Add-on therapy with montelukast or formoterol in patients with the glycine-16 beta2-receptor genotype.
OBJECTIVE
We assessed whether montelukast or formoterol provides additive effects to asthmatics not controlled on inhaled corticosteroids, by studying patients who were considered to be genetically susceptible to beta2-receptor down regulation and subsensitivity, and who expressed the homozygous glycine-16 beta2-receptor genotype.


METHODS
Fifteen corticosteroid-treated, mild to moderate persistent asthmatics received montelukast 10 mg once daily or formoterol 9 micro g twice daily for 2 weeks, separated by a 2-week placebo run-in and washout, in a double-blind, double-dummy, randomized crossover design. Bronchoprotection against adenosine monophosphate (AMP) challenge (primary endpoint), spirometry and blood eosinophils were measured at trough after placebo, first and last doses.


RESULTS
For AMP PC20vs placebo, there were sustained significant (P < 0.05) doubling dilution improvements following first (1.1; 95% CI 0.4, 1.9) and last (1.0; 95% CI 0.3, 1.8) doses of montelukast, and following first (1.3; 95% CI 0.1, 2.6) but not last (0.3; 95% CI -0.9, 1.6) doses of formoterol. Blood eosinophils (x 10(6) l(-1)) were significantly (P < 0.05) suppressed after the last dose of montelukast (-71; 95% CI -3, -140) compared with placebo, while formoterol exhibited a nonsignificant rise (20; 95% CI -92, 132). Neither treatment significantly improved FEV1, FEF25-75 or PEF after 2 weeks.


CONCLUSIONS
In genetically susceptible patients with the homozygous glycine-16 genotype, montelukast, but not formoterol, conferred sustained anti-inflammatory properties in addition to inhaled corticosteroid, which were dissociated from changes in lung function after 2 weeks. Thus, assessing lung function may miss potentially beneficial anti-inflammatory effects of montelukast when used as add-on therapy.
Sims
Erika J
EJ
Department of Clinical Pharmacology and Therapeutics, Asthma & Allergy Research Group, Ninewells University Hospital and Medical School, Dundee, UK.
Jackson
Catherine M
CM
Lipworth
Brian J
BJ
D000085:Acetates / Q000008:administration & dosage*; D000328:Adult; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage*; D001249:Asthma / Q000188:drug therapy*; D001993:Bronchodilator Agents / Q000008:administration & dosage*; D018592:Cross-Over Studies; D003521:Cyclopropanes; D004311:Double-Blind Method; D015536:Down-Regulation; D004359:Drug Therapy, Combination; D004983:Ethanolamines / Q000008:administration & dosage*; D005541:Forced Expiratory Volume / Q000187:drug effects; D000068759:Formoterol Fumarate; D006801:Humans; D010366:Peak Expiratory Flow Rate / Q000187:drug effects; D011804:Quinolines / Q000008:administration & dosage*; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics* / Q000378:metabolism; D013440:Sulfides
D000085:Acetates; D018927:Anti-Asthmatic Agents; D001993:Bronchodilator Agents; D003521:Cyclopropanes; D004983:Ethanolamines; D011804:Quinolines; D018343:Receptors, Adrenergic, beta-2; D013440:Sulfides; C093875:montelukast; D000068759:Formoterol Fumarate