FEV1 recovery following methacholine challenge in asthma: Variability and comparison of methods.

BACKGROUND: Methacholine challenges have been used in clinical trials to assess therapeutic effects and potential adverse reactions of interventions on pulmonary function in a sensitive population, such as in subjects with asthma. Here, we evaluate the variability of the methacholine challenge recovery model, and compare the results obtained for both incremental and bolus challenge methods. METHODS: The extent, time course and variability of change in forced expiratory volume in 1 s (FEV1) following repeated methacholine challenges in subjects with mild asthma were investigated in an open-label, four-period, fixed-sequence, two-method, replicate crossover study. At Visits 1 and 2, subjects underwent an incremental challenge using doubling doses of methacholine until a ≥20% decrease in FEV1 was observed; at Visits 3 and 4, subjects underwent a bolus challenge, inhaling a single dose of methacholine calculated from the cumulative dose established during Visit 1. RESULTS: A total of 19 subjects were included in the study. Both the mean FEV1 area under the curve (FEV1 AUC0-tz) and mean maximum reductions in FEV1 (absolute and relative) 120 min post-challenge values were higher for the incremental challenges than the bolus challenges, with no reported difference between repetitions of the same methodology. FEV1 AUC0-tz decrease 120 min post challenge demonstrated an intra-subject coefficient of variation (CV) of 47.2% (incremental) and 78.3% (bolus), suggesting considerable between-visit variability. The mean absolute, and similarly relative, maximum reductions in FEV1 compared with post-diluent baseline values demonstrated lower intra-subject variability (incremental 21.16%, bolus 40.67%) than the FEV1 AUC0-tz-based endpoint. There was a trend towards faster recovery following the bolus challenge than with the incremental challenge. The provocative dose of methacholine inducing a ≥20% decrease in FEV1 resulted in a between-group mean difference of 27.20% in the incremental challenge periods, with a high intra-subject CV of 80.64%, demonstrating considerable variability. CONCLUSION: Maximum reduction in FEV1 had the lowest variability. There was little difference between repetitions of the same methodology, as indicated by overlapping confidence intervals. There was a trend towards faster recovery following bolus challenge than with the incremental challenge. The results of this trial could be of value when designing future clinical trials using the methacholine challenge methodology.

Low incidence of paradoxical bronchoconstriction in asthma and COPD patients during chronic use of Respimat soft mist inhaler.

Respimat Soft Mist Inhaler (SMI) is a new-generation inhaler that offers improved lung deposition compared with chlorofluorocarbon metered dose inhalers (CFC-MDIs). Bronchodilators administered via Respimat SMI are preserved and stabilised with low concentrations of benzalkonium chloride and ethylene diamine tetra-acetic acid, both of which have been reported to cause dose-related paradoxical bronchoconstriction. The aim of this analysis was to compare the incidence of paradoxical bronchoconstriction after chronic use of bronchodilators via Respimat SMI and CFC-MDI. Data from three clinical trials, in which patients with asthma or chronic obstructive pulmonary disease (COPD) received ipratropium bromide alone or in combination with fenoterol hydrobromide, or placebo via Respimat SMI or CFC-MDI for 12 weeks, were included in the analysis. In order to evaluate the risk of paradoxical bronchoconstriction, we identified four respiratory events that might have occurred within 30 min of inhalation on four test days; these were: 'bronchospasm', 'other respiratory adverse events', 'rescue medication use' and 'asymptomatic drop in FEV(1) 15% from baseline'. In total, 631 asthma and 1538 COPD patients participated in the three studies. No occurrences of bronchospasm were reported with Respimat SMI on any test day. Overall, the incidence of respiratory events possibly indicative of paradoxical bronchoconstriction was low and similar for both devices. There was no increase in the incidence of events during 12 weeks' treatment. Delivery of bronchodilators by Respimat SMI is safe with regard to paradoxical bronchoconstriction during chronic use in patients with asthma or COPD.

Dry powder ipratropium bromide is as safe and effective as metered-dose inhaler formulation: a cumulative dose-response study in chronic obstructive pulmonary disease patients.

A multi-center, open, randomized, 2-way crossover study was conducted with chronic obstructive pulmonary disease (COPD) patients to compare the safety and efficacy of cumulative doses of ipratropium bromide administered from a pressurized metered-dose inhaler (MDI) or from a breath-activated dry powder inhaler (DPI). Enrolled in the study were 39 patients with moderate to severe COPD and who showed a > or= 15% increase in baseline forced expiratory volume in the first second (FEV(1)) after 80 microg of ipratropium bromide. Thirty-six patients were evaluable for efficacy analysis, and 38 patients were included in the safety analysis group. A significant improvement in pulmonary function was observed following inhalation of cumulative doses of ipratropium bromide (from 20 to 320 microg), but no statistically significant difference was found between the 2 formulations. The dose-response curves were similar. There was no statistical difference in area-under-the-curve during the 180 min period after the last dose for any of the pulmonary function variables. Overall, effects on pulse rate, blood pressure, and QT interval on electrocardiogram were no different between the devices. Six mild adverse events occurred in 4 patients: ventricular ectopic beats on electrocardiogram at 270 min with MDI, bad taste with both MDI and DPI, slight transient increase in blood pressure in the same patient during each study day with both MDI and DPI. Two moderate adverse events occurred in 2 patients: transient ventricular ectopic beats on electrocardiograms with DPI at 270 min, moderate bronchospasm with MDI at 200 min. Patients expressed a preference for DPI, which was found to have a better acceptability and appeared to be easier to use than MDI. The new lactose powder formulation of ipratropium bromide inhaled via the breath-activated DPI is a safe and effective alternative to the chlorofluorocarbon-propelled MDI.