他汀类药物
他汀类药物(HMG-CoA 还原酶抑制剂)是 COPD 的新兴治疗药物,研究显示,对于中重度 COPD 患者,此药物可改善部分结局,还可使肺功能得到部分改善。[212]Janda S, Park K, FitzGerald JM, et al. Statins in COPD: a systematic review. Chest. 2009 Sep;136(3):734-43.
http://www.ncbi.nlm.nih.gov/pubmed/19376844?tool=bestpractice.com
尽管一些回顾性研究表明采用他汀类药物治疗的患者中病情加重的发生率和严重程度、住院治疗和死亡率都有所下降(特别对于同时存在心血管疾病 [cardiovascular disease, CVD] 或高脂血症的患者而言),但一项前瞻性研究却未能证明这一获益。[213]Criner GJ, Connett JE, Aaron SD, et al; COPD Clinical Research Network; Canadian Institutes of Health Research. Simvastatin for the prevention of exacerbations in moderate-to-severe COPD. N Engl J Med. 2014 Jun 5;370(23):2201-10.
https://www.nejm.org/doi/full/10.1056/NEJMoa1403086
http://www.ncbi.nlm.nih.gov/pubmed/24836125?tool=bestpractice.com
研究者针对他汀类药物治疗 COPD 患者的多项随机对照临床试验开展了一项荟萃分析,结果显示,同时存在 CVD、基线 C 反应蛋白(C-reactive protein, CRP)水平升高或胆固醇水平升高的患者接受他汀类药物治疗后临床结局更好。[214]Zhang W, Zhang Y, Li CW, et al. Effect of statins on COPD: a meta-analysis of randomized controlled trials. Chest. 2017 Dec;152(6):1159-68.
http://www.ncbi.nlm.nih.gov/pubmed/28847550?tool=bestpractice.com
支持 CVD 患者获得更佳结局的进一步证据包括对 COPD 和合并肺动脉高压患者进行的荟萃分析,结果显示他汀类药物治疗后,肺动脉压力和 6 分钟步行距离均有所改善。[215]Wang G, Shang W, Ren Y, et al. Benefits of statins in chronic obstructive pulmonary disease patients with pulmonary hypertension: a meta-analysis. Eur J Intern Med. 2019 Dec;70:39-42.
http://www.ncbi.nlm.nih.gov/pubmed/31679886?tool=bestpractice.com
另一项荟萃分析将高强度他汀类药物与安慰剂在 COPD 患者中进行了比较。使用他汀类药物降低了 CRP 和白细胞介素-6 水平,但没有使运动能力或生活质量发生显著改变。[216]Walsh A, Perrem L, Khashan AS, et al. Statins versus placebo for people with chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2019 Jul 31;7:CD011959.
https://www.doi.org/10.1002/14651858.CD011959.pub2
http://www.ncbi.nlm.nih.gov/pubmed/31425628?tool=bestpractice.com
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How do statins compare with placebo for people with chronic obstructive pulmonary disease (COPD)?/cca.html?targetUrl=https://www.cochranelibrary.com/cca/doi/10.1002/cca.2982/full展示答案
其他药物治疗
随着炎症在COPD中的作用越来越受到关注,人们开始考虑研发针对炎症级联反应中攻击不同靶点的药物。许多治疗 COPD 的广谱抗炎药物正在处于III 期临床试验阶段,可能在随后的 10 年内进入COPD市场。这些新型治疗药物包括一氧化氮抑制剂、白三烯调节剂和肿瘤坏死因子拮抗剂。[217]Brindicci C, Ito K, Torre O, et al. Effects of aminoguanidine, an inhibitor of inducible nitric oxide synthase, on nitric oxide production and its metabolites in healthy control subjects, healthy smokers, and COPD patients. Chest. 2009 Feb;135(2):353-67.
