特发性肺纤维化治疗药吡非尼酮

特发性肺纤维化（IPF）为一种预后不良的进行性疾病,至今仍无有效的治疗手段。而新型的抗纤维化药物吡非尼酮（5-甲基-1-苯基吡啶-2[1H]-酮）已被证明可减缓IPF患者的疾病恶化进程。用肺纤维化动物模型进行的体内和体外研究表明：     

吡非尼酮治疗特异性肺纤维化的研究进展

摘要：吡非尼酮（PFD）作为一种新型抗纤维化药物,在临床上已经成为治疗特发性肺纤维化（IPF）的一线用药。前期多项体内外研究中,PFD均表现出明显抗纤维化活性。新型冠状病毒肺炎（COVID-19）的部分患者表现出肺部纤维化特征。本文从IPF的发病机制和PFD的药理作用、药动学、临床研究、安全性等方面进行总结概括,并探讨其用于COVID-19伴肺纤维化患者对症治疗的可能性。     

吡非尼酮治疗特发性肺纤维化的临床疗效及不良反应

目的探讨吡非尼酮治疗特发性肺纤维化(IPF)的临床疗效及不良反应。方法将40例处于稳定期的IPF患者分为对照组和试验组,每组20例。对照组给予镇咳、平喘等对症治疗,试验组在此基础上给予吡非尼酮胶囊,0.4 g,口服,每日3次,疗程48周。记录治疗前后两组患者用力肺活量(FVC)、第1秒用力呼气容积(FEV_1)和一氧化碳弥散量(DL_(CO))的变化,观察不良反应发生情况。结果治疗前两组FVC、FEV_1和DL_(CO)无显著差异(P>0.05)。治疗12、24、36周末两组FVC差异无显著意义(P>0.05),治疗48周末对照组FVC低于试验组[(2.31±0.93)L vs.(2.86±0.78)L,P<0.05]。治疗12、24、36、48周末对照组FEV_1均低于试验组(P<0.05),DL_(CO)组间无显著差异(P>0.05),但试验组DL_(CO)下降趋势相对较缓。试验组不良反应发生率为65%(13/20),多为光敏反应、食欲减退、腹部不适、倦怠,程度多为轻至中度,患者均可耐受。结论吡非尼酮治疗IPF具有良好的临床疗效和耐受性。     

吡非尼酮联合尼达尼布治疗特发性肺纤维化患者的临床研究

目的 观察吡非尼酮联合尼达尼布治疗特发性肺纤维化的疗效及肺功能的影响。方法 将95例特发性肺纤维化患者随机分为对照组（47例）和试验组（48例）。对照组给予吡非尼酮,每次200 mg,每日3次,口服;试验组在对照组治疗的基础上,给予乙磺酸尼达尼布软胶囊,每次150 mg,每日2次,口服。2组均持续治疗12周。比较2组的临床疗效、第1秒用力呼气容积（FEV1）、用力肺活量（FVC）、一氧化碳弥散量占预计值的百分比（DLco%）及血清透明质酸（HA）、层粘连蛋白（LN）、涎液化糖链抗原-6（KL-6）水平。结果 对照组和试验组的总有效率分别为77.27%和93.18%,差异有统计学意义（P<0.05）。治疗后,试验组和对照组的FEV1分别为（73.63±5.49）%和（68.94±5.82）%,FVC分别为（2.91±0.43）和（2.53±0.46）L,DLco%分别为（50.65±10.32）%和（49.57±6.35）%,血清HA分别为（83.47±14.01）和（95.12±15.36）μg·L^-1,LN分别为（96.52±14.47）和（115.24±...     

