罗氟司特:慢性阻塞性肺病治疗研究进展

慢性阻塞性肺病(COPD)目前居全球死亡原因的第4位,在我国,COPD同样是严重危害人民身体健康的重要慢性呼吸系统疾病。慢性阻塞性肺病的典型病理变化包括,气道慢性炎症以及肺气肿,慢性炎症导致气道壁损伤和修复过程反复循环发生,进一步导致气道壁结构重塑[1]。现有的COPD治疗主要是在急性加重期控制病情恶化,稳定期延缓疾病的进展。目前的药物治疗包括吸入支气管扩     

罗氟司特治疗慢性阻塞性肺病的研究进展

慢性阻塞性肺病是最常见的呼吸系统慢性疾病之一,目前尚缺乏有效的干预治疗手段。罗氟司特是一种选择性磷酸二酯酶4抑制剂,是目前进入临床研究的新型治疗慢性阻塞性肺病药物。本文概述了罗氟司特在慢性阻塞性肺病中的基础及临床研究。     

治疗慢性阻塞性肺疾病新药罗氟司特

慢性阻塞性肺疾病(COPD)是以不完全可逆的气流受限为特征的慢性肺部疾病,临床上常表现为反复发作的咳嗽、咳痰、呼吸困难等症状,通常呈现出进行性进展的特点,包括了绝大部分慢性支气管炎和肺气肿。随着疾病发展,导致气道重构,最终发     

罗氟司特可用于重度至极重度亚裔慢性阻塞性肺病患者

罗氟司特（roflumilast）是可用于治疗慢性阻塞性肺病（COPD）的唯一可口服的磷酸二酯酶4抑制剂。为了评价该药在以华人为主的亚裔COPD患者中的有效性和安全性，钟南山院士及其领导的研究团队进行了一项安慰剂对照、双盲、平行、多中心的Ⅲ期临床研究，发现罗氟司特能明显改善重度至极重度亚裔COPD患者的肺功能，并可被良好地耐受，可成为该类患者理想的治疗选择。研究结果在线发表于近期的《胸》杂志（CHEST）上。     

磷酸二酯酶-4抑制剂罗氟司特的药理与临床研究新进展

罗氟司特为磷酸二酯酶-4(PDE4)抑制剂,对肺部系统具有高效的抗炎活性。动物和临床试验结果显示,其对慢性阻塞性肺病(COPD)具有很好的疗效,且不良反应较少。罗氟司特可减轻伴慢性支气管炎和有加重史患者严重COPD恶化的风险,更多的研究有待进一步评价。现对罗氟司特治疗COPD的作用机制、药效学、药动学、临床评价和安全性做一综述。     

罗氟司特合成路线图解

罗氟司特（roflumilast,1）化学名为N-（3,5-二氯吡啶4-基）-3-环丙甲氧基4-二氟甲氧基苯甲酰胺,是由德国安达（Altana）公司研发,瑞士奈科明公司（Nycomed Pharma GmbH）完成Ⅲ期临床试验的磷酸二酯酶4（PDFA）抑制剂,于2010年7月在欧洲获得批准,随后在德国、英国和西班牙上市,商品名为Daxas。2011年3月又获得美国FDA批准,在美国上市。     

罗氟司特新合成工艺的研究

目的：优化罗氟司特的合成工艺。方法以3,4－二羟基苯甲醛为起始原料,经 Boc酸酐保护、醚化、脱保护、二氟一氯甲烷醚化、氧化、酰胺化反应得到目标物罗氟司特。结果与结论目标化合物的结构经MS、1 H－NMR等确证。该方法原料易得,反应条件温和,危险性小,后处理简单,收率较高,有利于工业放大生产,总收率为36．3％。     

罗氟司特的药动学和安全性研究进展

摘要 罗氟司特是新的选择性磷酸二酯酶-4（PDE-4）抑制药，近年已分别被欧盟和美国批准上市。该药是治疗慢性阻塞性肺疾病（COPD）的第一个新型药效类别药物，可望能延缓COPD的进展速度。主要用于辅助支气管扩张药维持治疗重度COPD。对其体内药动学及特殊人群、合并用药的影响进行综述，并总结其现有的安全性研究结果。     

