Bronchodilator reversibility in COPD

COPD is a preventable and treatable disease characterized by airflow limitation that is not fully reversible. The diagnosis of COPD is based on spirometric evidence of airways obstruction following bronchodilator administration. Although it used to be commonly believed that patients with COPD have largely irreversible airflow obstruction, evidence now suggests that a considerable proportion of patients exhibit clinically significant bronchodilator reversibility. The complexity and inherent variability of a patient's acute response to a bronchodilator and the lack of a standardized procedure for assessing bronchodilator reversibility have led to significant confusion surrounding this concept. Although bronchodilator reversibility commonly is defined based on thresholds for improvement in FEV(1), lung volume-based measures of pulmonary function may be of particular importance in patients with severe COPD. The usefulness of acute reversibility to short-acting bronchodilators in predicting a patient's long-term response to bronchodilator maintenance therapy is also unclear, although most studies suggest that a lack of acute response to short-acting bronchodilators does not preclude a beneficial long-term response to maintenance bronchodilator treatment. This review outlines recent findings about the prevalence and usefulness of bronchodilator reversibility in patients with COPD based on the available literature and proposes areas of future research.     

Lung deposition and efficacy of inhaled formoterol in patients with moderate to severe COPD

BACKGROUND: Little is known about the impact of COPD on lung deposition of inhaled drugs and the relationship between lung-dose and response of pulmonary function measurements. METHODS: Nineteen patients with varying degrees of COPD were randomized to inhale single doses of formoterol (Oxis) Turbuhaler 4.5, 9, 18, and 36 microg in a double blind, placebo-controlled, crossover design. Urinary excreted formoterol during 32 h was used to determine absolute lung deposition. Peak inspiratory flow (PIF) and inhaled volume (IV) were recorded to assess the patients' ability to use Turbuhaler. Efficacy was measured by spirometry, inspiratory capacity (IC), airway conductance (sG(AW)), and absolute lung volumes. RESULTS: Mean pulmonary bioavailability of formoterol was about 24% of the nominal delivered dose after inhalation for the different treatments. No significant correlations between lung deposition and baseline FEV(1), PIF or IV were shown. All formoterol doses produced statistically significant increases in FEV(1), FVC, IC, and sG(AW) relative to placebo. Linear dose/response relationships were observed for these variables, with more narrow limits of the slopes for the lung-dose/response relationships than for the nominal-dose/response relationships. Moreover, 36 and 18 microg formoterol statistically significantly decreased functional residual capacity (FRC) and residual volume (RV) relative to placebo. CONCLUSIONS: This study could not show any difference in lung deposition of formoterol inhaled via Turbuhaler between patients with moderate and severe COPD. Moreover, the effect of formoterol on various pulmonary function measurements were more closely related to lung deposition than the inhaled nominal dose.     

Use of 6-min and 12-min walking test for assessing the efficacy of formoterol in COPD

Exercise tolerance is an important outcome measure in patients with COPD, mostly because there is evidence that exercise testing is superior to other functional measurements obtained at rest in demonstrating the positive effect of a specific intervention. We assessed the effect of a 5-day treatment with formoterol 12mug twice daily on lung function, exercise capacity and dyspnea in 22 stable COPD patients, and compared 6-MWT with 12-MWT in evaluating formoterol efficacy. All subjects entered a crossover design. They underwent 6-MWT or 12-MWT in a randomised order and soon after started the 5-day treatment. After a 3-day washout, patients who had first performed 6-MWT, underwent 12-MWT, and the contrary. Formoterol induced a progressively significant increase in pre-drug FEV1 and IC and also significant changes in these parameters 2h after its inhalation at each test day. Moreover, it increased the walked distance by 53.6m at the end of 6-MWT and 59.9m at the end of 12-MWT. Formoterol also induced a significant change in Borg score for dyspnea caused by the 6-MWT when compared with the pre-treatment values, whereas it significantly changed dyspnea induced by 12-MWT only after the first dose. Our study not only strengthens the importance of walking tests as a useful tool for evaluating the impact of a bronchodilator on some COPD patient-centred outcomes, but also indicates that 6-MWT seems to be a more appropriate instrument than 12-MWT for assessing the exercise response to a bronchodilator in COPD.     

