Aclidinium bromide/formoterol fumarate fixed-dose combination for the treatment of chronic obstructive pulmonary disease

Introduction: Hospital-acquired pneumonia is the most common life-threatening hospital-acquired infection, and the majority of cases are associated with mechanical ventilation. Once pneumonia develops, the appropriateness of the initial antibiotic regimen is a vital determinant of outcome. The slow rate of development of newer antimicrobials has led to the rediscovery of the 'old' and 'forgotten' antibiotic ‘Colistin’, and it is increasingly being used as salvage therapy in patients with multidrug-resistant gram-negative bacteria infections.

Areas covered: This article covers medical literature published in any language since 1990 until November 2011, on 'hospital pneumonia', identified using PubMed, MEDLINE and clinicaltrial.gov. The search terms used were ‘ventilator associated pneumonia’, ‘management’ and ‘new antibiotics’.

Expert opinion: Many controversies still remain in the management of hospital-acquired pneumonia. A continuous evaluation of the antimicrobial therapeutic options, along with their pharmacodynamic and pharmacokinetic profiles, is mandatory to optimize therapy and reduce hospital pneumonia-related mortality.     

Aclidinium bromide plus formoterol for the treatment of chronic obstructive pulmonary disease

Introduction: Drugs that target dynamic hyperinflation such as long-acting β-2 agonists and long-acting antimuscarinic antagonists form a cornerstone of chronic obstructive pulmonary disease (COPD) management. The idea of combining these two medications in a single formulation, which may potentially improve patient compliance, is novel and attractive.

Areas covered: The pharmacologic profiles of aclidinium bromide and formoterol fumarate are discussed. However, studies to define drug interactions and alterations in the pharmacodynamics and pharmacokinetics of the fixed dose combination (FDC) of aclidinium bromide/formoterol fumarate in large populations remain unpublished. Results of Phase II and two Phase III pivotal trials, ACLIFORM/COPD and AUGMENT COPD, evaluating the FDC are discussed.

Expert opinion: Initial data for the aclidinium/formoterol inhaler appears to be promising for impacting the lung function. To define if this benefit translates into improved long-term outcomes of decreased exacerbation frequency, improved quality of life and decreased disease-specific mortality are important. The introduction of this combination will likely have a significant impact on the prescribing habits of physicians across the world.     

Aclidinium bromide for the treatment of chronic obstructive pulmonary disease

Introduction: Although there are some challenges with current therapies, the growing evidence that tiotropium bromide is important in the maintenance treatment of chronic obstructive pulmonary disease (COPD) has led to enthusiastic investigation in search of novel muscarinic antagonists which share some of the beneficial characteristics of tiotropium and perhaps improve upon less desirable ones.

Areas covered: Aclidinium bromide is a new muscarinic antagonist that has been developed to relieve symptoms in patients with COPD. Preclinical data showed that it has an intriguing pharmacodynamic and pharmacokinetic profile. Aclidinium bromide was initially assessed as a once-daily bronchodilator. Subsequently, it has been evaluated as a twice-daily agent to increase the size of the clinical effect. Pivotal Phase III trials have documented that aclidinium bromide 400 μg twice-daily shows clinically meaningful effects in lung function and other important supportive outcomes, such as health-related quality of life, dyspnea and night-time/early morning symptoms, and is safe.

Expert opinion: Aclidinium bromide can to be used as an alternative to tiotropium or a long-acting β₂-agonist. It is likely that the device used to deliver aclidinium, Genuair inhaler, a novel, multidose and a breath-actuated dry powder inhaler (DPI), will be important for the possible success of this drug. However, additional Phase III trials to assess advantages over tiotropium bromide and long-acting β₂-agonists are required to allow the place of aclidinium bromide to be fully elucidated.     

