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• W2958471454 abstract "We read with interest the study by Cardet et al,1Cardet J.C. Jiang X. Lu Q. Gerard N. McIntire K. Boushey H.A. et al.Loss of bronchoprotection with ICS+LABA, beta-receptor dynamics, and the effect of alendronate.J Allergy Clin Immunol. 2019; 144: 416-425.e7Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar which showed that 38% of asthmatic patients receiving an inhaled corticosteroid (ICS) and a long-acting β-agonist (LABA; ie, fluticasone/salmeterol) experienced loss of bronchoprotection. We believe that their results need to be interpreted in light of the potential interaction between the LABA moiety and the arginine/glycine genotype at position 16 (Arg16Gly) of the β2-adrenoceptor. For example, a post hoc genotype-stratified pooled analysis of 152 patients from randomized placebo-controlled trials showed that the degree of protection after chronic dosing with ICS/LABA treatment was 1.49 (95% CI, 0.5-2.48) doubling dose less in patients who possessed ArgArg or ArgGly genotypes (comprising about 60% of patients) compared with those who had the GlyGly genotype (about 40% of patients).2Lee D.K. Currie G.P. Hall I.P. Lima J.J. Lipworth B.J. The arginine-16 beta2-adrenoceptor polymorphism predisposes to bronchoprotective subsensitivity in patients treated with formoterol and salmeterol.Br J Clin Pharmacol. 2004; 57: 68-75Crossref PubMed Scopus (118) Google Scholar Moreover, chronic exposure to the higher-efficacy agonist formoterol was associated with 3.0 (95% CI, 1.01-4.99) doubling-dose lower protection compared with the lower-efficacy agonist salmeterol. In terms of individual responders as change from placebo after the last dose of ICS/LABA, there were 60% of patients with the Arg genotype who had more than 1 doubling-dose decrease in protection with formoterol compared with 18% with salmeterol, whereas in the Gly genotype there were 29% and 11%, respectively. The results of Cardet et al1Cardet J.C. Jiang X. Lu Q. Gerard N. McIntire K. Boushey H.A. et al.Loss of bronchoprotection with ICS+LABA, beta-receptor dynamics, and the effect of alendronate.J Allergy Clin Immunol. 2019; 144: 416-425.e7Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar also suggested that downregulation of airway β2-adrenoceptors was not reflected by commensurate changes in PBMCs. This is not consistent with findings in asthmatic patients taking an ICS with formoterol, in whom loss of bronchoprotection and its acute restoration by a 1600-μg bolus of budesonide was mirrored by changes seen in PMBC β2-adrenoceptor density.3Aziz I. Lipworth B.J. A bolus of inhaled budesonide rapidly reverses airway subsensitivity and β2-adrenoceptor down-regulation after regular inhaled formoterol.Chest. 1999; 115: 623-628Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar Hence we believe that it might not be possible to generalize the findings of Cardet et al1Cardet J.C. Jiang X. Lu Q. Gerard N. McIntire K. Boushey H.A. et al.Loss of bronchoprotection with ICS+LABA, beta-receptor dynamics, and the effect of alendronate.J Allergy Clin Immunol. 2019; 144: 416-425.e7Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar to different ICS/LABA combinations, such as fluticasone furoate and vilanterol, the latter also being a higher-efficacy β2-agonist.4Slack R.J. Barrett V.J. Morrison V.S. Sturton R.G. Emmons A.J. Ford A.J. et al.In vitro pharmacological characterization of vilanterol, a novel long-acting beta2-adrenoceptor agonist with 24-hour duration of action.J Pharmacol Exp Ther. 2013; 344: 218-230Crossref PubMed Scopus (84) Google Scholar Loss of bronchoprotection with ICS plus LABA treatment, β-receptor dynamics, and the effect of alendronateJournal of Allergy and Clinical ImmunologyVol. 144Issue 2PreviewLoss of bronchoprotection (LOBP) with a regularly used long-acting β2-adrenergic receptor agonist (LABA) is well documented. LOBP has been attributed to β2-adrenergic receptor (B2AR) downregulation, a process requiring farnesylation, which is inhibited by alendronate. Full-Text PDF ReplyJournal of Allergy and Clinical ImmunologyVol. 144Issue 3PreviewWe thank Lipworth et al1 for their comments on our article. Full-Text PDF" @default.
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• W2958471454 date "2019-09-01" @default.
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• W2958471454 title "Bronchoprotective tolerance with inhaled corticosteroid/long-acting β-agonist treatment" @default.
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• W2958471454 doi "https://doi.org/10.1016/j.jaci.2019.05.028" @default.
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