The combination of ipratropium and albuterol optimizes pulmonary function reversibility testing in patients with COPD

STUDY OBJECTIVES: To determine whether the combination of ipratropium bromide and albuterol results in greater and more consistent pulmonary function test (PFT) response rates than ipratropium bromide or albuterol alone in patients with COPD. DESIGN: Retrospective review of two recently completed 3-month, randomized, double-blind, parallel, multicenter, phase III trials. SETTING: Outpatient. PATIENTS: A total of 1,067 stable patients with COPD. INTERVENTIONS: Ipratropium bromide (36 microg qid), albuterol base (180 microg qid), or an equivalent combination of ipratropium bromide and albuterol sulfate (42 microg and 240 microg qid, respectively). MEASUREMENTS AND RESULTS: PFT response rates were analyzed using 12% and 15% increases in FEV1 compared with baseline values and were measured in the various treatment groups on days 1, 29, 57, and 85 in these trials. Regardless of whether a 12% or a 15% increase in FEV1 was used to define a positive response, an equivalent combination of ipratropium bromide and albuterol sulfate was superior to the individual agents (p < 0.05; all comparisons within 30 min). In addition, a 15% or more increase in FEV1 was seen in > 80% of patients who received the combination of ipratropium and albuterol sulfate during the initial PFT and continued to be observed 3 months after initial testing. CONCLUSIONS: Use of a combination of ipratropium bromide and albuterol sulfate is superior to the individual agents in identifying PFT reversibility in patients with COPD.     

Flow and volume responses after routine salbutamol reversibility testing in mild to very severe COPD

BACKGROUND: Flow response after administration of a bronchodilator is widely used as an indicator of reversibility of airflow limitation in chronic obstructive pulmonary disease (COPD). We hypothesized that the association between flow and volume responses would reverse along with the progression of the disease. METHODS: We used the database of a large primary care diagnostic centre containing pre- and postbronchodilator tests of patients referred for spirometry by their GP. Patients 40 years with a smoking history were categorized into Global initiative for chronic obstructive lung disease (GOLD) stages I-IV. Flow and volume responses (DeltaFVC and DeltaFEV(1), respectively) were calculated and compared between the GOLD stages using linear regression analysis. RESULTS: About 2210 patients (63% males, 49% current smokers) were analysed. Four hundred and forty-two patients were classified into GOLD stage I, 1297 in GOLD II, 426 in GOLD III, and 45 in GOLD IV. The overall mean values for DeltaFEV(1) and DeltaFVC were 0.180 (sd 0.150) and 0.226l (sd 0.227). DeltaFEV(1) decreased as the GOLD stage was more severe, whereas DeltaFVC increased (P<0.001). There was a clear positive correlation between DeltaFEV(1) and DeltaFVC within each GOLD stage (P<0.01), but when FVC response was plotted against FEV(1) response the slope of the regression line became gradually steeper with each more severe GOLD stage (P<0.001). CONCLUSIONS: Our hypothesis that COPD patients on the mild side of the severity spectrum differ from patients on the severe side regarding the association between their bronchodilator flow and volume responses was confirmed. The difference is probably explained by the higher degree of loss of lung elastic recoil and/or compression of the smaller airways due to enlarged air spaces that accompanies the progression of COPD to the more severe stages.     

Bronchodilator response to formoterol Turbuhaler in patients with COPD under regular treatment with formoterol Turbuhaler

Formoterol Turbuhaler has been suggested for as-needed use in asthmatic patients. We investigated whether regular treatment with formoterol would modify the dose-response curves to formoterol in patients with partially reversible COPD. In this randomised, double-blind, cross-over study taking place over four non-consecutive days 16 outpatients with moderate to severe COPD, who were under regular treatment with formoterol Turbuhaler (18 microg in two daily doses) from at least 4 months, inhaled a conventional dose of formoterol Turbuhaler 9 microg or placebo. Two hours later, a FEV(1) value was established, following which a dose-response curve to formoterol (4.5 microg/inhalation) or placebo was constructed using four inhalations (1+1+2)--total cumulative delivered dose of 18 microg formoterol--with the following sequences: (1) formoterol pre-treatment + formoterol 18 microg, (2) formoterol pre-treatment + placebo, (3) placebo pre-treatment + formoterol 18 microg, (4) placebo pre-treatment + placebo. Formoterol 9 microg induced significant (P < 0.0001) bronchodilation at 2 h after inhalation (best mean increase in FEV(1): 0.170 L). Afterwards, dose-dependent increases in FEV(1) occurred with formoterol (maximum mean increase from 2-h value with formoterol: 0.072 after formoterol pre-treatment, and 0.201 L after placebo pre-treatment). Both maximum values of bronchodilation after the last inhalation of formoterol were statistically different (P < 0.001) from 2-h levels. These results show that dose-dependent bronchodilatation of formoterol is maintained despite regular treatment.     

