Subsensitivity of bronchodilator and systemic beta 2 adrenoceptor responses after regular twice daily treatment with eformoterol dry powder in asthmatic patients.

Newnham, D M; Grove, A; McDevitt, DG; Lipworth, Brian J.

doi:10.1136/thx.50.5.497

Cited by 128 publications

(62 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, it has been more difficult to demonstrate tolerance to their bronchodilator effects. Reduced bronchodilator response after regular short-and long-acting b-agonists has been reported [4][5][6][7] but the findings have been inconsistent [8][9][10][11]. A possible explanation for these negative results is that bronchodilator responses were measured in patients with stable asthma in whom the margin from baseline to maximum bronchodilatation was not sufficient for the effects of tolerance to be detected.…”

mentioning

confidence: 64%

Bronchodilator tolerance: the impact of increasing bronchoconstriction

Wraight

Hancox²,

Herbison³

et al. 2003

Eur Respir J

View full text Add to dashboard Cite

Chronic exposure to b-agonists causes tolerance to their bronchodilator effects, which is best demonstrated during acute bronchoconstriction. The aim of the present study was to assess whether tolerance becomes more evident with increasing bronchoconstriction, as might occur in acute asthma.In a randomised, double-blind, placebo-controlled, crossover study comprising 15 patients, the treatments were salbutamol 400 mg q.i.d. or placebo given via Diskhaler1 for 28 days with a 2-week washout between treatments. Patients attended on days 14, 21 and 28. Bronchoconstriction was induced on two of these three occasions to achieve a reduction in the forced expiratory volume in one second (FEV1) of 0 (no methacholine), 15 and 30% (using methacholine) in a randomised order. Immediately after this, salbutamol 100 mg, 100 mg and 200 mg was inhaled at 0, 5, and 10 min. FEV1 was measured over 40 min. Dose/response curves were plotted and values for the area under the curve (AUC)0-40 FEV1 were compared between treatments and by degree of bronchoconstriction.Regular salbutamol resulted in attenuation of the acute response to b-agonist, which was increasingly evident with greater bronchoconstriction. With a reduction in FEV1 of 0, 15 and 30%, the AUC0-40 FEV1 with salbutamol were 11.2, -14.6 and -35.7% respectively, compared to placebo. There was a linear relationship between the magnitude of bronchoconstriction and the between-treatment differences in AUC0-40 FEV1.Increasing bronchoconstriction conferred greater susceptibility to the effects of bronchodilator tolerance. b-agonists are widely prescribed for symptomatic relief in asthma. They are very effective as bronchodilators and as functional antagonists against a wide range of constricting stimuli. However, chronic exposure of b-adrenoceptors (b-AR) to b-agonist drugs leads to reduced responsiveness (desensitisation) and a decrease in the number of receptors (downregulation) [1].In the clinical setting, tolerance to the nonbronchodilator effects of b-agonists is readily demonstrated [2,3]. However, it has been more difficult to demonstrate tolerance to their bronchodilator effects. Reduced bronchodilator response after regular short-and long-acting b-agonists has been reported [4][5][6][7] but the findings have been inconsistent [8][9][10][11]. A possible explanation for these negative results is that bronchodilator responses were measured in patients with stable asthma in whom the margin from baseline to maximum bronchodilatation was not sufficient for the effects of tolerance to be detected.Recently, HANCOX et al. [12] have described a method that reliably demonstrates bronchodilator tolerance to b-agonists. In that study, a 36% reduction in the area under the curve (AUC) for forced expiratory volume (FEV1) was observed in patients who had been using regular inhaled b-agonist compared to placebo. Subsequently, other authors have used the same methodology to show similar effects in patients using long-acting b-agonists [13,14]. In both of these studies, measuring...

show abstract

mentioning

confidence: 64%

Bronchodilator tolerance: the impact of increasing bronchoconstriction

Wraight

Hancox²,

Herbison³

et al. 2003

Eur Respir J

View full text Add to dashboard Cite

show abstract

“…What are the mechanisms underlying the results? With prolonged usage of LAB, and prolonged b 2 -receptor occupancy, downregulation of the b 2 -receptor is likely to occur [17], through uncoupling of the receptor from the membranous G s protein, internalization of the receptor, a decline in steady state b 2 -receptor messenger ribonucleic acid (mRNA) and/or reduced transcription [18 -20]. Such downregulation or uncoupling of b 2 -receptor numbers can be reflected by a reduced protective effect of LAB against bronchoconstrictor stimuli such as methacholine [7] and exercise [4].…”

Section: Discussionmentioning

confidence: 99%

Effect of oral prednisolone on the bronchoprotective effect of formoterol in patients with persistent asthma

2001

View full text Add to dashboard Cite

Tolerance to the bronchoprotective effects by long-acting b 2 -agonists (LAB) in patients with asthma is not prevented by inhaled corticosteroids (ICS). This study examined whether oral prednisolone can restore the bronchoprotective effects of formoterol in 24 patients with persistent asthma already treated with ICS (at least 800 mg budesonide . day -1 or equivalent) and LAB, using a parallel-group design. During a 2-week run-in period and during the study, patients used formoterol 12 mg twice daily by Turbuhaler1, instead of their own LAB. At baseline and at the end of 7-days treatment with oral placebo or prednisolone (30 mg . day -1 ), provocative concentration of histamine causing a 20% fall in forced expiratory volume in one second (PC20 histamine) was measured on two separate days after randomized singledose inhalation of placebo (postP) or formoterol (postF). In addition, PC20postF was measured 24 h after starting oral treatment. The protective effect by formoterol at baseline and during treatment was calculated as the difference between the logs of PC20postP and PC20postF.The mean¡SEM in doubling dose (DD) bronchoprotective effect at baseline was 0.8¡0.4 DD in the placebo group and 1.0¡0.4 DD in the prednisolone group. At the end of the treatment period, the protective effect changed to 1.0¡0.5 DD and 0.8¡0.6 DD in the placebo and prednisolone treated groups, respectively. This change was not different between the groups (pw0.4).In conclusion, the bronchoprotective effect by formoterol is not influenced by 1 week prednisolone treatment in patients with asthma who are using regular inhaled corticosteroids and long-acting b 2 -agonists. These findings indicate that tolerance to long-acting b 2 -agonists cannot be restored by oral steroid therapy.

show abstract

“…Clinically, desensitization is typically termed tachyphylaxis, which refers to a loss of clinical effectiveness of a therapeutic agent upon repetitive administration. In asthma, chronic ␤-agonist administration has been associated with tachyphylaxis in some 18,19 but clearly not all 20,21 studies. In addition, excessive ␤-agonist use has been associated with increased asthma mortality 22 and morbidity.…”

Section: Pharmacogenetics Of ␤-Agonists In Asthmamentioning

confidence: 99%