吡非尼酮抗纤维化作用的研究进展

目的:对吡非尼酮的抗纤维化作用和临床应用进行探讨。方法:收集发表的相关文章,对吡非尼酮的药物代谢动力学、药理作用、临床试验和真实世界研究进行分析总结。结果:吡非尼酮是一种新型小分子化合物,具有抗纤维化、抗炎和抗氧化作用。在动物实验中,它能够抑制促纤维化因子包括转化生长因子-β的表达,减少成纤维细胞增殖和胶原沉积;同时抑制多种炎性因子释放,减轻炎症反应;通过清除自由基、抑制脂质过氧化反应,减轻氧化应激。临床试验和真实世界研究均表明,吡非尼酮可以减少特发性肺纤维化(IPF)患者的肺功能下降、延缓疾病进展。结论:吡非尼酮具有广谱抗纤维化作用,轻中度IPF患者服用吡非尼酮能获益。     

吡非尼酮对特发性肺纤维化患者肺功能及血清标志物水平的影响

目的分析吡非尼酮对特发性肺纤维化(IPF)患者肺功能及血清标志物水平的影响。方法选择2016年3月至2019年2月我院诊治的60例IPF患者,随机分为对照组和试验组,每组30例。对照组给予常规的止咳、平喘等治疗;试验组在此基础上给予吡非尼酮400 mg,3次/d口服。疗程共6个月。对比两组患者治疗前后肺功能指标、血清KL-6、CCL18、miR-21水平的变化。结果治疗后,对照组FVC%pred、FEV1%pred、DLco%pred均降低(P<0.05);试验组DLco%pred降低(P<0.05),但FVC%pred、FEV1%pred差异无统计学意义(P>0.05)。试验组治疗前后FVC%pred、FEV1%pred差值(治疗前-治疗后)小于对照组(P<0.01),两组DLco%pred差值比较差异无统计学意义(P>0.05)。治疗后,试验组miR-21水平低于对照组(P<0.05),两组KL-6比较差异无统计学意义(P>0.05)。试验组CCL18、miR-21治疗前后差值(治疗后-治疗前)小于对照组(P<0.05),两组KL-6差值比较差异无统计学意义(P>0.05)。对照组治疗前后血清KL-6、CCL18、miR-21差值与FVC%pred、DLco%pred、FEV1%pred差值呈显著负相关(P<0.05)。结论吡非尼酮可延缓IPF患者肺功能的下降,降低患者血清miR-21水平,抑制CCL18升高,检测miR-21、CCL18表达可为吡非尼酮的疗效判定提供依据。     

吡非尼酮治疗特发性肺纤维化的有效性与安全性系统评价

目的系统评价吡非尼酮治疗特发性肺纤维化(IPF)的有效性与安全性。方法计算机检索Medline,EMBase,The Cochrane Library,中国期刊全文数据库、万方数据库和中文科技期刊全文数据库,检索吡非尼酮治疗IPF的随机对照试验(RCT),检索时限为自建库至2019年1月,由2位研究人员独立进行文献筛选、数据提取和研究偏倚风险评价,使用RevMan 5. 3软件进行Meta分析。结果共纳入6个RCT研究。Meta分析结果显示,随访24周时,吡非尼酮组患者用力肺活量(FVC)提高程度优于对照组[MD=0. 10,95%CI(0. 04,0. 15),P=0. 000 7],随访48周时与对照组比较无显著差异[MD=0. 08,95%CI(0. 00,0. 17),P=0. 05];第1秒用力呼气容积(FVC1)改善程度在24周时纳入文献仅有1篇,故作描述性分析,在48周时两组比较无显著差异[MD=0. 05,95%CI(-0. 08,0. 18,P=0. 43];吡非尼酮组在24周[MD=0. 56,95%CI(-0. 02,1. 14),P=0. 06]或48周[MD=0. 71,95%CI(0. 01,1. 42),P=0. 76]时的一氧化碳弥散量(DLCO)与对照组相比均无显著差异;吡非尼酮组FVC较基线下降≥10%例数[MD=0. 63,95%CI(0. 47,0. 85),P=0. 002]、6 min步行距离(6MWD)较基线缩短≥50 m例数[MD=0. 73,95%CI(0. 63,0. 85),P <0. 000 1]均优于对照组;两组全因死亡率相比无显著差异[MD=0. 71,95%CI(0. 47,1. 05),P=0. 09];两组不良反应发生率相比无显著差异[MD=0. 06,95%CI(-0. 02,0. 14),P=0. 13]。结论吡非尼酮治疗IPF疗效较好,且安全性较高。     

