The role of combination therapy with corticosteroids and long-acting ��2-agonists in the prevention of exacerbations in COPD

Acute exacerbations of COPD can complicate the course of the disease in patients with severe airway obstruction. Reduction of exacerbations is an important clinical outcome in evaluating new therapies in COPD. Combination therapies with long-acting β-agonists and inhaled corticosteroids have now been approved for use. Three 1-year randomized clinical trials, which studied the effect of combining a long-acting β₂-agonist with an inhaled corticosteroid in COPD, documented that exacerbation frequency was lower with therapy than placebo. Combination therapy had a similar effect to its monocomponents in the trial evaluating salmeterol/fluticasone combination. However, when patients with more severe COPD were studied using a combination of budesonide and formoterol, a clear improvement was seen in the overall exacerbation rates compared with the use of a long-acting β₂-agonist alone.     

Effective management of COPD in primary care - the role of long-acting beta agonist/inhaled corticosteroid combination therapy.

Chronic obstructive pulmonary disease (COPD) is the internationally preferred term for chronic, progressive lung disorders which are characterised by airflow limitation that is not fully reversible. The symptoms of COPD - including breathlessness, cough, excessive sputum production and reduced muscle tone and muscle wasting - reflect the complex pathophysiology of the disease. In order to address these symptoms, treatment regimens should take into account the multiple components that contribute to COPD. Clinical evidence has emerged indicating that, especially in patients with severe COPD, long-acting beta(2)-agonists (LABAs) and inhaled corticosteroids (ICS) result in improvements in symptoms, reduce the frequency and severity of exacerbations, and improve health-related quality of life. This review evaluates the clinical evidence for the potential of LABA/ICS treatment to address the symptoms of COPD and whether combination therapy of this nature adds significant benefit to patients.     

Formoterol in the management of chronic obstructive pulmonary disease

Bronchodilators represent the hallmark of symptomatic treatment of Chronic Obstructive Pulmonary Disease (COPD). There are four categories of bronchodilators: anticholinergics, methylxanthines, short-acting β₂-agonists, and long-acting β₂-agonists such as formoterol. Significant research has been performed to investigate the efficacy, safety and tolerability of formoterol in the therapeutic field of COPD. Formoterol exhibits a rapid onset of bronchodilation similar to that observed with salbutamol, yet its long bronchodilatory duration is comparable to salmeterol. In addition, formoterol presents with a clear superiority in lung function improvement compared with either ipratropium bromide or oral theophylline, while its efficacy improves when administered in combination with ipratropium. Formoterol has been shown to better reduce dynamic hyperinflation, which is responsible for exercise intolerance and dyspnea in COPD patients, compared with other bronchodilators, whereas it exerts synergistic effect with tiotropium. Moreover, formoterol reduces exacerbations, increases days free of use of rescue medication and improves patients’ quality of life and disease symptoms. Formoterol has a favorable safety profile and is better tolerated than theophylline. Collectively, data extracted from multicenter clinical trials support formoterol as a valid therapeutic option in the treatment of COPD.     

Circulating levels of soluble Fas ligand and soluble Fas in patients with chronic obstructive pulmonary disease

Fas- and tumour necrosis factor (TNF) receptor-mediated apoptosis are known to be two principal apoptotic mechanisms in humans. Although there are several distinctions between these two systems, in vitro studies have demonstrated similar hypoxic activation and a functional relationship. Since patients with chronic obstructive pulmonary disease (COPD) show chronic hypoxaemia and the activation of the TNF-alpha system, we investigated whether these pathophysiological changes influence the Fas-Fas ligand system. We measured the circulating soluble Fas ligand (sFas-L) level, an inducer of apoptosis, and the soluble Fas receptor (sFas) level, an inhibitor of apoptosis, in 34 COPD patients and 35 age-matched healthy controls. In addition, we investigated the relationships between the levels of sFas-L or sFas and clinical variables including the TNF-alpha system; circulating TNF-alpha and soluble TNF-receptor (sTNF-Rs: sTNF-R55 and R75) levels, in the COPD patients. Although circulating TNF-alpha, sTNF-R55 and R75 levels were significantly higher in the COPD patients than in the healthy controls, serum level of sFas-L (Fisher's exact probability test; P = 0.26) and plasma level of sFas [COPD patients vs. controls; mean (SD); 3.74 (0.63) vs. 3.67 (0.48) ng/ml; P = 0.89) were not increased in the COPD patients. There was no significant correlation between the levels of sFas-L or sFas and clinical variables in COPD patients. These results suggest that the Fas-Fas ligand system does not independently play an important role in the pathophysiology of patients with COPD.     

