Spironolactone inhibits production of proinflammatory cytokines, including tumour necrosis factor-α and interferon-γ, and has potential in the treatment of arthritis
Spironolactone inhibits production of proinflammatory cytokines, including tumour necrosis factor-α and interferon-γ, and has potential in the treatment of arthritis
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DOI：
10.1046/j.1365-2249.2003.02249.x
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发表时间：
2003-10-01
影响因子：
4.6
通讯作者：
Rieneck, K
中科院分区：
文献类型：
--
作者：
Bendtzen, K;Hansen, PR;Rieneck, K
证据表明，螺内酯是一种醛固酮拮抗剂，它对许多类型的细胞都有作用，不依赖于它与胞浆中的盐皮质激素受体的结合。我们通过基因表达分析(GeneChip(R)，12000个基因)和定量分泌的促炎和抗炎细胞因子的酶免疫分析，测试了螺内酯对体外激活的人血白细胞的影响。此外，为了评价螺内酯作为抗炎药物的安全性和有效性，对21例类风湿关节炎(RA)、幼年特发性关节炎(JIA)或其他关节炎患者进行了长达22个月的治疗，剂量为1~3 mg/kg/d。螺内酯在体内可达剂量，显著抑制几种致炎细胞因子的转录，并相应地抑制肿瘤坏死因子、淋巴毒素、干扰素-γ、粒-巨噬细胞集落刺激因子和白介素6的释放(抑制率为70-90%)。每天两次接受50 mg螺内酯的RA患者全血检测时，这些细胞因子的释放也受到抑制，这表明药物使用可能抑制炎性细胞因子的释放。螺内酯治疗总体上耐受性良好，尽管有两名成年人不得不停止同时服用甲氨蝶呤的治疗。16例(76%)患者反应良好。9名RA患者中有6名达到美国风湿病学会标准(ACR)20或更高；4名达到ACR70。9例JIA患者中有8例好转。总而言之，螺内酯可抑制多种致炎细胞因子的产生，这些细胞因子被认为在许多免疫性炎症性疾病中具有重要的致病作用，并对慢性关节炎患者显示出积极的效果。它作为一种抗炎药物的作用值得探讨，因为与许多现代抗炎疗法相比，延长螺内酯疗法是相当安全和经济的。
Evidence suggests that spironolactone, an aldosterone antagonist, has effects on many cell types independent of its binding to cytosolic mineralocorticoid receptors. We tested the effects of spironolactone on ex vivo-activated human blood leucocytes using gene expression analyses (GeneChip(R), 12 000 genes) and enzyme immunoassay for quantitating secreted pro- and anti-inflammatory cytokines. Furthermore, to evaluate the safety and efficacy of spironolactone as an anti-inflammatory drug 21 patients with rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA) or other arthritides were treated for up to 22 months with 1-3 mg/kg/day. Spironolactone, at in vivo attainable doses, markedly suppressed transcription of several proinflammatory cytokines and, accordingly, inhibited release of tumour necrosis factor, lymphotoxin, interferon-gamma, granulocyte-macrophage colony-stimulating factor and interleukin 6 (70-90% inhibition). Release of these cytokines was also suppressed when testing whole blood from RA patients receiving 50 mg spironolactone twice daily, indicating that pharmaceutical use of the drug may suppress the release of inflammatory cytokines. Spironolactone therapy was generally well tolerated, although treatment had to be stopped in two adults on concomitant methotrexate therapy. Sixteen patients (76%) responded favourably. American College of Rheumatology criteria (ACR)20 or better was achieved in six of nine RA patients; four reached ACR70. Eight of nine JIA patients improved. In conclusion, spironolactone inhibits production of several proinflammatory cytokines considered to be of pathogenic importance in many immunoinflammatory diseases and shows positive effect in patients with chronic arthritis. Its effect as an anti-inflammatory drug should be explored, because prolonged spironolactone therapy is reasonably safe and economically attractive compared with many modern anti-inflammatory therapies.