西洛司特干预慢性阻塞性肺疾病的系统评价
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摘要
目的：客观评价西洛司特干预慢性阻塞性肺疾病的有效性和安全性。
背景：慢性阻塞性肺疾病(Chronic obstructive Pulmonary Disease,COPD)是一种具有气流受限特征的疾病,气流受限不完全可逆,呈进行性发展,与肺部对有害气体或有害颗粒的异常炎症反应有关。该病不仅影响肺,也可以引起显著的全身炎症反应,病情恶化导致劳动力丧失,生活质量下降,最终发展成为呼吸衰竭、肺源性心脏病。目前,全球约有2.7亿COPD患者,每年新增患者600余万人,并有近300万名患者死于该病,截止到2007年,COPD已经成为继心血管疾病脑血管疾病和急性呼吸道感染性疾病之后,与艾滋病并列的全球第4大死亡因,死因顺位从1980年的第12位上升到目前的第4位,COPD已成为全球性健康问题。COPD是一种慢性“肺部异常炎症反应”性疾病,其发病机制与氧化-抗氧化失衡、蛋白酶-抗蛋白酶、感染、细胞凋亡、细胞因子等诸多因素有关,其中细胞因子学说尤为重要,与心脑血管疾病、艾滋病不同的是,到目前为止,戒烟是阻止COPD进展最有效的干预措施,除此之外,COPD尚无有效的药物治疗手段来延长COPD患者的生存时间。现在的药物治疗仅减轻COPD患者的症状和提高生活质量一定的作用,大部分药物治疗手段来源于哮喘的治疗。理论上讲,针对肺组织炎症的治疗将是控制COPD症状和阻止其进展的关键所在,目前对COPD的药物治疗效果仍非常有限,有抗炎作用的药物主要有糖皮质激素和茶碱。激素长期应用治疗COPD的效果目前尚有争议,激素能减少哮喘的嗜酸性粒细胞增多,诱导嗜酸性粒细胞凋亡,但并不能抑制中性粒细胞、AM和CD8+T淋巴细胞分泌炎性介质和细胞因子,相反,激素能延长中性粒细胞存活,使体内中性粒细胞数量增多,这对控制COPD的炎症反应不利。研究表明激素对COPD患者合成LTB4和PGE2也无抑制作用。所以,激素不能有效抑制COPD患者肺内的中性粒细胞性炎症。而茶碱类药物作为非选择性的PDE抑制剂,有一定的抗气道非特异性炎症的作用,口服小剂量氨茶碱可显著减少COPD患者诱导痰中中性粒细胞数量,及IL-8和趋化4肽的水平,茶碱还可以抑制中性粒细胞的活性,减少氧自由基的释放。但茶碱类药物的抗炎活性较弱,并不能有效地阻断COPD病情的自然发展过程,并防止肺功能的逐年恶化,茶碱主要通过扩张支气管、改善呼吸肌功能抗炎和免疫调节等多方面对COPD起到治疗作用,治疗剂量和中毒剂量接近,因此治疗COPD的疗效并不理想。选择性PDE抑制剂则可以有效避免上述缺点。业已证实PDE4抑制剂可抑制与COPD发病的主要炎性细胞,如中性粒细胞、肺泡巨噬细胞、CD8+T细胞、气道皮细胞等产生细胞因子和炎症介质的作用,从而干预COPD的炎症过程。Cilomilast是葛兰素史克公司开发的新一代选择性PDE4抑制剂,国外的Ⅱ/Ⅲ期临床试验证实它对于治COPD、哮喘等具有较好的疗效,且安全性和耐受性均良好。国外一些初步的研究结果提示,选择性抑制剂可能是一类有前途的抗COPD肺部炎症的治疗药物,在体外研究中发现其调控的病理生理过程与慢性阻塞性肺病直接相关。研究表明cilomilast有松弛气道平滑肌、抑制免疫和炎症细胞活化、抑制细胞浸润和介质的释放等作用。另有报道cilomilast对慢性阻塞性肺病患者、正常人和吸烟者支气管上皮细胞和诱导痰液细胞(鳞状细胞和免疫细胞)的影响,Cilomilast可以显著降低支气管上皮细胞、诱导痰细胞中肿瘤坏死因子诱导痰细胞GM-CSF的释放。Cilomilast亦可显著降低痰和支气管上皮细胞上清液中中性粒细胞趋化。此外,在吸入脂多糖诱导的肺水肿动物模型中发现口服高剂量cilomilast同样可以有效减少中性粒细胞,这表明cilomilast对于中性粒细胞的作用可能对慢性阻塞性肺病炎症有益。因此自1999年起国内外出现一系列旨在探讨cilomilast治疗慢性阻塞性肺病有效性及安全性及抗炎作用的临床研究,但结果不一致,存在较大的争议,故本研究旨在收集当前全世界cilomilast治疗慢性阻塞性肺病随机对照试验,采用系统评价方法,进行效应量合并做Meta-分析,以期评价cilomilast治疗慢性阻塞性肺病的临床疗效及安全性,为cilomilast治疗慢性阻塞性肺病提供更加可靠的循证医学证据。
方法：根据循证医学的原则,采用Cochrane系统评价的方法,计算机检索MEDLINE(from OvID,1966-2011.2)、EMBASE(1984-2011)、Cochrane图书馆(2011年第1期)、中国生物医学文献数据库CBMdisc(1978—2011.2)、中国学术期刊全文数据库CNKI(1994—2011.2)、中文科技期刊全文数据库(VIP,1977-2011.2)、手工检索1998—2011相关杂志。两个评价员首先独立地阅读文章题目,对相关文献再阅读摘要,如为随机或半随机对照试验则阅读全文,将符合纳入标准的文献进行评价。不同意见通过讨论解决或由第三者判断。对纳入研究的方法学质量从随机方法、分配隐藏、盲法、有无失访几方面进行评价,采用RevMan5.1软件进行统计分析。对可以合并分析的指标作Meta分析(包括单个研究)；对不能进行Meta分析的指标用描述性方法分析结果。对同质性较好的多个研究结果,可用固定效应模型合并分析,对有统计学异质性者,分析异质原因,采用敏感性分析、亚组分析和随机效应模型处理。连续性变量采用加权均数差(WMD)或标准均数差(SMD)表示、二分类变量采用相对危险度(RR)、比值比(OR),二者均计算95%的可信区间(CI)。
结果：共纳入16个随机对照试验,6910例病人,根据Cochrane Review Handbook5.1推荐的简单方法(Simple approaches)对研究的方法学进行质量评价,16个随机对照试验均为B级。
本评价结果表明,西洛司特治疗COPD,在肺功能方面可以改善COPD患者的FEV1, SMD:0.20,95%CI[0.11,0.30], P<0.0001;可以改善COPD患者的FVC, WMD:0.07,95%CI[0.02,0.11], P=0.003;可以改善COPD患者的FEV1%pred；可以改善COPD患者的FVC%pred;可以改善COPD患者的RV%pred;可以改善COPD患者的RV/TLC;不能改善COPD患者的,FRC SMD:-0.20,95%CI[-0.48,0.08],P=0.16；不能改善COPD患者的RV, SMD:-0.23,95%CI[-0.65,0.19],P=0.29；不能改善COPD患者的PEF；不能改善COPD患者的IC。在健康状况方面,西洛司特不能改善COPD患者的圣乔治呼吸问卷得分,SMD:-0.08,95%CI[0.11,0.30],P=0.13;不能改善COPD患者的呼吸吸困难评分,WMD:-0.06,95%CI[-0.25,0.13];不能改善COPD患者的症状评分,WMD：-0.06,95%CI[-0.25,0.13],P=0.53；不能改善COPD患者的6分钟步行试验,SMD：0.15,95%CI[-0.35,0.04],P=0.12；可以改善COPD患者的咳嗽评分；可以改善COPD患者的咳痰评分。在COPD恶化方面,西洛司特不能减少COPD患者COPD的恶化,OR:1.26,95%CI[0.95,1.67],P=0.23,及二级、三级恶化,OR：1.40,95%CI[0.81,2.43],P=0.10。在不良反应方面,西洛司特组AE事件发生情况较对照组增多,0R：1.34,95%CI[1.09,1.64],P=0.005；西洛司特治疗组与对照组在SAE事件发生上不存在差异,OR：0.92,95%CI[0.74,1.12],P=0.42；西洛司特治疗组恶心发生的情况较对照组明显增多,OR：3.59,95%CI[2.84,4.55].P<0.0001；西洛司特治疗组的腹泻发生的情况较对照组明显增多,OR：2.51,95%CI[2.04,3.09],西洛司特治疗组同对照组差异有统计学意义,P<0.0001；西洛司特治疗组的腹痛发生的情况较对照组明显增多,OR：2.03,95%CI[1.55,2.66],P<0.0001；西洛司特治疗组的呕吐发生的情况较对照组明显增多,OR：4.80,95%CI[3.24,7.09],P<0.00001；西洛司特治疗组头痛发生的情况与对照组无明显差异OR：1.27,95%CI[1.03,1.56],P=0.03,；西洛司特治疗组头晕发生的情况较对照组增多OR：1.88,95%CI[1.10,3.21],P=0.02,；西洛司特治疗组上呼吸道感染发生的情况与对照组无明显差异,OR：1,95%CI[0.79,1.27],P<0.00001；西洛司特治疗组消化不良发生的情况较对照组明显增多OR：2.94,95%CI[2.11,4.10],P<0.00001。
结论：本系统评价综合分析结果表明,西洛司特可以显著改善COPD患者的肺功能,包括FEV1.FEV1%pred.FVC.FVC%pred.RV%pred.RV/TLC；而对COPD患者的FRC.RV.PEF及IC无显著影响。
西洛司特可以改善COPD患者的咳嗽评分和咳痰评分；不能改善COPD患者的呼吸困难评分、症状评分、6分钟步行试验；也不能改善COPD患者的生活质量(圣乔治呼吸问卷得分)。
西洛司特不能降低COPD患者COPD的恶化率及二级、三级恶化率。
西洛司特组不良事件(AE)如恶心、腹泻、腹痛、呕吐、头痛、头晕、消化不良发生情况较对照组明显增加；而在严重不良事件(SAE)、上呼吸道感染发生上与对照组无显著差异。
上述结论部分来自单个研究,因此使用这些结论必须谨慎,所有研究结果均不能作为推荐临床应用的证据仍有必要开展一系列多中心、前瞻性、随机双盲、设计实施良好的临床随机对照试验,尤其要提高试验的质量,从而为西洛司特的临床应用提供更加充足的证据。
Objective:To evaluate the efficacy and safety of cilomilast therapy for Chronic Obstructive Pulmonary Disease
Background:COPD is a common disease which is usually characterized by partially reversible airflow limitation, progressive loss of lung function and an abnormal inflammatory response in the lung to noxious substances, the most common of which is cigarette smoke. The disease is associated with increased frequency of exacerbations and deterioration of health status, as well as the development of non pulmonary complications. The pathogenesis of COPD remains unclear but chronic inflammation throughout airways, parenchyma and pulmonary vasculature is believed to have a central role. There is a need for a novel anti-inflammatory treatment, as experimental data indicate that the inflammatory process in COPD, particularly those that are neutrophil mediated, may be resistant to the anti-inflammatory effects of corticosteroids.Novel anti-inflammatory therapies are therefore being developed as potential therapeutic agents, including selective phosphodiesterase (PDE) inhibitors. Cilomilast is a potent and selective PDE4 inhibitor which modulates pathophysiological processes of direct relevance to COPD. In preclinical studies,cilomilast relaxed airway smooth muscle, inhibited immune and inflammatory cell activation and inhibited cellular infiltration and mediator release. The effect of cilomilast on airway cells was evaluated using bronchial epithelial cells and induced sputum cells (squamous and immune cells) from COPD patients, normal controls and smokers. Cilomilast significantly reduced TNFa release by bronchial epithelial and sputum cells, and GM-CSF release by sputum cells. Supernatants of sputum and bronchial epithelial cells treated with cilomilast also demonstrated significantly reduced neutrophi chemotaxis. Furthermore, cilomilast attenuated