噻托溴铵替代ICS/LABA治疗极重度频繁发作COPD疗效的回顾性分析

目的探讨噻托溴铵策略性替代ICS/LABA治疗极重度慢性阻塞性肺疾病(COPD表型为C型或D型)的临床疗效。方法根据入组标准和排除标准选取2010年1月至2014年1月在我院进行治疗的COPD患者88例,38例患者选择停用ICS/LABA,换用噻托溴铵治疗(噻托溴铵组);50例患者选择继续使用ICS/LABA治疗(ICS/LABA组),观察并比较两组患者治疗前后1年的COPD年急性加重次数、年住院次数、肺功能下降速率(FEV_1的下降速率)。结果两组患者入组时在性别、年龄、COPD患病时间(年)、吸烟时间(年)、是否戒烟、肺功能(FEV_1、FEV_1/预计值%、FVC、FEV_1/FVC%)、过去1年急性加重次数及住院次数方面差异无统计学意义(P0.05),具有可比性。与1年前相比,噻托溴铵组年急性加重次数及年住院次数明显减少(P0.05),肺功能下降速率明显下降(P0.05)。1年后噻托溴铵组患者年急性加重次数、年住院次数及肺功能下降速率均明显低于ICS/LABA组,差异均有统计学意义(P0.05)。结论对于极重度COPD(慢性阻塞性肺疾病表型为C型或D型)患者,噻托溴铵的疗效优于ICS/LABA,可以降低肺功能下降速率、减少急性加重及住院次数。     

Bronchial asthma and the role ofβ 2-agonists

Asthma is defined as reversible airflow obstruction; the mechanism for this airflow obstruction is considered to be caused by a combination of an inflammatory process leading to a thickened edematous airway lining and bronchial smooth muscle constriction. The identification of specificβ-receptors in the autonomic system led to the development in the early 1960s of selectiveβ ₂-agonists with their precise effects on the bronchial smooth muscle without direct action on cardiac muscle. The earlyβ ₂-agonists such as salbutamol have a comparatively short bronchodilator action but a rapid onset of action, making them useful as “rescue” bronchodilators. Regularβ ₂-agonists alone may mask the underlying pathogenesis of asthma and may be associated with tachyphylaxis or rebound bronchial hyperreactivity. The observation that a thickened airway lining may lead to disproportionate increases in airways resistance with small changes in bronchial muscle shortening suggestsβ ₂-agonists should be given in conjunction with anti-inflammatory therapy. With their long duration of action but slow onset the newβ ₂-agonists may have a role in prophylaxis of asthma rather than rescue bronchodilation.     

Improvement of pulmonary function and dyspnea by tiotropium in COPD patients using a transdermal beta(2)-agonist

BACKGROUND: A combination of bronchodilators may be effective in the treatment of chronic obstructive pulmonary disease (COPD). We examined the effect of adding a long-acting anti-cholinergic agent (tiotropium) to a transdermal-type beta(2)-agonist (tulobuterol) on dyspnea as well as pulmonary function. METHODS: In a multicentre, randomized, parallel design study, 60 COPD patients treated with the transdermal beta(2)-agonist tulobuterol were divided into a tiotropium added group (Tulo+Tio group, n=40) or transdermal beta(2)-agonist tulobuterol alone group (Tulo group, n=20), and then treated for 4 weeks after a 2 week run-in period. Pulmonary function and a dyspnea (Medical Research Council (MRC)) scale were assessed before and after the treatment. Daily peak expiratory flow (PEF) monitoring was also performed. RESULTS: After 4 weeks, the Tulo+Tio group showed a significant increase in pulmonary function compared with the Tulo group; DeltaFVC (0.31+/-0.06 L vs. 0.06+/-0.05 L, p< 0.01), DeltaFEV(1) (0.15+/-0.03 L vs. -0.02+/-0.02 L, p<0.0001), and DeltaPEF (41.0+/-5.1 L/min vs. 0.5+/-3.5 L/min, p<0.0001). The MRC dyspnea scale was also significantly improved in Tulo+Tio, but not in Tulo group. CONCLUSION: These results suggest that tiotropium caused a significant improvement in both pulmonary function and dyspnea in COPD patients already treated with the transdermal beta(2)-agonist tulobuterol.     