http://www.ncbi.nlm.nih.gov/pubmed/18719059?tool=bestpractice.com
长期(≥6 个月)使用乙酰半胱氨酸治疗可能会降低病情加重的患病率,但似乎不会影响加重的发病率、肺容积或 FEV1。[218]Fowdar K, Chen H, He Z, et al. The effect of N-acetylcysteine on exacerbations of chronic obstructive pulmonary disease: a meta-analysis and systematic review. Heart Lung. 2017 Mar-Apr;46(2):120-8.
http://www.ncbi.nlm.nih.gov/pubmed/28109565?tool=bestpractice.com
抗血小板治疗可降低 COPD 患者的全因死亡率,与心血管风险无关。[219]Pavasini R, Biscaglia S, d'Ascenzo F, et al. Antiplatelet treatment reduces all-cause mortality in COPD patients: a systematic review and meta-analysis. COPD. 2016 Aug;13(4):509-14.
http://www.ncbi.nlm.nih.gov/pubmed/26678708?tool=bestpractice.com
表皮生长因子受体激酶可以抑制黏液分泌过多。抑制纤维化的治疗正处于研发阶段。还有一项研究,针对丝氨酸蛋白酶和基质金属蛋白酶抑制剂防止肺破坏和随之而来的肺气肿,以及对这一过程甚至可能形成逆转的药物(例如视黄醛)进行展开。[220]Malhotra S, Man SF, Sin DD. Emerging drugs for the treatment of chronic obstructive pulmonary disease. Expert Opin Emerg Drugs. 2006 May;11(2):275-91.
http://www.ncbi.nlm.nih.gov/pubmed/16634702?tool=bestpractice.com
介入治疗
目标肺叶减容是择期经支气管镜肺减容的一项新技术,目前已经可用。这项技术是将一个单向活瓣置入过度充气和肺气肿的肺段,导致无功能的肺段萎陷。关于接受这项治疗患者的病例系列研究已经报告具有前景的结果。这种治疗为可能需要手术进行外科肺减容的 COPD 患者提供了另一选择。[221]Fishman A, Martinez F, Naunheim K, et al; National Emphysema Treatment Trial Research Group. A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema. N Engl J Med. 2003 May 22;348(21):2059-73.
https://www.nejm.org/doi/full/10.1056/NEJMoa030287
http://www.ncbi.nlm.nih.gov/pubmed/12759479?tool=bestpractice.com
[222]Valipour A, Herth FJ, Burghuber OC, et al. Target lobe volume reduction and COPD outcome measures after endobronchial valve therapy. Eur Respir J. 2014 Feb;43(2):387-96.
http://www.ncbi.nlm.nih.gov/pubmed/23845721?tool=bestpractice.com
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How does lung volume reduction surgery compare with usual medical care in people with diffuse emphysema?/cca.html?targetUrl=https://cochranelibrary.com/cca/doi/10.1002/cca.1510/full展示答案
药物基因组治疗
药物基因组治疗可能对COPD较为重要。明确为何某些重度吸烟者会罹患COPD而其他人不患病的遗传因素非常重要识别使患者易患COPD的基因可能提供新的治疗目标。[223]Barnes PJ, Stockley RA. COPD: current therapeutic interventions and future approaches. Eur Respir J. 2005 Jun;25(6):1084-106.
http://erj.ersjournals.com/content/25/6/1084.full
http://www.ncbi.nlm.nih.gov/pubmed/15929966?tool=bestpractice.com
[224]Sandford AJ, Silverman EK. Chronic obstructive pulmonary disease. 1: Susceptibility factors for COPD the genotype-environment interaction. Thorax. 2002 Aug;57(8):736-41.
