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.     

Efficacy and safety of inhaled corticosteroids in combination with a long-acting beta2-agonist in asthmatic children under age 5.

The incidence of asthma in children under age 5 is higher than in any other segment of the population. Current NAEPP guidelines recommend treatment of some asthmatics in this age group with the combination of an inhaled corticosteroid and a long-acting beta2-agonist even though this practice has never been studied with children younger than 4. This retrospective study analyzes the efficacy and safety of a combination of fluticasone propionate (FP) and salmeterol (SA) in children under 5. Fifty patients who started using FP/SA before the age of 60 months were included in the analysis. To determine efficacy, we tracked the change in emergency room visits, hospitalizations, and the frequency of wheezing as a result of treatment. Emergency room visits were reduced from 78 to 5 (p<0.001), hospitalizations were reduced from 43 to 2 (p<0.001) and frequency of wheezing, daily, weekly, or monthly, was also reduced significantly (p<0.003). In terms of safety, there was only a 3.4% reduction in height percentile (p=0.37). Combination therapy is highly efficacious and safe for asthmatics under the age of 5. A well-designed prospective study is necessary to further evaluate the benefits and risks of this treatment method.     

Inhaled combination therapy with long-acting beta 2-agonists and corticosteroids in stable COPD

Long-acting beta(2)-agonists (LABAs) have been shown to be effective first-line bronchodilators in the treatment of COPD patients, and inhaled corticosteroids (ICSs) have been shown to reduce the frequency and/or severity of exacerbations in COPD patients. The concomitant use of a LABA and an ICS can influence both airway obstruction (ie, smooth muscle contraction, increased cholinergic tone, and loss of elastic recoil), and airway inflammation (ie, increased numbers of neutrophils, macrophages, and CD8+ lymphocytes, elevated interleukin-8 and tumor necrosis factor-alpha levels, and protease/antiprotease imbalance). They are also able to reduce the total number of bacteria adhering to the respiratory mucosa in a concentration-dependent manner without altering the bacterial tropism for mucosa, and to preserve ciliated cells. Several clinical trials support the concept of inhaled combination therapy with LABAs and corticosteroids in stable COPD patients. This type of therapy not only improves airflow obstruction but also provides clinical benefits, as manifested by sustained reduction in overall symptoms, improvements in health-related quality of life, and reductions in exacerbations. All of these effects are very important because, despite recent advances in our understanding of COPD and its treatment, therapy remains suboptimal for a considerable number of patients.     

Survival of COPD patients using inhaled corticosteroids and long-acting beta agonists

We conducted a historical cohort study to examine the relationship between survival and use of inhaled corticosteroids (ICS) and/or long-acting beta agonists (LABA) in patients with chronic obstructive pulmonary disease (COPD). All COPD patients aged 40 years who were enrolled in one of two regional managed care organizations during 1995-2000, and who had 90 days use of an ICS and/or LABA (N=1288) or of a short-acting bronchodilator (N=397), were identified. Of patients treated with ICS and/or LABA, 14.4% died during the follow-up period, as compared to 28.2% of comparison patients (P<0.01). In a Cox proportional hazards model that controlled for age, sex, comorbidities, COPD severity, and asthma status, a reduced risk of death was found for ICS treatment (HR 0.59 [95% CI 0.46-0.78]), LABA (HR 0.55 [0.34-0.89]), and ICS plus LABA treatment (HR 0.34 [0.21-0.56]). A second model that excluded any patient who also had an ICD-9 code for asthma (N=840) still found improved survival among those using the combination of ICS plus LABA (HR 0.35 [CI 0.17-0.71]). Additional analyses that varied the exposure criteria also found a consistent treatment benefit. Inclusion of ICS or bronchodilator treatment during the follow-up period as a time-dependent function appears to negate the survival benefit; however, the underlying assumptions for valid time-dependent modeling are clearly violated in this situation. In conclusion, we found that COPD patients who used ICS alone or in combination with LABA had substantially improved survival even after adjustment for asthma and other confounding factors.     

A comparison of the effects of anticholinergic and beta 2-agonist and combination therapy on respiratory impedance in COPD.

