Erika J Sims1, Brian J Lipworth. 1. Asthma & Allergy Research Group, Department of Clinical Pharmacology and Therapeutics, Ninewells Hospital, University of Dundee Medical School, DD1 9SY, Scotland, UK.
Abstract
BACKGROUND: Predisposition to subsensitivity with long-acting beta(2)-agonists (LABA) or regular short-acting beta(2)-agonists (SABA) is related to polymorphisms at codon 16 of the beta(2)-adrenoceptor. OBJECTIVE: To determine whether the use of occasional SABA induces further baseline downregulation of the beta(2)-adrenoceptor to that of endogenous catecholamines alone, in Gly-16 patients. METHODS: A post-hoc analysis of two studies was performed. Twenty-three homozygous Gly-16 asthmatic patients received 12 microg inhaled formoterol either o.d. or b.i.d. for 2 weeks. Patients had been supplied with ipratropium bromide (IB) to use as reliever therapy preferentially over salbutamol. Spirometry and adenosine monophosphate (AMP) bronchial challenge was performed after 7-14 days of placebo and after active treatment. RESULTS: A review of domiciliary diary card data indicated 13 patients (mean FEV(1): 76.8% pred., AMP PC(20): 23.4 mg/ml) did not require salbutamol, and 10 patients (mean FEV(1): 77.9% pred., AMP PC(20): 27.9 mg/ml) required occasional salbutamol (1.67 puffs/day) during run-in and/or formoterol periods. No significant difference in spirometry or AMP PC(20) were found between the populations after placebo. After formoterol, compared with placebo, patients requiring occasional salbutamol had no improvement in AMP PC(20) [geometric mean PC(20) (and 95% CI): 28.0 mg/ml (20.5-38.4) versus 34.46 mg/ml (25.1-47.3)], while those patients not requiring salbutamol had a significant ( p<0.05) improvement in AMP PC(20) with formoterol compared with placebo [89.9 mg/ml (52.4-154.3) versus 30.6 mg/ml (17.8-52.5)]. This amounted to a 3.12-fold (95% CI: 0.16-6.07) geometric mean fold difference between groups. CONCLUSIONS: Our results indicate that homozygous Gly-16 patients using occasional salbutamol have reduced responsiveness to formoterol in terms of bronchoprotection to AMP than patients not using salbutamol. Patients expressing the homozygous gly-16 genotype of the beta(2)-adrenoceptor genotype receiving a LABA may benefit from the substitution of their usual SABA for an alternative reliever.
RCT Entities:
BACKGROUND: Predisposition to subsensitivity with long-acting beta(2)-agonists (LABA) or regular short-acting beta(2)-agonists (SABA) is related to polymorphisms at codon 16 of the beta(2)-adrenoceptor. OBJECTIVE: To determine whether the use of occasional SABA induces further baseline downregulation of the beta(2)-adrenoceptor to that of endogenous catecholamines alone, in Gly-16 patients. METHODS: A post-hoc analysis of two studies was performed. Twenty-three homozygous Gly-16 asthmatic patients received 12 microg inhaled formoterol either o.d. or b.i.d. for 2 weeks. Patients had been supplied with ipratropium bromide (IB) to use as reliever therapy preferentially over salbutamol. Spirometry and adenosine monophosphate (AMP) bronchial challenge was performed after 7-14 days of placebo and after active treatment. RESULTS: A review of domiciliary diary card data indicated 13 patients (mean FEV(1): 76.8% pred., AMP PC(20): 23.4 mg/ml) did not require salbutamol, and 10 patients (mean FEV(1): 77.9% pred., AMP PC(20): 27.9 mg/ml) required occasional salbutamol (1.67 puffs/day) during run-in and/or formoterol periods. No significant difference in spirometry or AMP PC(20) were found between the populations after placebo. After formoterol, compared with placebo, patients requiring occasional salbutamol had no improvement in AMP PC(20) [geometric mean PC(20) (and 95% CI): 28.0 mg/ml (20.5-38.4) versus 34.46 mg/ml (25.1-47.3)], while those patients not requiring salbutamol had a significant ( p<0.05) improvement in AMP PC(20) with formoterol compared with placebo [89.9 mg/ml (52.4-154.3) versus 30.6 mg/ml (17.8-52.5)]. This amounted to a 3.12-fold (95% CI: 0.16-6.07) geometric mean fold difference between groups. CONCLUSIONS: Our results indicate that homozygous Gly-16 patients using occasional salbutamol have reduced responsiveness to formoterol in terms of bronchoprotection to AMP than patients not using salbutamol. Patients expressing the homozygous gly-16 genotype of the beta(2)-adrenoceptor genotype receiving a LABA may benefit from the substitution of their usual SABA for an alternative reliever.