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.     

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.     

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 oral aminophylline and terbutaline versus aerosol albuterol in patients with chronic obstructive pulmonary disease

Bronchodilator efficacy of oral administration of aminophylline (400 mg) and terbutaline sulfate (5 mg) was compared with inhalation of three puffs of albuterol sulfate in 17 patients with stable chronic obstructive pulmonary disease in a double-blind crossover study. Two hours after either form of therapy, the patients were treated again with three puffs of albuterol. Forced expiratory volume in one second (FEV₁) increased significantly more from the baseline value after albuterol aerosol than after oral medication at 30, 60, and 120 minutes (paired t test, p < 0.01). After three puffs of albuterol at 120 minutes, FEV₁ increased to similar values an hour later on both days in 14 of 17 patients. Thirteen patients complained of side effects during oral therapy and none during aerosol therapy. Maximum bronchodilatation was achieved by albuterol aerosol in 14 of 17 patients, and addition of oral therapy produced no further increase of flow rate in these patients. Bronchodilator aerosol is the logical choice for treatment of chronic obstructive pulmonary disease because it is more effective than oral therapy and because it is free from side effects.     

Bronchodilator efficacy of the fixed combination of ipratropium and albuterol compared to albuterol alone in moderate-to-severe persistent asthma

BACKGROUND: The potential of anticholinergics to provide bronchodilatory benefits over short-acting beta(2)-agonists (SABA) alone in patients with moderate-to-severe persistent asthma has not been well defined. METHODS: An outpatient, randomized, double-blind, single-dose, crossover study in adult asthmatics with moderate-to-severe obstruction despite treatment with inhaled corticosteroids (ICS) was conducted comparing the fixed combination of ipratropium and albuterol (IB+ALB) to albuterol alone (ALB). Serial spirometry was performed over 6h. SABA were withheld for 8h, ICS and LABA for 24h. RESULTS: A total of 113 patients were randomized, 106 completed the study (males n=47; mean+/-SD age=51+/-13 years). Mean+/-SD baseline FEV(1)=1.4+/-0.5 L (49+/-12% predicted). IB+ALB resulted in significantly greater improvements over ALB in the average improvement over baseline in FEV(1) as approximated from the area under the curve from 0 to 6h after drug administration (72 ml, p<0.01) and mean peak FEV(1) response (55 ml, p<0.01) as well as higher FEV(1) responses at individual time points from 0.5 to 6h postdose (p<0.01 for all). Time to onset of response was similar between groups but time to peak and duration of response were longer with IB+ALB versus ALB (120 versus 60 min and 245 versus 106 min, respectively). CONCLUSION: IB+ALB resulted in significantly greater improvement in FEV(1) and longer duration of response compared to ALB alone in patients with moderate-to-severe persistent asthma (Trial number: 1012.50; ClinicalTrial.gov NCT00096616).     

Bronchodilator response during acute viral bronchiolitis in infancy

Bronchodilator responsiveness was assessed by measuring specific respiratory conductance before and after inhalation of aerosolized bronchodilator in 50 infants who had acute bronchiolitis due to respiratory syncytial virus infection. Thirty per cent of the infants showed an improvement in specific conductance. Responders could not be differentiated from nonresponders by family histories of atopy, eosinophil counts, or immunoglobulin levels in blood and nasal secretions. Eighty-three per cent of the families and 54% of the mothers of the infants were smokers. Babies of smoking mothers had lower specific conductances than did those of nonsmoking mothers but showed no differences in bronchodilator response. The clinical significance of this bronchodilator-responsive sub-group has yet to be defined.     

Glycemic response during exercise after administration of insulin lispro compared with that after administration of regular human insulin

To examine the glycemic response during exercise after administration of short-acting insulin lispro, we compared changes in plasma glucose concentrations during exercise performed by patients with diabetes after the administration of either insulin lispro or regular human insulin. Seven patients with diabetes (two with type 1 and five with type 2) participated in this study. Each of the insulin-depleted subjects received the same number of units of either insulin lispro or regular human insulin, delivered subcutaneously to the abdomen. The next day, each subject received a similar injection of the solution not previously administered. After each injection, the subjects were fed a standard meal of approximately 9 kcal/kg body weight. One hour after eating the test meal, the subjects performed 30 min of cycle ergometer exercise at 50% maximal oxygen uptake. Plasma glucose, insulin, glucagon, growth hormone (GH), and catecholamine concentrations were then measured at specific intervals. Insulin concentrations were higher and peaked earlier after administration of insulin lispro than after administration of regular human insulin. The length of time, needed to reach minimum plasma glucose concentration after exercise was begun, was significantly shorter after administration of insulin lispro, and the percentage of plasma glucose decrease induced by exercise relative to the peak concentration was significantly greater. No differences were found in the concentration changes of counterregulatory hormones between the insulin lispro data and the regular human insulin data. Compared with regular human insulin, insulin lispro induces a more rapid and greater decrease in plasma glucose concentration during exercise because of its faster absorption.     