Onset of action of formoterol/budesonide in single inhaler vs. formoterol in patients with COPD

Formoterol is a beta(2)-agonist bronchodilator that combines a fast onset of action with a long duration of broncholytic effect. An increasing documentation is showing that the combination of a long acting beta(2)-adrenoceptor agonist bronchodilator and an inhaled corticosteroid targets the airways obstruction in patients with COPD. In this study, we have explored whether the acute addition of an inhaled corticosteroid influences the fast bronchodilator response to formoterol. A total of 20 patients with stable COPD were randomized. Single doses of formoterol/budesonide 2 x (4.5/160)microg or formoterol 2 x 4.5 microg were given via Turbuhaler. Serial measurements of FEV(1) were performed over 60 min. Formoterol/budesonide elicited a significantly larger mean FEV(1)-AUC(0-15 min) than formoterol alone. Also the change in FEV(1) 15 min after inhalation of formoterol/budesonide combination (0.197 l; 95% CI: to 0.142-0.252) was greater than that induced by formoterol alone (0.147 l; 95% CI: to 0.092-0.201). The mean increases in FEV(1) were always higher after budesonide/formoterol than formoterol alone, although both treatments induced a significant improvement over baseline at each explored time point. Even the FEV(1)-AUC(0-60 min) after formoterol/budesonide was significantly larger than that after formoterol. Both treatments induced a significant reduction in VAS score but did not modify heart rate in a statistically significant manner. This study indicates that the addition of budesonide influences the fast onset of action of formoterol, but does not induce systemic effects, in patients with stable COPD.     

Anti-inflammatory effects of combined budesonide/formoterol in COPD exacerbations

Systemic corticosteroids and additional short-acting beta2-agonists are commonly used in exacerbations of chronic obstructive pulmonary disease (COPD). In this double-blind study, the combination of a high-dose inhaled corticosteroid with a rapid-onset long-acting beta2-agonist was evaluated in the treatment of out-patient COPD exacerbations. The primary aim was to compare 14-day treatment effects of budesonide/formoterol to placebo on sputum eosinophils and, secondarily, on other indices of inflammation, forced expiratory flow in one second (FEV(1)), symptoms, health status, and adverse events. Forty-five patients not using steroids (37 male, 21/24 current/ex smoker, median packyears 38, age 65 years, FEV(1) 61% predicted), experiencing a COPD exacerbation, were treated at home with budesonide/formoterol (320/9 microg 4 times daily), prednisolone (30 mg daily), or placebo for 14 days. Sputum eosinophils were significantly reduced by budesonide/formoterol (-57%) compared to placebo (+24%) (p = 0.01). Budesonide/formoterol reduced total symptom scores significantly (p = 0.01) compared to placebo. The increase in FEV(1) by 2 weeks of treatment with budesonide/formoterol (125 ml) was not significantly different from that of placebo (43 ml) (p = 0.07). Budesonide/ formoterol treatment did not suppress morning serum cortisol compared to placebo (-16%; p = 0.50). In conclusion, budesonide/formoterol reduces sputum eosinophils and improves symptoms in the treatment of out-patient COPD exacerbations.     

Bronchodilator effects of indacaterol and formoterol in patients with COPD

BackgroundResting inspiratory capacity (IC) reflects static hyperinflation in chronic obstructive pulmonary disease (COPD). This study compared the effects of formoterol and indacaterol, a novel once-daily ultra-long-acting β₂-agonist (or ultra-LABA), on resting IC and forced expiratory volume in 1 s (FEV₁).MethodsThirty patients with COPD (mean FEV₁/FVC 0.49, mean FEV₁ 56% predicted) each inhaled three treatments (two in randomized sequence followed by open-label formoterol) on separate study days: a single dose of indacaterol 300 μg, matching placebo, and two doses of formoterol 12 μg 12 h apart.ResultsIndacaterol and formoterol increased FEV₁ and IC at all time points relative to placebo (p < 0.001). Peak effects on FEV₁ were similar, while indacaterol had a greater effect on peak IC (31% vs 23% from pre-dose; p = 0.034). Indacaterol had a greater effect than formoterol on FEV₁ at 8 h (1.47 vs 1.39 L; p = 0.014) and 24 h (1.44 vs 1.35 L; p = 0.003), and on IC from 4 to 24 h (differences of 0.13–0.19 L; p < 0.05). At 24 h, indacaterol and formoterol increased FEV₁ by 17.7% and 7.5%, respectively, from pre-dose.ConclusionsThis study discriminated between the effects on IC and FEV₁ of once daily indacaterol and twice daily formoterol. The greater effect of indacaterol on IC may translate into improved long-term clinical outcomes.     