the inhaled lipopolysaccharide-induced pulmonary neutrophilia and oedema with equivalent effectiveness to that of high-dose, orally administered prednisolone in an animal model. This suggested a possible beneficial role for cilomilast on the neutrophilic inflammation in COPD. Since 1999, there was a series clinical research designed to explore the effectiveness and safety of the cilomilast treatment of chronic obstructive pulmonary disease, but the results were quite conflicting. The objective of the present meta-analysis was to evaluate the efficacy and safety of cilomilast in COPD.
Methods:We searched the CochraneLibrary(Issuel,2011), MEDLNE(1966 to February,2011), EMBASE(1984 to 2011), the China Biological Medicine Database(1978 to February,2011), VIP(1977 to February,2011), CMAC(1994 to 2011)and hand-searched several related Chinese journals.Two reviewers independently screened the studies for eligibility, evaluated the quality and extracted the data from the eligible studies, with the confirmation of cross-check. Different opinions would be decided by the third party. The quality of the included trials such as randomization, blind, allocation concealment and following-up was assessed.Meta-analysis was Performed by RevMan5.1 software. After heterogeneity test, data without heterogeneity could be pooled using fixed effect model, and those with Heterogeneity could be solved by sensitivity analysis, subgroup analysis as well as randomized effect model. We will compare outcome measures for binary data using relative risks(RR) or odds ratio(OR) with 95% confidence intervals(Cl).For continuous data, the weighted means difference(WMD) or standardlzed mean difference (SMD) will be used.
Results:sixteen studies involving 6910 patients with Chronic Obstruetive Pulmonary Disease were included. Results suggested that In terms of lung function FEV1 in patients with COPD can be improved by cilomilast therapy, SMD:0.20, 95%CI[0.11,0.30], P<0.0001; FVC in patients with COPD can be improved by cilomilast therapy, WMD:0.07,95%CI[0.02,0.11], P=0.003; FEV1% pred in patients with COPD can be improved by cilomilast therapy; FVC% pred in patients with COPD can be improved by cilomilast therapy; RV% pred in patients with COPD can be improved by cilomilast therapy; RV/TLC in patients with COPD can be improved by cilomilast therapy; FRC in patients with COPD can not be improved by cilomilast therapy, SMD:-0.20,95%CI[-0.48,0.08], P=0.16; RV in patients with COPD can not be improved by cilomilast therapy, SMD:-0.23,95%CI[-0.65,0.19], P=0.29; PEF in patients with COPD can not be improved by cilomilast therapy; IC in patients with COPD can not be improved by cilomilast therapy。In terms of health status, SGRQ in patients with COPD can not be improved by cilomilast therapy, SMD:-0.08,95%CI[0.11,0.30], P=0.13; Borg scale in patients with COPD can not be improved by cilomilast therapy, WMD:-0.06,95%CI[-0.25,0.13]; Summary symptom score in patients with COPD can not be improved by cilomilast therapy,WMD:-0.06, 95%CI[-0.25,0.13], P=0.53; Six-minute walk in patients with COPD can not be improved by cilomilast therapy, SMD:0.15,95%CI[-0.35,0.04], P=0.12;COPD exacerbation rates in patients with COPD can not be decreased by cilomilast therapy,OR:1.26,95%CI[0.95,1.67], P=0.23;Level 2 and level 3 COPD exacerbation rates in patients with COPD can not be decreased by cilomilast therapy, OR:1.40, 95%CI[0.81,2.43], P=0.10。In terms of adverse reactions, The occurrence of AE events increased in treatment group than in the control group,OR:1.34,95%CI[1.09, 1.64], P=0.005; There were no significant differences between treatment group and control group in the SAE events, OR:0.92,95%CI[0.74,1.12], P=0.42; The occurrence of nausea events increased in treatment group than in the control group,,OR:3.59,95%CI[2.84,4.55].P<0.0001; The occurrence of diarrhea events increased in treatment group than in the control group, OR:2.51,95%CI[2.04,3.09], P<0.0001; The occurrence of abdominal pain events increased in treatment group than in the control group, OR:2.03,95%CI[1.55,2.66], P<0.0001; The occurrence of vomitting events increased in treatment group than in the control group,, OR:4.80,95%CI[3.24,7.09], P<0.00001; There were no significant differences between treatment group and control group in the headache events, OR:1.27, 95%CI[1.03,1.56], P=0.03,; The occurrence of dizziness events increased in treatment group than in the control group OR:1.88,95%CI[1.10,3.21], P=0.02,; There were no significant differences between treatment group and control group in the upper respiratory tract infection events, OR:1,95%CI[0.79,1.27], P<0.00001; The occurrence of dyspepsia events increased in treatment group than in the control group OR:2.94,95%CI[2.11,4.10], P<0.00001.