布地奈德福莫特罗吸入粉雾剂治疗支气管哮喘-慢性阻塞性肺疾病重叠综合征的效果分析

目的分析布地奈德福莫特罗吸入粉雾剂治疗支气管哮喘-慢性阻塞性肺疾病重叠综合征的临床效果。方法70例支气管哮喘-慢性阻塞性肺疾病重叠综合征患者,采用随机数字表法分为对照组和观察组,每组35例。对照组患者给予噻托溴铵粉雾剂治疗,观察组采取布地奈德福莫特罗吸入粉雾剂治疗。比较两组症状消失时间、临床疗效、不良反应发生情况及治疗前后第1秒用力呼气容积、用力肺活量、呼出气一氧化氮水平。结果观察组哮喘症状消失时间(5.68±1.01)d、咳嗽消失时间(7.21±2.51)d及肺啰音消失时间(6.45±1.21)d均短于对照组的(7.56±2.21)、(9.21±3.18)、(9.21±2.91)d,差异具有统计学意义(P<0.05)。治疗后,两组第1秒用力呼气容积、用力肺活量、呼出气一氧化氮均较治疗前改善,且观察组第1秒用力呼气容积、用力肺活量、呼出气一氧化氮改善程度显著大于对照组,差异有统计学意义(P<0.05)。观察组治疗总有效率为94.29%,高于对照组的74.29%,差异有统计学意义(P<0.05)。两组治疗过程中未发生不良反应。结论采用布地奈德福莫特罗吸入粉雾剂治疗支气管哮喘-慢性阻塞性肺疾病重叠综合征,其临床效果确切,可有效改善患者的肺功能,加速各种症状消失,缩短治疗时间。     

噻托溴铵联合福莫特罗吸入治疗慢性阻塞性肺疾病

目的观察噻托溴铵联合福莫特罗吸入治疗慢性阻塞性肺疾病(COPD)的效果及安全性。方法46例COPD患者随机分为2组,对照组23例,常规给予福莫特罗治疗;治疗组23例,噻托溴铵联合福莫特罗吸入治疗,疗程4周。观察治疗前、后的临床症状及肺功能变化。结果治疗组对FEV1的改善显著高于对照组(P<0.05)。治疗组减轻日常症状的效果优于对照组。各组均未出现明显不良反应。结论吸入噻托溴铵与福莫特罗联合治疗COPD,疗效优于单药治疗。     

噻托溴铵治疗慢性阻塞性肺病的进展

噻托溴铵（tiotropium bromide）是一个新型的治疗慢性阻塞性肺病（COPD）的吸入型支气管扩张药物,通过与M3受体结合阻滞乙酰胆碱的作用从而缓解支气管平滑肌的痉挛,吸入一次疗效持续24h以上.临床试验结果表明该药对中重度COPD具有良好疗效,在改善呼吸困难、生活质量、减少住院次数方面优于沙美特罗,噻托溴铵qd对支气管的舒张作用明显好于溴化异丙托品qid和沙美特罗bid,且能改善通气功能和肺容积,耐受性和安全性较好.主要不良反应为口干.     

Aclidinium bromide inhalation powder for the long-term,maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease including chronic bronchitis and emphysema

Aclidinium is a twice-daily long-acting muscarinic receptor antagonist (LAMA) with an interesting pharmacological profile. Recent evidence indicates that this LAMA, in addition to causing a significant improvement in lung function and other important supportive outcomes, such as health related quality of life, dyspnea and nighttime/early morning symptoms in patients suffering from COPD, is also able to significantly reduce the rate of exacerbations of any severity, is extremely effective in controlling the COPD symptoms, is able to reduce lung hyperinflation, and has an excellent cardiovascular safety profile. Consequently, aclidinium should be considered a first-line approach at least for the symptomatic treatment of COPD although there are still few head-to-head studies comparing this LAMA with other bronchodilators. In any case, aclidinium can be taken into account in the treatment of different COPD phenotypes (emphysema, chronic bronchitis, exacerbators and patients with overlap COPD asthma).     

