Acute effect of pretreatment with single conventional dose of salmeterol on dose-response curve to oxitropium bromide in chronic obstructive pulmonary disease

Background - An earlier study documented that, in patients with chronic obstructive pulmonary disease (COPD), addition of ipratropium bromide at the clinically recommended dose (40 μg) does not produce any further bronchodilation than that achieved with salmeterol 50 μg alone. However, the dose of ipratropium bromide needed to produce near maximal bronchodilation is several times higher than the customary dosage. The full therapeutic potential of combined salmeterol plus an anticholinergic drug can therefore only be established using doses higher than those currently recommended in the marketing of these agents. A study was undertaken to examine the possible acute effects of higher than conventional doses of an anticholinergic agent on the single dose salmeterol induced bronchodilation in patients with stable and partially reversible COPD. Methods - Thirty two outpatients received 50 μg salmeterol or placebo. Two hours after inhalation a dose-response curve to inhaled oxitropium bromide (100 μg/puff) or placebo was constructed using one puff, one puff, two puffs, and two puffs - that is, a total cumulative dose of 600 μg oxitropium bromide. Dose increments were given at 20 minute intervals with measurements being made 15 minutes after each dose. On four separate days all patients received one of the following: (1) 50 μg salmeterol + 600 μg oxitropium bromide; (2) 50 μg salmeterol + placebo; (3) placebo + 600 μg oxitropium bromide; (4) placebo + placebo. Results - Salmeterol induced a good bronchodilation (mean increase 0.272 1; 95% CI 0.207 to 0.337) two hours after its inhalation. Oxitropium bromide elicited an evident dose-dependent increase in forced expiratory volume in one second (FEV1) and this occurred also after pretreatment with salmeterol with a further mean maximum increase of 0.152 1 (95% CI of differences 0.124 to 0.180). Conclusions - This study shows that acute pretreatment with 50 μg salmeterol does not block the possibility of inducing more bronchodilation with an anticholinergic agent when a higher than normal dosage of the muscarinic antagonist is used.