Conclusions:Results suggested that In terms of lung function FEV1 in patients with COPD can be improved by cilomilast therapy; FVC in patients with COPD can be improved by cilomilast therapy; FEV1% pred in patients with COPD can be improved by cilomilast therapy; FVC% pred in patients with COPD can be improved by cilomilast therapy; RV% pred in patients with COPD can be improved by cilomilast therapy; RV/TLC in patients with COPD can be improved by cilomilast therapy; FRC in patients with COPD can not be improved by cilomilast therapy; RV in patients with COPD can not be improved by cilomilast therapy; PEF in patients with COPD can not be improved by cilomilast therapy; IC in patients with COPD can not be improved by cilomilast therapy。In terms of health status, SGRQ in patients with COPD can not be improved by cilomilast therapy; Borg scale in patients with COPD can not be improved by cilomilast therapy; Summary symptom score in patients with COPD can not be improved by cilomilast therapy; Six-minute walk in patients with COPD can not be improved by cilomilast therapy;COPD exacerbation rates in patients with COPD can not be decreased by cilomilast therapy;Level 2 and level 3 COPD exacerbation rates in patients with COPD can not be decreased by cilomilast therapy。In terms of adverse reactions, The occurrence of AE events increased in treatment group than in the control group; There were no significant differences between treatment group and control group in the SAE events,; The occurrence of nausea events increased in treatment group than in the control group,; The occurrence of diarrhea events increased in treatment group than in the control group.; The occurrence of abdominal pain events increased in treatment group than in the control group,; The occurrence of vomitting events increased in treatment group than in the control group,,; There were no significant differences between treatment group and control group in the headache events; The occurrence of dizziness events increased in treatment group than in the control group; There were no significant differences between treatment group and control group in the upper respiratory tract infection events,; The occurrence of dyspepsia events increased in treatment group than in the control group。
背景：慢性阻塞性肺疾病(Chronic obstructive Pulmonary Disease,COPD)是一种具有气流受限特征的疾病,气流受限不完全可逆,呈进行性发展,与肺部对有害气体或有害颗粒的异常炎症反应有关。该病不仅影响肺,也可以引起显著的全身炎症反应,病情恶化导致劳动力丧失,生活质量下降,最终发展成为呼吸衰竭、肺源性心脏病。目前,全球约有2.7亿COPD患者,每年新增患者600余万人,并有近300万名患者死于该病,截止到2007年,COPD已经成为继心血管疾病脑血管疾病和急性呼吸道感染性疾病之后,与艾滋病并列的全球第4大死亡因,死因顺位从1980年的第12位上升到目前的第4位,COPD已成为全球性健康问题。COPD是一种慢性“肺部异常炎症反应”性疾病,其发病机制与氧化-抗氧化失衡、蛋白酶-抗蛋白酶、感染、细胞凋亡、细胞因子等诸多因素有关,其中细胞因子学说尤为重要,与心脑血管疾病、艾滋病不同的是,到目前为止,戒烟是阻止COPD进展最有效的干预措施,除此之外,COPD尚无有效的药物治疗手段来延长COPD患者的生存时间。现在的药物治疗仅减轻COPD患者的症状和提高生活质量一定的作用,大部分药物治疗手段来源于哮喘的治疗。理论上讲,针对肺组织炎症的治疗将是控制COPD症状和阻止其进展的关键所在,目前对COPD的药物治疗效果仍非常有限,有抗炎作用的药物主要有糖皮质激素和茶碱。激素长期应用治疗COPD的效果目前尚有争议,激素能减少哮喘的嗜酸性粒细胞增多,诱导嗜酸性粒细胞凋亡,但并不能抑制中性粒细胞、AM和CD8+T淋巴细胞分泌炎性介质和细胞因子,相反,激素能延长中性粒细胞存活,使体内中性粒细胞数量增多,这对控制COPD的炎症反应不利。研究表明激素对COPD患者合成LTB4和PGE2也无抑制作用。所以,激素不能有效抑制COPD患者肺内的中性粒细胞性炎症。而茶碱类药物作为非选择性的PDE抑制剂,有一定的抗气道非特异性炎症的作用,口服小剂量氨茶碱可显著减少COPD患者诱导痰中中性粒细胞数量,及IL-8和趋化4肽的水平,茶碱还可以抑制中性粒细胞的活性,减少氧自由基的释放。但茶碱类药物的抗炎活性较弱,并不能有效地阻断COPD病情的自然发展过程,并防止肺功能的逐年恶化,茶碱主要通过扩张支气管、改善呼吸肌功能抗炎和免疫调节等多方面对COPD起到治疗作用,治疗剂量和中毒剂量接近,因此治疗COPD的疗效并不理想。选择性PDE抑制剂则可以有效避免上述缺点。业已证实PDE4抑制剂可抑制与COPD发病的主要炎性细胞,如中性粒细胞、肺泡巨噬细胞、CD8+T细胞、气道皮细胞等产生细胞因子和炎症介质的作用,从而干预COPD的炎症过程。Cilomilast是葛兰素史克公司开发的新一代选择性PDE4抑制剂,国外的Ⅱ/Ⅲ期临床试验证实它对于治COPD、哮喘等具有较好的疗效,且安全性和耐受性均良好。国外一些初步的研究结果提示,选择性抑制剂可能是一类有前途的抗COPD肺部炎症的治疗药物,在体外研究中发现其调控的病理生理过程与慢性阻塞性肺病直接相关。研究表明cilomilast有松弛气道平滑肌、抑制免疫和炎症细胞活化、抑制细胞浸润和介质的释放等作用。另有报道cilomilast对慢性阻塞性肺病患者、正常人和吸烟者支气管上皮细胞和诱导痰液细胞(鳞状细胞和免疫细胞)的影响,Cilomilast可以显著降低支气管上皮细胞、诱导痰细胞中肿瘤坏死因子诱导痰细胞GM-CSF的释放。Cilomilast亦可显著降低痰和支气管上皮细胞上清液中中性粒细胞趋化。此外,在吸入脂多糖诱导的肺水肿动物模型中发现口服高剂量cilomilast同样可以有效减少中性粒细胞,这表明cilomilast对于中性粒细胞的作用可能对慢性阻塞性肺病炎症有益。因此自1999年起国内外出现一系列旨在探讨cilomilast治疗慢性阻塞性肺病有效性及安全性及抗炎作用的临床研究,但结果不一致,存在较大的争议,故本研究旨在收集当前全世界cilomilast治疗慢性阻塞性肺病随机对照试验,采用系统评价方法,进行效应量合并做Meta-分析,以期评价cilomilast治疗慢性阻塞性肺病的临床疗效及安全性,为cilomilast治疗慢性阻塞性肺病提供更加可靠的循证医学证据。
方法：根据循证医学的原则,采用Cochrane系统评价的方法,计算机检索MEDLINE(from OvID,1966-2011.2)、EMBASE(1984-2011)、Cochrane图书馆(2011年第1期)、中国生物医学文献数据库CBMdisc(1978—2011.2)、中国学术期刊全文数据库CNKI(1994—2011.2)、中文科技期刊全文数据库(VIP,1977-2011.2)、手工检索1998—2011相关杂志。两个评价员首先独立地阅读文章题目,对相关文献再阅读摘要,如为随机或半随机对照试验则阅读全文,将符合纳入标准的文献进行评价。不同意见通过讨论解决或由第三者判断。对纳入研究的方法学质量从随机方法、分配隐藏、盲法、有无失访几方面进行评价,采用RevMan5.1软件进行统计分析。对可以合并分析的指标作Meta分析(包括单个研究)；对不能进行Meta分析的指标用描述性方法分析结果。对同质性较好的多个研究结果,可用固定效应模型合并分析,对有统计学异质性者,分析异质原因,采用敏感性分析、亚组分析和随机效应模型处理。连续性变量采用加权均数差(WMD)或标准均数差(SMD)表示、二分类变量采用相对危险度(RR)、比值比(OR),二者均计算95%的可信区间(CI)。