Muscarinic receptor antagonists for the treatment of chronic obstructive pulmonary disease

Introduction: Long-acting muscarinic receptor antagonists (LAMAs) are central to the treatment of chronic obstructive pulmonary disease (COPD) because of the important role of the cholinergic system in the pathophysiology of this disorder.

Areas covered: LAMAs show clinically meaningful effects in lung function and other important supportive outcomes, such as exacerbations, health-related quality of life, dyspnea, rescue medication use and nighttime/early morning symptoms, and are safe. Muscarinic receptor antagonists could exert other useful actions such as the anti-inflammatory, anti-remodeling, mucus-modifying, and anti-cough effects. Concerns have been raised about possible associations of muscarinic receptor antagonists with cardiovascular morbidity and mortality. Muscarinic receptor antagonists can be combined with long-acting β₂-agonists (LABAs), inhaled corticosteroids (ICSs) and LABA + ICS. There are number of LAMAs that are being identified but only few have reached the clinical development. Fixed-dose combination formulations of both novel and established LAMAs with LABAs are being developed.

Expert opinion: There are important questions concerning the use of LAMAs in the treatment of patients suffering from stable COPD that need conclusive answers.     

Umeclidinium bromide + vilanterol for the treatment of chronic obstructive pulmonary disease

A solid scientific rationale and an increasing body of clinical evidence fully support the use of an antimuscarinic agent combined with a β-agonist in chronic obstructive pulmonary disease. In this article, we focus on the development of an inhaled fixed dose combination (FDC) of two 24-h bronchodilators, umeclidinium bromide and vilanterol (UMEC/VI) (ANORO). Several pivotal clinical trials have documented the impact of this combination on lung function and other outcome measures such as quality of life, dyspnea, rescue medication use and exercise capacity, with no clinically meaningful treatment-related changes in vital signs or clinical laboratory parameters. These results allow us to predict that UMEC/VI will have a role in the maintenance treatment of chronic obstructive pulmonary disease. It remains to determine its impact on exacerbations. In any case, trials comparing UMEC/VI with other dual bronchodilator FDCs, and also with inhaled corticosteroid/long-acting β-agonist FDCs, are needed to assess the advantages, if any, of UMEC/VI FDC over other therapies.     

Co-deposition of a triple therapy drug formulation for the treatment of chronic obstructive pulmonary disease using solution-based pressurised metered dose inhalers

Objectives The formulation of multi‐drug pressurised metered dose inhalers (pMDIs) opens up exciting therapeutic opportunities for the treatment of asthma and chronic obstructive pulmonary disease (COPD). We have investigated the formulation of a solution‐based triple therapy pMDI containing ipratropium, formoterol, budesonide and ethanol as co‐solvent. Methods This system was characterised for in‐vitro performance and compared with marketed pMDIs (Atrovent and Symbicort). Key findings No significant difference was found in the stage deposition of each drug from the triple therapy formulation, suggesting that the droplets contained a fixed ratio of the three components used. Stage deposition of formoterol and budesonide from the suspension‐based marketed Symbicort were significantly different, suggesting that the two drugs were deposited as separate entities. Calculation of the mass median aerodynamic diameter (MMAD) of each formulation suggested Atrovent (ipratropium, MMAD = 0.9 ± 0.0 µm) to have a small particle size, similar to the triple therapy formulation. Atrovent, like the triple therapy formulation was solution based and it contained ethanol as a co‐solvent (triple therapy formulation, MMAD = 1.3 ± 0.0 µm). Conclusions This study demonstrated the feasibility of formulating a solution‐based pMDI containing a triple therapy with identical deposition pattern for the treatment of several respiratory diseases where multi‐drug cell targeting is required.     