Bronchodilator effect of inhaled formoterol vs salbutamol over 12 hours

The bronchodilator effects were compared in 16 stable asthma patients for 12 hours after either 12 micrograms formoterol or 200 micrograms salbutamol from a metered-dose aerosol in a randomized, double-blind, crossover study. The FEV1 measured before 1, 2, 4, 6, 8, 10 and 12 hours after administration was used as the parameter. From 2 hours onwards after dosage, the bronchodilator effect of formoterol was statistically significantly greater than that of salbutamol. The effect of formoterol lasted longer, and even after 12 hours, the FEV1 was still 20 percent above the baseline value. This is clinically significant and offers new possibilities for treatment of the so-called "morning dip." Both agents were well tolerated.     

Bronchodilator tolerance and rebound bronchoconstriction during regular inhaled beta-agonist treatment

There is uncertainty about the development of airway tolerance to beta-agonists and the phenomenon of rebound bronchoconstriction on beta-agonist withdrawal. We have recently completed a study of the regular terbutaline and budesonide treatment in asthma. We report our observations on the effect of starting and stopping terbutaline treatment on morning and evening peak flows. The study was a randomized four-way, double-dummy, cross-over comparison of regular inhaled terbutaline (500-1000 microg four times daily), budesonide, combined treatment and matching placebo. Each treatment was given for 6 weeks following a 4 week single-blind placebo washout. Ipratropium was used for symptom relief. No other asthma medication was permitted during either the treatment or wash-out periods. Evaluable data were obtained from 52 subjects for both placebo and terbutaline treatment. Changes in mean morning and evening peak flows during terbutaline treatment were compared to the baseline peak flows during the last 2 weeks of the preceding washout. The peak flow changes on stopping terbutaline were also analysed. Mean morning peak flow was not significantly different during terbutaline treatment when compared to either baseline or placebo treatment. Evening peak flows were significantly higher during terbutaline treatment [mean increase 23.1 l min(-1) (95% CI = 18.8, 27.4)]. Analysis of the peak flow changes on a day-by-day basis revealed an initial increase in morning peak flows for the first 2 days of treatment of 19.2 and 13.41 min(-1) [increases of 25.0 and 17.31 min(-1) in comparison with the corresponding values during placebo (P<0.01)] followed by a return to baseline. The increase in evening peak flows was also greater for the first 2 days of treatment than for the remainder of the treatment period (P<0.01). On ceasing terbutaline treatment there was a fall in mean morning peak flow below the baseline on the following morning of 21.6 l min(-1) (P<0.05 compared to placebo). The temporary increase in morning peak flows and greater than expected rise in evening peak flows for the first 2 days of treatment suggest the development of tolerance to the bronchodilator effect of terbutaline. Similarly, the fall in morning peak flows on treatment withdrawal suggests rebound bronchoconstriction. These effects are likely to be mediated by downregulation of the beta-receptor during treatment. The clinical significance of these changes is uncertain in view of the stability of overall asthma control during terbutaline treatment, but sudden withdrawal of beta-agonist treatment could conceivably lead to a deterioration in asthma control.     

Salmeterol does not compromise the bronchodilator response to albuterol during acute episodes of asthma.

PURPOSE: The present study was undertaken to determine whether regular use of salmeterol reduces the emergency effectiveness of albuterol. PATIENTS AND METHODS: Acutely ill asthmatic patients chronically taking salmeterol, and similar patients who were not taking salmeterol, were treated with albuterol, either as three aerosols of 2.5 mg every 20 minutes for 1 hour or two doses of 5.0 mg every 20 minutes. Peak expiratory flow measurements were monitored before and after each treatment. The time to disposition and the number of return visits were also recorded. RESULTS: One hundred fourteen patients, 57 who took salmeterol and 57 who served as control patients, completed the study. Thirty-three patients in each group received the lower dose of albuterol, and 24 were given the larger amount. There were no significant pretreatment differences between the salmeterol and control groups in the severity of symptoms or the degree of airway obstruction. Both albuterol regimens improved peak flow. Responses in the control group and in the salmeterol group were similar (low-dose albuterol increase in peak flow = 49%, control = 35%, P = 0.37; high-dose albuterol increment in peak flow = 43%, control = 41%, P = 0.81). There were no significant differences between the control group and the salmeterol group in the mean length of stay, the proportion of subjects admitted to the hospital, or the number of return visits. CONCLUSIONS: In patients with asthma, chronic use of salmeterol doses not interfere with the effects of standard doses of albuterol for the treatment of acute decompensations.     