Bronchodilator response to formoterol after regular tiotropium or to tiotropium after regular formoterol in COPD patients

We conducted a randomized, crossover trial with tiotropium 18 microg once daily (group A), and formoterol 12 microg twice daily (group B) over a 5-day period for each drug, with a 10-day washout, in 20 COPD patients. At the end of each period, patients inhaled both drugs separated by 180 min in alternate sequence (group A: tiotropium 18 microg+formoterol 12 microg; group B: formoterol 12 microg+tiotropium 18 microg). FEV1 and FVC were measured at baseline and after 30, 60, 120, 180, 210, 240, 300 and 360 min. FEV1 and FVC further improved after crossover with both sequences. The mean maximal change in FEV1 over baseline was 0.226 L (0.154-0.298) after tiotropium+formoterol and 0.228 L (0.165-0.291) after formoterol+tiotropium; the mean maximal change in FEV1 over pre-inhalation the second drug value was 0.081 L (0.029-0.133) after tiotropium+formoterol and 0.054 L (0.016-0.092) after formoterol+tiotropium. The mean maximal change in FVC over baseline was 0.519 L (0.361-0.676) after tiotropium+formoterol and 0.495 L (0.307-0.683) after formoterol+tiotropium; the mean maximal change in FVC over pre-inhalation of the second drug value was 0.159 L (0.048-0.270) after tiotropium+formoterol and 0.175 L (0.083-0.266) after formoterol+tiotropium. The FEV1 AUCs(0-360 min) were 62.70 (45.67-79.74) after tiotropium+formoterol and 69.20 (50.84-87.57) after formoterol+tiotropium, the FEV1 AUCs(0-180 min) were 24.70 (18.19-31.21) after tiotropium+formoterol and 29.74 (21.02-38.46) after formoterol+tiotropium, whereas the FEV1 AUCs(180-360 min) were 15.70 (10.88-20.52) after tiotropium+formoterol and 11.71 (7.21-16.21) after formoterol+tiotropium. Differences between the two treatments were not statistically significant (P>0.05). The addition of second different long-acting bronchodilator to a regularly administered long-acting bronchodilator seems to be to patient's advantage.     

Comparison of the efficacy, tolerability, and safety of formoterol dry powder and oral, slow-release theophylline in the treatment of COPD

STUDY OBJECTIVE: To compare the efficacy, tolerability, and safety of therapy with formoterol and oral slow-release theophylline (THEO) in patients with COPD. DESIGN: A randomized, parallel-group study, with double-blind arms for formoterol and placebo (PL) and an open arm for oral slow-release THEO administered in individual doses on the basis of plasma concentrations. SETTING: Eighty-one centers worldwide. PATIENTS: Eight hundred fifty-four patients with symptomatic COPD. INTERVENTION: Comparison of twice-daily inhaled formoterol dry powder (12 or 24 microg), PL, and THEO (individualized doses) over 12 months. MEASUREMENTS AND RESULTS: Compared to PL, doses of formoterol and THEO both significantly improved the area under the curve for FEV(1) measured over a period of 12 h following the morning dose of study medication at 3 and 12 months (p < 0.001 for all comparisons). Therapy with formoterol, 12 microg, was significantly more effective than that with THEO (p < or = 0.026). Formoterol significantly reduced the percentage of "bad days" (i.e., days with at least two individual symptom scores > or = 2 and/or a reduction in peak expiratory flow from a baseline of > 20%; p < or = 0.035 vs. PL and THEO), and the use of salbutamol rescue medication (p < or = 0.003 vs PL) over the whole treatment period, while the effect of THEO was similar to that of PL. Therapy with formoterol and THEO was more effective than PL at improving quality of life for > 12 months (p < or = 0.030). Treatment-related adverse events and discontinuations were more frequent among patients receiving THEO than among those receiving formoterol. CONCLUSIONS: Long-term treatment with inhaled formoterol dry powder is more effective and better tolerated than treatment with therapeutically appropriate doses of oral slow-release THEO in symptomatic patients with COPD.     

