Improved health outcomes in patients with COPD during 1 yr's treatment with tiotropium.

Tiotropium, a novel once-daily inhaled anticholinergic, has been shown to improve lung function over a 24-h period. In order to extend these findings, health-outcomes were evaluated over 1 yr in chronic obstructive pulmonary disease (COPD) patients. Spirometric results, peak expiratory flow rate (PEFR), salbutamol use and effects on dyspnoea, health-related quality of life and COPD exacerbations were assessed in two identical 1-yr randomized double-blind double-dummy studies of tiotropium 18 microg once daily (n=356) compared with ipratropium 40 microg q.i.d. (n=179). Screening forced expiratory volume in one second (FEV1) were 1.25+/-0.43 L (41.9+/-12.7% of the predicted value) (tiotropium) and 1.18+/-0.37 L (39.4+/-10.7% pred) (ipratropium). Trough FEV1 at 1 yr improved by 0.12+/-0.01 L with tiotropium and declined by 0.03+/-0.02 L with ipratropium (p<0.001). Significant improvement in PEFR, salbutamol use, Transition Dyspnea Index focal score, and the St George's Respiratory Questionnaire total and impact scores were seen with tiotropium (p<0.01). Tiotropium reduced the number of exacerbations (by 24%, p<0.01), and increased time to first exacerbation (p<0.01) and time to first hospitalization for a COPD exacerbation (p<0.05) compared with ipratropium. Apart from an increased incidence of dry mouth in the tiotropium group, adverse events were similar between treatments. Tiotropium was effective in improving dyspnoea, exacerbations, health-related quality of life and lung function in patients with chronic obstructive pulmonary disease, and exceeds the benefits seen with ipratropium. The data support the use of tiotropium once-daily as first-line maintenance treatment in patients with chronic obstructive pulmonary disease.     

A comparison of the effects of salbutamol and ipratropium bromide on exercise endurance in patients with COPD

STUDY OBJECTIVE: Inhaled bronchodilators are the first-line pharmacotherapy against COPD. The purpose of the present study was to investigate the effects of beta(2)-agonists and anticholinergic agents on the exercise capacity of patients with COPD. METHODS: A total of 67 stable patients with COPD were recruited at the Kyoto University Hospital. After inhaling 400 micro g salbutamol, 80 micro g ipratropium bromide, or an identical placebo in a randomized, double-blind, crossover fashion, the patients performed cycle endurance tests at a constant workload of 80% of the maximum work rate reached on progressive cycle ergometry, and the endurance time was recorded. RESULTS: Both salbutamol and ipratropium bromide significantly improved the endurance time by 29 s (15%; p < 0.001) and 27 s (14%; p < 0.001), respectively, in comparison with the placebo. However, there was no statistically significant difference between them (p = 0.71). The dyspnea ratios were also similarly reduced by both bronchodilators. The difference in the endurance time between therapy with salbutamol and placebo was significantly, but moderately, related to the difference between therapy with ipratropium bromide and placebo. In addition, there were no relationships, or only weakly significant relationships, between the change in FEV(1) and the change in the endurance time, the highest oxygen uptake, and the highest minute ventilation for both salbutamol and ipratropium bromide. CONCLUSIONS: Therapy with both salbutamol and ipratropium bromide improved exercise capacity, as evaluated by the endurance time, and reduced dyspnea similarly in patients with COPD. In addition, the effects of the different bronchodilators on exercise capacity varied within individuals, and a complex mechanism may be responsible for the different effects of these two bronchodilators on exercise capacity vs airflow limitation. These results support the conclusion that both types of inhaled bronchodilators can be used as first-line drugs for the treatment of stable patients with COPD.     

In patients with COPD, treatment with a combination of formoterol and ipratropium is more effective than a combination of salbutamol and ipratropium : a 3-week, randomized, double-blind, within-patient, multicenter study