Olodaterol + tiotropium bromide for the treatment of chronic obstructive pulmonary disease

A solid scientific rationale and an increasing body of clinical evidence for combining a β₂-agonist with an antimuscarinic agent in COPD fully support the opinion that patients not controlled by a single bronchodilator should be given two bronchodilators with different mechanisms of action. Tiotropium is an established choice for the management of patients with stable COPD, and olodaterol is a new effective and safe once-daily long-acting β2-agonist. The parallel bronchodilating modes of action of olodaterol and tiotropium make them an attractive combination in COPD. The large ongoing TOviTO Phase III trial program is documenting the efficacy and safety of olodaterol/tiotropium fixed dose combination delivered via the Respimat Soft Mist Inhaler as maintenance therapy in patients with moderate to very severe COPD. However, we must still know whether this fixed-dose combination will affect exacerbations and hospitalizations, and ultimately death, and also the precise estimates of its relative cardiovascular safety.     

Investigational beta-2 adrenergic agonists for the treatment of chronic obstructive pulmonary disease

Introduction: Long-acting bronchodilators are pivotal in the therapeutic management of COPD patients with moderate-to-severe airflow obstruction. New ultra-long-acting β2-agnoists (ultra-LABAs) have been developed, some of which have been licensed for use as monotherapy and/or in combination with other bronchodilators or inhaled corticosteroids, for use in COPD patients with persistent symptoms and worsening airflow limitation. These new agents are faster in onset and have a prolonged duration of action, with a similar safety profile to the traditional twice-daily bronchodilators which may have an impact on patient concordance.

Areas covered: A number of these ultra-LABAs are still under development and bi-functional hybrid molecules containing regions functioning as β2-agonists, and as muscarinic agonists (MABAs) has been developed. This review summarizes these (excluding the licensed ultra-LABAs) with attention on phase II studies data available to-date on their pharmacological profiles, clinical efficacy and safety, and future perspectives.

Expert opinion: Despite all the new agents’ available, the challenges that persist include any differences in efficacy and safety between the various possible LAMA/LABA combinations, relative advantages of MABAs over fixed-dose LAMA/LABAs, and the impact of these new molecules in terms of long term safety, especially in certain populations in co-morbidities frequently associated with COPD.     

Budesonide and formoterol combination for the treatment of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality throughout the world. Current guidelines recommend the addition of inhaled steroids to bronchodilators, which are central to the symptomatic management of COPD in patients with severe disease. Budesonide/formoterol is a combination inhaled steroid and long-acting bronchodilator delivered by a dry-powder inhaler, approved for use in COPD. Two large, randomised, double-blind, 12-month studies found that combination budesonide/formoterol is more effective than either component alone in addressing many important aspects of the disease, such as pulmonary function, symptoms, use of relief medication, health-related quality of life and exacerbation in patients suffering from severe COPD. This review discusses the pharmacological and clinical properties of the drug.     

The discovery and development of aclidinium bromide for the treatment of chronic obstructive pulmonary disease

Introduction: Bronchodilators, including long-acting muscarinic receptor antagonists (LAMAs), are a mainstay of the pharmacological treatment of chronic obstructive pulmonary disease (COPD). LAMAs act as bronchodilators principally by antagonizing airway smooth muscle cells M₃ muscarinic receptors. Aclidinium bromide is a twice-daily LAMA which was developed to improve on the efficacy and/or safety of previous LAMAs.

Area covered: Herein, the authors present the pharmacotherapeutic role of aclidinium in COPD and point out unmet need in this research area. The following aspects are covered: a) the discovery and medicinal chemistry of aclidinium bromide; b) an overview of the market; c) its mechanism of action; d) its pharmacokinetic/pharmacodynamic profile derived from pre-clinical studies; e) the clinical studies which led to its licensing; f) the evidence from meta-analyses; g) the aclidinium/formoterol fixed dose combination for COPD and h) priorities in this area of research.

Expert opinion: Aclidinium bromide has the pharmacological properties, safety and efficacy profile and inhaler characteristics which makes it a valuable therapeutic option for pharmacological management of patients with COPD. Due to its rapid biotransformation into inactive metabolites, aclidinium is potentially one of the safest LAMAs. Further head-to-head randomized clinical trials are required to define efficacy and safety of aclidinium when compared to once-daily LAMAs. The clinical relevance of airway anti-remodeling effects of aclidinium has to be defined.     

