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The relationship between β2-adrenoceptor polymorphisms and bronchoprotective response with long-acting β2-adrenoceptor agonists is unknown. We retrospectively analysed data from six placebo-controlled randomized studies in corticosteroid treated asthmatics where formoterol or salmeterol were administered over a 1–2-week period, with prior 1–2 week washout, assessing the primary end point of methacholine P D20 and adenosine monophosphate P C20, following first and last dose, expressed as doubling dose difference from placebo. There was no significant heterogeneity between the different studies. Patients who had homozygous or heterozygous genotypes containing the arginine-16 polymorphism (Arg16-Arg16 or Arg16-Gly16) had greater bronchoprotective subsensitivity compared with the homozygous glycine-16 genotype (Gly16-Gly16), amounting to a mean doubling dose difference of 1.49 (95% CI 0.50, 2.48), after the last dose. Subsensitivity of response was greater with formoterol than salmeterol after the last dose in all genotypes, especially with the arginine-16 polymorphism, amounting to a doubling dose difference of 3.00 (95% CI 1.01, 4.99) between formoterol and salmeterol. Our retrospective analysis showed that the arginine-16 polymorphism was associated with subsensitivity of response for bronchoprotection, which was greater for formoterol than salmeterol. A prospective study will be required in order to further evaluate these findings, particularly to assess whether these differences are mirrored by exacerbations. [ABSTRACT FROM AUTHOR]

The relationship between β2-adrenoceptor polymorphisms at positions 16 and 27, and the acute systemic β2-adrenoceptor effects of inhaled salbutamol is unclear. We therefore elected to evaluate the influence of common homozygous β2-adrenoceptor haplotypes on the acute systemic β2-adrenoceptor effects following inhaled salbutamol in asthmatic subjects. An initial database search of 531 asthmatic subjects identified the two commonest homozygous haplotypes at positions 16 and 27 to be Arg16-Gln27 (12%) and Gly16-Glu27 (19%). After a 1-week washout period where all β2-adrenoceptor agonists were withdrawn, 16 Caucasian subjects (Arg16-Gln27: n = 8 and Gly16-Glu27: n = 8) were given a single dose of inhaled salbutamol (1200 µg), followed by serial blood sampling for serum potassium, along with measurements of diastolic blood pressure and heart rate, at 5-min intervals for 20 min. The two groups were well matched for age, sex, FEV1, and inhaled corticosteroid dose. Baseline values for serum potassium, diastolic blood pressure and heart rate were not significantly different comparing Arg16-Gln27 vs Gly16-Glu27. The mean ± SEM maximum serum potassium change from baseline over 20 min was significantly greater ( P = 0.04) for Arg16-Gln27: −0.37 ± 0.05 mmol l−1 vs Gly16-Glu27: −0.23 ± 0.04 mmol l−1; 95% CI for difference: −0.01 to −0.28 mmol l−1. The maximum diastolic blood pressure change from baseline over 20 min was significantly greater ( P = 0.0008) for Arg16-Gln27: −13 ± 1 mmHg vs Gly16-Glu27: −4 ± 2 mmHg; 95% CI for difference: −5, 14 mmHg. There was no significant difference comparing the maximum heart rate change from baseline for Arg16-Gln27: 10 ± 3 beats min−1 vs Gly16-Glu27: 10 ± 3 beats min−1. Caucasian asthmatic subjects with the Arg16-Gln27 haplotype exhibited a greater systemic response to inhaled salbutamol, compared with those with the Gly16-Glu27 haplotype. The attenuated β2-adrenoceptor response in the Gly16-Glu27 haplotype would be in keeping with increased susceptibility to prior down-regulation by endogenous catecholamines. [ABSTRACT FROM AUTHOR]