吡非尼酮治疗特发性肺纤维化疗效与安全性的系统评价

目的系统评价吡非尼酮治疗特发性肺纤维化的疗效与安全性,为临床提供循证参考和用药建议。方法检索中国期刊全文数据库、万方数据库和中国生物医学文献数据库2020年4月30日前发表的吡非尼酮在中国治疗特发性肺纤维化的临床随机对照研究,采用Cochrane偏倚评价量表进行质量评价,对主要研究指标进行汇总分析。结果共纳入6个临床随机对照研究,涉及393例患者。与对照组患者相比,观察组患者在接受吡非尼酮治疗后,1秒用力呼气容积(FEV1)、用力肺活量(FVC)、FEV1/FVC、一氧化碳弥散量(DLco)、动脉氧分压(PaO2)、最大呼气流量(PEF)等均有改善,差异有统计学意义(P<0.05);与治疗前相比,观察组患者在接受吡非尼酮治疗后,上述有效性指标均有改善,差异有统计学意义(P<0.05)。观察组不良反应发生率为8.90%(35/393),主要为胃肠道反应、过敏反应、转氨酶升高,程度多为轻至中度,患者均可耐受。结论吡非尼酮在中国治疗特发性肺纤维化患者的疗效和安全性良好。     

吡非尼酮的合成

2-氨基-5-甲基吡啶经重氮化、水解得到5-甲基-2（1H）-吡啶酮,再与碘苯在CuCl催化下进行N-芳基化反应得到吡非尼酮,总收率50%.     

A safety evaluation of pirfenidone for the treatment of idiopathic pulmonary fibrosis

ABSTRACT

Introduction: Pirfenidone is a novel oral anti-fibrotic agent approved for the treatment of idiopathic pulmonary fibrosis (IPF). Since IPF is a chronic and progressive disease most commonly encountered in an older population, therapeutic options should be not only effective, but also free from drug interactions and as safe and tolerable as possible.

Areas covered: Comprehensive data from randomized controlled trials, meta-analyses, safety studies, and post-marketing data are available to assess the efficacy and safety of pirfenidone in the treatment of IPF. Information on efficacy, adverse events, drug tolerability and discontinuation rates both in clinical trials and real-world clinical experiences are reported.

Expert opinion: Pirfenidone has an abundance of data supporting its use in mild-to-moderate IPF. Observational evidence suggests a similar efficacy in severe IPF. In clinical trials, observational studies and real-world use, adverse events are frequent, though generally mild and well tolerated, especially with adequate patient education. Preventative strategies, along with timely and appropriate management of adverse events are critical in improving patient compliance, thereby ensuring the benefits of long-term treatment with pirfenidone.     

Effects and mechanisms of pirfenidone,prednisone and acetylcysteine on pulmonary fibrosis in rat idiopathic pulmonary fibrosis models

Context: Previous studies have reported that caveolin-1 (Cav-1) is associated with lung fibrosis. However, the role of Cav-1 expression in pirfenidone-treated idiopathic pulmonary fibrosis (IPF) is unknown.

Objective: This study investigated Cav-1 expression in pirfenidone-treated IPF, and compared the effects of pirfenidone with acetylcysteine and prednisone on IPF.

Materials and methods: Rat IPF model was established by endotracheal injection of 5?mg/kg bleomycin A5 into the specific pathogen-free Wistar male rats. Pirfenidone (P, 100?mg/kg once daily), prednisone (H, 5?mg/kg once daily) and acetylcysteine (N, 4?mg/kg 3 times per day) were used to treat the rat model by intragastric administration for 45 consecutive days, respectively. The normal rats without IPF were used as the controls. After 15, 30 and 45 days of drug treatment, lung histopathology was assessed. The expression of Cav-1 was determined using real-time quantitative PCR and Western blot; the expression of tumour necrosis factor-α (TNF-α), transforming growth factor-β1 (TGF-β1) and platelet-derived growth factor (PDGF) was determined by enzyme-linked immunosorbent assay.

