Loss of salmeterol bronchoprotection against exercise in relation to ADRB2 Arg16Gly polymorphism and exhaled nitric oxide.
BACKGROUND
β2-Agonists are the treatment of choice for exercise-induced bronchoconstriction (EIB) and act through specific receptors (ADRB2). Arg16Gly polymorphisms have been shown to affect responses to regular use of β2-agonists.


OBJECTIVE
To evaluate the influence of the Arg16Gly receptor polymorphism on salmeterol bronchoprotection in EIB and assess predictors of bronchoprotection.


METHODS
A prospective, genotype-blinded, randomized trial was performed in 26 subjects (12 Arg16Arg and 14 Gly16Gly) with EIB who were not on controller therapy. Subjects were administered salmeterol, 50 μg twice a day for 2 weeks, and underwent an exercise challenge 9 hours after the first and last drug dose. In addition to genotype, FEV1, response to salmeterol, degree of EIB, and exhaled nitric oxide (FE(NO)) at baseline were examined for their association with loss of bronchoprotection (LOB).


RESULTS
The maximum exercise-induced FEV1 fall was 27.9 ± 1.4% during the run-in period, 8.1 ± 1.2% (70.3 ± 4.1% bronchoprotection) after the first salmeterol dose, and 22.8 ± 3.2% (18.9 ± 11.5% bronchoprotection) after 2 weeks of salmeterol (P = 0.0001). The Arg16Gly polymorphisms were not associated with the LOB in response to salmeterol. FeNO values at baseline were significantly related to the LOB (r = 0.47; P = 0.01). Mean change was a 74 ± 13% LOB in subjects with FE(NO) levels greater than 50 ppb and a 7 ± 16% gain in bronchoprotection in those with FE(NO) levels less than 25 ppb (P = 0.01).


CONCLUSIONS
The LOB that occurs with chronic long-acting β2-agonists use is not affected by ADRB2 Arg16Gly polymorphisms. High FE(NO) was associated with marked LOB. Use of long-acting β2-agonists before achieving a reduction in FeNO may need to be avoided. Clinical trial registered with www.clinicaltrials.gov (NCT 00595361).
1 Asthma Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; and.
Matteo
M
Bonini
Perdita
P
Permaul
Tejaswini
T
Kulkarni
Shamsah
S
Kazani
Alex
A
Segal
Christine A
CA
Sorkness
Michael E
ME
Wechsler
Elliot
E
Israel
D000293:Adolescent; D000328:Adult; D000420:Albuterol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D001250:Asthma, Exercise-Induced / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D001980:Bronchi / Q000187:drug effects; D001993:Bronchodilator Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004361:Drug Tolerance / Q000235:genetics*; D005080:Exercise Test; D005260:Female; D005819:Genetic Markers; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics*; D000068299:Salmeterol Xinafoate; D016896:Treatment Outcome; D055815:Young Adult
C553443:ADRB2 protein, human; D015415:Biomarkers; D001993:Bronchodilator Agents; D005819:Genetic Markers; D018343:Receptors, Adrenergic, beta-2; D009569:Nitric Oxide; D000068299:Salmeterol Xinafoate; D000420:Albuterol