http://www.ncbi.nlm.nih.gov/pubmed/12149538?tool=bestpractice.com
提高Club细胞分泌蛋白 16 的水平
Club 细胞蛋白 16 (Club cell protein, CC16) 主要由呼吸道上皮中的 Club 细胞(以前被称为克拉拉细胞)产生。CC16 对于暴露于烟草的肺脏具有抗炎特性,且 COPD 与 CC16 缺乏有关。实验性增加CC16 水平能减轻炎症和细胞损伤 的水平,因此 CC16 增强可能是针对 COPD 的新的疾病改善治疗。[225]Laucho-Contreras ME, Polverino F, Tesfaigzi Y, et al. Club cell protein 16 (CC16) augmentation: a potential disease-modifying approach for chronic obstructive pulmonary disease (COPD). Expert Opin Ther Targets. 2016 Jul;20(7):869-83.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4977029
http://www.ncbi.nlm.nih.gov/pubmed/26781659?tool=bestpractice.com
单克隆抗体
越来越多证据表明嗜酸性粒细胞(一种通常与过敏性疾病有关的白细胞)参与了 COPD 炎症级联反应。[29]David B, Bafadhel M, Koenderman L, et al. Eosinophilic inflammation in COPD: from an inflammatory marker to a treatable trait. Thorax. 2021 Feb;76(2):188-95.
https://www.doi.org/10.1136/thoraxjnl-2020-215167
http://www.ncbi.nlm.nih.gov/pubmed/33122447?tool=bestpractice.com
针对白细胞介素(interleukin, IL)-5 或其受体的单克隆抗体治疗已被证明对重度嗜酸性粒细胞哮喘有效,因此对于 COPD 和嗜酸性粒细胞表型患者可有所获益。[226]Zhang C, Wang Y, Zhang M, et al. Monoclonal antibodies targeting IL-5 or IL-5Rα in eosinophilic chronic obstructive pulmonary disease: a systematic review and meta-analysis. Front Pharmacol. 2021;12:754268.
https://www.doi.org/10.3389/fphar.2021.754268
http://www.ncbi.nlm.nih.gov/pubmed/34795588?tool=bestpractice.com
[227]Donovan T, Milan SJ, Wang R, et al. Anti-IL-5 therapies for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2020 Dec 8;12:CD013432.
https://www.doi.org/10.1002/14651858.CD013432.pub2
http://www.ncbi.nlm.nih.gov/pubmed/33295032?tool=bestpractice.com
一项 Cochrane 评价发现,与安慰剂相比,使用 mepolizumab 或 benralizumab 进行治疗可更大程度减少中重度急性加重。对 COPD mepolizumab 3 期临床试验患者数据进行的后续荟萃分析表明,血嗜酸性粒细胞计数较高的患者将出现更明显的中重度急性加重减少。[228]Pavord ID, Chapman KR, Bafadhel M, et al. Mepolizumab for eosinophil-associated COPD: analysis of METREX and METREO. Int J Chron Obstruct Pulmon Dis. 2021;16:1755-70.
https://www.doi.org/10.2147/COPD.S294333
http://www.ncbi.nlm.nih.gov/pubmed/34163157?tool=bestpractice.com
mepolizumab 和 benralizumab 治疗 COPD 的 3 期研究正在进行中。其他正在为 COPD 进行临床研发的单克隆抗体主要针对急性加重,包括 IL-4 受体拮抗剂度普利尤单抗。[229]Cazzola M, Ora J, Cavalli F, et al. An overview of the safety and efficacy of monoclonal antibodies for the chronic obstructive pulmonary disease. Biologics. 2021;15:363-74.
https://www.doi.org/10.2147/BTT.S295409
http://www.ncbi.nlm.nih.gov/pubmed/34475751?tool=bestpractice.com
质子泵抑制剂
COPD 急性加重的最佳管理将有可能包括对于疾病合并症的治疗。胃食管反流病(gastro-oesophageal reflux disease, GORD)是 COPD 患者常见合并症;它与呼吸道微量吸入胃酸具有相关性,而这可能会诱发 COPD 急性加重。质子泵抑制剂可减少胃酸分泌,为 GORD 一线治疗方法。一项对质子泵抑制剂在 COPD 中的有效性和安全性进行评估的 Cochrane 评价得出结论,当前证据不足以确定其在这种疾病中的价值。[230]Kikuchi S, Imai H, Tani Y, et al. Proton pump inhibitors for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2020 Aug 25;8:CD013113.
https://www.doi.org/10.1002/14651858.CD013113.pub2
http://www.ncbi.nlm.nih.gov/pubmed/32844430?tool=bestpractice.com