罗氟司特治疗慢性阻塞性肺疾病的研究进展

目的:为临床合理使用罗氟司特治疗慢性阻塞性肺疾病(COPD)提供参考。方法:查阅近年来国内外相关文献,对罗氟司特治疗COPD的药效学、药动学、药物相互作用、临床有效性和安全性等方面的进展进行归纳和总结。结果:罗氟司特具有强大的抗炎作用和中等程度的支气管扩张作用,可以有效改善肺功能,显著降低中/重度COPD患者的平均恶化率,预防急性加重;其活性代谢产物N-氧化物(RNO)在体内可以逆转糖皮质激素依赖,单用或与糖皮质激素联用均能发挥强大的抗炎效应,且不增加COPD患者严重不良心血管事件的发生率。结论:在充分评估患者严重程度和急性加重风险的基础上,罗氟司特联合支气管扩张剂治疗能使患者获益,但尚需进一步开展国际性、大规模、多中心综合临床研究。     

慢性阻塞性肺病治疗新药罗氟司特

2010年7月,Nycomed公司开发的罗氟司特（roflumilast/Daxas）获得欧盟委员会批准,用于辅助支气管扩张剂维持治疗重度慢性阻塞性肺病患者。罗氟司特为磷酸二酯酶-4抑制剂,可以口服用药,是全球十数年来批准用于慢性阻塞性肺病治疗的第一个新型药效类别药物。     

Roflumilast Altana Pharma

Roflumilast is a specific PDE4 inhibitor being developed by Altana Pharma (formerly known as Byk Gulden) for the potential treatment of asthma and chronic obstructive pulmonary disease [312928].     

Roflumilast for COPD

Patients with chronic obstructive pulmonary disease (COPD) and chronic bronchitis have a reduction in lung function and a higher risk of suffering exacerbations, which result in a deterioration in their quality of life, an accelerated progression of the disease and a greater mortality. COPD is currently considered an inflammatory disease involving airways and lung parenchyma. The symptoms that are typical of chronic bronchitis (chronic cough and sputum production) are markers of underlying inflammation, characteristic of COPD. Roflumilast, an antiinflammatory drug that belongs to the new therapeutic class of phosphodiesterase PDE4 inhibitors, is the first drug developed for the treatment of a specific phenotype of COPD (COPD associated with chronic bronchitis). The results of clinical trials indicated that in patients with COPD associated with chronic bronchitis and a history of exacerbations, roflumilast improves lung function and reduces the frequency of exacerbations that require medical interventions. This effect remained when it was added to a regular treatment with long-acting bronchodilators such as tiotropium or long-acting β?-adrenoceptor agonists (LABAs) such as salmeterol. Roflumilast has been shown to be generally well tolerated. Side effects were typically mild to moderate and included diarrhea, nausea, weight decrease and headache. Gastrointestinal side effects mainly occurred within the first weeks of therapy and mostly resolved on continued treatment.     

HPLC法测定罗氟司特有关物质方法研究

目的建立测定罗氟司特有关物质的高效液相色谱法。方法采用高效液相色谱法：色谱柱为C18柱,流动相A为0．1％的磷酸溶液,流动相B为乙腈,梯度洗脱,检测波长为210nm,流速为1．0mL／min。结果罗氟司特溶液浓度在0．00025～0．005mg／mL范围内．溶液浓度与峰面积线性关系良好（r=0．9999）。各反应物料、副产物及降解杂质溶液浓度均在0．00005～0．001mg／mL范围内,溶液浓度与峰面积线性关系良好（r≥0．9995）,各杂质回收率为89．2％～104．1％,方法准确度良好。结论本方法操作简便,结果可靠．重复性好,可以用于罗氟司特有关物质的检测。     