结果：共纳入16个随机对照试验,6910例病人,根据Cochrane Review Handbook5.1推荐的简单方法(Simple approaches)对研究的方法学进行质量评价,16个随机对照试验均为B级。
本评价结果表明,西洛司特治疗COPD,在肺功能方面可以改善COPD患者的FEV1, SMD:0.20,95%CI[0.11,0.30], P<0.0001;可以改善COPD患者的FVC, WMD:0.07,95%CI[0.02,0.11], P=0.003;可以改善COPD患者的FEV1%pred；可以改善COPD患者的FVC%pred;可以改善COPD患者的RV%pred;可以改善COPD患者的RV/TLC;不能改善COPD患者的,FRC SMD:-0.20,95%CI[-0.48,0.08],P=0.16；不能改善COPD患者的RV, SMD:-0.23,95%CI[-0.65,0.19],P=0.29；不能改善COPD患者的PEF；不能改善COPD患者的IC。在健康状况方面,西洛司特不能改善COPD患者的圣乔治呼吸问卷得分,SMD:-0.08,95%CI[0.11,0.30],P=0.13;不能改善COPD患者的呼吸吸困难评分,WMD:-0.06,95%CI[-0.25,0.13];不能改善COPD患者的症状评分,WMD：-0.06,95%CI[-0.25,0.13],P=0.53；不能改善COPD患者的6分钟步行试验,SMD：0.15,95%CI[-0.35,0.04],P=0.12；可以改善COPD患者的咳嗽评分；可以改善COPD患者的咳痰评分。在COPD恶化方面,西洛司特不能减少COPD患者COPD的恶化,OR:1.26,95%CI[0.95,1.67],P=0.23,及二级、三级恶化,OR：1.40,95%CI[0.81,2.43],P=0.10。在不良反应方面,西洛司特组AE事件发生情况较对照组增多,0R：1.34,95%CI[1.09,1.64],P=0.005；西洛司特治疗组与对照组在SAE事件发生上不存在差异,OR：0.92,95%CI[0.74,1.12],P=0.42；西洛司特治疗组恶心发生的情况较对照组明显增多,OR：3.59,95%CI[2.84,4.55].P<0.0001；西洛司特治疗组的腹泻发生的情况较对照组明显增多,OR：2.51,95%CI[2.04,3.09],西洛司特治疗组同对照组差异有统计学意义,P<0.0001；西洛司特治疗组的腹痛发生的情况较对照组明显增多,OR：2.03,95%CI[1.55,2.66],P<0.0001；西洛司特治疗组的呕吐发生的情况较对照组明显增多,OR：4.80,95%CI[3.24,7.09],P<0.00001；西洛司特治疗组头痛发生的情况与对照组无明显差异OR：1.27,95%CI[1.03,1.56],P=0.03,；西洛司特治疗组头晕发生的情况较对照组增多OR：1.88,95%CI[1.10,3.21],P=0.02,；西洛司特治疗组上呼吸道感染发生的情况与对照组无明显差异,OR：1,95%CI[0.79,1.27],P<0.00001；西洛司特治疗组消化不良发生的情况较对照组明显增多OR：2.94,95%CI[2.11,4.10],P<0.00001。
结论：本系统评价综合分析结果表明,西洛司特可以显著改善COPD患者的肺功能,包括FEV1.FEV1%pred.FVC.FVC%pred.RV%pred.RV/TLC；而对COPD患者的FRC.RV.PEF及IC无显著影响。
西洛司特可以改善COPD患者的咳嗽评分和咳痰评分；不能改善COPD患者的呼吸困难评分、症状评分、6分钟步行试验；也不能改善COPD患者的生活质量(圣乔治呼吸问卷得分)。
西洛司特不能降低COPD患者COPD的恶化率及二级、三级恶化率。
西洛司特组不良事件(AE)如恶心、腹泻、腹痛、呕吐、头痛、头晕、消化不良发生情况较对照组明显增加；而在严重不良事件(SAE)、上呼吸道感染发生上与对照组无显著差异。
上述结论部分来自单个研究,因此使用这些结论必须谨慎,所有研究结果均不能作为推荐临床应用的证据仍有必要开展一系列多中心、前瞻性、随机双盲、设计实施良好的临床随机对照试验,尤其要提高试验的质量,从而为西洛司特的临床应用提供更加充足的证据。
Objective:To evaluate the efficacy and safety of cilomilast therapy for Chronic Obstructive Pulmonary Disease
Background:COPD is a common disease which is usually characterized by partially reversible airflow limitation, progressive loss of lung function and an abnormal inflammatory response in the lung to noxious substances, the most common of which is cigarette smoke. The disease is associated with increased frequency of exacerbations and deterioration of health status, as well as the development of non pulmonary complications. The pathogenesis of COPD remains unclear but chronic inflammation throughout airways, parenchyma and pulmonary vasculature is believed to have a central role. There is a need for a novel anti-inflammatory treatment, as experimental data indicate that the inflammatory process in COPD, particularly those that are neutrophil mediated, may be resistant to the anti-inflammatory effects of corticosteroids.Novel anti-inflammatory therapies are therefore being developed as potential therapeutic agents, including selective phosphodiesterase (PDE) inhibitors. Cilomilast is a potent and selective PDE4 inhibitor which modulates pathophysiological processes of direct relevance to COPD. In preclinical studies,cilomilast relaxed airway smooth muscle, inhibited immune and inflammatory cell activation and inhibited cellular infiltration and mediator release. The effect of cilomilast on airway cells was evaluated using bronchial epithelial cells and induced sputum cells (squamous and immune cells) from COPD patients, normal controls and smokers. Cilomilast significantly reduced TNFa release by bronchial epithelial and sputum cells, and GM-CSF release by sputum cells. Supernatants of sputum and bronchial epithelial cells treated with cilomilast also demonstrated significantly reduced neutrophi chemotaxis. Furthermore, cilomilast attenuated
the inhaled lipopolysaccharide-induced pulmonary neutrophilia and oedema with equivalent effectiveness to that of high-dose, orally administered prednisolone in an animal model. This suggested a possible beneficial role for cilomilast on the neutrophilic inflammation in COPD. Since 1999, there was a series clinical research designed to explore the effectiveness and safety of the cilomilast treatment of chronic obstructive pulmonary disease, but the results were quite conflicting. The objective of the present meta-analysis was to evaluate the efficacy and safety of cilomilast in COPD.