补肺活血胶囊联合布地奈德福莫特罗及噻托溴铵治疗慢性阻塞性肺疾病稳定期的临床效果研究

目的 探索补肺活血胶囊联合布地奈德福莫特罗及噻托溴铵治疗慢性阻塞性肺疾病(COPD)稳定期患者的临床效果研究.方法 回顾性分析87例慢性阻塞性肺疾病稳定期患者临床资料,将所有患者根据治疗方法不同分为对照组(43例)和实验组(44例).对照组采用采取布地奈德福莫特罗联合噻托溴铵治疗,实验组在对照组的基础上结合补肺活血胶囊...     

噻托溴铵联合沙美特罗/氟替卡松治疗慢性阻塞性肺疾病的临床疗效

目的观察噻托溴铵与沙美特罗/氟替卡松联合治疗对慢性阻塞性肺疾病(COPD)的疗效。方法选取我院2013年3月至2015年1月收治的COPD患者40例,随机分为对照组与治疗组,对照组予以单纯沙美特罗/氟替卡松治疗,治疗组予以噻托溴铵与沙美特罗/氟替卡松联合治疗,对比两组治疗前后肺功能指标、动脉血气参数、呼吸困难评分、再入院率、不良反应。结果治疗前两组FEV1、FVC、FEV1%Pred、Pa O2、Pa CO2、呼吸困难评分比较差异均无统计学意义(P>0.05);治疗后治疗组平均FEV1、FVC、FEV1%Pred、Pa O2、Pa CO2、呼吸困难评分分别为(1.36±0.42)L、(2.48±0.48)L、50.12±10.30、(10.17±1.02)k Pa、(5.05±1.22)k Pa、(1.57±0.74)分,均显著优于治疗前,且优于同期对照组(P<0.05)。治疗组出院后病情平均急性加重(1.13±0.16)次,显著低于对照组(P<0.05)。治疗组4例咽部不适、1例窦性心动过速,均未影响正常治疗(P>0.05)。结论噻托溴铵与沙美特罗/氟替卡松联合治疗COPD能持久、稳定、显著地改善动脉血气、肺功能指标及呼吸状况,不良反应不明显,安全有效。     

噻托溴铵联合布地奈德福莫特罗吸入剂治疗稳定期慢性阻塞性肺疾病的临床疗效研究

目的 分析噻托溴铵联合布地奈德福莫特罗吸入剂治疗稳定期慢性阻塞性肺疾病（COPD）的临床疗效。方法 以2014年5月-2016年5月中航工业西安医院收治的稳定期COPD患者80例为研究对象,根据随机数字表法分为观察组和对照组,每组40例。对照组给予布地奈德福莫特罗吸入剂,观察组在此基础上加用噻托溴铵粉吸入剂。两组均连续治疗2个月。比较两组治疗前后的肺功能,包括第1秒用力呼气容积（FEV1）、用力肺活量（FVC）、FEV1占预计值百分比（FEV1%）,并计算FEV1/FVC的值,以及生活质量、血清基质金属蛋白酶-9（MMP-9）和白介素-6（IL-6）水平,用药期间不良反应及治疗后半年内的急性加重发作次数。结果 治疗后,两组的FEV1、FEV1/FVC、FEV1%均较治疗前显著升高,同组治疗前后比较差异有统计学意义（P<0.05）;且观察组的以上指标均显著高于对照组,组间比较差异有统计学意义（P<0.05）。两组治疗后的SGRQ评分、血清MMP-9、IL-6水平均较治疗前显著降低,同组治疗前后比较差异有统计学意义（P<0.05）;且观察组的显著低于对照组,组间比较差异有统计学意义（P<0.05）。两组的总不良反应发生率比较,差异均无统计学意义;观察组发生急性加重1次及以上的人数显著少于对照组,且平均急性加重次数亦显著低于对照组,组间比较差异有统计学意义（P<0.05）。结论 噻托溴铵联合布地奈德福莫特罗吸入剂治疗稳定期慢性阻塞性肺疾病的临床疗效显著,可有效改善患者的肺功能、生活质量,降低急性加重的发生次数,且可显著降低患者血清中MMP-9、IL-6水平。     

