Breathomics for Assessing the Effects of Treatment and Withdrawal With Inhaled Beclomethasone/Formoterol in Patients With COPD
電子鼻用于評估慢性阻塞性肺病患者吸入倍氯米松/*治療和戒斷效果呼吸氣體分析
Paolo Montuschi 1*†, Giuseppe Santini 1†, Nadia Mores 1†, Alessia Vignoli 2†, Francesco Macagno3, Rugia Shoreh4, Leonardo Tenori 2, Gina Zini 5, Leonello Fuso3,
Chiara Mondino6, Corrado Di Natale7, Arnaldo D’Amico7, Claudio Luchinat 2, Peter J. Barnes 8 and Tim Higenbottam9
1 Department of Pharmacology, Faculty of Medicine, Catholic University of the Sacred Heart, University Hospital Agostino Gemelli Foundation, Rome, Italy,
2Magnetic Resonance Center (CERM), University of Florence, Florence, Italy,
3 Department of Internal Medicine and Geriatrics, Catholic University of the Sacred Heart, University Hospital Agostino Gemelli Foundation, Rome, Italy,
4 Department of Drug Sciences, Faculty of Pharmacy, University “G. d’Annunzio”, Chieti, Italy,
5 Department of Hematology, Faculty of Medicine, Catholic University of the Sacred Heart, University Hospital Agostino Gemelli Foundation, Rome, Italy,
6 Department of Allergology, ‘Bellinzona e Valli’ Hospital, Bellinzona, Switzerland,
7 Department of Electronic Engineering, University of Tor Vergata, Rome, Italy,
8 Airway Disease Section, Faculty of Medicine, National Heart and Lung Institute, Imperial College, London, United Kingdom,
9 Faculty of Pharmaceutical Medicine, Royal College of Physicians, London, United Kingdom
Background:Prospective pharmacological studies on breathomics profiles in COPD patients have not been previously reported. We assessed the effects of treatment and withdrawal of an extrafine inhaled corticosteroid (ICS)-long-acting b2-agonist (LABA) fixed dose combination (FDC) using a multidimensional classification model including breathomics.
關于慢性阻塞性肺病患者的呼吸組學資料的前瞻性藥理學研究尚未報道。我們采用包括呼吸計量學在內的多維分類模型評估了超精細吸入皮質類固醇(ICS)長效B2激動劑(LABA)固定劑量組合(FDC)的治療和停藥的效果。
Methods:A pilot, proof-of-concept, pharmacological study was undertaken in 14 COPD patients on maintenance treatment with inhaled fluticasone propionate/salmeterol (500/50 μg b.i.d.) for at least 8 weeks (visit 1). Patients received 2-week treatment with inhaled beclomethasone dipropionate/formoterol (100/6 μg b.i.d.) (visit 2), 4-week treatment with formoterol alone (6 μg b.i.d.) (visit 3), and 4-week treatment with beclomethasone/formoterol (100/6 μg b.i.d.) (visit 4). Exhaled breath analysis with two e-noses, based on different technologies, and exhaled breath condensate (EBC) NMR-based metabolomics were performed. Sputum cell counts, sputum supernatant and EBC prostaglandin E2 (PGE2) and 15-F2t-isoprostane, fraction of exhaled nitric oxide, and spirometry were measured.
在14名慢性阻塞性肺病患者中進行了一項試點、概念驗證和藥理研究，采用吸入倍氯米松/*(500/50μg b.i.d.)維持治療至少8周(visit1)?；颊呓邮芰?周的吸入倍氯米松/*治療(100/6μg b.i.d.)(visit2)，4周的單獨使用*治療(6μg b.i.d.)(visit3)，4周的使用倍氯米松/*治療(100/6μg b.i.d.)(visit4)。利用兩個電子鼻，基于不同的技術進行呼氣分析，并利用基于呼氣冷凝液(EBC)的核磁共振代謝組學進行呼氣分析。測量痰細胞計數、痰上清液和EBC前列腺素E2(pge2)和15-f2t-異前列素、呼氣中一氧化氮的分數和肺活量。
Results:Compared with formoterol alone, EBC acetate and sputum PGE2, reflecting airway inflammation, were reduced after 4-week beclomethasone/formoterol. Three independent breathomics techniques showed that extrafine beclomethasone/formoterol short-term treatment was associated with different breathprints compared with regular fluticasone propionate/salmeterol. Either ICS/LABA FDC vs. formoterol alone was associated with increased pre-bronchodilator FEF25−75% and FEV1/FVC (P = 0.008–0.029). The multidimensional model distinguished fluticasone propionate/salmeterol vs. beclomethasone/formoterol, fluticasone propionate/salmeterol vs. formoterol, and formoterol vs. beclomethasone/formoterol (accuracy > 70%, P < 0.01).
與單用*相比，4周倍氯米松/*后，反映氣道炎癥的EBC醋酸鹽和痰PGE2降低。三種獨立的呼吸測量技術表明，與常規的*/沙美特羅相比，特細倍氯米松/*短期治療與不同的呼吸圖相關。與單用*相比，ICS/LABA FDC與支氣管擴張劑前FEF25-75%和FEV1/FVC增加相關(p=0.008-0.029)。多維模型區分了*/沙美特羅與倍氯米松/*、*/沙美特羅與*、*與倍氯米松/*(精確度>70%，p<0.01)
Conclusions:Breathomics could be used for assessing ICS treatment and withdrawal in COPD patients. Large, controlled, prospective pharmacological trials are required to clarify the biological implications of breathomics changes. EUDRACT number: 2012-001749-42
呼吸計量學可用于評估慢性阻塞性肺病患者的ICS治療和戒斷。需要進行大規模的、對照的、前瞻性的藥理學試驗來闡明呼吸系統變化的生物學意義。EUDRACT號：2012-001749-42
Keywords: breathomics, inhaled corticosteroids, long-acting b2-agonists, COPD, pharmacotherapy
關鍵詞：呼吸組學，吸入皮質類固醇，長效B2激動劑，慢性阻塞性肺病，藥物治療
