Joseph J. Smeets

Comparison of tiotropium once daily, formoterol twice daily and both combined once daily in patients with COPD

This study compared the bronchodilator effects of tiotropium, formoterol and both combined in chronic obstructive pulmonary disease (COPD). A total of 71 COPD patients (mean forced expiratory volume in one second (FEV1) 37% predicted) participated in a randomised, double-blind, three-way, crossover study and received tiotropium 18 μg q.d., formoterol 12 μg b.i.d. or both combined q.d. for three 6-week periods. The end-points were 24-h spirometry (FEV1, forced vital capacity (FVC)) at the end of each treatment, rescue salbutamol and safety. Compared with baseline (FEV1 prior to the first dose in the first period), tiotropium produced a significantly greater improvement in average daytime FEV1 (0–12 h) than formoterol (127 versus 86 mL), while average night-time FEV1 (12–24 h) was not different (tiotropium 43 mL, formoterol 38 mL). The most pronounced effects were provided by combination therapy (daytime 234 mL, night-time 86 mL); both differed significantly from single-agent therapies. Changes in FVC mirrored the FEV1 results. Compared with both single agents, daytime salbutamol use was significantly lower during combination therapy (tiotropium plus formoterol 1.81 puffs·day−1, tiotropium 2.41 puffs·day−1, formoterol 2.37 puffs·day−1). All treatments were well tolerated. In conclusion, in chronic obstructive pulmonary disease patients, tiotropium q.d. achieved a greater improvement in daytime and comparable improvement in night-time lung function compared with formoterol b.i.d. A combination of both drugs q.d. was most effective and provided an additive effect throughout the 24-h dosing interval.

Salmeterol versus formoterol in patients with moderately severe asthma: onset and duration of action

We evaluated the profile of the bronchodilatory effect of three inhaled beta2-agonists, 24 microg formoterol, 50 microg salmeterol and 200 microg salbutamol, in patients with stable, moderately severe asthma. Thirty asthmatics (mean+/-SD age 54+/-8 yrs; forced expiratory volume in one second (FEV1) 58+/-12% predicted; reversibility of FEV1 21+/-8% from baseline) participated in a single-centre, double-blind, randomized, single-dose, cross-over study. FEV1 was obtained in baseline condition and 10, 20, 30, 60 min, and every hour up to 12 h after inhalation of the trial drug. Specific airway conductance (sGaw) was measured at baseline condition and 1, 3, 5, 7, 10, 20, 30, 60 min, and every hour up to 12 h after inhalation. Formoterol produced a mean increase in sGaw (as % of baseline) of 44% after 1 min, maximal (135%) after 2 h, and 56% after 12 h. The mean increase in FEV1 was maximal (27%) after 2h, and 10% after 12 h. After salmeterol, mean increase in sGaw amounted to 16% after 3 min, maximal (111%) after 2-4 h, and 58% after 12 h. The mean increase in FEV1 was maximally 25% after 3h, being 11% after 12 h. After salbutamol, mean increase in sGaw was 44% after 1 min and maximal (100%) after 30 min. The peak increase in FEV1 was 25%. We conclude that formoterol (24 microg) and salmeterol (50 microg) had an equal bronchodilatory capacity, which was similar to that of 200 microg salbutamol and lasted for at least 12 h in patients with asthma. However, formoterol had a more rapid onset of action than salmeterol, equal to that of salbutamol.

Pharmacodynamic steady state of tiotropium in patients with chronic obstructive pulmonary disease