STUDY OBJECTIVES: To compare the efficacy of adding formoterol or salbutamol to regular ipratropium bromide treatment in COPD patients whose conditions were suboptimally controlled with ipratropium bromide alone. DESIGN: A randomized, double-blind, double-dummy, two-period, crossover clinical trial. SETTING: Twenty-four clinics and university medical centers in nine countries. PATIENTS: One hundred seventy-two patients with baseline FEV(1) < or = 65% predicted, with FEV(1) reversibility to salbutamol not exceeding the normal variability of the measurement, and symptomatic despite regular treatment with ipratropium bromide. INTERVENTIONS: Each patient received two treatments in random order: either inhaled formoterol dry powder, 12 microg bid, in addition to ipratropium bromide, 40 microg qid for 3 weeks, followed by salbutamol, 200 microg qid, in addition to ipratropium, 40 microg qid for 3 weeks, or vice versa. MEASUREMENTS AND RESULTS: Efficacy end points included morning premedication peak expiratory flow (PEF) during the last week of treatment (primary end point), the area under the curve (AUC) for FEV(1) measured for 6 h after morning dose on the last day of treatment, and symptom scores (from daily diary recordings). Morning PEF and the AUC for FEV(1) were significantly better for formoterol/ipratropium than for salbutamol/ipratropium (p = 0.0003 and p < 0.0001, respectively). The formoterol/ipratropium combination also induced a greater improvement in mean total symptom scores (p = 0.0042). The safety profile of the two treatments was comparable. CONCLUSIONS: In COPD patients requiring combination bronchodilator treatment, the addition of formoterol to regular ipratropium treatment is more effective than the addition of salbutamol.     

The role of domiciliary nebulizers in managing patients with severe COPD

The difficulty of assessing nebulizer responses in chronic obstructive pulmonary disease (COPD) has been demonstrated before. This study aims to re-examine both the role of domiciliary nebulizers in COPD and also bronchodilator (BD) assessment in individuals. In a double-blind, randomized, cross-over trial, 19 stable patients with severe COPD were given the following medication 6-hourly for 2-week periods: (1) nebulized salbutamol 2.5 mg with ipratropium 0.5 mg and placebo inhalers (MDI) with spacer; (2) placebo nebules and inhaled salbutamol 400 microg with ipratropium 80 microg via MDI with spacer; (3) inhaled salbutamol 400 microg with ipratropium 80 microg via MDI with spacer (but no placebo nebulized drugs). Both nebulized and MDI drugs produced highly significant improvements in forced expiratory volume in 1 sec (FEV1), forced vital capacity (FVC), specific airways conductance, 6-min walking distance (6MWD) and residual volume. There were no significant differences between BD responses obtained after active nebulized and active MDI BDs. From the diary cards, 2 weeks of active nebulized BDs produced a slightly higher median peak expiratory flow (PEF) than active MDI BDs (236 and 219 l m(-1), respectively, P=0.01) and slightly less extra inhaler use (0.8 and 1.1 puffs, respectively, P<0.05) but no significant difference in dyspnoea or quality of life (QOL) scores. There were significant correlations between domiciliary PEF and acute BD-induced changes in FVC and 6MWD, and also between domiciliary dyspnoea scores and acute changes in both total lung capacity and 6MWD. In conclusion, nebulized medication conferred little clinical advantage over the regular use of inhalers with spacers in this group of patients with severe COPD. However, acute changes in total lung capacity, FVC and 6MWD may be useful predictors of the longer-term effects of nebulized BDs in individual patients.     

Does a single dose of the phosphodiesterase 4 inhibitor,cilomilast (15 mg), induce bronchodilation in patients with chronic obstructive pulmonary disease?

Maintenance treatment with PDE(4) inhibitor cilomilast improves FEV(1) in chronic obstructive pulmonary disease (COPD) patients. We investigated the acute bronchodilating effects of a single dose of cilomilast with or without concomitant administration of inhaled salbutamol and/or ipratropium bromide in 21 patients with COPD (mean (SD) age 64 (8.1) y, post-salbutamol FEV(1) 47.7 (13.2) %predicted). FEV(1) was measured before and up to 8 hourly intervals after intake of placebo, cilomilast, or cilomilast in combination with inhaled salbutamol 400 microg and/or ipratropium bromide 80 microg. Maximum increase in FEV(1) from pre-dose baseline was calculated after each treatment and differences between treatment arms were analyzed by ANOVA. The mean (SEM) maximum increase in FEV(1) was 139.6 (18.5) ml following cilomilast and 151.5 (18.5) ml following placebo (95% C.I. for mean difference between cilomilast and placebo: -67.3, 43.6 ml). Furthermore, combined treatment of cilomilast with salbutamol or ipratropium resulted in a maximum increase in FEV(1) of 280.7 (25.6) and 297.0 (25.9) ml, respectively, while this was 379.0 (24.6) ml following cilomilast with both salbutamol and ipratropium (p < 0.01). We conclude that a single dose of cilomilast does not produce acute bronchodilation in patients with COPD who otherwise respond to inhaled bronchodilators. Our results implicate that the change in lung function seen after long-term treatment with cilomilast is not the result of acute bronchodilation in patients with COPD.     

