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

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Background

The use of combination inhaled budesonide and formoterol as maintenance and reliever therapy significantly improves the risk and the time to exacerbations in asthma.

Objectives

To explore the mechanisms underlying the effect of the reliever dose on exacerbations by examining the effect of combination therapy on the allergen challenge model when given after allergen exposure.

Methods

In a randomized, double-blind crossover study, single doses of budesonide/formoterol (400/12 μg), formoterol (12 μg), budesonide (400 μg), or placebo were administered during the acute bronchoconstriction response (early airway response) immediately after allergen inhalation in 15 patients with mild asthma. Allergen-induced late airway response (LAR), sputum inflammatory markers, airway hyperresponsiveness, and exhaled nitric oxide were measured.

Results

All active treatments significantly attenuated the LAR, with budesonide/formoterol significantly better than its monocomponents (maximum FEV1 fall: placebo, [mean ± SEM] 21.2% ± 3.1%; budesonide/formoterol, 4.2% ± 1.4%; formoterol, 7.5% ± 1.7%; budesonide, 10.4% ± 1.6%). Allergen-induced change in methacholine PC20 was significantly attenuated by budesonide/formoterol, but not by its monocomponents. Sputum cell counts and exhaled nitric oxide increased significantly after all allergen challenges, with no significant attenuation by any of the treatments. Therapy with combination and formoterol alone, but not budesonide, significantly reduced the early airway response.

Conclusion

A single dose of budesonide/formoterol was superior to its monocomponents in attenuating the allergen-induced LAR and airway hyperresponsiveness. These effects may represent the contribution of the reliever dose to the budesonide/formoterol maintenance and reliever regimen.

Clinical implications

The protective effect against allergic airway responses with a single reliever dose of budesonide/formoterol is predominantly related to greater functional antagonism of airway smooth muscles.

Section snippets

Methods

Sixteen atopic adults (≥18 years) with stable mild asthma and FEV1 ≥80% predicted were recruited. All were nonsmokers, taking only short-acting β2-agonists as needed, and demonstrated a methacholine PC20 of <16 mg/mL. Subjects also demonstrated a maximum fall in FEV1 ≥20% to inhaled allergen within 0 to 3 hours (early airway response; EAR) and ≥15% between 3 and 7 hours (late airway response; LAR) at screening challenge. The same dose of allergen causing the dual response was subsequently used

Results

One subject was withdrawn before randomization because of an asthma exacerbation. Screening baseline characteristics for the 15 completed subjects are presented in Table I. Baseline values for the 4 randomized periods were not significantly different, and no carryover effect was detected. Furthermore, no significant difference in FEV1 and FEV1/vital capacity was seen on days 1 to 3 between the periods (Table II). Serial FEV1 measurements after each allergen challenge (and treatment) up to 7

Discussion

This study demonstrated that single doses of budesonide/formoterol, formoterol, and budesonide administered after allergen inhalation significantly attenuated the LAR. Budesonide/formoterol was superior to its monocomponents in this regard and provided protection against allergen-induced airway hyperresponsiveness (AHR), whereas treatment with the monocomponents did not achieve this benefit. Treatments with formoterol and budesonide/formoterol were equally effective in alleviating the EAR.

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    Supported in part by AstraZeneca, Lund, Sweden.

    Disclosure of potential conflict of interest: G. Gauvreau has consultant arrangements with Topigen Pharma Inc, Tanox, Novartis Pharma UK Ltd, MedImmune Inc, and Altana Inc and has received grant support from Pfizer, Altana, GlaxoSmithKline, Topigen, and MedImmune. P. M. O'Byrne has consultant arrangements with Altana, AstraZeneca, GlaxoSmithKline, Topigen, and Biolipox and has received grant support from Altana, AstraZeneca, GlaxoSmithKline, Topigen, Biolipox, MedImmune, Pfizer, IVAX, and Boehringer Ingleheim. The rest of the authors have declared that they have no conflict of interest.

    Some of the data from this paper were presented in abstract form at the American Thoracic Society Meeting, May 2006, San Diego, Calif.

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