Methods:We searched the CochraneLibrary(Issuel,2011), MEDLNE(1966 to February,2011), EMBASE(1984 to 2011), the China Biological Medicine Database(1978 to February,2011), VIP(1977 to February,2011), CMAC(1994 to 2011)and hand-searched several related Chinese journals.Two reviewers independently screened the studies for eligibility, evaluated the quality and extracted the data from the eligible studies, with the confirmation of cross-check. Different opinions would be decided by the third party. The quality of the included trials such as randomization, blind, allocation concealment and following-up was assessed.Meta-analysis was Performed by RevMan5.1 software. After heterogeneity test, data without heterogeneity could be pooled using fixed effect model, and those with Heterogeneity could be solved by sensitivity analysis, subgroup analysis as well as randomized effect model. We will compare outcome measures for binary data using relative risks(RR) or odds ratio(OR) with 95% confidence intervals(Cl).For continuous data, the weighted means difference(WMD) or standardlzed mean difference (SMD) will be used.
Results:sixteen studies involving 6910 patients with Chronic Obstruetive Pulmonary Disease were included. Results suggested that In terms of lung function FEV1 in patients with COPD can be improved by cilomilast therapy, SMD:0.20, 95%CI[0.11,0.30], P<0.0001; FVC in patients with COPD can be improved by cilomilast therapy, WMD:0.07,95%CI[0.02,0.11], P=0.003; FEV1% pred in patients with COPD can be improved by cilomilast therapy; FVC% pred in patients with COPD can be improved by cilomilast therapy; RV% pred in patients with COPD can be improved by cilomilast therapy; RV/TLC in patients with COPD can be improved by cilomilast therapy; FRC in patients with COPD can not be improved by cilomilast therapy, SMD:-0.20,95%CI[-0.48,0.08], P=0.16; RV in patients with COPD can not be improved by cilomilast therapy, SMD:-0.23,95%CI[-0.65,0.19], P=0.29; PEF in patients with COPD can not be improved by cilomilast therapy; IC in patients with COPD can not be improved by cilomilast therapy。In terms of health status, SGRQ in patients with COPD can not be improved by cilomilast therapy, SMD:-0.08,95%CI[0.11,0.30], P=0.13; Borg scale in patients with COPD can not be improved by cilomilast therapy, WMD:-0.06,95%CI[-0.25,0.13]; Summary symptom score in patients with COPD can not be improved by cilomilast therapy,WMD:-0.06, 95%CI[-0.25,0.13], P=0.53; Six-minute walk in patients with COPD can not be improved by cilomilast therapy, SMD:0.15,95%CI[-0.35,0.04], P=0.12;COPD exacerbation rates in patients with COPD can not be decreased by cilomilast therapy,OR:1.26,95%CI[0.95,1.67], P=0.23;Level 2 and level 3 COPD exacerbation rates in patients with COPD can not be decreased by cilomilast therapy, OR:1.40, 95%CI[0.81,2.43], P=0.10。In terms of adverse reactions, The occurrence of AE events increased in treatment group than in the control group,OR:1.34,95%CI[1.09, 1.64], P=0.005; There were no significant differences between treatment group and control group in the SAE events, OR:0.92,95%CI[0.74,1.12], P=0.42; The occurrence of nausea events increased in treatment group than in the control group,,OR:3.59,95%CI[2.84,4.55].P<0.0001; The occurrence of diarrhea events increased in treatment group than in the control group, OR:2.51,95%CI[2.04,3.09], P<0.0001; The occurrence of abdominal pain events increased in treatment group than in the control group, OR:2.03,95%CI[1.55,2.66], P<0.0001; The occurrence of vomitting events increased in treatment group than in the control group,, OR:4.80,95%CI[3.24,7.09], P<0.00001; There were no significant differences between treatment group and control group in the headache events, OR:1.27, 95%CI[1.03,1.56], P=0.03,; The occurrence of dizziness events increased in treatment group than in the control group OR:1.88,95%CI[1.10,3.21], P=0.02,; There were no significant differences between treatment group and control group in the upper respiratory tract infection events, OR:1,95%CI[0.79,1.27], P<0.00001; The occurrence of dyspepsia events increased in treatment group than in the control group OR:2.94,95%CI[2.11,4.10], P<0.00001.
Conclusions:Results suggested that In terms of lung function FEV1 in patients with COPD can be improved by cilomilast therapy; FVC in patients with COPD can be improved by cilomilast therapy; FEV1% pred in patients with COPD can be improved by cilomilast therapy; FVC% pred in patients with COPD can be improved by cilomilast therapy; RV% pred in patients with COPD can be improved by cilomilast therapy; RV/TLC in patients with COPD can be improved by cilomilast therapy; FRC in patients with COPD can not be improved by cilomilast therapy; RV in patients with COPD can not be improved by cilomilast therapy; PEF in patients with COPD can not be improved by cilomilast therapy; IC in patients with COPD can not be improved by cilomilast therapy。In terms of health status, SGRQ in patients with COPD can not be improved by cilomilast therapy; Borg scale in patients with COPD can not be improved by cilomilast therapy; Summary symptom score in patients with COPD can not be improved by cilomilast therapy; Six-minute walk in patients with COPD can not be improved by cilomilast therapy;COPD exacerbation rates in patients with COPD can not be decreased by cilomilast therapy;Level 2 and level 3 COPD exacerbation rates in patients with COPD can not be decreased by cilomilast therapy。In terms of adverse reactions, The occurrence of AE events increased in treatment group than in the control group; There were no significant differences between treatment group and control group in the SAE events,; The occurrence of nausea events increased in treatment group than in the control group,; The occurrence of diarrhea events increased in treatment group than in the control group.; The occurrence of abdominal pain events increased in treatment group than in the control group,; The occurrence of vomitting events increased in treatment group than in the control group,,; There were no significant differences between treatment group and control group in the headache events; The occurrence of dizziness events increased in treatment group than in the control group; There were no significant differences between treatment group and control group in the upper respiratory tract infection events,; The occurrence of dyspepsia events increased in treatment group than in the control group。
引文
[1]Rabe KF, Hurd S, Anzueto A, et al. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis,management, and prevention of chronic obstructive pulmonary disease:GOLD executive summary. Am J Respir Crit Care Med 2007; 176:532-55
[2]Hogg JC. Pathophysiology of airflow limitation in chronic obstructive pulmonary disease. Lancet 2004; 364:709-21
[3]CalverleyPM, AndersonJA, CelliB, FergusonGT, JenkinsC, JonesPW, Yates JC, VesthoJ.Salmeterol and flutieasone ProPionate and survival in chronic obstruetivePulmonary disease.N Engl Jmed 2007:356:775-789.
[4]Hogg JC, Chu F, Utokaparch S, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med 2004; 350:2645-53
[5]Barnes PJ. Mechanisms in COPD:differences from asthma.Chest 2000; 117 Suppl.2:10S-4S
[6]Sutherland ER, Martin RJ. Airway inflammation in chronic obstructive pulmonary disease:comparisons with asthma. J Allergy Clin Immunol 2003; 112:819-27
[7]Turato G, Zuin R, Miniati M, et al. Airway inflammation in severe chronic obstructive pulmonary disease:relationship with lung function and radiologic emphysema. Am J Respir Crit Care Med 2002; 166:105-10
[8]Di Stefano A, Capelli A, Lusuardi M, et al. Severity of airflow limitation is associated with severity of airway inflammation in smokers. Am J Respir Crit Care Med 1998; 158:1277-85
[9]O'Shaughnessy TC, Ansari TW, Barnes NC, et al. Inflammation. in bronchial biopsies of subjects with chronic bronchitis:inverse relationship of CD8+T lymphocytes with FEV1. Am J Respir Crit Care Med 1997; 155:852-7
[10]Jeffery PK. Investigation and assessment of airway and lung inflammation:we now have the tools, what are the questions?Eur Respir J 1998; 11:524-8
[11]4.BarnesPJ, HanselTT.2004.Pros Pects for new drugs for chronic obstructive Pulmonary disease.Laneet,364:985-6.
