Loss of bronchoprotection with ICS plus LABA treatment, ß-receptor dynamics, and the effect of alendronate.
J Allergy Clin Immunol
; 144(2): 416-425.e7, 2019 08.
Article
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| MEDLINE
| ID: mdl-30872116
ABSTRACT
BACKGROUND:
Loss of bronchoprotection (LOBP) with a regularly used long-acting ß2-adrenergic receptor agonist (LABA) is well documented. LOBP has been attributed to ß2-adrenergic receptor (B2AR) downregulation, a process requiring farnesylation, which is inhibited by alendronate.OBJECTIVE:
We sought to determine whether alendronate can reduce LABA-associated LOBP in inhaled corticosteroid (ICS)-treated patients.METHODS:
We conducted a randomized, double-blind, placebo-controlled, parallel-design, proof-of-concept trial. Seventy-eight participants with persistent asthma receiving 250 µg of fluticasone twice daily for 2 weeks were randomized to receive alendronate or placebo while initiating salmeterol for 8 weeks. Salmeterol-protected methacholine challenges (SPMChs) and PBMC B2AR numbers (radioligand binding assay) and signaling (cyclic AMP ELISA) were assessed before randomization and after 8 weeks of ICS plus LABA treatment. LOBP was defined as a more than 1 doubling dose reduction in SPMCh PC20 value.RESULTS:
The mean doubling dose reduction in SPMCh PC20 value was 0.50 and 0.27 with alendronate and placebo, respectively (P = .62). Thirty-eight percent of participants receiving alendronate and 33% receiving placebo had LOBP (P = .81). The after/before ICS plus LABA treatment ratio of B2AR number was 1.0 for alendronate (P = .86) and 0.8 for placebo (P = .15; P = .31 for difference between treatments). The B2AR signaling ratio was 0.89 for alendronate (P = .43) and 1.02 for placebo (P = .84; P = .44 for difference). Changes in lung function and B2AR number and signaling were similar between those who did and did not experience LOBP.CONCLUSION:
This study did not find evidence that alendronate reduces LABA-associated LOBP, which relates to the occurrence of LOBP in only one third of participants. LOBP appears to be less common than presumed in concomitant ICS plus LABA-treated asthmatic patients. B2AR downregulation measured in PBMCs does not appear to reflect LOBP.Palabras clave
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Bases de datos:
MEDLINE
Asunto principal:
Asma
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Corticoesteroides
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Receptores Adrenérgicos beta 2
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Alendronato
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Xinafoato de Salmeterol
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Fluticasona
Tipo de estudio:
Clinical_trials
Límite:
Adult
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Female
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Humans
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Male
Idioma:
En
Revista:
J Allergy Clin Immunol
Año:
2019
Tipo del documento:
Article