Results: After 15, 30 and 45 days of drug treatment, comparison of the three drug-treated groups with the model group showed significantly lower (p?p?p?r?=??0.506, p?r?=?-0.676, p?r?=??0.590, p?r?=??0.530, p?r?=??0.553, p?Discussion and conclusion: Pirfenidone, prednisone and acetylcysteine can inhibit airsacculitis and pulmonary fibrosis in rat IPF models, which may be related with enhanced caveolin-1, reduced TNF-α, TGF-β1, PDGF.     

吡非尼酮联合乙酰半胱氨酸治疗特发性肺间质纤维化的疗效观察

目的观察吡非尼酮胶囊联合乙酰半胱氨酸颗粒治疗特发性肺间质纤维化的临床疗效。方法选取2016年1月—2018年3月成都市中西医结合医院收治的特发性肺间质纤维化患者67例为研究对象,根据随机数字表法随机分为对照组(32例)和治疗组(35例)。对照组饭后口服乙酰半胱氨酸颗粒,0.2 g/次,3次/d。治疗组在对照组的基础上口服吡非尼酮胶囊,初始用量200 mg/次,两周后调整为400 mg/次,3周后调整为600 mg/次,3次/d。两组均持续治疗4个月。观察两组临床疗效,比较治疗前后高分辨率CT(HRCT)改变阳性率,肺功能指标和肺纤维化指标。结果治疗后,对照组和治疗组的总有效率分别为71.88%、88.57%,两组比较差异具有统计学意义(P0.05)。治疗后,对照组网格影阳性率显著降低,治疗组网格影、斑片影阳性率均显著降低,同组治疗前后比较差异具有统计学意义(P0.05);且治疗组网格影、斑片影阳性率显著低于对照组,两组比较差异具有统计学意义(P0.05)。治疗后,两组患者最大呼气流量(PEF)、用力肺活量(FVC)、一秒用力呼气容积(FEV1)水平均显著升高,同组治疗前后比较差异具有统计学意义(P0.05),且治疗后治疗组肺功能指标显著高于对照组,两组比较差异具有统计学意义(P0.05)。治疗后,两组患者Ⅲ型胶原(Ⅲ-C)、IV型胶原(Ⅳ-C)、透明质酸(HA)水平均显著降低,同组治疗前后比较差异具有统计学意义(P0.05);且治疗组肺功能指标显著低于对照组,两组比较差异具有统计学意义(P0.05)。结论吡非尼酮胶囊联合乙酰半胱氨酸颗粒治疗特发性肺间质纤维化疗效显著,能明显改善肺功能和肺纤维化指标,安全性高,具有一定的临床推广应用价值。     

特发性肺纤维化药物治疗的研究进展

特发性肺纤维化(IPF)是一种慢性、渐进性的细胞间质病,病因和发病机制尚不明确。2种或2种以上药物联合使用可减少药物使用剂量,减轻不良反应,增加治疗靶通路,是目前IPF研究的关注热点。吡非尼酮和尼达尼布是FDA首次批准治疗IPF的多靶点治疗药物,其联合用药正处于临床试验阶段。本文对IPF的多靶点治疗进展进行综述,进一步讨论联合用药的利弊,浅谈中医在治疗IPF中的优势。     

Pharmacokinetic evaluation of tissue distribution of pirfenidone and its metabolites for idiopathic pulmonary fibrosis therapy

