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Cross tolerance to salbutamol occurs independently of ß₂ adrenoceptor genotype-16 in asthmatic patients receiving regular formoterol or salmeterol

¹ Asthma and Allergy Research Group, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK
² Tayside Centre for General Practice, University of Dundee, Dundee DD1 9SY, UK

Correspondence to:
Correspondence to:
Professor B J Lipworth
Asthma and Allergy Research Group, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK; b.j.lipworth{at}dundee.ac.uk

Background: The development of tolerance following the use of long acting ß₂ agonists in asthmatic patients with either the homozygous arginine (Arg-16) or glycine (Gly-16) genotypes is poorly documented, especially in relation to the acute reliever response to salbutamol in constricted airways. A study was undertaken to evaluate the Arg-16 and Gly-16 genotypes for the acute salbutamol response following methacholine bronchial challenge between the first and last doses of formoterol (FM) and salmeterol (SM) combination inhalers.

Methods: Parallel groups of 10 matched homozygous Arg-16 and 10 homozygous Gly-16 patients completed a randomised, double blind, double dummy, crossover study. Following a 1 week washout period, patients received treatment for 2 weeks with either inhaled budesonide (BUD) 200 µg + FM 6 µg (two puffs twice daily) or inhaled fluticasone propionate (FP) 250 µg + SM 50 µg (one puff twice daily). After washouts and randomised treatments (1 hour after the first and last inhalation) a methacholine challenge was performed followed by salbutamol 200 µg, with recovery over 30 minutes (the primary outcome).

Results: Washout values for forced expiratory volume in 1 second (FEV₁), methacholine hyperreactivity, and salbutamol recovery were similar for both treatments and genotypes. Pre-challenge FEV₁ values for both genotypes did not differ significantly between the first and last doses of each treatment. Salbutamol recovery as mean (SE) area under the 30 minute time-response curve was significantly delayed (p<0.05) equally in both genotype and treatment groups. There were no differences in salbutamol recovery in either genotype or treatment group.

Conclusion: Acute salbutamol recovery in methacholine constricted airways was significantly delayed to a similar degree in both genotypes due to cross tolerance induced by FM or SM.

Abbreviations: BUD, budesonide; FEV₁, forced expiratory volume in 1 second; FM, formoterol; FP, fluticasone propionate; PEF, peak expiratory flow; SM, salmeterol

Keywords: asthma; formoterol; genotype; salbutamol; salmeterol

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