Dose-related effects of formoterol on airway responsiveness to adenosine 5′‐monophosphate and histamine

Abstract

Inhaled short-acting b 2 -agonists provide greater protection against airway responsiveness (AR) to the mast-cell stimulus, adenosine 59-monophosphate (AMP), than to histamine, a direct spasmogen. Both terbutaline and albuterol exhibit this mast-cell stabilizing property in a dose-dependent manner. A single dose of the long-acting b 2 -agonist formoterol has also been reported to have a mast cell-stabilizing effect, whereas salmeterol has not. To explore the dose-related actions of the longacting b 2 -agonist formoterol on AR, the authors compared the acute effects of three doses of formoterol and terbutaline on AR to AMP and histamine.In a double-blind, randomized, placebo-controlled, cross-over study, 25 mild, steroid naive, asthmatic subjects attended on 10 occasions. At each visit, subjects inhaled either a single dose of terbutaline (500 mg), formoterol (6, 12 or 24 mg) or a matched placebo, administered via Turbuhaler1, 30 min prior to challenge with both AMP and histamine.Each dose of b 2 -agonist reduced AR to AMP and histamine. The bronchoprotective effects of formoterol (6 mg) and terbutaline (500 mg) were similar in magnitude in reducing AR to histamine (mean¡SD: 3.6¡0.3 and 3.1¡0.3 doubling doses (DD)) and AR to AMP (3.5¡0.5 and 3.3¡0.4 DD, respectively). Overall, formoterol reduced AR to both spasmogens in a dose-dependent manner. In addition, formoterol (12 and 24 mg) provided a significantly greater protective effect against AMP than against histamine challenge. It decreased AR by 5.7¡0.6 and 6.3¡0.7 DD against AMP and 4.3¡0.4 and 4.8¡0.43 DD against histamine, respectively.The results of this study indirectly demonstrated an in vivo dose-dependent mast-cell stabilizing effect of formoterol, in addition to functional antagonism on airway smooth muscle. The long-acting b 2 -agonists formoterol and salmeterol are effective bronchodilators with a much longer duration of action than the short-acting b 2 -agonists albuterol and terbutaline [1]. Their addition to low-dose inhaled glucocorticosteroids (GCS) is now recommended as an alternative to the use of high-dose inhaled corticosteroids in asthma management, especially in patients with nocturnal asthma or exerciseinduced symptoms [2]. In a similar manner to short-acting b 2 -agonists, a single dose of formoterol may have a greater bronchoprotective effect on the indirect spasmogen, adenosine 59-monophosphate (AMP), than on the direct-acting spasmogen, histamine [3][4][5]. In vitro and in vivo evidence of mast-cell mediator release and the attenuation of the bronchoconstrictive effects of AMP by the cromones and antihistamines suggest that AMP acts primarily as a mast-cell stimulus [6][7][8]. This implies an in vivo mastcell stabilizing effect of formoterol, in addition to functional antagonism on airway smooth muscle, an observation which, to date, has not been demonstrated with salmeterol [9,10].To further evaluate the in vivo mechanisms of formoterol, the effects of a single dose of formoterol (6, 12 and 24 mg), terbutaline 500 mg (contro...

Scientific rationale for using a single inhaler for asthma control

“…This can be demonstrated in asthmatic patients in vivo by the greater protective effect of b 2 -agonists against adenosine-induced bronchoconstriction, which is mast cell dependent, compared to direct bronchoconstrictors, such as histamine or methacholine [38,39]. The protective effect of formoterol against adenosine monophosphate (AMP)-induced bronchoconstriction can be seen 2 h after administration, indicating a rapid mast cell stabilisation effect [40].…”

The effects of inhaled budesonide and formoterol in combination and alone when given directly after allergen challenge

“…27 Indeed, a dose-response effect has been demonstrated for the bronchodilator action of formoterol 28 and recently for its antiinflammatory activity. 29 Likewise, higher doses of ICS are more likely to offer protection 11,30 than lower doses 12,24 even when given after allergen inhalation. 31,32 However, the addition of LABA to low-dose ICS significantly improves the protection against allergen-induced AHR.…”

The role of endogenous and exogenous AMP in asthma and chronic obstructive pulmonary disease

“…The differential bronchoprotective effect of formoterol seems to be greater than that of albuterol or terbutaline, whereas no difference in bronchoprotective effect with AMP versus methacholine was found with salmeterol either 2 or 14 hours after a single dose. [93][94][95] The lack of such a differential bronchoprotective effect of salmeterol may reflect the fact that it is a partial agonist compared with formoterol, albuterol, or terbutaline.…”