Comparison of Salmeterol and Albuterol-induced Bronchoprotection Against Adenosine Monophosphate and Histamine in Mild Asthma

Abstract

Short-acting beta(2)-agonists provide greater protection to bronchoconstriction induced by adenosine-5'-monophosphate (AMP) than does methacholine. Because AMP produces bronchoconstriction through release of mediators from mast cells, and methacholine directly constricts airway smooth muscle, this suggests that beta(2)-agonists stabilize mast cells in vivo. This in vivo property has not been demonstrated with long-acting beta(2)-agonists. We undertook two double-blind, randomized, crossover, placebo-controlled studies to investigate the effects of salmeterol and albuterol on airway responsiveness (AR) to AMP and histamine in patients with mild asthma. In the first study, 19 patients attended on four occasions to inhale salmeterol 50 micrograms or placebo 2 h before challenge with AMP or histamine. In the second study 16 patients (13 of whom had participated in the first study) were studied in a similar fashion but inhaled albuterol 400 micrograms or placebo 30 min prior to challenge. Salmeterol reduced AR to AMP and histamine by 3.4 +/- 0.3 and 3.9 +/- 0.3 doubling doses, respectively (NS). In contrast, albuterol demonstrated a greater protective effect on AMP than on histamine, reducing AR by 5.1 +/- 0.3 and 3.8 +/- 0.2 doubling doses, respectively (p < 0.005). Thus, in contrast to albuterol, salmeterol did not demonstrate mast-cell stabilizing properties in vivo at a time corresponding to maximal bronchodilatation. These findings might be explained by the unique pharmacologic profile of salmeterol in combination with the differential beta(2)-adrenoceptor pharmacology of bronchial mast cells and bronchial smooth muscle.

Unaltered perception of dyspnoea during treatment with long-acting β2-agonists

“…In the present study, the slope of the methacholine dose-response curve did not show a difference between placebo and long acting b 2 -agonist pretreatment, confirming similar studies investigating the slope of the dose response curves for both histamine and adenosine monophosphate after formoterol [13] and salmeterol treatment [14]. These results differ from the previous report by BEL et al [3] when the protective effect of salbutamol was followed by a sudden fall in FEV1.…”

“…An alternative way of investigating the perception of dyspnoea involves the measurement of dyspnoea during inhalation against different resistances. With this methodology, the perception of dyspnoea was improved slightly after prior inhalation of salbutamol [12].In the present study, the slope of the methacholine dose-response curve did not show a difference between placebo and long acting b 2 -agonist pretreatment, confirming similar studies investigating the slope of the dose response curves for both histamine and adenosine monophosphate after formoterol [13] and salmeterol treatment [14]. These results differ from the previous report by BEL et al [3] when the protective effect of salbutamol was followed by a sudden fall in FEV1.…”

Effect of oral prednisolone on the bronchoprotective effect of formoterol in patients with persistent asthma

“…To ensure that all patients had an adequate duration of treatment by formoterol, they participated in a 2-week run-in period, before entering the baseline period of the study. This design succeeded in inducing tolerance since the bronchoprotective effect by single-dose formoterol at baseline was less than one doubling concentration of histamine, which is far less than that observed in patients not treated by regular LAB [6] and comparable to the residual bronchoprotective effect after a few weeks of such treatment [7,12,13]. Second, to study the short-term effects of oral prednisolone on bronchoprotection bronchial hyperresponsiveness to histamine was also measured after formoterol inhalation at 24 h after starting oral treatment.…”

Scientific rationale for inhaled combination therapy with long-acting β2-agonists and corticosteroids

“…The increased protection against AMP challenge compared with the directly-acting constrictors may reflect an additional effect on airway mast cells, since AMP-induced bronchoconstriction in asthmatics is reduced by an antihistamine [35], and adenosine-induced constriction of asthmatic bronchi in vitro is inhibited by histamine and leukotriene antagonists [36]. Formoterol has a greater protective effect against AMP than against histamine challenge, whereas these differences are less marked with salbutamol and salmeterol [37,38]. This difference between salmeterol and formoterol may be due to the differences between a nearly full agonist and a partial agonist, if occupation of all b 2 -receptors is needed for the mast cell stabilizing effect.…”