[12]Burge PS.EUROSCOP,ISOLDE and the Copenhagen city lung study.Thorax,1999,54:287-288.
[13]Anthonisen NR,Connett JE,Kiley JP,et al.Effects of smoking intervention and the useof an inhaled anticholinergic bronchodilator on the rate of decline of FEV1.The Lung Health Study.JAMA,1994,272:1497-1505.
[14]Ikeda A,Nishimura K,Koyama H,et al.Dose response study of ipratropium bromide aerosol on maximum exercise performance in stable patients with chronic obstructive pulmonary disease.Thorax,1996,51:48-53.
[15]Guyatt GH,Townsend M,Pugsley SO,etal.Bronchodilators in chronic air-flow limitation.Effects on airway function,exercise capacity,and quality of life.Am Rev Respir Dis,1987,135:1069-1074.
[16]Paggiaro PL,Dahle R,Bakran I,et al.Multicentre randomised placebo-controlled trial of inhaled fluticasone propionate in patients with chronic obstructive pulmonary disease. International COPD Study Group.Lancet, 1998,351:773-780.
[17]Ram FS,Jones PW,Castro AA,et al.Oral theophylline for chronic obstructive pulmonary disease.Cochrane Database Syst Rev,2002,(4):CD003902.
[18]Culpitt SV,Matos C,Russell RE,et al.Effect of theophylline on induced sputum inflammatory indices and neutrophil chemotaxis in chronic obstructive pulmonary disease.Am J Respir Crit Care Med,2002,165(10):1371-1376.
[19]Muise ES,Chute LC,David Claveau,et al.Comparison of inhibition of ovalbumin-induced bronchoconstriction in guinea pigs and in vitro inhibition of tumor necrosis factor-a formation with phosphodiesterase 4(PDE4)selective inhibitors.Biochemical Pharmacology,2002,63:1527-1535.
[20]Barnes PJ.Cytokine-directed therapies for the treatment of chronic airway diseases.Cytokine&Growth Factor Reviews,2003,14:511-522.
[21]Trifilieff A,Wyss D,Walker C,et al.Pharmacological profile of a novel phosphodiesterase 4 inhibitor,4-(8-benzo [1,2,5] oxadiazol-5-yl-[1,7] naphthyridin-6-yl)-benzoic acid(NVP-ABE171),a 1,7-naphthyridine derivative, with anti-inflammatory activities.The Journal of Pharmacology and Experimental Therapeutics,2002,301(1):241-248.
[22]David M,Essayan MD. Molecular mechanisms in allergy and clinical immunology cyclic nucleotide phosphodiesterases [J]. Journal of Allergy and Clinical Immunology,2001,108:671-680
[23]Souness JE,Aldous D,Sargent C. Immunosuppressive and anti2inflammatory effects of cyclic AMP phosphodiseterase (PDE) type4 inhibitors[J] Immunopharmacology,2000,47:127
[24]Catherine Bardelle,Caroline Smales,Masashi Ito, et al. Phosphodiesterase4 conformers preparation of recombinant enzymes and assay for inhibitors[J] Analytical Biochemistry,1999,275:148-155
[25]Sturton Graham, Fitzgerald Mary. Phosphodiesterase 4 inhibitors for thetreatment of COPD[J]. Chest,2002,121 (Suppl5):192-196S
[26]Profita M,Chiappara G,Mirabella F, et al. Effect of cilomilast (Ariflo) on TNF2alpha, IL28, and GM2CSF release by airway cells of patients with COPD[J]. Thorax,2003,58 (7):573-579
[27]Martoin C,Goggel R,Vergelli C, et al. Airway relaxant and anti2inflammatory properties of a PDE4 inhibitor with low affinity for the high affinity rolipram binding site[J]. Naunyn2Schmiedeberg's Archives of Pharmacolo2gy,2002,365 (4):284-289
[28]Muise ES,Chute LC,David Claveau, et al. Comparison of inhibition of ovalbumin2induced bronchoconstriction in guinea pigs and in vitro inhibition of tumor necrosis factor-aformation with phosphodiesterase 4 (PDE4) se2 lective inhibitors[J].Biochemical pharmacology,2002,63:1527-1535
[29]Grootendorst DC,Gauw SA,Baan R, et al. Does a single dose of the phosphodiesterase 4 inhibitor,cilomilast (15mg),induce bronchodilation in patients with chronic obstructive pulmonary disease[J] Pulmoar Pharmacol2 ogy & Therapeutics,2003,16 (2):115-120
[30]Underwood DC, Kotzer CJ, Bochnowicz S, et al. Comparison of phosphodiesterase Ⅲ, Ⅳ and dual Ⅲ/Ⅳ inhibitors on bronchospasm and pulmonary eosinophil influx in guinea pigs. J Pharmacol Exp Ther 1994; 270: 250-9
[31]Kohyama T, Liu X, Wen FQ, et al. PDE4 inhibitors attenuate fibroblast chemotaxis and contraction of native collagen gels.Am J Respir Cell Mol Biol 2002; 26:694-701
[32]Barnette MS, Christensen SB, Essayan DM, et al. SB 207499 Ariflo), a potent and selective second-generation phosphodi- esterase4 inhibitor:in vitro anti-inflammatory actions. J Pharmacol Exp Ther 1998; 284:420-6
[33]Underwood DC, Bochnowicz S, Osborn RR, et al. Antiasthmatic activity of the second generation phosphodiesterase 4(PDE4) inhibitor SB 207499 (Ariflo) in the guinea pig. J Pharmacol Exp Ther 1998; 287:988-95
[34]Gamble E, Grootendorst DC, Brightling CE, et al. Antiinflam-matory effects of the phosphodiesterase-4 inhibitor cilomilast(Ariflo) in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2003; 168:976-82
[35]Compton CH, Gubb J, Nieman R, et al. Cilomilast, a selective phosphodiesterase-4 inhibitor for treatment of patients with chronic obstructive pulmonary disease:a randomised, dose- ranging study. Lancet 2001; 358: 265-70
[36]Rennard SI, Schachter N, Strek M, et al. Cilomilast for COPD:results of a 6-month, placebo-controlled study of a potent, selective inhibitor of phosphodiesterase 4. Chest 2006; 129:56-66
[37]A 12-week, multicenter, double-blind, placebo-controlled, par- allel-group study to evaluate the anti-inflammatory activity of cilomilast 15 mg twice daily in patients with chronic obstruc tive pulmonary disease (COPD) (SB207499/110) [GSK Clin- ical Trial Registry; online]. Available from URL: http://www.gsk-clinicalstudyregister.com [Accessed 2008 Nov
[38]A 13-week randomised, double-blind, parallel group, multicen-tre study to compare the bronchial anti-inflammatory activity of oral cilomilast (15 mg bd) with placebo twice daily in subjects with chronic obstructive pulmonary disease (COPD)(SB207499/181) [GSK Clinical Trial Registry; online]. Avail- able from URL:http://www.gsk-clinicalstudyregister.com[Accessed 2008 Nov 17]
[39]A randomized,24-week, double-blind, placebo-controlled, par-allel-group study to evaluate the efficacy, safety and tolerabili-ty of cilomilast (15mg twice daily) in patients with chronic obstructive pulmonary disease (COPD) (SB207499/042)[GSK Clinical Trial Registry; online]. Available from URL: http://www.gsk-clinicalstudyregister.com [Accessed 2008 Nov 17]
[40]A randomized,24-week, double-blind, placebo-controlled, par- allel-group study followed by a 2-week, randomized, double-blind, run-out phase to evaluate the efficacy, safety, tolerability and discontinuation of SB207499 (15mg twice daily) in patients with chronic obstructive pulmonary disease (COPD)(SB207499/091) [GSK Clinical Trial Registry; online]. Avail-able from URL:http://www.gsk-clinical studyregister.com[Accessed 2008 Nov 17]