Comparison and optimal use of fixed combinations in the management of COPD

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Indications for the use of long-acting β₂-agonists (LABAs) and inhaled corticosteroids (ICS) in patients with COPD are described in the various international guidelines, but no special recommendations are made concerning the use of combination inhalers containing a LABA as well as an ICS. To determine the place of combination inhalers in the treatment of COPD we reviewed recent literature concerning this subject. On molecular level ICS/LABA combination therapy has anti-inflammatory properties which cannot be attributed to ICS alone. All clinical studies indicate that the two available combinations (salmeterol/fluticasone and formoterol/budesonide) significantly reduce exacerbation rate of moderate/severe exacerbations when compared with placebo. Some studies also showed a significant reduction in exacerbation rate compared with LABA monotherapy, but not compared with ICS monotherapy. From the patient’s perspective, ICS/LABA combination inhalers are the first choice when both need to be prescribed, possibly improving patient compliance for ICS. Currently little evidence is available to predict if flexible treatment with LABA/ICS combination inhalers will improve disease control in COPD. Further studies are needed to elucidate the clinical benefit of combination inhalers versus the individual components in different inhalers, and to investigate the clinical benefit of flexible dosing of combination inhalers in patients with COPD.     

The role of long-acting muscarinic antagonist/long-acting β agonist fixed-dose combination treatment for chronic obstructive pulmonary disease in China: a narrative review

ObjectiveTo provide an overview of the existing international and Chinese evidence regarding dual bronchodilator inhalation therapy and to make recommendations for the further improvement of chronic obstructive pulmonary disease (COPD) management in clinical practice in China.BackgroundCOPD is a progressive lung disease that is characterized by persistent airflow limitation and is a major contributor to the disease burden in China. Symptoms in Chinese patients are relatively more severe. Currently, many Chinese COPD patients are undertreated. Dual bronchodilator therapy consisting of a long-acting muscarinic antagonist (LAMA) and a long-acting β agonist (LABA) is considered a good choice for COPD patients due to the increased bronchodilation without an increase in adverse events; these combinations can fill in the gap in currently available COPD treatments and provide new pharmacotherapy options for Chinese patients. LAMA/LABA fixed-dose combinations (FDCs) have become more important in clinical practice and guidelines in China regarding their therapeutic effects and safety.MethodsClinical trials on LAMA/LABA in COPD were retrieved in ClinicalTrials.gov, while important COPD guidelines published in English or Chinese were found in PubMed and Wanfang Database.ConclusionsWe recommend the adoption of a clinical pathway in China that includes an assessment and management algorithm that considers the clinical characteristics in China and classifies the phenotypic characteristics of COPD according to a suitable system. Based on the current information, we can conclude that LAMA/LABA FDCs are a suitable and economically viable choice to reduce symptoms and improve the quality of life (QoL) of patients.     

Clinical and inflammatory factors associated with body mass index in elderly patients with chronic obstructive pulmonary disease

Aim: Body mass index (BMI) is closely associated with mortality in chronic obstructive pulmonary disease (COPD). Systemic inflammation has been suggested as one of the mechanisms of malnutrition in COPD. This study investigated the relationships of clinical variables and inflammatory biomarkers with BMI in COPD in an aging population. Methods: Baseline levels of serum biomarkers were determined for 69 patients with stable male COPD. Multivariate logistic regression was used to evaluate associations between clinical variables, including emphysema scores, and biomarkers with BMI. Results: Twenty eight patients were categorized as low BMI (<20 kg/m²). BMI was inversely correlated with serum α1‐antitrypsin (α1‐AT) concentration and emphysema scores, and was positively correlated with forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV₁). Multivariate logistic regression analysis showed that α1‐AT was independently associated with BMI. Conclusion: Low BMI was associated with the severity of emphysema and systemic inflammation reflected by elevated α1‐AT level. Geriatr Gerontol Int 2011; 11: 32–38.     

