Treatment Effects of Low-Dose Theophylline Combined With an Inhaled Corticosteroid in COPD
Treatment Effects of Low-Dose Theophylline Combined With an Inhaled Corticosteroid in COPD
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DOI：
10.1378/chest.09-2363
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发表时间：
2010-06-01
期刊：
影响因子：
9.6
通讯作者：
Barnes, Peter J.
中科院分区：
文献类型：
--
作者：
Ford, Paul A.;Durham, Andrew L.;Barnes, Peter J.
背景：吸入性皮质类固醇（ICS）在减轻COPD气道炎症方面的效果令人失望。然而，先前的研究表明，低剂量的茶碱增强了一种关键的皮质类固醇相关辅阻遏蛋白--组蛋白去乙酰化酶（HDAC）2的活性，而组蛋白去乙酰化酶（HDAC）2在COPD中降低。这可能至少部分地解释了皮质类固醇的相对抵抗。因此，ICS和低剂量茶碱的联合治疗可能对COPD的治疗有益。方法：为了验证ICS和茶碱比单独茶碱具有更大治疗效果的假设，30名COPD患者接受安慰剂茶碱胶囊和吸入丙酸氟替卡松（FP）（500 μ g bid）或吸入安慰剂4周。结果：在交叉组比较中，FP和茶碱联合治疗并不能减少痰液中性粒细胞总数，但能显著减少痰液嗜酸性粒细胞总数（P <0.05）。另外的跨组比较表明痰中性粒细胞和痰趋化因子（C-X-C基序）配体8/IL-8的百分比进一步降低（P <0.05）。此外，组内观察数据也显示，仅联合治疗后用力呼气中段流速和FEV1%预测值增加（P <0.05）。在一项开放标签研究中，低剂量茶碱吸入FP时，增加总HDAC活性在外周血单核细胞9倍（P <0.01）相比，FP单独从同一patients with COPD.Conclusions：吸入皮质类固醇和低剂量茶碱联合治疗可能会减轻COPD患者的气道炎症。
Background: Inhaled corticosteroids (ICS) have proved disappointing at reducing airway inflammation in COPD. However, previous studies indicate that low doses of theophylline enhance the activity of a key corticosteroid-associated corepressor protein, histone deacetylase (HDAC)2, which is reduced in COPD. This may account, at least in part, for the relative corticosteroid resistance. Thus, combination therapy with an ICS and low-dose theophylline may be of benefit in the treatment of COPD.Methods: To test the hypothesis that ICS and theophylline have a greater therapeutic effect than theophylline alone, 30 patients with COPD were treated with placebo theophylline capsules and either inhaled fluticasone propionate (FP) (500 mu g bid) or inhaled placebo for 4 weeks in a double-dummy, randomized, double-blind, parallel study. After a 2-week washout, patients were given active theophylline capsules (plasma level of 8.8-12.4 mg/L).Results: In an across-arm comparison, combination treatment with FP and theophylline did not reduce total sputum neutrophils but significantly reduced total sputum eosinophils (P < .05). Additional across-arm comparisons suggest a further reduction in percentage sputum neutrophils and sputum chemokine (C-X-C motif) ligand 8/IL-8 (P < .05). Furthermore, within-arm observational data also demonstrated increases in forced midexpiratory flow rate and FEV1% predicted (P < .05) following combination treatment only. In an open-label study, low-dose theophylline when added to inhaled FP increased total HDAC activity in peripheral blood monocytes ninefold (P < .01) compared with FP alone from the same patients with COPD.Conclusions: Combination therapy with an inhaled corticosteroid and low-dose theophylline may attenuate airway inflammation in patients with COPD.