beta(2)-adrenoceptor polymorphism and bronchoprotective sensitivity with regular short- and long-acting beta(2)-agonist therapy

The aim of the present study was to investigate bronchoprotective sensitivi ty in patients receiving regular treatment with short- and long-acting beta (2)-agonists and to evaluate any possible association with genetic polymorp hism. Thirty-eight patients with stable mild to moderate asthma and receivi ng inhaled corticosteroids were randomized in a parallel group, double-blin d, double-dummy fashion to receive 2 weeks of treatment with either formote rol (12 mu g once daily, 6 mu g twice daily or 24 mu g twice daily) or terb utaline (500 mu g four times daily). Bronchoprotection against methacholine challenge (as a provocative dose to produce a 20% fall in forced expirator y volume in 1.0 s: PD20) was measured at baseline (unprotected) after an in itial I week run-in without beta(2)-agonist, and at 1 h after the first and last doses of each treatment. The PD20 values were log-transformed and cal culated as change from baseline. Percentage desensitization of log PD20 for first- versus last-dose bronchoprotection was calculated and analysed acco rding to effects of treatment and beta(2)-adrenoceptor polymorphism at codo n 16 or 27. The mean degree of desensitization for bronchoprotection was co mparable with all four treatments and there were no significant differences in absolute PD20 values after 2 weeks of chronic dosing. The PD20 values w ere (as mu g of methacholine, geometric means +/- S.E.M.): formoterol, 12 m u g once daily, 99 +/- 42 mu g; formoterol, 6 mu g twice daily, 107 +/- 44 mu g; formoterol, 24 mu g twice daily, 108 +/- 45 mu g; terbutaline, 500 mu g four times daily, 88 +/- 37 mu g. All patients receiving formoterol, 24 mu g twice daily, exhibited a loss of protection greater than 30% which was unrelated to polymorphism at codon 16 or 27. For codon 16, the use of lowe r doses of formoterol (12 mu g once daily or 6 mu g twice daily) showed wid er variability in the propensity for protection loss in patients who were h eterozygous, in contrast to a more uniform protection loss seen with homozy gous glycine patients. The amount of protection loss was not significantly related to polymorphism at codon 16 or 27, expressed as values (mean +/- S. E.M.) for percentage desensitization according to each genotype (pooled tre atments): Gly-16, 66 +/- 11%; Het-16, 53 +/- 8%; Arg-16, 69 +/- 18%; Glu-27 , 68 +/- 12%; Het-27, 58 +/- 8%; Gln-27, 52 +/- 12%. The results of this pr eliminary study showed that bronchoprotective desensitization occurred read ily in response to short- or long-acting beta(2)- agonist exposure irrespec tive of beta(2)-adrenoceptor polymorphism at codon 16 or 27. Further studie s with larger patient numbers are required to further evaluate the effects of polymorphisms with lower doses of regular formoterol.