Evaluation of the efficacy and safety of levalbuterol in subjects with COPD

The efficacy and safety of nebulized levalbuterol in adults with chronic obstructive pulmonary disease (COPD) was evaluated in this multicenter, randomized, double-blind, parallel design study. Randomized subjects (n = 209) received levalbuterol (LEV) 0.63 mg or 1.25 mg, racemic albuterol (RAC) 2.5 mg, or placebo (PBO) TID for 6 weeks. Serial spirometry was completed in-clinic after study drug alone (weeks 0, 2, and 6) or in combination with ipratropium bromide 0.5 mg (week 4). The primary endpoint was the averaged FEV1 AUC(0-8 hrs) over weeks 0, 2 and 6 compared with placebo. Other endpoints included rescue medication use, safety parameters, COPD exacerbations, and global evaluations. All active treatments demonstrated improvements in the percent change in FEV1 AUC(0-8 hrs) over the double-blind period and at each visit vs PBO (p < 0.05). Rescue medication use vs. baseline (doses/day) changed over time: PBO +0.38 +/- 3.3; LEV 0.63 mg +0.07 +/- 3.3; LEV 1.25 mg -0.84 +/- 3.8 (p = 0.02 vs. RAC); RAC +0.97 +/- 2.5. The overall rate of adverse events was PBO 56.4%, LEV 0.63 mg 56.6%, LEV 1.25 mg 67.3%, and RAC 65.4%. Protocol-defined COPD exacerbations occurred in all groups (PBO 12.7%, LEV 0.63 mg 11.3%; LEV 1.25 mg 18.4%; RAC 21.2%). Withdrawals due to COPD exacerbations were significantly higher in the RAC group compared with PBO (PBO 0%; LEV 0.63 mg 1.9%; LEV 1.25 mg 4.1%; RAC 9.6% p = 0.01 vs. PBO). In this study, levalbuterol treatment in subjects with COPD was generally well tolerated, produced significant bronchodilation compared with PBO, and improved clinical control of COPD as evidenced by reductions in rescue medication use compared with PBO and/or RAC.     

Effect of 1-year treatment with roflumilast in severe chronic obstructive pulmonary disease

RATIONALE: The oral phosphodiesterase-4 (PDE4) inhibitor, roflumilast, can improve lung function in moderate chronic obstructive pulmonary disease (COPD). Whether treatment is effective in more severe COPD (GOLD [Global Initiative for Chronic Obstructive Lung Disease] stages III and IV) over a longer period is unknown. OBJECTIVES: To determine whether roflumilast improves lung function and decreases exacerbation frequency over 1 year in patients with stable COPD. METHODS: We conducted a randomized, placebo-controlled, double-blind, parallel-group trial for 1 year. We recruited 1,513 patients (mean post-bronchodilator FEV1 41% predicted), 760 receiving oral 500 microg roflumilast and 753 receiving placebo once daily. MEASUREMENTS AND MAIN RESULTS: We recorded post-bronchodilator FEV1, exacerbation rate, St. George's Respiratory Questionnaire total score at the study end point, and number and type of reported adverse events during treatment. Post-bronchodilator FEV1 increased by 39 ml with roflumilast compared with placebo by 52 weeks (p=0.001). The mean exacerbation rate was low and comparable in both treatment groups (0.86 vs. 0.92 exacerbations/patient/yr for roflumilast and placebo, respectively). In a retrospective analysis, the exacerbation rate in patients in GOLD stage IV disease was 36% lower in patients treated with roflumilast than in those treated with placebo (1.01 vs. 1.59 exacerbations/patient/year, respectively; p=0.024). The St. George's Respiratory Questionnaire total score did not differ between treatments. The commonest adverse events related to roflumilast treatment were diarrhea, nausea, and headache, which usually subsided during continued treatment. However, roflumilast resulted in more withdrawals within the first 3 to 4 weeks of administration. CONCLUSIONS: In severe, stable COPD, PDE4 inhibition with roflumilast produced a modest but significant improvement in lung function without changing the exacerbation rate or health status. However, patients with very severe disease experienced fewer exacerbations with roflumilast.     