Short- and long-term efficacy of fluticasone propionate in subjects with early signs and symptoms of chronic obstructive pulmonary disease. Results of the DIMCA study

BACKGROUND: Early treatment with inhaled corticosteroids may prevent progression of irreversible obstruction in COPD, especially in patients with bronchial hyperresponsiveness. We investigated the clinical effects of early introduction of inhaled steroids in subjects showing early signs and symptoms of COPD without a prior clinical diagnosis. METHODS: Study subjects were detected in a general population screening and monitoring program. Those with a moderately accelerated annual FEV1 decline and persistent respiratory symptoms were invited to participate in a 2-year randomized controlled trial comparing fluticasone propionate DPI 250 microg b.i.d. with placebo. Pre- and post-bronchodilator (BD) FEV1, PC20 histamine, functional status (COOP/WONCA charts) and occurrence of exacerbations were periodically assessed. Subjects recorded respiratory symptoms. Post-BD FEV1 decline served as the main outcome. Multivariable repeated measurements analysis techniques were applied. RESULTS: 48 subjects were randomized (24 fluticasone, 24 placebo). After 3 months, the post-BD FEV1 had increased with 125 ml (SE = 68, P = 0.075) and the pre-BD FEV1 with 174 ml (SE 90, P = 0.059) in the fluticasone relative to the placebo group. The subsequent post-BD and pre-BD FEV1 decline were not beneficially modified by fluticasone treatment. There were no statistically significant differences in respiratory symptoms, functional status, or exacerbations favoring fluticasone. Subgroup analysis indicated that the presence of bronchial hyperresponsiveness modified the initial FEV1 response on fluticasone, but not the subsequent annual FEV1 decline. CONCLUSION: Early initiation of inhaled steroid treatment does not seem to affect the progressive deterioration of lung function or other respiratory health outcomes in subjects with early signs and symptoms of COPD. In subjects at risk for, or in an early stage of COPD, long-term inhaled steroid treatment should not be based on a single spirometric evaluation after 3 months.     

Use of a long-acting inhaled beta2-adrenergic agonist, salmeterol xinafoate, in patients with chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a condition in which continuous bronchodilation may have clinical advantages. This study evaluated salmeterol, a beta-agonist bronchodilator with a duration of action substantially longer than that of short-acting beta-agonists, compared with ipratropium, an anticholinergic bronchodilator, and placebo in patients with COPD. Four hundred and five patients with COPD received either salmeterol 42 microg twice daily, ipratropium bromide 36 microg four times daily, or placebo for 12 wk in this randomized, double-blind, parallel-group study. Patients were stratified on the basis of bronchodilator response to albuterol (> 12% and > 200-ml improvement) and were randomized within each stratum. Bronchodilator response was measured over 12 h four times during the treatment period. Salmeterol provided similar maximal bronchodilatation to ipratropium but had a longer duration of action and a more constant bronchodilatory effect with no evidence of bronchodilator tolerance. Both active treatments were well tolerated. Salmeterol was an effective bronchodilator with a consistent effect over this 12-wk study in patients with COPD, including those "unresponsive" to albuterol. The long duration of action of salmeterol offers the advantage of twice daily dosing compared with the required four times a day dosing with ipratropium.     

Cilomilast (Ariflo) does not potentiate the cardiovascular effects of inhaled salbutamol

We investigated the safety and potential pharmacodynamic interactions arising from the co-administration of inhaled beta(2)-agonist salbutamol and cilomilast (Ariflo), a new oral phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease and asthma. This was a randomised, double-blind, placebo-controlled, multiple-dose, three-period crossover study involving non-smoking volunteers between the ages of 18 and 50 years. Volunteers were randomly assigned to receive cilomilast plus nebulised salbutamol, cilomilast plus nebulised placebo or placebo plus nebulised salbutamol. Each volunteer received cilomilast (10 mg twice daily) or placebo for 5 days. On day 5, the morning dose of cilomilast or placebo was followed 1 h later with a single dose of nebulised salbutamol (2.5 mg) or placebo. Primary variables were average change from pre- to 1.5 h post-salbutamol or placebo inhalation in blood pressure, pulse rate, 12-lead ECG and total number of heartbeats measured by 4-h Holter ECG. Thirteen volunteers completed the study. There was no evidence of a clinically important pharmacodynamic interaction between cilomilast and salbutamol in healthy volunteers. Both agents were well tolerated. In conclusion, the pharmacodynamic effects associated with salbutamol inhalation were unaffected by co-administration of cilomilast.     