Inhalers combining long acting β2-adrenoceptor agonists (LABA) and corticosteroids (ICS) are indicated at Step 3 of current asthma guidelines. We evaluated the relative effects of LABA + ICS combination vs ICS alone on pulmonary function, bronchoprotection, acute salbutamol recovery following methacholine bronchial challenge, and surrogate inflammatory markers in patients with moderate persistent asthma. Twenty-nine patients with mean FEV1 (± SEM) of 78 ± 3% predicted completed a randomized, double-blind, double-dummy, cross-over study. Patients received either 4 weeks of budesonide 400 µg + formoterol 12 µg (BUD + FM) combination twice daily followed by 1 week of BUD 400 µg alone twice daily, or 4 weeks of fluticasone propionate 250 µg + salmeterol 50 µg (FP + SM) combination twice daily followed by 1 week of FP 250 µg alone twice daily. Measurements were made at baseline and following each randomized treatment. FEV1 increase from pretreatment baseline as mean (± SEM) % predicted was significantly higher ( P < 0.05) for BUD + FM (8 ± 1%) vs BUD (2 ± 1%), and for FP + SM (8 ± 1%) vs FP (2 ± 1%). The fall in FEV1 following methacholine challenge as percentage change from prechallenge baseline FEV1 was not significantly different in all four groups; BUD + FM (22 ± 1%), BUD (24 ± 1%), FP + SM (23 ± 1%) and FP (23 ± 1%). Salbutamol recovery over 30 min following methacholine challenge as area under curve (AUC %.min) was significantly blunted ( P < 0.05) with BUD + FM (486.7 ± 35.5) vs BUD (281.1 ± 52.8), and with FP + SM (553.1 ± 34.1) vs FP (368.3 ± 46.7). There were no significant differences between respective combination inhalers or between respective ICS alone. Decreases in exhaled nitric oxide (NO) and serum eosinophilic cationic protein (ECP) from baseline were not significantly different between treatments. Combination inhalers improve pulmonary function without potentiating anti-inflammatory effects on exhaled NO and serum ECP as compared with ICS alone, but delay acute salbutamol recovery after bronchoconstriction. [ABSTRACT FROM AUTHOR]

Aim Cysteinyl leukotrienes are important pro-inflammatory mediators in the pathogenesis of asthma, while leukotriene C[sub 4] synthase is a key enzyme in their biosynthesis. Our aim is to evaluate whether responsiveness to leukotriene receptor antagonists was determined by expression of the variant (C) or wild-type (A) polymorphism of this enzyme. Methods We carried out a retrospective analysis of 8 randomised, placebo-controlled trials performed m our department in mild-to-moderate asthmatics. In all trials, effect of leukotriene receptor antagonist was compared to placebo, where the primary outcome was bronchial hyperresponsiveness to adenosine monophosphate or methacholine. Secondary outcomes were forced expiratory volume in 1 second, exhaled nitric oxide and peripheral blood eosinophils. Results For the primary outcome of attenuation of bronchial hyperresponsiveness by leukotriene receptor antagonist vs placebo, there were significant effects within each genotype on adenosine monophosphate (AMP) (n = 78): 2.21 and 2.07-fold improvements for AA and AC/CC, respectively; while for methacholine (n = 81) there were 1.39 and 1.36-fold improvements, respectively. There were no significant differences between genotypes (i.e. AA vs AC/CC): geometric mean fold-differences of 1.07 (95%CI 0.63-1.81) and 1.02 (95%CI 0.70-1.50) for AMP and methacholine, respectively. There were also no differences between genotypes for all secondary outcomes. Conclusion Polymorphisms of leukotriene C[sub 4] synthase did not determine responsiveness, in terms of attenuation of bronchial hyperresponsiveness, to leukotriene receptor antagonists m mild-to-moderate asthmatics. Further prospective large pharmacogenetic studies are required in more severe patients, where there may be greater improvements in pharmacodynamic outcome measures such as bronchial hyperresponsiveness and exhaled nitric oxide. [ABSTRACT FROM AUTHOR]