+ memory B cells is suppressed by the specific IKCa1 inhibitor TRAM-34 but not by the potent Kv1.3 blocker Stichodactyla helianthus toxin, whereas the proliferation of class-switched memory B cells is suppressed by Stichodactyla helianthus toxin but not TRAM-34. These changes parallel those reported for T cells. Therefore, specific Kv1.3 and IKCa1 inhibitors may have use in therapeutic manipulation of selective lymphocyte subsets in immunological disorders.

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“…The systemic use of clotrimazole at high doses (eg 80 mg/kg per day and higher) may be limited by gastrointestinal and urinary side-effects and elevation of hepatic enzymes and plasma cortisol levels. 17,23,25,53 Some of the most severe side-effects are likely to reflect clotrimazole inhibition of cytochrome P450-dependent enzymes. 27,[53][54][55] Interestingly, however, recently developed clotrimazole analogues that have potent and selective IK channel-blocking activity do not inhibit cytochrome P450-dependent enzymes.…”

Section: Figurementioning

confidence: 99%

“…19 Second, clotrimazole has been shown to inhibit normal lymphocyte proliferation, 20,21 at least partially by blocking IK channels, 15,22 and it reportedly exerts beneficial effects in patients with rheumatoid arthritis. 23,24 Importantly, concentrations of clotrimazole and its metabolites that effectively interfere with Ca 2+ metabolism and block IK channels are achievable in vivo. [25][26][27] We investigated the effects of clotrimazole on ALL cells and found that the drug markedly suppresses the recovery of ALL cells from culture.…”

Section: Introductionmentioning

confidence: 99%

The antifungal antibiotic clotrimazole alters calcium homeostasis of leukemic lymphoblasts and induces apoptosis

et al. 2002

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Clotrimazole is an antimycotic imidazole derivative that interferes with cellular Ca 2+ homeostasis. We investigated the effects of clotrimazole on acute lymphoblastic leukemia (ALL) cells. Treatment with 10 M clotrimazole (a concentration achievable in vivo) reduced cell recovery from cultures of all nine ALL cell lines studied (B-lineage: OP-1, SUP-B15, RS4;11, NALM6, REH, and 380; T-lineage: MOLT4, CCRF-CEM, and CEM-C7). After 4 days of culture, median cell recovery was 10% (range, Ͻ1% to 37%) of cell recovery in parallel untreated cultures. Clotrimazole also inhibited recovery of primary ALL cells cultured on stromal feeder layers. After leukemic cells from 16 cases of ALL were cultured for 7 days with 10 M clotrimazole, median cell recovery was Ͻ1% (range, Ͻ1% to 16%) of that in parallel untreated cultures. Clotrimazole was active against leukemic cells with genetic abnormalities associated with poor response to therapy and against multidrug-resistant cell lines. In contrast, mature T lymphocytes and bone marrow stromal cells were not affected. Clotrimazole induced depletion of intracellular Ca 2+ stores in ALL cells, which was followed by apoptosis, as shown by annexin V binding and DNA fragmentation. Thus, clotrimazole is cytotoxic to ALL cells at concentrations achievable in vivo.

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Clotrimazole in rheumatoid arthritis.

Cited by 41 publications

References 8 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

K+ Channel Expression during B Cell Differentiation: Implications for Immunomodulation and Autoimmunity

The antifungal antibiotic clotrimazole alters calcium homeostasis of leukemic lymphoblasts and induces apoptosis

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