The p38 mitogen activated protein kinase inhibitor losmapimod in chronic obstructive pulmonary disease patients with systemic inflammation, stratified by fibrinogen: A randomised double-blind placebo-controlled trial.
The p38 mitogen activated protein kinase inhibitor losmapimod in chronic obstructive pulmonary disease patients with systemic inflammation, stratified by fibrinogen: A randomised double-blind placebo-controlled trial.
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DOI：
10.1371/journal.pone.0194197
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Wilkinson IB
中科院分区：
文献类型：
--
作者：
Fisk M;Cheriyan J;Mohan D;Forman J;Mäki-Petäjä KM;McEniery CM;Fuld J;Rudd JHF;Hopkinson NS;Lomas DA;Cockcroft JR;Tal-Singer R;Polkey MI;Wilkinson IB
心血管疾病是COPD患者发病和死亡的主要原因。与COPD相关的全身性炎症通常被假设为因果因素。p38丝裂原活化蛋白激酶在COPD和动脉粥样硬化的炎症发病机制中起关键作用。本研究旨在评价p38丝裂原活化蛋白激酶（MAPK）抑制剂losmapimod对伴有全身炎症（定义为血浆纤维蛋白原> 2.8g/l）的慢性阻塞性肺疾病（COPD）患者血管炎症和内皮功能的影响。这是一项随机、双盲、安慰剂对照的II期试验，招募了血浆纤维蛋白原>2.8g/l的COPD患者。参与者通过在线程序随机分配到losmapimod 7.5mg或安慰剂片剂，每天两次，持续16周。对主动脉和颈动脉进行了给药前和给药后18 F-氟脱氧葡萄糖正电子发射断层扫描与计算机断层扫描（FDG PET/CT）共配准成像，以量化动脉炎症，通过扫描图像的组织-血液比（TBR）定义。采用肱动脉血流介导的舒张功能（FMD）评价内皮功能。我们筛选了160名患者，其中36名和37名被随机分配到losmapimod或安慰剂组。与安慰剂相比，losmapimod的治疗效果不显著，对于TBR为-0统计学05（95%CI：-0统计学17，0.07），p = 0.42，对于FMD为+0统计学40%（95%CI：-1统计学66，2.47），p = 0.70。两个治疗组报告的不良事件频率相似。在这项富含血浆纤维蛋白原的研究中，losmapimod在治疗16周时对动脉炎症和内皮功能没有影响，尽管它耐受性良好，没有显著的安全性问题。这些发现不支持losmapimod是COPD不良心血管表现的有效治疗的概念。
Cardiovascular disease is a major cause of morbidity and mortality in COPD patients. Systemic inflammation associated with COPD, is often hypothesised as a causal factor. p38 mitogen-activated protein kinases play a key role in the inflammatory pathogenesis of COPD and atherosclerosis. This study sought to evaluate the effects of losmapimod, a p38 mitogen-activated protein kinase (MAPK) inhibitor, on vascular inflammation and endothelial function in chronic obstructive pulmonary disease (COPD) patients with systemic inflammation (defined by plasma fibrinogen >2·8g/l). This was a randomised, double-blind, placebo-controlled, Phase II trial that recruited COPD patients with plasma fibrinogen >2.8g/l. Participants were randomly assigned by an online program to losmapimod 7·5mg or placebo tablets twice daily for 16 weeks. Pre- and post-dose 18F-Fluorodeoxyglucose positron emission tomography co-registered with computed tomography (FDG PET/CT) imaging of the aorta and carotid arteries was performed to quantify arterial inflammation, defined by the tissue-to-blood ratio (TBR) from scan images. Endothelial function was assessed by brachial artery flow-mediated dilatation (FMD). We screened 160 patients, of whom, 36 and 37 were randomised to losmapimod or placebo. The treatment effect of losmapimod compared to placebo was not significant, at -0·05 for TBR (95% CI: -0·17, 0·07), p = 0·42, and +0·40% for FMD (95% CI: -1·66, 2·47), p = 0·70. The frequency of adverse events reported was similar in both treatment groups. In this plasma fibrinogen-enriched study, losmapimod had no effect on arterial inflammation and endothelial function at 16 weeks of treatment, although it was well tolerated with no significant safety concerns. These findings do not support the concept that losmapimod is an effective treatment for the adverse cardiovascular manifestations of COPD.
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影响因子：
168.9
作者：
Newby, L. Kristin;Marber, Michael S.;Granger, Christopher B.
通讯作者：
Granger, Christopher B.
影响因子：
9.6
作者：
Donaldson, Gavin C.;Hurst, John R.;Wedzicha, Jadwiga A.
通讯作者：
Wedzicha, Jadwiga A.
DOI：
10.1513/pats.200404-032ms
发表时间：
2005-01-01
期刊：
Proceedings of the American Thoracic Society
影响因子：
--
作者：
Sin, Don D;Man, S F Paul
通讯作者：
Man, S F Paul
影响因子：
3
作者：
Fisk, Marie;Gajendragadkar, Parag R.;Cheriyan, Joseph
通讯作者：
Cheriyan, Joseph
影响因子：
39.3
作者：
NIEUWENHUIZEN, W
通讯作者：
NIEUWENHUIZEN, W