Bronchodilating effect of combined therapy with ipratropium bromide and ondansetron in patients with COPD

The objectives of this study were to determine the effect of single and repeat dosing with oral ondansetron, a 5-HT3-specific receptor blocker, on the degree and duration of bronchodilation induced by inhaled ipratropium bromide in patients with COPD. Five clinics and university medical centers in four countries participated in the study; 47 patients with COPD were randomized to treatment; 44 completed all treatments. Patients had a baseline (pre-bronchodilator) FEV1>1L and post-bronchodilator (200 mcg salbutamol) FEV1<90% of predicted, with FEV1 reversibility (to 80 mcg inhaled ipratropium bromide and 400 mcg salbutamol) of at least 12% or 200 mL over baseline. The study was divided into two parts. In Part A, each patient received in a random order, four-way crossover manner, single doses of ondansetron placebo (oral) plus ipratropium bromide placebo (inhaled), ondansetron placebo plus ipratropium bromide 40 mcg inhaled via MDI, ondansetron 24 mg oral plus ipratropium bromide placebo and ondansetron 24 mg plus ipratropium bromide 40 mcg. In Part B, each patient received in a random order, two-way crossover manner, ipratropium bromide 40 mcg tid via MDI plus ondansetron 8 mg oral, qid, for 2 days; on day 3 patients received a single dose of ipratropium bromide 40 mcg plus 8 mg oral ondansetron. Alternatively, patients received ipratropium bromide via MDI and oral ondansetron placebo, as described above. Statistically significant differences in weighted mean FEV1 (0-6h), peak FEV1 and FEV1 determined 6h post-dose were noted comparing ipratropium bromide to placebo. Similar positive results were observed for sGaw and FVC. Addition of ondansetron to ipratropium bromide did not significantly modify values obtained with ipratropium alone. Ipratropium bromide induced a marked bronchodilation, compared to placebo. Addition of ondansetron (single or repeated doses) did not significantly increase the degree or duration of bronchodilation induced by ipratropium alone. sGaw was consistently more sensitive than FEV1 in measuring extent and duration of bronchodilation.     

Concomitant treatment with nebulized formoterol and tiotropium in subjects with COPD: a placebo-controlled trial

Adding a long-acting beta(2)-agonist (LABA) by dry powder inhaler (DPI) to tiotropium provides significantly increased and sustained bronchodilation in chronic obstructive pulmonary disease (COPD) patients over either product alone. To demonstrate similar benefits with a nebulized LABA, a placebo-controlled trial was conducted to evaluate the efficacy and safety of formoterol fumarate inhalation solution in subjects receiving tiotropium as a maintenance treatment for COPD. After a 7-14-day screening period using tiotropium 18 microg once daily, subjects with diagnosed COPD (> or = 25% to <65% predicted FEV(1)) were randomized to receive 20 microg formoterol fumarate inhalation solution twice daily for nebulization plus tiotropium (FFIS/TIO) or nebulized placebo twice daily plus tiotropium (PLA/TIO) for 6 weeks. Efficacy was assessed with spirometry at each visit (Day 1, Week 1, 3, 6), the transition dyspnea index (TDI), and St. George's Respiratory Questionnaire (SGRQ). Baseline characteristics were comparable, including mean FEV(1)% predicted. At Week 6, FEV(1) AUC(0-3) was 1.52 L for FFIS/TIO-treated subjects vs. 1.34 L for PLA/TIO-treated subjects (p<0.0001). The mean TDI scores in the FFIS/TIO and PLA/TIO groups were 2.30 and 0.16, respectively (p=0.0002). SGRQ did not change significantly with 6 weeks treatment, with the exception of FFIS/TIO improvements in symptom score vs. PLA/TIO (p=0.04). More PLA/TIO- than FFIS/TIO-treated subjects experienced AEs (39.7% vs. 22.9%), COPD exacerbations (7.9% vs. 4.5%), and serious AEs (3.2% vs. 1.5%). Nebulized formoterol fumarate in combination with tiotropium provided statistically and clinically significant improvements in bronchodilation and symptom control over tiotropium alone and demonstrated good tolerability.     

Effect of ipratropium bromide treatment on oxygen saturation and sleep quality in COPD.