Tiotropium (Spiriva®) is a new once-daily inhaled anticholinergic that has its effect through prolonged muscarinic (M)3 receptor antagonism. It has a clinically documented, long duration of action with once-daily dosing in chronic obstructive pulmonary disease (COPD). A single-centre, double-blind, ipratropium-controlled study was conducted in order to characterize the onset of pharmacodynamic steady state of tiotropium in patients with COPD. Thirty-one patients (25 male, six female) with a mean age of 62 yrs and a mean forced expiratory volume in one second (FEV1) of 1.13 L (38% of predicted) were randomly assigned to receive either tiotropium 18 µg once-daily from a dry-powder inhaler (HandiHaler®, 20 patients), or ipratropium 40 µg four-times daily from a pressurized metered-dose inhaler (11 patients) for a period of 1 week. FEV1 and forced vital capacity (FVC) were measured 1 h prior to, and just before inhalation (mean value of the two measurements on test-day 1 was the baseline value, while on all other test days it was the trough value), and 0.5, 1, 2, 3, 4, 5, and 6 h after inhalation of the morning dose of the study drug (one capsule and two puffs) on days 1, 2, 3, and 8. Trough FEV1 following 8 days of tiotropium was 0.19 L (18%) above baseline. Approximately 90% of this increase was achieved within 24 h of the first dose (0.17 L, 16%). Trough FVC increased 0.67 L (27%) on test-day 8. Approximately 70% of the improvement was observed after two tiotropium doses (0.47 L, 19%). Achievement of FVC steady state was delayed compared to FEV1. Ipratropium performed typically with an onset of action within 30 min, a peak response between 1–2 h postdosing and a duration of action of ∼4 h. It was concluded that forced expiratory volume in one second steady state with tiotropium is reached within 48 h, while continued improvements in forced vital capacity can be expected over or beyond the first week of therapy. The continued increases in forced vital capacity beyond 48 h suggests that maintenance bronchodilator therapy is required to achieve maximal changes in hyperinflation.

Combining tiotropium and salmeterol in COPD: Effects on airflow obstruction and symptoms.

BACKGROUND Clinical information on 24-h spirometric efficacy of combining tiotropium and salmeterol compared to single-agent therapy is lacking in patients with COPD. METHODS A randomized, double-blind, four-way crossover study of 6-week treatment periods comparing combination therapy of tiotropium 18 microg plus qd or bid salmeterol 50 microg versus single-agent therapy. Serial 24-h spirometry (FEV(1), FVC), effects on dyspnea (TDI focal score) and rescue salbutamol use were evaluated in 95 patients. RESULTS Tiotropium plus qd salmeterol was superior to tiotropium or salmeterol alone in average FEV(1) (0-24h) by 72 mL and 97 mL (p<0.0001), respectively. Compared to this qd regimen, combination therapy including bid salmeterol provided comparable daytime (0-12h: 12 mL, p=0.38) bronchodilator effects, but significantly more bronchodilation during the night-time (12-24h: 73 mL, p<0.0001). Clinically relevant improvements in TDI focal score were achieved with bronchodilator combinations including salmeterol qd or bid (2.56 and 2.71; p<0.005 versus components). Symptom benefit of combination therapies was also reflected in less need for reliever medication. All treatments were well tolerated. CONCLUSION Compared to single-agent therapy, combination therapy of tiotropium plus salmeterol in COPD provided clinically meaningful improvements in airflow obstruction and dyspnea as well as a reduction in reliever medication.

A comparison of the onset of action of salbutamol and formoterol in reversing methacholine-induced bronchoconstriction

This single-centre, randomized, double-blind, double-dummy four-way cross-over study in 24 moderately severe asthmatic patients compared the speed of onset of recommended doses of salbutamol (200 micrograms) and formoterol (12 micrograms) delivered by metered-dose inhaler in reversing the bronchoconstriction induced by a cumulative dose of methacholine to produce a 20% decrease (PD20) in forced expiratory volume in 1 s (FEV1). Specific airway conductance (SGAW) and airway resistance (RAW) were measured in baseline condition, immediately after challenge and 0.5, 1.5, 3, 5, 10, 15, 30, 60 min and every hour up to 4 h after inhalation of the trial drug. FEV1 was measured in baseline condition, after challenge and 15, 30 and 60 min and then every 30 min up to 4 h after inhalation of the study drug. The primary efficacy parameter was the change in SGAW. Salbutamol produced a two-fold increase in SGAW within 4 min and a maximum increase after 79.3 min. Formoterol produced a two-fold increase in SGAW after 5 min and a maximum increase after 119.6 min. Changes in SGAW were slightly, but consistently, higher during the first 2 h after inhalation of salbutamol, both in absolute values and as a percentage of the maximum response. Differences were significant at 10, 15 and 30 min time points. There was no significant difference between the maximum values of SGAW after the two drugs. Changes in RAW and FEV1 reflected the differences in SGAW. It was concluded that in methacholine-induced bronchoconstriction both formoterol and salbutamol have a very fast onset of action, achieving prechallenge values of SGAW within 3 min, salbutamol being slightly faster than formoterol.

Delivery of fenoterol via Respimat, a novel 'soft mist' inhaler. a randomised, double-blind (within device), placebo-controlled, cross-over, dose-ranging study in asthmatic patients.