The effects of three different regimens of inhaled bronchodilators on spirometry and respiratory impedance as measured with the technique of forced oscillations were compared in a double-blind crossover study in 22 patients with stable chronic obstructive pulmonary disease (FEV1 less than 70 percent predicted). On three trial days, patients inhaled, in random order, 40 micrograms ipratropium bromide, 200 micrograms fenoterol hydrobromide, or a combination of 40 micrograms ipratropium and 100 micrograms fenoterol from a powder inhaler, followed by a second dose of the same drug after 60 min. The effects were measured at baseline and 20, 40, 60, and 120 min after the first inhalation. No significant decrease in total respiratory resistance at 8 Hz (Rrs [8]) was observed after ipratropium, whereas Rrs (8) decreased significantly 20 min after fenoterol and 40 min after the combination regimen (p less than 0.05). All three studied drugs resulted in a significant increase in the reactance (p less than 0.01) and decrease in resonant frequency. Both fenoterol (delta FEV1 34 percent, p less than 0.0001) and the combination regimen (delta FEV1 38 percent, p less than 0.0001) resulted in a significantly larger increase in FEV1 than ipratropium alone (delta FEV1 17 percent, p less than 0.0001). A second dose of fenoterol and of the combination regimen resulted in a further significant increase in FEV1 after 120 min (p less than 0.05). A second dose of ipratropium did not result in a further significant increase in FEV1. The changes in respiratory impedance were qualitatively similar for all three drug regimens, but larger in absolute terms after fenoterol and the combination regimen than after ipratropium. The similar effect of these drugs on the reactance can be explained by an increase in the capacitance of the respiratory system, and in combination with a decrease in frequency dependence of resistance, by assuming a decrease in peripheral airway resistance.     

Addition of inhaled corticosteroid on combined bronchodilator therapy in patients with COPD

PURPOSE: Bronchodilator therapy is the first step treatment in patients with COPD. The beneficial effects of corticosteroids either in health status or in airway inflammation in COPD have been previously studied. The aim of this study was to evaluate whether adding inhaled corticosteroids to combined bronchodilator therapy has additive clinical and anti-inflammatory effects in COPD patients. SUBJECTS AND METHODS: Thirty patients with COPD were included in the study. All patients were receiving inhaled anticholinergic and long-acting beta-2 agonist. Inhaled corticosteroid (budesonide 800 microg daily) was added to their current medications for 12 weeks. Before and after this treatment period, spirometric values and arterial blood gas parameters were determined, blood was drawn for measurement of serum inflammatory markers and sputum was induced. RESULTS: All patients were male, mean age was 67.7+/-8.7 years and duration of disease was 9.7+/-4.3 years. The induced sputum total cell counts, eosinophil and neutrophil counts decreased with corticosteroid treatment. The induced sputum IL-8 and TNF-alpha levels decreased significantly (IL-8; 835.9+/-217 versus 378.4+/-105 pg/ml, p=0.0001, TNF-alpha; 320.7+/-129 versus 201.3+/-52 pg/ml, p=0.003). Serum inflammatory markers and sputum LTB4 levels did not change with treatment. CONCLUSION: These results suggested that the addition of inhaled corticosteroids to combined bronchodilator therapy might have anti-inflammatory effects in patients with COPD.     

Hemodynamic effects of inhaled ipratropium bromide, alone and combined with an inhaled beta 2-agonist

Inhaled ipratropium bromide's reported lack of cardiovascular side effects has led to recommendations for its use as a bronchodilator in patients with coexisting cardiovascular disease and in combination regimens with adrenergic agents. To assess the hemodynamic effects of ipratropium, we monitored 10 volunteers by M-mode echocardiography following metered-dose ipratropium administered alone and with fenoterol. On 2 separate days, subjects were monitored for 90 min as they received either 160 micrograms of ipratropium or placebo in divided doses plus 400 micrograms of fenoterol at time 60 min. Following ipratropium alone, heart rate (HR) decreased 3 beats/min, a small but significant difference from placebo (p less than 0.04). Stroke volume (SV) and ejection fraction rose significantly (3 ml and 2%, respectively; p = 0.05) so that cardiac output (CO) was unchanged. By contrast, fenoterol alone (following placebo) produced marked increases in HR (13 beats/min), SV (14 ml), and CO (44%), with a marked fall in total peripheral vascular resistance (29%). Ipratropium administered before and with fenoterol had minimal additive effect. Although SV was slightly higher with the combination of drugs than with fenoterol alone (100.1 ml versus 93 ml; p = 0.05), CO was not significantly greater (6.9 L/min versus 6.4 L/min; p greater than 0.10). We conclude that metered-dose ipratropium alone has small and clinically unimportant hemodynamic effects and produces no clinically significant increases in the cardiovascular side effects of the bronchodilator regimen when given with fenoterol.     