HPLC法测定罗氟司特原料药的含量

目的：建立高效液相色谱法测定罗氟司特原料药含量的分析方法。方法选用Agilent C18色谱柱（250mm ＆#215;4.6mm,5μm）;以0.005mol · L ^-1甲酸铵溶液（pH 3.5）-乙腈（40∶60,v/v）为流动相;柱温30℃;流速：1.0mL· min ^-1;检测波长：250nm。结果罗氟司特的线性关系良好（25.05～100.2μg· mL^ -1,r＝0.9998）;平均加样回收率为100.0％,RSD＝1.0％（n＝9）;检测限与定量限分别为1.7ng和5.0ng;重复性、中间精密度均符合要求。结论本方法专属性强,简捷,准确,可用于罗氟司特原料药的含量测定。     

Roflumilast: a selective phosphodiesterase 4 inhibitor

Roflumilast is a selective phosphodiesterase (PDE) 4 inhibitor with a range of anti-inflammatory properties and potential for treatment of inflammatory disease. The therapeutic effects of roflumilast are thought to be mediated via increased levels of cellular 3',5'-cyclic adenosine monophosphate (cAMP) and include inhibition of microvascular leakage, inhibition of trafficking, release of cytokines and chemokines from inflammatory cells, and bronchodilation. The anti-inflammatory and bronchodilator properties of roflumilast have resulted in clinical studies to investigate the effects of roflumilast in inflammatory airway diseases such as asthma and chronic obstructive pulmonary disease. In asthma, roflumilast taken as a once-daily oral dose of 500 ug has been shown to improve clinical symptoms and airway function, reduce exercise-induced asthma and decrease bronchial airway hyperresponsiveness. In chronic obstructive pulmonary disease, roflumilast taken as a once-daily oral dose of 500 ug has been shown to reduce the frequency of exacerbations with small effects on improving lung function. Side effects of roflumilast appear to be mild and short lasting. It is likely that this new class of selective PDE4 inhibitor may provide a therapeutic option for patients with inflammatory airway disease.     

Roflumilast for the treatment of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a progressive disease of the airways that is triggered primarily by smoking. It manifests clinically with dyspnea, cough and sputum production, all of which become aggravated with disease progression. The only intervention that can halt the decline in lung function in COPD is smoking cessation--other interventions and therapeutic treatments can only slow down the progression of the disease. Pharmacologic treatment of stable COPD consists primarily of bronchodilators, which are used for relieving symptoms and reducing lung function decline, and corticosteroids, which are used for minimizing the associated inflammation. Methylxanthines are non-selective phosphodiesterase (PDE) inhibitors with bronchodilatory and anti-inflammatory effects; however, their use in COPD and other respiratory conditions is limited by their narrow therapeutic index and poor safety profile. Cilomilast and roflumilast are selective PDE4 inhibitors that are currently in pre-registration and phase III clinical trials, respectively, for the treatment of COPD (cilomilast and roflumilast) and asthma (roflumilast).     

影响罗氟司特片溶出度的关键工艺参数

目的 考察影响罗氟司特片溶出度的关键工艺参数.方法 采用正交试验及单因素法考察不同因素对罗氟司特片溶出度的影响.结果 在诸多因素中,原料药的粒径对罗氟司特片溶出度的影响最为关键.结论 原料药的粒径是影响罗氟司特片溶出度的关键工艺参数,需控制粒径D90＜ 10 μm.     

HPLC法测定罗氟司特片中的有关物质

目的 建立高效液相色谱法测定罗氟司特片的有关物质.方法 采用Zorbax SB-C18(4.6 mm×150 mm,5 μm)色谱柱,0.005 mol·L-1磷酸二氢钾溶液-乙腈为流动相,梯度洗脱,流速为1.0 mL·min-1,检测波长为250 nm.结果 罗氟司特及各杂质在相应的浓度范围内,峰面积与浓度均呈良好的线性关系,相关系数均大于0.999.结论 建立的方法快速、灵敏、准确,适用于罗氟司特片中的有关物质测定.