吸入性糖皮质激素给药时间对哮喘治疗效果的影响： 一项随机三交叉试验
2025/08/18
摘要
背景：哮喘具有明显的昼夜节律特征，其气流受限和气道炎症通常在夜间达到高峰。将药物的给药时间与疾病节律相匹配（即时间疗法），可能有助于提升治疗效果。
目的：本研究旨在评估吸入性糖皮质激素于不同时间给药对哮喘治疗效果的影响。
方法：本研究为一项随机三交叉试验。纳入轻至中度特应性哮喘患者，随机接受以下三种丙酸倍氯米松吸入方案：(1) 每日上午08:00–09:00单次吸入400 μg（ODAM组）；(2) 每日下午15:00–16:00单次吸入400 μg（ODPM组）；(3) 每日上午08:00–09:00和晚上20:00–21:00各吸入200 μg（BD组）。每种治疗方案持续28天，各治疗期间设有2周洗脱期。于基线及各治疗期末进行24小时内每6小时一次的肺功能与生物标志物检测。
结果：共25名受试者入组，其中21人完成全部治疗方案。ODPM组在改善22:00时的第一秒用力呼气容积（FEV₁）方面优于ODAM组和BD组（中位数[IQR]：ODPM +160 [+70, +270] ml；ODAM −20 [−80, +230] ml；BD +80 [−20, +200] ml）。在夜间（22:00和04:00）血液嗜酸性粒细胞计数的抑制方面，ODPM组同样优于ODAM组和BD组。三种治疗方案均能改善哮喘控制、降低呼出气一氧化氮（FeNO）和血清皮质醇水平，三组间无显著差异。
结论：相比ODAM和BD方案，ODPM给药方案能更有效地抑制夜间肺功能下降与嗜酸性粒细胞计数峰值，且未观察到不良事件风险的增加。未来应在真实世界研究中验证本结果，并进一步明确哪些患者人群最可能从时间疗法中获益。
关键词： 哮喘；时间治疗；吸入性糖皮质激素；给药时间；交叉试验；昼夜节律；肺功能；嗜酸性粒细胞；呼出气一氧化氮
Background：Asthma demonstrates a robust daily rhythm, with airflow obstruction and airway inflammation peaking overnight. Aligning the timing of drug administration with rhythms in disease (chronotherapy) may improve therapeutic efficacy.
Objective：We aimed to evaluate the impact of dosage timing for inhaled corticosteroids in asthma.
Methods：This is a randomised three-way crossover trial. Participants with mild to moderate atopic asthma were randomised to beclometasone dipropionate: (1) 400 µg once daily between 08:00 and 09:00 (ODAM); (2) 400 µg once daily between 15:00 and 16:00 (ODPM); and (3) 200 µg twice daily between 08:00 and 09:00 and between 20:00 and 21:00 (BD) for 28 days, with a 2 week washout period in between treatment periods. Six-hourly spirometry and biomarkers were measured over 24 hours following the run-in period and at the end of each treatment period.
Results：Of 25 participants, 21 completed all regimens. ODPM was superior in improving 22:00 FEV1 (median (IQR): +160 (+70, +270) ml) compared with ODAM (−20 (−80, +230) ml) and BD (+80 (−20, +200) ml). ODPM resulted in better overnight (22:00 and 04:00) suppression in blood eosinophil counts compared with BD and ODAM. All regimens improved asthma control and reduced fractional exhaled nitric oxide and serum cortisol levels with no difference among dosing regimens.
Conclusion：ODPM better suppresses the nocturnal dip in lung function and peak of blood eosinophil counts compared with BD and ODAM; this was without an increase in adverse events. Future trials are warranted to validate these findings in real-life settings and to determine which population may best benefit from chronotherapy.
