Inhaled Corticosteroids Do Not Prevent the Development of Tolerance to the Bronchoprotective Effect of Salmeterol

Arg/Arg homozygotes for the Gly16Arg polymorphism in the b 2 -adrenoreceptor gene (ADRB2) have a reduced response to short-acting b 2 -agonists but no effect has been associated with long-acting b 2 -agonists (LABAs).We selected 604 subjects with current asthma from the European Community Respiratory Health Study to evaluate whether asthma control and lung function decline were associated with Gly16Arg polymorphism, and to test whether LABA or inhaled corticosteroid (ICS) use modified these effects.There was an increased risk of noncontrolled asthma (OR 1.33, 95% CI 1.01-1.75; p50.046) for each Arg allele. Among nonusers of ICS, the odds ratio of noncontrolled asthma among Arg/Arg versus Gly/Gly subjects was 2.73 (95% CI 1.28-5.82; p50.009). No increased risk of noncontrolled asthma associated with the Arg allele was observed among ICS and/or LABA users. For each Arg allele, a mean¡SE decrease in decline in forced expiratory volume in 1 s of 7.7¡2.5 mL?yr -1 was found (p-value for trend 0.003), irrespective of ICS or LABA use. Arg/Arg subjects had an increased risk of bronchial hyperresponsiveness (BHR) versus Gly/Gly subjects, with an odds ratio of 2.51 (95% CI 1.12-5.63; p50.025) if they did not use ICS. The Arg allele was associated with poorer asthma control, a steeper lung function decline and BHR. Absence of genotypic effects on asthma control among ICS users may be due to reversed b 2 -adrenoreceptor desensitisation.

Section: Discussionmentioning

confidence: 99%

ADRB2Gly16Arg polymorphism, asthma control and lung function decline

Rebordosa¹,

Kogevinas

Guerra

et al. 2011

“…Eur Respir J 1998;11: 1091-1097 agonist receptors in vitro, had not been explored until recently, and their influence on this phenomenon remains to be further defined [15][16][17][18]. A study by KALRA et al [18] showed that tolerance to the acute bronchoprotective effects of salmeterol could be observed after only two doses in asthmatic subjects on inhaled corticosteroids and persisted after the seventh dose. This reduction in bronchoprotective effect was observed as soon as 1 h after dosing with salmeterol [10,18].…”

Section: Tolerance To the Protective Effects Of Salmeterol On Methachmentioning

confidence: 99%

“…A study by KALRA et al [18] showed that tolerance to the acute bronchoprotective effects of salmeterol could be observed after only two doses in asthmatic subjects on inhaled corticosteroids and persisted after the seventh dose. This reduction in bronchoprotective effect was observed as soon as 1 h after dosing with salmeterol [10,18]. The effect of corticosteroids on the tolerance to the bronchoprotective effects of salmeterol should, therefore, be examined further over a longer time-period, and the clinical relevance of reduced bronchoprotection on the control of asthma and medication needs to be documented.…”

Section: Tolerance To the Protective Effects Of Salmeterol On Methachmentioning

confidence: 99%

Tolerance to the protective effects of salmeterol on methacholine-induced bronchoconstriction: influence of inhaled corticosteroids

Cartier²,

Milot³

et al. 1998

Long-acting beta2-adrenoceptor agonists such as salmeterol reduce airway responsiveness for at least 12 h, but this effect seems to decrease with regular use. We evaluated the time-course of the protective effects of salmeterol on methacholine-induced bronchoconstriction, its modulation by inhaled corticosteroids (ICS) and its influence on asthma control. Thirty two subjects (13 males and 19 females) with mild to moderate stable asthma were divided into two groups according to their medication needs: bronchodilators (BD) alone (n=16) or with ICS (n=16). After a 2 week run-in period, a double-blind crossover study was conducted. Subjects from both groups received salmeterol 50 microg b.i.d. or a placebo for 4 weeks each in random order, separated by a 2 week washout period. The provocative concentration of methacholine causing a 20% fall in forced expiratory volume in one second (PC20) was measured before and after each treatment period, 1 h prior to inhalation of salmeterol or placebo and 1 and 12 h after. Baseline forced expiratory volume in one second (FEV1) increased significantly after salmeterol, both after the first dose and at 4 weeks (BD group: 19 and 17%; ICS: 22 and 13%). On the first day of administration, salmeterol provided significant protection in both groups up to 12 h with a PC20 before and 1 and 12 h postdose of 2.2, 21.7 and 12.4, mg x mL(-1), respectively, in the BD group and 2.1, 11.6 and 55 mg x mL(-1), respectively, in the ICS group. After 4 weeks, this effect was significantly attenuated in both groups with a PC20 before, 1 and 12 h postdose of 3.3, 10.9 and 7.1 mg x mL(-1), respectively, in the BD group and 2.1, 5.0 and 2.3 mg x mL(-1), respectively, in the ICS group. This loss of protective effect was of similar magnitude in both groups. Respiratory symptoms, rescue beta2-agonist use and baseline FEV1 did not change significantly throughout the study in both groups. In conclusion, the bronchoprotective effect of salmeterol decreased with regular use both 1 and 12 h postdose; inhaled corticosteroids did not prevent this reduction. However, the development of tolerance was not associated with loss of asthma control.

“…They also found that a supplementary dose of salbutamol, 200 µg, used as "rescue therapy" during salmeterol treatment gave substantially reduced protection (from 3.7 to 1.9 doubling dose shift in PC20). These effects occur both in subjects treated with inhaled corticosteroid and those using β-agonists only [33,34]. Our results suggest that use of a single (p.r.n.)…”

Section: Discussionmentioning

confidence: 68%

Effects of long-acting and short-acting beta-agonists on methacholine dose-response curves in asthmatics

Wong¹,

O'Shaughnessy²,

Walker³

et al. 1997

Regular use of short-acting β-agonists may decrease control of asthma and increase airway responsiveness to bronchoconstrictor stimuli. The aim of this study was to determine the effects of regular treatment with the long-acting β-agonist, salmeterol, on the methacholine dose-response curve (DRC) in mild-tomoderate asthmatics.Changes in methacholine airway responsiveness were measured in 14 stable adult asthmatics, randomized in a double-blind, three-way cross-over design to receive salmeterol 50 µg, salbutamol 200 µg or placebo, each twice daily for 4 days. Two baseline methacholine DRC, were performed, one without premedication and one following a single dose of 200 µg salbutamol. Following 4 days of regular treatment, methacholine DRC to plateau were carried out commencing 15 min after the final dose of trial medication.There were no significant differences in mean baseline forced expiratory volume in one second (FEV1) between treatments. Four days treatment with salmeterol and salbutamol shifted the DRC to the right, but salmeterol provided less protection than salbutamol. The point of inflection of the curve from baseline moved 1.9 and 3.2 doubling doses, respectively, compared to placebo (p≤0.001), and the provocative concentration of methacholine required to produce a 20% fall in FEV1 (PC20) increased 1.6 and 3.1 doubling doses, respectively (p≤0.001). The slope of the DRC was increased slightly by both β-agonists compared to placebo (log slope 3.11, 3.06 and 2.77 for salmeterol, salbutamol and placebo, respectively). This effect of regular salmeterol on slope was more marked in subjects with lower baseline FEV1. Maximal response plateaus did not differ between the three treatments.These results suggest that regular use either of short-or long-acting β-agonists could increase the risk of a more precipitous asthma episode associated with "breakthrough" bronchoconstrictor responses, particularly in those with more severe initial airflow obstruction, if subjects are exposed to a sufficiently potent stimulus.