Background: The phase-out of chlorofluorocarbons (CFCs) for metered dose inhalers (MDIs) has prompted the development of alternative propellants and the design of propellant-free devices for inhalation therapy. Objective: This study was carried out to determine the dose of fenoterol inhaled from Respimat® (RMT), a new propellant-free soft mist inhaler, which is equivalent in terms of efficacy and safety to 1 puff of either 100 or 200 µg fenoterol inhaled from a conventional CFC-MDI (Berotec®). Methods: Sixty-two asthmatic patients (35 male, 27 female) with a mean baseline FEV1 of 1.7 liters, corresponding to 55% of the predicted normal value, were randomized at two study centers to 4 of a total of 8 possible treatments: placebo; 12.5, 25, 50, 100, or 200 µg fenoterol via RMT, and 100 or 200 µg fenoterol delivered via the MDI. Results: Fifty-nine patients completed the study as planned. Results of the therapeutic equivalence test for the primary endpoint, average FEV1 (AUC0–6)/6 and for the secondary endpoint, peak FEV1, showed that the 12.5- and 25-µg fenoterol doses administered via RMT were equivalent to the 100 µg fenoterol dose from the MDI. The 50-, 100- and 200-µg fenoterol doses delivered by RMT did not meet the criterion for therapeutic equivalence with the 100-µg dose from the MDI, and if tested for a difference would have been significantly different in favor of RMT. All 5 RMT fenoterol doses were therapeutically equivalent to the MDI 200-µg fenoterol dose. Headache, reported by 4 patients on test days and 2 patients between test days in those randomized to RMT, was the most common adverse event, but the active treatments were generally well tolerated with no dose-dependent increases in incidence or severity of adverse events observed. Conclusions: The results from the study suggest that safe and efficacious bronchodilation can be obtained from single-dose fenoterol administered via RMT. Use of lower absolute doses to obtain a clinically significant improvement in pulmonary function may be possible because of the increased lung deposition achievable with the novel soft mist inhaler.

Therapeutic equivalence of a novel HFA134a-containing metered-dose inhaler and the conventional CFC inhaler (Berodual) for the delivery of a fixed combination of fenoterol/ipratropium bromide. A randomized double-blind placebo-controlled crossover study in patients with asthma.

The efficacy and safety of a novel fenoterol/ipratropium bromide metered-dose inhaler (MDI) formulated with a non-chlorinated propellant, HFA134a, has been compared with placebo and the conventional chlorofluorocarbon (CFC)-containing fenoterol/ipratropium bromide inhaler (Berodual) in asthmatic patients. Fifty-two patients were enrolled in two centres. The fenoterol/ ipratropium bromide treatment produced significantly (P < 0.0001) greater bronchodilatation than placebo. There were no significant differences between the mean peak and average forced expiratory volume in the first second (FEV1) for patients receiving 2 puffs of the fenoterol/ipratropium bromide HFA134a inhaler and the conventional CFC inhaler. In addition, time to onset and duration of efficacy were comparable for these two treatments. None of the patients showed a fall of > or = 15% in baseline FEV1 or needed rescue medication within 30 min after inhalation of the test drug. No paradoxical bronchoconstriction was observed as measured by sGaw. The two inhaler formulations were well tolerated. A taste-related complaint, lasting for a few minutes after inhalation, was reported by a higher proportion of patients who inhaled the HFA134a formulation, mainly by patients selected in one of the two centres. In conclusion, a dose of 100 micrograms fenoterol/40 micrograms ipratropium bromide inhaled from a MDI containing HFA134a propellant is safe and provides effective bronchodilatation of equivalent degree, onset and duration of action to the same dose from the conventional CFC formulation.

Comparative Study of the Bronchospasmolytic Effect of Fenoterol (0.2 mg) and Salbutamol (0.4 mg) as Powder inhalations in 20 Patients with Reversible Bronchial Obstruction

In a double-blind crossover study, the effects of fenoterol powder inhaled from capsules (0.2 mg) and the powder inhaler with salbutamol capsules (0.4 mg) were compared. A single dose of each was administered on 2 subsequent days in random order. The effects on lung function test results were followed from 15 to 360 min after administration. Apart from the overall comparison, special attention was paid to the beginning and the end of the test periods. Statistically significant differences were found only in a few parameters and showed a trend for fenoterol to have a somewhat longer effect and for salbutamol to have a faster onset of effect. The differences between the effects of the two drugs were clinically not relevant. Blood pressure and heart rate were unaffected by either treatment.