STUDY OBJECTIVES: Patients with COPD are at risk of experiencing a deterioration in arterial oxygen saturation (SaO2) during sleep, which is generally most pronounced during rapid eye movement (REM) sleep. Increased cholinergic tone has been suggested as a contributing factor to this decrease in SaO2. Therefore, we investigated whether 4-week treatment with ipratropium bromide inhalation solution 0.02% (qid) could improve sleep characteristics in COPD. DESIGN: Randomized, placebo-controlled, double-blind, two-arm parallel study of 4 weeks of treatment with ipratropium bromide solution or placebo. SETTING: Multicenter investigation. PATIENTS: Thirty-six patients with moderate-to-severe COPD (FEV1 < 65% of predicted). MEASUREMENTS AND RESULTS: Evaluation included polysomnographic, pulmonary function, and subjective quality of sleep (visual analog scale [VAS]) assessments. It was found that 4 week of treatment with ipratropium bromide solution in patients with COPD led to the following: (1) a significant (p = 0.05) improvement in mean nocturnal SaO2 with the more severe the nocturnal desaturation, the greater the improvement in SaO2; (2) significant (p = 0.03) improvement in perceived sleep quality (VAS: 5.5 +/- 0.5 after placebo; 7.2 +/- 0.5 after ipratropium); (3) a significant (p = 0.05) increase in REM sleep time (48.6 +/- 6.3 min after placebo; 66.5 +/- 6.4 min after ipratropium) with no effect on other sleep stages or total sleep time; and (4) a significant (p = 0.01) increase in pre-sleep FVC and flow rate at 50% of the vital capacity. CONCLUSIONS: These findings demonstrate that ipratropium bromide therapy can improve sleep SaO2 as well as sleep quality in patients with moderate-to-severe COPD.     

Acute bronchodilator trials in chronic obstructive pulmonary disease.

Short-term trials of bronchodilator drugs are widely used to assess patients with stable chronic obstructive pulmonary disease (COPD), but there is an uncertainty about the equivalence of the FEV1 response to beta-agonists and anticholinergic drugs, their relative ability to identify patients likely to improve with corticosteroids, the most appropriate way to express the results of these tests, and whether age or allergic status affects the beta-agonist and anticholinergic response differently. We studied 100 consecutive patients with stable COPD (mean FEV1, 0.96 +/- 0.48 L; mean age, 62 +/- 8 yr). Spirometry was measured before and after either 5 mg of nebulized salbutamol or 500 micrograms of nebulized ipratropium bromide and repeated after 2 wk of 30 mg of oral prednisolone daily. Total IgE, specific RAST, and skin prick testing values were recorded. Using modified American Thoracic Society response criteria, 33 patients failed to bronchodilate after the acute trials, 16 responded only to nebulized salbutamol, 17 to nebulized ipratropium, and 34 to both drugs. Twenty-two patients improved after corticosteroids. This was usually detected by a positive acute trial response (salbutamol 90% specific; ipratropium 84% specific). Baseline FEV1 differed between days, and in those who responded on only 1 day, this variation correlating with the response to ipratropium (r = 0.66). Expressing the response criterion as a percentage change in the available bronchodilatation increased the numbers responding with a high baseline FEV1, and vice versa. Neither age nor allergic status was related to the change in FEV1 after either drug in these patients. In COPD patients, testing with high-dose nebulized bronchodilators identifies a substantial number of partially reversible patients whatever age it is employed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of nebulized budesonide and oral prednisolone with placebo in the treatment of acute exacerbations of chronic obstructive pulmonary disease: a randomized controlled trial

Nebulized budesonide has been used successfully to treat acute asthma exacerbation, and we hypothesized that it could also be effective for exacerbations of chronic obstructive pulmonary disease (COPD). In this multicenter, double-blind, randomized, placebo-controlled trial, the efficacy of nebulized budesonide (Pulmicort Respules/Nebuamp), oral prednisolone, and placebo was compared in 199 patients with acute exacerbations of COPD requiring hospitalization. Patients received from randomization (H(0)) to 72 h (H(72)), 2 mg of budesonide every 6 h (n = 71), 30 mg of oral prednisolone every 12 h (n = 62), or placebo (n = 66). All received standard treatment, including nebulized beta(2)-agonists, ipratropium bromide, oral antibiotics, and supplemental oxygen. The mean change (95% confidence interval) in postbronchodilator FEV(1) from H(0) to H(72) was greater with active treatments than with placebo: budesonide versus placebo, 0.10 L (0.02 to 0.18 L); prednisolone versus placebo, 0.16 L (0.08 to 0.24 L). The difference in FEV(1) between budesonide and prednisolone was not significant, -0.06 L (-0.14 to 0.02 L). The occurrence of serious adverse events was similar for all groups. Budesonide had less systemic activity than prednisolone as indicated by a higher incidence of hyperglycemia observed with prednisolone. Both budesonide and prednisolone improved airflow in COPD patients with acute exacerbations when compared with placebo. Nebulized budesonide may be an alternative to oral prednisolone in the treatment of nonacidotic exacerbations of COPD but further studies should be done to evaluate its long-term impact on clinical outcomes after an initial episode of COPD exacerbation.     