Key words：Asthma; Chronotherapy; Inhaled corticosteroids; Dosage timing; Crossover trial; Circadian rhythm; Lung function; Eosinophils; Fractional exhaled nitric oxide
背景：哮喘具有明显的昼夜节律特征，其气流受限和气道炎症通常在夜间达到高峰。将药物的给药时间与疾病节律相匹配（即时间疗法），可能有助于提升治疗效果。
目的：本研究旨在评估吸入性糖皮质激素于不同时间给药对哮喘治疗效果的影响。
方法：本研究为一项随机三交叉试验。纳入轻至中度特应性哮喘患者，随机接受以下三种丙酸倍氯米松吸入方案：(1) 每日上午08:00–09:00单次吸入400 μg（ODAM组）；(2) 每日下午15:00–16:00单次吸入400 μg（ODPM组）；(3) 每日上午08:00–09:00和晚上20:00–21:00各吸入200 μg（BD组）。每种治疗方案持续28天，各治疗期间设有2周洗脱期。于基线及各治疗期末进行24小时内每6小时一次的肺功能与生物标志物检测。
结果：共25名受试者入组，其中21人完成全部治疗方案。ODPM组在改善22:00时的第一秒用力呼气容积（FEV₁）方面优于ODAM组和BD组（中位数[IQR]：ODPM +160 [+70, +270] ml；ODAM −20 [−80, +230] ml；BD +80 [−20, +200] ml）。在夜间（22:00和04:00）血液嗜酸性粒细胞计数的抑制方面，ODPM组同样优于ODAM组和BD组。三种治疗方案均能改善哮喘控制、降低呼出气一氧化氮（FeNO）和血清皮质醇水平，三组间无显著差异。
结论：相比ODAM和BD方案，ODPM给药方案能更有效地抑制夜间肺功能下降与嗜酸性粒细胞计数峰值，且未观察到不良事件风险的增加。未来应在真实世界研究中验证本结果，并进一步明确哪些患者人群最可能从时间疗法中获益。
关键词： 哮喘；时间治疗；吸入性糖皮质激素；给药时间；交叉试验；昼夜节律；肺功能；嗜酸性粒细胞；呼出气一氧化氮
（南方医科大学南方医院 黄海伦 龚钊乾 赵文驱 赵海金 ）
（Wang R, Maidstone R, Singh D, et al. The impact of dosage timing for inhaled corticosteroids in asthma: a randomised three-way crossover trial[J]. Thorax, 2025: thorax-2024-222073. DOI: 10.1136/thorax-2024-222073.）
AbstractBackground：Asthma demonstrates a robust daily rhythm, with airflow obstruction and airway inflammation peaking overnight. Aligning the timing of drug administration with rhythms in disease (chronotherapy) may improve therapeutic efficacy.
Objective：We aimed to evaluate the impact of dosage timing for inhaled corticosteroids in asthma.
Methods：This is a randomised three-way crossover trial. Participants with mild to moderate atopic asthma were randomised to beclometasone dipropionate: (1) 400 µg once daily between 08:00 and 09:00 (ODAM); (2) 400 µg once daily between 15:00 and 16:00 (ODPM); and (3) 200 µg twice daily between 08:00 and 09:00 and between 20:00 and 21:00 (BD) for 28 days, with a 2 week washout period in between treatment periods. Six-hourly spirometry and biomarkers were measured over 24 hours following the run-in period and at the end of each treatment period.
Results：Of 25 participants, 21 completed all regimens. ODPM was superior in improving 22:00 FEV1 (median (IQR): +160 (+70, +270) ml) compared with ODAM (−20 (−80, +230) ml) and BD (+80 (−20, +200) ml). ODPM resulted in better overnight (22:00 and 04:00) suppression in blood eosinophil counts compared with BD and ODAM. All regimens improved asthma control and reduced fractional exhaled nitric oxide and serum cortisol levels with no difference among dosing regimens.
Conclusion：ODPM better suppresses the nocturnal dip in lung function and peak of blood eosinophil counts compared with BD and ODAM; this was without an increase in adverse events. Future trials are warranted to validate these findings in real-life settings and to determine which population may best benefit from chronotherapy.
Key words：Asthma; Chronotherapy; Inhaled corticosteroids; Dosage timing; Crossover trial; Circadian rhythm; Lung function; Eosinophils; Fractional exhaled nitric oxide
上一篇：
补体C5在重度哮喘嗜酸性粒细胞炎症中的作用
下一篇：
基于可治疗特征的哮喘管理：一项可行性研究
