The arginine-16 beta2-adrenoceptor polymorphism predisposes to bronchoprotective subsensitivity in patients treated with formoterol and salmeterol.
OBJECTIVE
The relationship between beta2-adrenoceptor polymorphisms and bronchoprotective response with long-acting beta2-adrenoceptor agonists is unknown.


METHODS
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 PD20 and adenosine monophosphate PC20, following first and last dose, expressed as doubling dose difference from placebo.


RESULTS
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.


CONCLUSIONS
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.
Lee
Daniel K C
DK
Asthma & Allergy Research Group, Department of Clinical Pharmacology, Ninewells Hospital & Medical School, University of Dundee, Dundee DD1 9SY, Scotland, UK.
Currie
Graeme P
GP
Hall
Ian P
IP
Lima
John J
JJ
Lipworth
Brian J
BJ
D000420:Albuterol / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy* / Q000503:physiopathology; D001993:Bronchodilator Agents / Q000627:therapeutic use*; D004311:Double-Blind Method; D004983:Ethanolamines / Q000627:therapeutic use*; D005541:Forced Expiratory Volume / Q000502:physiology; D000068759:Formoterol Fumarate; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D011110:Polymorphism, Genetic / Q000235:genetics*; D016032:Randomized Controlled Trials as Topic; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics*; D012189:Retrospective Studies; D000068299:Salmeterol Xinafoate
D001993:Bronchodilator Agents; D004983:Ethanolamines; D018343:Receptors, Adrenergic, beta-2; D000068299:Salmeterol Xinafoate; D000420:Albuterol; D000068759:Formoterol Fumarate