Dose response to ipratropium as a nebulized solution in patients with chronic obstructive pulmonary disease. A three-center study

We performed a dose-response study of ipratropium bromide as a nebulized solution in patients with stable chronic obstructive pulmonary disease (COPD) using a double-blind crossover format. Five doses from 0.05 to 0.6 mg of ipratropium bromide as a nebulized solution, the standard dose of ipratropium bromide by metered-dose inhaler, 40 micrograms, and placebo were given in random order on separate days. End points were the maximal increase in FEV1 and FVC, and the area under the FEV1 and FVC curves in the 8 h after administration of each of the seven treatments. Forty-two patients completed all seven study days. By each of the above end points for FEV1, 0.4 and 0.6 mg of nebulized ipratropium bromide achieved significantly more bronchodilatation than did each of the other treatments. These two doses were not significantly different from each other, suggesting that the optimal dose in this patient population is 0.4 mg. After this dosage, the FEV1 increased by 440 +/- 194 (mean +/- 1 SD) ml at peak effect between 1 and 2 h, and significant bronchodilatation persisted for 6.5 h. Ipratropium bromide by metered-dose inhaler (40 micrograms) was equivalent to approximately 0.1 mg by nebulized solution and achieved only 63 to 73% of the bronchodilatation achieved by optimal doses of the nebulized solution. In terms of FVC, all treatments with ipratropium were significantly better than with placebo. The area under the FVC curve was significantly greater after 0.4 and 0.6 mg of nebulized solution than after other treatments. No significant adverse experiences occurred with any of the treatments.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ipratropium bromide hydrofluoroalkane inhalation aerosol is safe and effective in patients with COPD

STUDY OBJECTIVE: To compare the efficacy and safety of ipratropium bromide reformulated with the chlorofluorocarbon (CFC)-free propellant hydrofluoroalkane (HFA)-134a (ipratropium bromide HFA) to that of the marketed ipratropium bromide inhalation aerosol (containing CFC) in patients with COPD. DESIGN: This was a randomized, double-blind, parallel-group, placebo-controlled, multicenter trial. The primary efficacy parameter was acute bronchodilator response. The primary end points were peak change in FEV(1) from baseline and area under the response-time curve. SETTING: Thirty-one clinical centers in the United States participated in this project. PATIENTS: A total of 507 patients with moderate-to-severe COPD were randomized, and 444 patients completed the trial. INTERVENTIONS: Twelve weeks of treatment four times daily with one of the following: ipratropium bromide HFA, 42 microg; ipratropium bromide HFA, 84 microg; HFA placebo; ipratropium bromide inhalation aerosol, 42 microg; or CFC placebo. Measurements and results: Patients in all active treatment groups had significant bronchodilator responses as shown by increases in mean FEV(1) from baseline of at least 15%. Bronchodilator response in all active treatment groups was also significantly more than their respective placebo treatments based on FEV(1), area under the time-response curve from 0 to 6 h, and peak response. FVC results were similar to those seen with FEV(1). There were no significant differences in adverse events, laboratory findings, or ECG findings among the treatment groups. CONCLUSIONS: Ipratropium bromide HFA, 42 and mgr;g, provided bronchodilation comparable to the marketed ipratropium bromide CFC, 42 and mgr;g, over 12 weeks of regular use.     

Effects of formoterol and ipratropium bromide in COPD: a 3-month placebo-controlled study.