Safety, tolerability and efficacy of indacaterol, a novel once-daily beta(2)-agonist, in patients with COPD: a 28-day randomised, placebo controlled clinical trial

In patients with chronic obstructive pulmonary disease (COPD) classified as moderate onwards, Global Initiative for Chronic Obstructive Lung Disease (GOLD) Guidelines recommend regular treatment with one or more long-acting bronchodilators, such as beta(2)-agonists or anticholinergics. In contrast to currently available long-acting beta(2)-agonists, which have a duration of action of 12 h, indacaterol has demonstrated effective 24-h bronchodilation on once-daily dosing. A double-blind, randomised, placebo-controlled study was conducted to compare the safety, tolerability and efficacy of indacaterol with that of placebo, over a 28-day period, in patients with moderate COPD (as defined by GOLD 2001 criteria; equivalent to moderate-to-severe COPD in the GOLD 2005 criteria). Patients were randomised 2:2:1 to receive indacaterol 400 microg or 800 microg or placebo once-daily (between 07:00 and 11:00 h) via a single-dose dry-powder inhaler for 28 days. Assessments included monitoring of adverse events (AEs), blood chemistry (including serum potassium and blood glucose), vital signs (blood pressure and heart rate), electrocardiograms and spirometry. One hundred and sixty-three patients were randomised, with 155 (95%) completing the study. There were no statistically significant differences between treatment groups in the overall incidence of AEs, with AEs reported by 35%, 51% and 25% of patients in the indacaterol 400 microg, 800 microg and placebo groups, respectively. The majority of AEs were mild or moderate in severity, and there were no study-drug related serious AEs. There were no statistically significant differences between indacaterol groups and placebo in mean pulse rate and QTc interval, and isolated statistically significant (p<0.05) treatment-placebo differences in mean blood pressure, blood glucose and serum potassium. There was a statistically significant improvement in FEV(1) vs placebo at all post-baseline timepoints for both indacaterol treatment groups; 30 min post-dose, adjusted mean+/-SE FEV(1) indacaterol-placebo differences were: Day 1, 220+/-36 ml and 210+/-36 ml; Day 14, 320+/-50 ml and 270+/-50 ml; Day 28, 260+/-61 ml and 200+/-61 ml for 400 and 800 microg, respectively (all p<0.01 vs placebo). Bronchodilation was still apparent after 24h, with pre-dose (i.e. trough) adjusted mean+/-SE FEV(1) indacaterol-placebo differences of: Day 14, 230+/-44 ml and 210+/-44 ml; Day 28, 220+/-49 ml and 210+/-49 ml for indacaterol 400 and 800 microg, respectively (all p<0.0001 vs placebo). Once-daily indacaterol was well tolerated at doses up to 800 microg with a good overall safety profile. There was no statistical difference at any dose between the safety of indacaterol and placebo. Furthermore, this study supports the previously demonstrated 24-h bronchodilator efficacy of indacaterol.     

The current place ofβ 2-agonists in the management of asthma

Inhaledβ ₂-stimulants are the most effective drugs for acute asthma attacks. This is probably due to the functional antagonism against a large variety of possible asthma mediators. A slight rebound increase of bronchial hyperreactivity 12 to 23 h after stopping regular treatment has been proposed. This finding is not well documented and must be further studied. There is no convincing evidence that tachyphylaxis of clinical importance to the bronchodilating effect occurs in asthmatics receiving normal doses ofβ ₂-receptor stimulants but cannot be totally excluded. Candidates for regular inhaledβ ₂-agonist treatment always have inflammation in their airways and should be given inhaled steroids. Steroids not only seem to reduce airway inflammation and hyperreactivity but they also reverseβ ₂-receptor subsensitivity in experimental studies. Patients on purely prophylactic antiasthmatic drugs should be instructed always to carry theirβ ₂-stimulants inhalers.