Doppler echocardiographic assessment of the effects of inhaled long-acting beta2-agonists on pulmonary artery pressure in COPD patients

Increase in pulmonary artery pressure (PAP), which is common in severe chronic obstructive pulmonary disease (COPD), is a predictor of mortality independent of airflow limitation. beta-agonists might slightly attenuate this increase because they exert a vasodilating effect on pulmonary circulation when systematically administered. We have investigated the acute effects of salmeterol and formoterol on echocardiographic systolic pulmonary artery pressure (sPAP) in 20 patients with COPD and a sPAP greater than 20mmHg at rest. Acute haemodynamic responses to inhaled formoterol or salmeterol were assessed in all patients, in a randomized, double-blind double-dummy fashion. On two consecutive days, patients received, in a randomized order, formoterol 12microg via Turbuhaler plus placebo via Diskus or salmeterol 50microg via Diskus plus placebo via Turbuhaler. Transthoracic Doppler echocardiography measurements of sPAP were made before and 15, 30, 60 and 180min after bronchodilator inhalation. Lung function, pulse oximetry and heart rate were also monitored at the same times. Mean sPAP significantly (p<0.05) decreased in comparison with baseline at 15, 30, and 60min post inhalation but returned towards control levels at 180min after both salmeterol and formoterol. There was no correlation between the maximum increase in FEV(1) and maximum decrease in sPAP either after inhalation of salmeterol (r(2)=0.071) or after that of formoterol (r(2)=0.0006). The increases in FEV(1) in comparison with baseline were always significant (p<0.05) from 15 to 180min post inhalation after either salmeterol or formoterol. Neither pulse oximetry nor heart rate changed in a significant manner (p>0.05). This study demonstrated that salmeterol and formoterol were equally beneficial for pulmonary haemodynamics in patients with COPD. A direct vasodilatation due to the activation of beta-adrenoceptors that are present in pulmonary vessels is a likely mechanism of their action in inducing the decrease in sPAP.     

Airway mucosal thickening and bronchial hyperresponsiveness induced by inhaled beta 2-agonist in mice

BACKGROUND: Patients with chronic persistent asthma require frequent use of inhaled beta(2)-agonist, which may result in aggravation of asthma symptoms. Our recent in vitro study has shown that beta(2)-agonist stimulates the growth of human airway epithelial cell lines. STUDY OBJECTIVE: To determine whether beta(2)-agonist likewise affects airway epithelial cell proliferation in vivo and, if so, what the mechanism of action is, we examined the effect of salbutamol on the morphology of murine airways. METHODS: Seventy-two BALB/c mice were administered aerosolized salbutamol using "flow-through" nose-only inhalation chambers at daily doses of 0.2 to 20 microg for up to 6 weeks. Morphology of tracheal mucosa, labeling of epithelial cells with 5-bromo-2'-deoxyuridine (BrdU), and bronchial responsiveness were assessed. RESULTS: Exposure to salbutamol increased the thickness of tracheal epithelial layer and the number of BrdU-positive epithelial cells in a dose- and time-dependent manner: the values in mice receiving 20 microg salbutamol for 6 weeks were 247% and 642%, respectively, of those in control animals receiving saline solution alone. These effects were inhibited by the mitogen-activated protein (MAP) kinase kinase inhibitors PD98059 and U0126. Salbutamol also caused a decrease in the provocative concentration of methacholine to achieve 400% of baseline enhanced pause. Combined treatment with inhaled budesonide attenuated salbutamol-induced airway morphologic changes and bronchial hyperresponsiveness. CONCLUSION: beta(2)-agonist stimulates proliferation of airway epithelial cells and produces airway wall thickening in vivo via MAP kinase-dependent pathway, and these effects are prevented by inhaled corticosteroid.     

吸入糖皮质激素/长效β2受体激动剂对慢性阻塞性肺疾病患者的影响

目的 探讨吸入糖皮质激素/长效β2受体激动剂(信必可)治疗对慢性阻塞性肺疾病(chronic obstructive pulmonary disease,COPD)患者肺功能进行性下降及气流阻力严重程度,以及患者急诊就诊率、住院率和住院天数的影响.方法 选择82例符合入选标准的稳定期Ⅲ-Ⅳ级COPD患者,随机分为治疗组(42例)和对照组(40例),治疗组在常规治疗基础上,加用糖皮质激素/长效β2受体激动剂(160/4.5/μg,2次/d,长期吸入);对照组仅给予常规治疗.在两年的临床研究期间,观察记录两组患者急诊就诊率、住院率和住院天数,入组前及临床观察结束后对患者进行呼吸功能测定及支气管舒张试验.结果 经2年的临床观察,治疗组患者FEV1进行性降低的程度显著低于对照组,深吸气量较对照组有明显改善(P值均＜0.05);治疗组两年期间的急诊就诊率、住院率及住院天数均低于对照组(P值均＜0.05).结论 长期吸入糖皮质激素并长效β2受体激动剂能够延缓患者肺功能的进行性下降,并能降低患者的急性加重次数及住院时间,减轻患者的家庭及社会负担.     