The aim of this study was to compare the effects of formoterol, ipratropium bromide and a placebo on walking distance, lung function, symptoms and quality of life (QoL) in chronic obstructive pulmonary disease (COPD) patients. A total of 183 patients (mean age 64 yrs, 86 female) with moderate-to-severe nonreversible COPD participated in this randomised, double-blind, parallel-group study. After a 2-week placebo run-in, patients were randomised to formoterol Turbuhaler 18 microg b.i.d. (delivered dose), ipratropium bromide 80 microg t.i.d. via a pressurised metered dose inhaler, or placebo for 12 weeks. Inhaled short-acting beta2-agonists were allowed as relief medication and inhaled glucocorticosteroids were allowed at a constant dose. The primary variable was walking distance in the shuttle walking test (SWT). Baseline mean SWT distance was 325 m, mean forced expiratory volume in one second (FEV1) was 40% predicted. Clinically significant improvements in SWT (>30 m) were seen in 41, 38 and 30% of formoterol, ipratropium and placebo patients, respectively (not significant). Mean increases from run-in were 19, 17 and 5 m in the formoterol, ipratropium and placebo groups, respectively. Both active treatments significantly improved FEV1, forced vital capacity, peak expiratory flow and daytime dyspnoea score compared with placebo. Formoterol reduced relief medication use compared with placebo. Neither active treatment improved QoL. Formoterol and ipratropium improved airway function and symptoms, without significant improvements in the shuttle walking test.     

A comparison of bronchodilating drugs in the treatment of stable COPD]

The purpose of this study was to establish the optimal bronchodilating drug among therapies currently available for clinical treatment of the stable phase of chronic obstructive pulmonary disease (COPD). The efficacy of ipratropium bromide 40 micrograms, salbutamol 200 micrograms, and ipratropium bromide 40 micrograms plus salbutamol 200 micrograms was compared in 14 patients with COPD. Daily PEFR was obtained during the last seven days of a 2 week period incorporating drug inhalation four times daily. FEV1 and FVC were assessed on the final day of the treatment period. In the absence of bronchodilating medication, FEV1 was 1.27 +/- 0.13 l (52.9 +/- 5.1% pred). With ipratropium bromide 40 micrograms alone, FEV1 was 1.43 +/- 0.13 l (59.8 +/- 5.3% pred). A similar value was obtained for salbutamol 200 micrograms: 1.45 +/- 0.14 l (61.0 +/- 5.4% pred). However, FEV1 following the administration of ipratropium bromide 40 micrograms in combination with salbutamol 200 micrograms was 1.51 +/- 0.13 l (63.6 +/- 5.3% pred). The percent increase in FEV1 (compared to the value obtained without medication) was significantly higher with combined ipratropium bromide 40 micrograms plus salbutamol 200 micrograms (122.2 +/- 3.8%) than with either ipratropium bromide 40 micrograms (114.8 +/- 5.5%) or salbutamol 200 micrograms (116.5 +/- 4.4%) alone. Furthermore, the daily post-dilator PEFR improved significantly more with the combined therapy four times a day (311 +/- 29 l/min) than with either ipratropium bromide 40 micrograms (296 +/- 30 l/min) or salbutamol 200 micrograms (303 +/- 29 l/min) therapy alone. There was no discernible difference between results obtained with ipratropium bromide 40 micrograms versus salbutamol 200 micrograms.(ABSTRACT TRUNCATED AT 250 WORDS)     

Detecting Improvements in Dyspnea in COPD Using a Three-Minute Constant Rate Shuttle Walking Protocol

Abstract

Rationale: We examined the responsiveness of a 3-minute constant rate shuttle walking protocol to detect improvements in exertional dyspnea following acute bronchodilation in COPD. Our hypothesis was that the 3-minute constant rate shuttle walking protocol would be able to adequately put forth improvements in exertional dyspnea following acute bronchodilation in this population. Methods: Using a placebo controlled, double-blind cross-over design, 39 patients with moderate to severe COPD performed a 3-min constant rate shuttle walking test during which they were asked to walk on a flat corridor at a speed that was externally imposed by an audio signal. During the test, dyspnea was graded using the 10-point modified Borg scale. The test was performed twice, following the administration of saline placebo or of 500 μg nebulized ipratropium bromide. Results: Improvements of respiratory pattern (respiratory rate and tidal volume) and statistically and clinically significant reductions in Borg dyspnea scores (? dyspnea score = 1.0 ± 0.2, p < 0.01) were seen during the 3-min shuttle walking protocol with ipratropium bromide compared to placebo. Conclusion: This 3-minute shuttle walking protocol adequately detected dyspnea and breathing pattern improvements following acute bronchodilation in COPD.     