[41]A randomised, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy, safety and tolerability of oral cilomilast (15 mg bid) when given as maintenance treatment for 12 months to subjects with chronic obstructive pulmonary disease (COPD) (SB207499/156) [GSK Clinical Trial Registry; online]. Available from URL:http://www.gsk-clinicalstudy register.com [Accessed 2008 Nov 17]
[42]A randomized,24-week, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy, safety and tolerability of ARIFLO (15mg BID) in patients with chronic obstructive pulmonary disease (COPD) (CIL103657) [ClinicalTrials.gov identifier NTC 00103922], ClinicalTrials.gov [online].Available from URL:http://www.gsk-clinicalstudyregister.com [Accessed 2008 Nov 17]
[43]A randomised, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy, safety and tolerability of oral cilomilast (15 mg bd) when given as maintenance treatment for 12 months to subjects with chronic obstructive pulmonary disease (COPD) (SB207499/157) [GSK Clinical Trial Registry; online]. Available from URL:http://www.gsk-clinicalstudy register.com [Accessed 2008 Nov 17]
[44]A randomized,12-week, double-blind, placebo-controlled, par-allel-group study to evaluate the safety and tolerability of cilomilast 15mg twice daily in patients with chronic obstructive pulmonary disease (COPD) (SB207499/168) [GSK Clin-ical Trial Registry; online], Available from URL: http://www.gsk-clinicalstudyregister.com [Accessed 2008 Nov 17]
[45]A randomized,12-week, double-blind, placebo-controlled, par-allel-group pilot study to evaluate the safety and additional efficacy of adding a new chemical entity (NCE) to treatment with ADVAIR 250/50 twice daily in patients with chronic obstructive pulmonary disease (COPD) (SB207499/125) [GSK Clinical Trial Registry; online]. Available from URL: http://www.gsk-clinicalstudyregister.com [Accessed 2008 Nov 17]
[46]A 12-week, randomized, double-blind, placebo-controlled, parallel-group study to investigate the effect of cilomilast (15 mg twice daily) on trapped gas volume in patients with chronic obstructive pulmonary disease (SB207499/111) [GSK ClinicalTrial Registry; online]. Available from URL: http://www.gsk-clinicalstudyregister.com [Accessed 2008 Nov 17]
[47]An 18-week randomized, double-blind, placebo-controlled,multicenter study designed to compare treatment with cilomi-last to that with placebo for changes in ventilatory mechanics and function (both at rest and during exercise), as well as related exertional dyspnea and exercise performance, in hyperinflated patients with stable COPD (SB207499/180) [GSK Clinical Trial Registry; online]. Available from URL: http://www.gsk-clinicalstudyregister.com [Accessed 2008 Nov 17]
[48]A randomized,24-week, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy, safety and tolerability of cilomilast (15mg BID) in patients with chronic obstructive pulmonary disease (COPD). (SB207499/121) [GSK Clinical Trial Registry; online]. Available from URL: http://www.gsk-clinicalstudyregister.com [Accessed 2008 Nov 17]
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[2]Hogg JC. Pathophysiology of airflow limitation in chronic obstructive pulmonary disease. Lancet 2004; 364:709-21
[3]CalverleyPM, AndersonJA, CelliB, FergusonGT, JenkinsC, JonesPW, Yates JC, VesthoJ.Salmeterol and flutieasone ProPionate and survival in chronic obstruetivePulmonary disease.N Engl Jmed 2007:356:775-789.
[4]Hogg JC, Chu F, Utokaparch S, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med 2004; 350:2645-53
[5]Barnes PJ. Mechanisms in COPD:differences from asthma.Chest 2000; 117 Suppl.2:10S-4S
[6]Sutherland ER, Martin RJ. Airway inflammation in chronic obstructive pulmonary disease:comparisons with asthma. J Allergy Clin Immunol 2003; 112:819-27
[7]Turato G, Zuin R, Miniati M, et al. Airway inflammation in severe chronic obstructive pulmonary disease:relationship with lung function and radiologic emphysema. Am J Respir Crit Care Med 2002; 166:105-10
[8]Di Stefano A, Capelli A, Lusuardi M, et al. Severity of airflow limitation is associated with severity of airway inflammation in smokers. Am J Respir Crit Care Med 1998; 158:1277-85
[9]O'Shaughnessy TC, Ansari TW, Barnes NC, et al. Inflammation. in bronchial biopsies of subjects with chronic bronchitis:inverse relationship of CD8+T lymphocytes with FEV1. Am J Respir Crit Care Med 1997; 155:852-7
[10]Jeffery PK. Investigation and assessment of airway and lung inflammation:we now have the tools, what are the questions?Eur Respir J 1998; 11:524-8
[11]4.BarnesPJ, HanselTT.2004.Pros Pects for new drugs for chronic obstructive Pulmonary disease.Laneet,364:985-6.
[12]Burge PS.EUROSCOP,ISOLDE and the Copenhagen city lung study.Thorax,1999,54:287-288.
[13]Anthonisen NR,Connett JE,Kiley JP,et al.Effects of smoking intervention and the useof an inhaled anticholinergic bronchodilator on the rate of decline of FEV1.The Lung Health Study.JAMA,1994,272:1497-1505.
[14]Ikeda A,Nishimura K,Koyama H,et al.Dose response study of ipratropium bromide aerosol on maximum exercise performance in stable patients with chronic obstructive pulmonary disease.Thorax,1996,51:48-53.
[15]Guyatt GH,Townsend M,Pugsley SO,etal.Bronchodilators in chronic air-flow limitation.Effects on airway function,exercise capacity,and quality of life.Am Rev Respir Dis,1987,135:1069-1074.
[16]Paggiaro PL,Dahle R,Bakran I,et al.Multicentre randomised placebo-controlled trial of inhaled fluticasone propionate in patients with chronic obstructive pulmonary disease. International COPD Study Group.Lancet, 1998,351:773-780.
[17]Ram FS,Jones PW,Castro AA,et al.Oral theophylline for chronic obstructive pulmonary disease.Cochrane Database Syst Rev,2002,(4):CD003902.
[18]Culpitt SV,Matos C,Russell RE,et al.Effect of theophylline on induced sputum inflammatory indices and neutrophil chemotaxis in chronic obstructive pulmonary disease.Am J Respir Crit Care Med,2002,165(10):1371-1376.
[19]Muise ES,Chute LC,David Claveau,et al.Comparison of inhibition of ovalbumin-induced bronchoconstriction in guinea pigs and in vitro inhibition of tumor necrosis factor-a formation with phosphodiesterase 4(PDE4)selective inhibitors.Biochemical Pharmacology,2002,63:1527-1535.
[20]Barnes PJ.Cytokine-directed therapies for the treatment of chronic airway diseases.Cytokine&Growth Factor Reviews,2003,14:511-522.
[21]Trifilieff A,Wyss D,Walker C,et al.Pharmacological profile of a novel phosphodiesterase 4 inhibitor,4-(8-benzo [1,2,5] oxadiazol-5-yl-[1,7] naphthyridin-6-yl)-benzoic acid(NVP-ABE171),a 1,7-naphthyridine derivative, with anti-inflammatory activities.The Journal of Pharmacology and Experimental Therapeutics,2002,301(1):241-248.