布地奈德福莫特罗联合噻托溴铵治疗慢阻肺稳定期的疗效及对生活质量的影响

目的探讨对慢性阻塞性肺疾病(慢阻肺)稳定期患者使用布地奈德福莫特罗联合噻托溴铵治疗的临床效果。方法 86例慢阻肺稳定期患者,随机分为对照组及实验组,各43例。对照组采用布地奈德福莫特罗治疗,实验组采用布地奈德福莫特罗联合噻托溴铵治疗。对比两组患者的治疗效果及生活质量评分。结果实验组总有效率95.35%高于对照组的76.74%,差异具有统计学意义(P<0.05)。对照组患者的社会功能评分为(13.62±1.68)分,情绪功能评分为(14.10±1.86)分,认知功能评分为(14.90±1.52)分,角色功能评分为(15.82±1.15)分,躯体功能评分为(15.65±1.47)分;实验组患者的社会功能评分为(18.22±1.71)分,情绪功能评分为(17.97±1.79)分,认知功能评分为(18.32±1.15)分,角色功能评分为(18.18±1.24)分,躯体功能评分为(18.78±1.42)分。实验组患者的生活质量评分均高于对照组,差异均具有统计学意义(P<0.05)。结论对慢阻肺稳定期患者采用布地奈德福莫特罗联合噻托溴铵用药方案进行治疗效果理想,且能够显著提高患者的生活质量,值得推广。     

双长效支气管扩张剂在慢性阻塞性肺疾病治疗中的研究进展

长效支气管扩张剂是稳定期慢性阻塞性肺疾病(chronic obstructive pulmonary disease,COPD)治疗的基石。固定剂量长效β2受体激动剂(long actingβ2 agonist,LABA)/长效抗胆碱能药物(long acting muscarinic antagonist,LAMA)复方制剂被慢性阻塞性肺疾病全球倡议推荐用于COPD的治疗。为了更深入了解已经上市的多种LABA/LAMA复方制剂如维兰特罗/乌美溴铵、茚达特罗/格隆溴铵、福莫特罗/格隆溴铵及奥达特罗/噻拖溴铵等的疗效和安全性,本文对LABA/LAMA一些重要临床研究作一综述,旨在为COPD患者提供个体化的治疗方案。     

Indacaterol maleate for the treatment of chronic obstructive pulmonary disease

Importance of the field: Chronic obstructive pulmonary disease (COPD) is a partially reversible, progressive obstructive disorder. Bronchodilators are the mainstay of treatment since they improve lung function and patient-reported outcomes and reduce acute exacerbations. Long-acting inhaled bronchodilators (at present including the once-daily antimuscarinic tiotropium, and the twice-daily β₂-agonists formoterol and salmeterol) are recommended as first-line treatment for patients with persistent symptoms. Indacaterol maleate has been developed as a new once-daily inhaled β₂-selective agonist.

Areas covered in this review: This article reviews the published literature on the pharmacologic properties and the Phase II and III trials that have evaluated the safety and efficacy of this new agent.

What the reader will gain: The reader will obtain an appreciation of the safety and efficacy of indacaterol and the role that it might play in the future management of COPD of varying severity.

Take home message: Indacaterol is a new, once-daily β₂-agonist with an onset of action within 5 min and a duration of bronchodilation of at least 24 h. In doses of 150 and 300 μg, it has sustained benefits over 6 – 12 months with respect to both bronchodilation and patient-reported outcomes and is well-tolerated with an acceptable safety profile.