Quality of life measurements and bronchodilator responsiveness in prescribing nebulizer therapy in COPD

Nebulized bronchodilators are widely regarded as the optimal treatment for maintenance therapy in patients with severe chronic obstructive pulmonary disease (COPD). The aim of the study was to assess whether detailed physiological, functional and quality of life-related measurements can assist in determining the requirement for nebulized bronchodilator therapy in patients with moderate to severe COPD. This was an unblinded, randomized, crossover study that compared intermediate (120 mcg ipratropium bromide and 600 mcg of salbutamol using metered dose inhaler (MDI) and spacer) and high dose (nebulized 500 mcg ipratropium bromide and 2.5 mg salbutamol) bronchodilator therapy, on physiological, functional and quality of life-related measurements in patients with COPD. A total of 25 patients (12 female), mean (SD) age 68 (7) years, FEV(1) 45 (10) % predicted completed the study. There was no statistically significant difference between the treatments in the pre- and post-bronchodilator lung function values, six-minute walk distance, breathlessness score or quality of life questionnaires. Fifteen patients preferred bronchodilator therapy with nebulizer and 10 with MDI and spacer. In 20 patients at least one positive response in quality of life score, lung function or six-minute walk, was observed on the preferred treatment. Only a proportion of patients with moderate or severe COPD prefer nebulized bronchodilator therapy. This study found that none of the parameters singly or in combination were consistently predictive of patients' preference for nebulized bronchodilator therapy. Therefore, we suggest that clinicians institute a trial of stepping up to an intermediate dose of bronchodilators prior to introducing nebulized therapy.     

Inhaled formoterol dry powder versus ipratropium bromide in chronic obstructive pulmonary disease.

We compared the effectiveness of inhaled formoterol with that of ipratropium in the treatment of chronic obstructive pulmonary disease (COPD). After a 2-wk run-in period, 780 patients with COPD were randomized to receive for 12 wk formoterol dry powder 12 or 24 microg twice daily, ipratropium bromide 40 microg four times daily, or placebo in a multicenter, double-blind, parallel-group study. The primary efficacy variable was the area under the curve for forced expiratory volume in 1 s (FEV(1)) measured over 12 h after 12 wk of treatment. Secondary variables included diary symptoms and quality of life. Both doses of formoterol and ipratropium significantly increased the area under the curve for FEV(1) in comparison with placebo (all p < 0.001). Both doses of formoterol were also significantly superior to ipratropium (all p < 0.025). Compared with placebo, both doses of formoterol significantly improved symptoms (all p < or = 0.007) and quality of life (p < 0.01 for total scores) whereas ipratropium did not show significant effects (all p > or = 0.3). All study treatments exhibited a similar safety profile. We conclude that formoterol is more effective than ipratropium bromide in the treatment of COPD, as the efficacy of ipratropium on airflow obstruction does not translate into a clinical benefit that patients can perceive.     

Efficacy and safety of formoterol fumarate delivered by nebulization to COPD patients

Nebulized solutions of long-acting bronchodilators provide an alternative to DPI and MDI delivery, particularly for COPD patients unable to use hand-held devices easily or correctly. The long-acting beta2-agonist, formoterol fumarate, is differentiated by its onset of significant bronchodilation within 5 min of administration. In a randomized, double-blind, double-dummy trial, COPD subjects (n=351, mean forced expiratory volume FEV1=1.3 L, 44% predicted) received nebulized formoterol fumarate (Perforomist inhalation solution; FFIS 20 microg) or DPI (Foradil Aerolizer; FA 12 microg), or placebo twice daily for 12 weeks. Efficacy was assessed with 12-h pulmonary function tests, and quality of life was assessed before and after treatment with the St. George's Respiratory Questionnaire (SGRQ). At the 12-week endpoint, FFIS significantly increased FEV1 AUC0-12h relative to placebo (p<0.0001). No evidence of tachyphylaxis was observed as indicated by maintained FEV1 AUC and reduced rescue albuterol use throughout treatment. FFIS also significantly increased peak FEV1, trough FEV1, and standardized FVC AUC0-12h compared with placebo. SGRQ assessment at Week 12 demonstrated significant and clinically meaningful improvements in total score (FFIS vs placebo, -4.9, p=0.0067), symptom, and impact scores. No significant differences in efficacy were observed between the two active treatments. Drug related AEs in the FFIS arm with a frequency > or = 1% and exceeding placebo were dry mouth, nausea, and insomnia. Nebulized FFIS provided significant improvement in respiratory status and quality of life in subjects with COPD relative to placebo and was well tolerated. The efficacy and safety profile of FFIS was comparable to FA DPI.