Long-term efficacy of formoterol compared to salbutamol

In a randomized, double-blind, between-patient, multicenter study in 301 patients with ROAD, the efficacy and tolerability of the new long-acting selectiveβ ₂-sympathicomimetic drug formoterol (12μg inhalation b.i.d.) was compared with salbutamol (200μg inhalation q.i.d.). There was no statistically significant (s.s.) difference in acute reversibility and long-term efficacy of both drugs, measured by the point in time of expected maximal effect. However, formoterol had a highly s.s. longer duration of action than salbutamol, as shown by peak expiratory flow (PEF) measurements: the overall mean morning PEF in the formoterol group was 341 L/min.14 h after the last taken dose and in the salbutamol group this measure was 304 L/min9 h after the last dose. The patients taking formoterol had s.s. less asthma attacks and needed s.s. less rescue medication than those taking salbutamol. In the global assessment of efficacy, formoterol was accepted as being s.s. better (“very good” + “good”: 76%) than salbutamol (“very good” + “good”: 50%). The tolerability of each drug, as reflected by adverse reactions and global assessment, was equally good in both groups. Ninety-one percent of the patients in the formoterol group wanted to receive the same drug again versus 79% in the salbutamol group.     

慢性阻塞性肺疾病支气管舒张试验47例临床分析

目的探讨支气管舒张试验不同结果的慢性阻塞性肺疾病(COPD)患者的临床特点。方法对2007年4月至2008年1月上海交通大学医学院附属新华医院呼吸内科住院的47例COPD患者进行肺功能及支气管舒张试验的检查,并收集患者相关临床资料,对于不同的支气管舒张试验结果进行比较分析。结果舒张试验阳性组的COPD患者吸烟史明显少于阴性组(P<0.05),而血清IgE则明显高于阴性组(P<0.05)。阳性组用力肺活量(FVC)改善率、第一秒钟用力呼气容积(FEV1)改善率、功能残气量(FRC)、75%肺活量时的最大呼气流量(MEF75%)改善率、50%肺活量时的最大呼气流量(MEF50%)改善率均高于阴性组(P<0.05),其中尤以FEV1改善率、MEF75%改善率、MEF50%改善率明显(P<0.01)。不同分级的COPD患者舒张试验的结果差异有统计学意义(P<0.05)。结论吸烟是影响COPD患者支气管舒张试验结果的一个因素。支气管舒张试验阳性的COPD患者具有更高的血清IgE水平,可能存在气道高反应性。舒张试验阳性的COPD患者气流受限的小气道的改善不明显,可能是以大中气道的改善为主。轻-中度的COPD患者更具有的气流受限的可逆性。     

Effects of formoterol on exercise tolerance in severely disabled patients with COPD

OBJECTIVE: We wished to evaluate the effects of inhaled formoterol, a long-acting beta(2)-adrenergic agonist, on exercise tolerance and dynamic hyperinflation (DH) in severely disabled chronic obstructive pulmonary disease (COPD) patients. DESIGN: In a two-period, crossover study, 21 patients with advanced COPD (FEV(1)=38.8+/-11.7% predicted, 16 patients GOLD stages III-IV) were randomly allocated to receive inhaled formoterol fumarate 12 microg twice daily for 14 days followed by placebo for 14 days, or vice versa. Patients performed constant work-rate cardiopulmonary exercise tests to the limit of tolerance (Tlim) on a cycle ergometer: inspiratory capacity (IC) was obtained at rest and each minute during exercise. Baseline and transitional dyspnoea indices (BDI and TDI) were also recorded. RESULTS: Eighteen patients completed both treatment periods. Formoterol treatment was associated with an estimated increase of 130 s in Tlim compared with placebo (P=0.052): this corresponded to a 37.8% improvement over placebo (P=0.012). Enhanced exercise tolerance after bronchodilator was associated with diminished DH marked by higher inspiratory reserve and tidal volumes at isotime and exercise cessation (P<0.05). There was no significant difference between formoterol and placebo on exercise dyspnoea ratings; however, all domains of the TDI improved (P相似文献