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Loss of bronchoprotection with ICS plus LABA treatment, ?-receptor dynamics, and the effect of alendronate.

ABSTRACT: BACKGROUND:Loss of bronchoprotection (LOBP) with a regularly used long-acting ?2-adrenergic receptor agonist (LABA) is well documented. LOBP has been attributed to ?2-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 ?g 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.

SUBMITTER: Cardet JC

PROVIDER: S-EPMC6950766 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Loss of bronchoprotection with ICS plus LABA treatment, β-receptor dynamics, and the effect of alendronate.

Cardet Juan Carlos JC Jiang Xiaofeng X Lu Quan Q Gerard Norma N McIntire Kristen K Boushey Homer A HA Castro Mario M Chinchilli Vernon M VM Codispoti Christopher D CD Dyer Anne-Marie AM Holguin Fernando F Kraft Monica M Lazarus Stephen S Lemanske Robert F RF Lugogo Njira N Mauger Dave D Moore Wendy C WC Moy James J Ortega Victor E VE Peters Stephen P SP Smith Lewis J LJ Solway Julian J Sorkness Christine A CA Sumino Kaharu K Wechsler Michael E ME Wenzel Sally S Israel Elliot E

The Journal of allergy and clinical immunology 20190311 2

<h4>Background</h4>Loss of bronchoprotection (LOBP) with a regularly used long-acting β<sub>2</sub>-adrenergic receptor agonist (LABA) is well documented. LOBP has been attributed to β<sub>2</sub>-adrenergic receptor (B2AR) downregulation, a process requiring farnesylation, which is inhibited by alendronate.<h4>Objective</h4>We sought to determine whether alendronate can reduce LABA-associated LOBP in inhaled corticosteroid (ICS)-treated patients.<h4>Methods</h4>We conducted a randomized, double ...[more]

PMID: 30872116

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Project description:Patients with COPD show a significant reduction of the lobar hyperinflation at the functional residual capacity level in the patients who improved >120 mL in forced expiratory volume in 1 second (FEV1) after 6 months of treatment with roflumilast in addition to inhaled corticosteroids (ICSs)/long-acting beta-2 agonists (LABAs)/long-acting muscarinic antagonists (LAMAs).Functional respiratory imaging was used to quantify lobar hyperinflation, blood vessel density, ventilation, aerosol deposition, and bronchodilation. To investigate the exact mode of action of roflumilast, correlations between lobar and global measures have been tested using a mixed-model approach with nested random factors and Pearson correlation, respectively.The reduction in lobar hyperinflation appears to be associated with a larger blood vessel density in the respective lobes (t=-2.154, P=0.040); lobes with a higher percentage of blood vessels reduce more in hyperinflation in the responder group. Subsequently, it can be observed that lobes that reduce in hyperinflation after treatment are better ventilated (t=-5.368, P<0.001). Functional respiratory imaging (FRI)-based aerosol deposition showed that enhanced ventilation leads to more peripheral particle deposition of ICS/LABA/LAMA in the better-ventilated areas (t=2.407, P=0.024). Finally, the study showed that areas receiving more particles have increased FRI-based bronchodilation (t=2.564, P=0.017), leading to an increase in FEV1 (R=0.348, P=0.029).The study demonstrated that orally administered roflumilast supports the reduction of regional hyperinflation in areas previously undertreated by inhalation medication. The local reduction in hyperinflation induces a redistribution of ventilation and aerosol deposition, leading to enhanced efficacy of the concomitant ICS/LABA/LAMA therapy. FRI appears to be a sensitive tool to describe the mode of action of novel compounds in chronic obstructive pulmonary disease. Future studies need to confirm the enhanced sensitivity and the potential of FRI parameters to act as surrogates for clinically relevant, but more difficult to measure, end points such as exacerbations.

Dataset Information

Loss of bronchoprotection with ICS plus LABA treatment, ?-receptor dynamics, and the effect of alendronate.

Publications

Loss of bronchoprotection with ICS plus LABA treatment, β-receptor dynamics, and the effect of alendronate.

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