Effects of inhaled corticosteroids/long-acting beta-2 agonist fix combinations in COPD

Chronic obstructive pulmonary disease (COPD) is an inflammatory disease characterized with progressive air flow limitation, and is expected to be the third leading cause of death until 2030 worldwide. The clinical trials in the last 10 years revealed that fix combinations (inhaled corticosteroids/long-acting beta-2 agonist; ICS/LABA) improve lung functions and quality of life, and reduced symptoms and exacerbation rates in patients with severe and very severe COPD.     

Comparison of bronchodilatory properties of transdermal and inhaled long-acting beta 2-agonists

BACKGROUND: Regular use of long-acting bronchodilators is recommended for symptomatic COPD patients. A transdermal type of beta 2-agonist, tulobuterol, was recently developed. This agent shows the pharmacokinetic property of a sustained serum concentration for 24h. However, little has been reported about the bronchodilatory properties of this agent. OBJECTIVES: The aim of the present study was to compare the bronchodilatory action of transdermal beta 2-agonist tulobuterol with that of inhaled long-acting beta 2-agonist salmeterol. METHODS: An open-label, randomized crossover study was performed. Eleven patients with stable COPD were enrolled in the study. Tulobuterol (2mg/day) or salmeterol (50 microg, twice daily) was administered in a randomized, crossover manner. Forced expiratory volume in 1s (FEV1), forced vital capacity (FVC) and inspiratory capacity (IC) were measured before administration, every 2h from 12 to 24h, and at 36 h after the initial administration. RESULTS: Transdermal beta 2-agonist tulobuterol showed an improvement in FEV1, FVC and IC after dosing compared with those at baseline. Salmeterol also improved all parameters of FEV1, FVC and IC, and showed a greater improvement compared with the transdermal beta 2-agonist tulobuterol (p<0.05). The values of the area under the curve (AUC) of FEV1, FVC and IC during the administration of tulobuterol were 2.98+/-1.05, 1.81+/-0.98, 0.75+/-0.85 L h, respectively, and during the administration of salmeterol they were 6.39+/-1.12, 6.61+/-1.34, 4.28+/-0.91 L h, respectively. CONCLUSION: The transdermal beta 2-agonist tulobuterol showed bronchodilatory action for at least 24h by once daily administration. However, its bronchodilatory potency was about three times less than that of the inhaled beta 2-agonist salmeterol.     

The long-acting beta2-agonist salmeterol xinafoate: effects on airway inflammation in asthma.

Salmeterol xinafoate is an inhaled long-acting beta2-adrenoceptor agonist recently introduced for the treatment of asthma. Both in vitro and animal studies suggest that it may have anti-inflammatory activities of benefit in this disease. To assess this directly, the effects of 6 weeks' treatment with salmeterol on indices of clinical activity, airway dysfunction and inflammation in subjects with stable atopic asthma were investigated. In a double blind study, asthmatic patients were randomized to 6 weeks' treatment with either salmeterol 50 microg twice daily (n=14) or placebo (n=12). They underwent bronchoscopy with bronchoalveolar lavage (BAL) and bronchial biopsy immediately before starting treatment and again after 6 weeks. Treatment with salmeterol improved clinical indices of asthma activity, but there were no changes in BAL differential cell counts or mediator levels, and no change in T-cell numbers or activation status. In the biopsy specimens there were no changes in numbers of inflammatory cells, sub-basement membrane collagen deposition or mast cell degranulation. Regular treatment with salmeterol improves clinical indices of asthma but has no effect on the underlying inflammatory process. These findings strengthen guideline recommendations that long-acting beta2-agonists should not be prescribed as sole antiasthma medication.     

Lipid peroxides in stable asthmatics receiving inhaled steroids and long-acting beta2 -agonists

BACKGROUND AND OBJECTIVE: The effect of inhaled steroids on oxidative stress in asthmatics is unclear. The levels of lipid peroxides in the serum of asthmatic patients, whose symptoms were controlled with inhaled corticosteroids and long-acting beta(2)-agonists, were measured in this study. METHODS: Twenty asthmatic patients and 17 matched, healthy controls were recruited. Oxidative stress levels were quantified by measuring thiobarbituric acid reactive substances. RESULTS: After 3 months of treatment, the mean lipid peroxide concentrations were significantly higher in asthmatic patients than in the healthy controls (4.2 +/- 0.13 micromol/mL vs. 3.6 +/- 0.07 micromol/mL, respectively). CONCLUSION: The level of lipid peroxides is higher in patients with asthma than in healthy controls, even when the asthma is well controlled after 3 months of treatment. A longer period of therapy may be required before lipid peroxidation normalizes.