The effects of regular inhaled formoterol and budesonide on preformed Th-2 cytokines in mild asthmatics

In a recent placebo-controlled study in mild atopic asthmatics, we observed a significant decrease in eosinophils in the bronchial submucosa, after 2 months oftreatment with inhaled formoterol and budesonide. Biopsy material from each treatment group; formoterol (24 microg bid), budesonide (400 microg b. i. d.) and placebo has been further assessed to investigatethe role of Th-2 cytokines by immunohistochemistry using Mabs to eosinophils as an index of inflammation, IL-4 and IL-5. Treatment with formoterol significantly reduced the number of eosinophils (EG2+) in the submucosa and epithelium, but this was not paralleled by changes in cytokine immunoreactivity In contrast, treatment with budesonide significantly reduced both the number of eosinophils (EG2+) and immunoreactivity for IL-4 and IL-5 in the submucosa. Thus, while budesonide has effects on cytokines involved in eosinophil recruitmentthis explanation does not apply tothe eosinopaenia observed with the long-acting beta2 adrenoreceptor agonist formoterol.     

Feasibility and response to budesonide as topical corticosteroid therapy for acute intestinal GVHD

Therapy of acute intestinal GVHD is still one of the main challenges after allogeneic transplantation. Increasing systemic immunosuppression (IS) is the first choice and includes corticosteroids and lymphocyte antibodies, often associated with severe side-effects. In inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, topical steroid therapy is used very successfully. Because of the similarity between these and acute intestinal GVHD we conducted a trial with oral budesonide (Budenofalk), a new topically active glucocorticoid, to treat patients with acute GVHD > or = grade II. After a diagnosis of aGVHD > or = grade II, 22 patients received increased IS, mainly systemic corticosteroids, and additionally budesonide 9 mg/day divided into three doses. Improvement in aGVHD, infectious side-effects, reduction of systemic IS and outcome were documented. Results were compared with the results of 19 control patients, who were treated only by increasing IS dose. In 17/22 patients (70%), treated with budesonide, the acute intestinal GVHD resolved and no relapse occurred after decreasing the systemic IS, while continuing budesonide. In only 8/19 patients in the control group did the acute intestinal GVHD resolve and 2/8 patients had a relapse of intestinal GVHD after decreasing IS, with an overall response of 33%. No severe intestinal infections occurred. We conclude that budesonide may be effective in acute intestinal GVHD as a topical corticosteroid and prospective, randomized studies should demonstrate its efficacy in allowing reduction of systemic immunosuppressive therapy, and its side-effects.     

The effect of polymorphisms of the beta(2)-adrenergic receptor on the response to regular use of albuterol in asthma

Inhaled beta-adrenergic agonists are the most commonly used medications for the treatment of asthma although there is evidence that regular use may produce adverse effects in some patients. Polymorphisms of the beta(2)-adrenergic receptor (beta(2)-AR) can affect regulation of the receptor. Smaller studies examining the effects of such polymorphisms on the response to beta-agonist therapy have produced inconsistent results. We examined whether polymorphisms at codon 16 (beta(2)-AR-16) and codon 27 (beta(2)-AR-27) of the beta(2)-AR might affect the response to regular versus as-needed use of albuterol by genotyping the 190 asthmatics who had participated in a trial examining the effects of regular versus as needed albuterol use. During the 16-wk treatment period there was a small decline in morning peak expiratory flow in patients homozygous for arginine at B(2)-AR-16 (Arg/Arg) who used albuterol regularly. This effect was magnified during a 4-wk run out period, during which all patients returned to using as-needed albuterol, so that by the end of the study Arg Arg patients who had regularly used albuterol had a morning peak expiratory flow 30. 5 +/- 12.1 L/min lower (p = 0.012) than Arg/Arg patients who had used albuterol on an as needed basis. There was no decline in peak flow with regular use of albuterol in patients who were homozygous for glycine at beta(2)-AR-16. Evening peak expiratory flow also declined in the Arg/Arg patients who used albuterol regularly but not in those who used albuterol on an as-needed basis. No significant differences in outcomes between regular and as-needed treatment were associated with polymorphisms at position 27 of the beta(2)-AR. No other differences in asthma outcomes that we investigated occurred in relation to these beta(2)-AR polymorphisms. Polymorphisms of the beta(2)-AR may influence airway responses to regular inhaled beta-agonist treatment.