Pirfenidone is the first and only clinically used anti‐fibrotic drug for the treatment of idiopathic pulmonary fibrosis (IPF). It was reported previously that pirfenidone metabolites (5‐hydroxypirfenidone and 5‐carboxypirfenidone) also have anti‐fibrotic effects. The present study evaluated the distribution of pirfenidone and its metabolites in the lung, liver and kidney tissues in rats. The time course for the different concentrations of pirfenidone, 5‐hydroxypirfenidone and 5‐carboxypirfenidone in the lung tissue following oral administration (30 mg/kg) to rats was lower than that in plasma, and the area under the drug concentration–time curve (AUC) ratios of lung/plasma for pirfenidone, 5‐hydroxypirfenidone and 5‐carboxypirfenidone were 0.52, 0.40 and 0.61, respectively. In in vitro transport experiments, the basolateral‐to‐apical transport of pirfenidone and its metabolites through the model of lung epithelial cell (Calu‐3) monolayers was not significantly different from their apical‐to‐basolateral transport. In binding experiments, the binding rate of these drugs to the lung tissue was lower than that to the plasma protein. These findings suggest that the low distribution of pirfenidone and its metabolites in the lungs was based on their low affinities with lung tissue and not the transport characteristics of lung epithelial cells. On the other hand, the AUC ratios of liver/plasma for pirfenidone and 5‐carboxypirfenidone were 2.3 and 6.5 and the AUC ratios of kidney/plasma were 1.5 and 20, respectively. The binding rates to the liver and kidney tissues were higher than those to the plasma protein. These results suggest that high concentrations of these drugs were found in the liver and kidney tissues. Copyright © 2014 John Wiley & Sons, Ltd.     

Pirfenidone: in idiopathic pulmonary fibrosis

Pirfenidone is an orally administered pyridine that has orphan designation for the treatment of mild to moderate idiopathic pulmonary fibrosis (IPF) in the EU. Pirfenidone 2403?mg/day for 72 weeks administered to patients with IPF was associated with a significantly lower mean decline in the percent predicted forced vital capacity than placebo (primary endpoint) according to data from one of two randomized, double-blind, multinational trials (studies 004 and 006 [also known as the CAPACITY trials]), and data from a pooled analysis of both trials. In another randomized, double-blind, multicentre Japanese trial, the adjusted mean in the change in vital capacity from baseline to week 52 was significantly lower in patients with IPF who received pirfenidone 1800?mg/day (considered to be comparable to the 2403?mg/day dose in studies 004 and 006 on a weight-normalized basis) than in those who received placebo (primary endpoint). Pirfenidone had an acceptable tolerability profile in clinical trials, with most adverse events being mild to moderate in severity.     

Bosentan for idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a debilitating, fatal, chronic fibrosing lung disease with no known effective therapy. Endothelin-1 may underlie the pathogenesis of lung fibrosis, therefore it was hypothesized that the oral dual endothelin receptor antagonist bosentan may have efficacy for the treatment of IPF. The BUILD-1 study evaluated the efficacy, safety and tolerability of bosentan in patients with IPF. Bosentan was associated with a trend toward delayed time to disease progression or death and improvement in quality-of-life, both of which were more pronounced in patients with a biopsy-confirmed IPF diagnosis. These observations are being investigated in the ongoing BUILD-3 trial.     

Interferon-gamma 1b: impact of new indications (idiopathic pulmonary fibrosis)

Idiopathic pulmonary fibrosis (IPF) is a relentlessly progressive disease with inadequate response to conventional treatment with corticosteroids and/or immunosuppressive agents in most patients. Interferon-gamma (IFN-gamma), an antifibrotic agent, has been proposed as a novel therapeutic approach. Several investigators have shown a relative decrease in systemic and pulmonary IFN-gamma activity in patients with IPF. Experimental evidence from animal and human studies also suggests that IFN-gamma administration may ameliorate lung fibrosis. Clinical experience is, however, limited to a single clinical trial that showed objective functional improvement in a small number of patients treated with IFN-gamma and low-dose corticosteroids. Further research is needed to characterise the efficacy, safety and optimum route of administration of this agent before it can be recommended for use in routine clinical practice.     

特发性肺纤维化的组学研究进展

特发性肺纤维化(IPF)是一种原因不明的以呼吸困难和肺功能进行性恶化为特征的慢性肺纤维化性疾病,预后不良。IPF的病因尚未完全阐明,与老化、遗传、环境暴露、氧化应激和微生物-宿主防御反应有关。基因突变、转录和翻译异常、表观基因调控改变及代谢紊乱均可能影响疾病的发生和发展。近年来,采用高通量技术的组学研究从多维度揭示了IPF的发病机制,为寻找生物标志物和治疗靶点提供了新视角。本文综述了应用基因组学、转录组学、表观基因组学、蛋白质组学和代谢组学技术阐明IPF发病机制、寻找生物标志物、提供治疗靶点的最新研究进展。