[22]David M,Essayan MD. Molecular mechanisms in allergy and clinical immunology cyclic nucleotide phosphodiesterases [J]. Journal of Allergy and Clinical Immunology,2001,108:671-680
[23]Souness JE,Aldous D,Sargent C. Immunosuppressive and anti2inflammatory effects of cyclic AMP phosphodiseterase (PDE) type4 inhibitors[J] Immunopharmacology,2000,47:127
[24]Catherine Bardelle,Caroline Smales,Masashi Ito, et al. Phosphodiesterase4 conformers preparation of recombinant enzymes and assay for inhibitors[J] Analytical Biochemistry,1999,275:148-155
[25]Sturton Graham, Fitzgerald Mary. Phosphodiesterase 4 inhibitors for thetreatment of COPD[J]. Chest,2002,121 (Suppl5):192-196S
[26]Profita M,Chiappara G,Mirabella F, et al. Effect of cilomilast (Ariflo) on TNF2alpha, IL28, and GM2CSF release by airway cells of patients with COPD[J]. Thorax,2003,58 (7):573-579
[27]Martoin C,Goggel R,Vergelli C, et al. Airway relaxant and anti2inflammatory properties of a PDE4 inhibitor with low affinity for the high affinity rolipram binding site[J]. Naunyn2Schmiedeberg's Archives of Pharmacolo2gy,2002,365 (4):284-289
[28]Muise ES,Chute LC,David Claveau, et al. Comparison of inhibition of ovalbumin2induced bronchoconstriction in guinea pigs and in vitro inhibition of tumor necrosis factor-aformation with phosphodiesterase 4 (PDE4) se2 lective inhibitors[J].Biochemical pharmacology,2002,63:1527-1535
[29]Grootendorst DC,Gauw SA,Baan R, et al. Does a single dose of the phosphodiesterase 4 inhibitor,cilomilast (15mg),induce bronchodilation in patients with chronic obstructive pulmonary disease[J] Pulmoar Pharmacol2 ogy & Therapeutics,2003,16 (2):115-120
[30]Underwood DC, Kotzer CJ, Bochnowicz S, et al. Comparison of phosphodiesterase Ⅲ, Ⅳ and dual Ⅲ/Ⅳ inhibitors on bronchospasm and pulmonary eosinophil influx in guinea pigs. J Pharmacol Exp Ther 1994; 270: 250-9
[31]Kohyama T, Liu X, Wen FQ, et al. PDE4 inhibitors attenuate fibroblast chemotaxis and contraction of native collagen gels.Am J Respir Cell Mol Biol 2002; 26:694-701
[32]Barnette MS, Christensen SB, Essayan DM, et al. SB 207499 Ariflo), a potent and selective second-generation phosphodi- esterase4 inhibitor:in vitro anti-inflammatory actions. J Pharmacol Exp Ther 1998; 284:420-6
[33]Underwood DC, Bochnowicz S, Osborn RR, et al. Antiasthmatic activity of the second generation phosphodiesterase 4(PDE4) inhibitor SB 207499 (Ariflo) in the guinea pig. J Pharmacol Exp Ther 1998; 287:988-95
[34]Gamble E, Grootendorst DC, Brightling CE, et al. Antiinflam-matory effects of the phosphodiesterase-4 inhibitor cilomilast(Ariflo) in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2003; 168:976-82
[35]Compton CH, Gubb J, Nieman R, et al. Cilomilast, a selective phosphodiesterase-4 inhibitor for treatment of patients with chronic obstructive pulmonary disease:a randomised, dose- ranging study. Lancet 2001; 358: 265-70
[36]Rennard SI, Schachter N, Strek M, et al. Cilomilast for COPD:results of a 6-month, placebo-controlled study of a potent, selective inhibitor of phosphodiesterase 4. Chest 2006; 129:56-66
[37]A 12-week, multicenter, double-blind, placebo-controlled, par- allel-group study to evaluate the anti-inflammatory activity of cilomilast 15 mg twice daily in patients with chronic obstruc tive pulmonary disease (COPD) (SB207499/110) [GSK Clin- ical Trial Registry; online]. Available from URL: http://www.gsk-clinicalstudyregister.com [Accessed 2008 Nov
[38]A 13-week randomised, double-blind, parallel group, multicen-tre study to compare the bronchial anti-inflammatory activity of oral cilomilast (15 mg bd) with placebo twice daily in subjects with chronic obstructive pulmonary disease (COPD)(SB207499/181) [GSK Clinical Trial Registry; online]. Avail- able from URL:http://www.gsk-clinicalstudyregister.com[Accessed 2008 Nov 17]
[39]A randomized,24-week, double-blind, placebo-controlled, par-allel-group study to evaluate the efficacy, safety and tolerabili-ty of cilomilast (15mg twice daily) in patients with chronic obstructive pulmonary disease (COPD) (SB207499/042)[GSK Clinical Trial Registry; online]. Available from URL: http://www.gsk-clinicalstudyregister.com [Accessed 2008 Nov 17]
[40]A randomized,24-week, double-blind, placebo-controlled, par- allel-group study followed by a 2-week, randomized, double-blind, run-out phase to evaluate the efficacy, safety, tolerability and discontinuation of SB207499 (15mg twice daily) in patients with chronic obstructive pulmonary disease (COPD)(SB207499/091) [GSK Clinical Trial Registry; online]. Avail-able from URL:http://www.gsk-clinical studyregister.com[Accessed 2008 Nov 17]
[41]A randomised, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy, safety and tolerability of oral cilomilast (15 mg bid) when given as maintenance treatment for 12 months to subjects with chronic obstructive pulmonary disease (COPD) (SB207499/156) [GSK Clinical Trial Registry; online]. Available from URL:http://www.gsk-clinicalstudy register.com [Accessed 2008 Nov 17]
[42]A randomized,24-week, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy, safety and tolerability of ARIFLO (15mg BID) in patients with chronic obstructive pulmonary disease (COPD) (CIL103657) [ClinicalTrials.gov identifier NTC 00103922], ClinicalTrials.gov [online].Available from URL:http://www.gsk-clinicalstudyregister.com [Accessed 2008 Nov 17]
[43]A randomised, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy, safety and tolerability of oral cilomilast (15 mg bd) when given as maintenance treatment for 12 months to subjects with chronic obstructive pulmonary disease (COPD) (SB207499/157) [GSK Clinical Trial Registry; online]. Available from URL:http://www.gsk-clinicalstudy register.com [Accessed 2008 Nov 17]
[44]A randomized,12-week, double-blind, placebo-controlled, par-allel-group study to evaluate the safety and tolerability of cilomilast 15mg twice daily in patients with chronic obstructive pulmonary disease (COPD) (SB207499/168) [GSK Clin-ical Trial Registry; online], Available from URL: http://www.gsk-clinicalstudyregister.com [Accessed 2008 Nov 17]
[45]A randomized,12-week, double-blind, placebo-controlled, par-allel-group pilot study to evaluate the safety and additional efficacy of adding a new chemical entity (NCE) to treatment with ADVAIR 250/50 twice daily in patients with chronic obstructive pulmonary disease (COPD) (SB207499/125) [GSK Clinical Trial Registry; online]. Available from URL: http://www.gsk-clinicalstudyregister.com [Accessed 2008 Nov 17]
[46]A 12-week, randomized, double-blind, placebo-controlled, parallel-group study to investigate the effect of cilomilast (15 mg twice daily) on trapped gas volume in patients with chronic obstructive pulmonary disease (SB207499/111) [GSK ClinicalTrial Registry; online]. Available from URL: http://www.gsk-clinicalstudyregister.com [Accessed 2008 Nov 17]
[47]An 18-week randomized, double-blind, placebo-controlled,multicenter study designed to compare treatment with cilomi-last to that with placebo for changes in ventilatory mechanics and function (both at rest and during exercise), as well as related exertional dyspnea and exercise performance, in hyperinflated patients with stable COPD (SB207499/180) [GSK Clinical Trial Registry; online]. Available from URL: http://www.gsk-clinicalstudyregister.com [Accessed 2008 Nov 17]
[48]A randomized,24-week, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy, safety and tolerability of cilomilast (15mg BID) in patients with chronic obstructive pulmonary disease (COPD). (SB207499/121) [GSK Clinical Trial Registry; online]. Available from URL: http://www.gsk-clinicalstudyregister.com [Accessed 2008 Nov 17]
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