Loss of bronchoprotection with ICS plus LABA treatment, β-receptor dynamics, and the effect of alendronate
Loss 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. We sought to determine whether...
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| creator | Cardet, Juan Carlos Jiang, Xiaofeng Lu, Quan Gerard, Norma McIntire, Kristen Boushey, Homer A. Castro, Mario Chinchilli, Vernon M. Codispoti, Christopher D. Dyer, Anne-Marie Holguin, Fernando Kraft, Monica Lazarus, Stephen Lemanske, Robert F. Lugogo, Njira Mauger, Dave Moore, Wendy C. Moy, James Ortega, Victor E. Peters, Stephen P. Smith, Lewis J. Solway, Julian Sorkness, Christine A. Sumino, Kaharu Wechsler, Michael E. Wenzel, Sally Israel, Elliot |
| description | Loss 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.
We sought to determine whether alendronate can reduce LABA-associated LOBP in inhaled corticosteroid (ICS)–treated patients.
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.
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.
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. |
| doi_str_mv | 10.1016/j.jaci.2019.01.049 |
| format | Article |
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We sought to determine whether alendronate can reduce LABA-associated LOBP in inhaled corticosteroid (ICS)–treated patients.
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.
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.
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.</description><identifier>ISSN: 0091-6749</identifier><identifier>EISSN: 1097-6825</identifier><identifier>DOI: 10.1016/j.jaci.2019.01.049</identifier><identifier>PMID: 30872116</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Administration, Inhalation ; Adrenal Cortex Hormones - administration & dosage ; Adrenergic receptors ; Adult ; Alendronate - administration & dosage ; Alendronic acid ; Asthma ; Asthma - drug therapy ; Asthma - pathology ; Asthma - physiopathology ; bisphosphonate ; Bisphosphonates ; bronchoprotection ; controller therapy ; Corticosteroids ; Cyclic AMP ; Double-Blind Method ; downregulation ; Enzyme-linked immunosorbent assay ; Female ; Fluticasone ; Fluticasone - administration & dosage ; Humans ; Inhalers ; Kinases ; loss of bronchoprotection ; Lungs ; Male ; Methacholine ; Peripheral blood mononuclear cells ; Proof of Concept Study ; Randomization ; Receptors, Adrenergic, beta-2 - metabolism ; Respiratory function ; Salmeterol ; Salmeterol Xinafoate - administration & dosage ; Smooth muscle ; Steroids ; Studies ; β2-Adrenergic receptor ; β2-agonists</subject><ispartof>Journal of allergy and clinical immunology, 2019-08, Vol.144 (2), p.416-425.e7</ispartof><rights>2019 American Academy of Allergy, Asthma & Immunology</rights><rights>Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.</rights><rights>2019. American Academy of Allergy, Asthma & Immunology</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c483t-b986741fecba29aef2e88d2e930147135b6e187dfc3a7e2c9a8802d2543be7e73</citedby><cites>FETCH-LOGICAL-c483t-b986741fecba29aef2e88d2e930147135b6e187dfc3a7e2c9a8802d2543be7e73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0091674919303471$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30872116$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cardet, Juan Carlos</creatorcontrib><creatorcontrib>Jiang, Xiaofeng</creatorcontrib><creatorcontrib>Lu, Quan</creatorcontrib><creatorcontrib>Gerard, Norma</creatorcontrib><creatorcontrib>McIntire, Kristen</creatorcontrib><creatorcontrib>Boushey, Homer A.</creatorcontrib><creatorcontrib>Castro, Mario</creatorcontrib><creatorcontrib>Chinchilli, Vernon M.</creatorcontrib><creatorcontrib>Codispoti, Christopher D.</creatorcontrib><creatorcontrib>Dyer, Anne-Marie</creatorcontrib><creatorcontrib>Holguin, Fernando</creatorcontrib><creatorcontrib>Kraft, Monica</creatorcontrib><creatorcontrib>Lazarus, Stephen</creatorcontrib><creatorcontrib>Lemanske, Robert F.</creatorcontrib><creatorcontrib>Lugogo, Njira</creatorcontrib><creatorcontrib>Mauger, Dave</creatorcontrib><creatorcontrib>Moore, Wendy C.</creatorcontrib><creatorcontrib>Moy, James</creatorcontrib><creatorcontrib>Ortega, Victor E.</creatorcontrib><creatorcontrib>Peters, Stephen P.</creatorcontrib><creatorcontrib>Smith, Lewis J.</creatorcontrib><creatorcontrib>Solway, Julian</creatorcontrib><creatorcontrib>Sorkness, Christine A.</creatorcontrib><creatorcontrib>Sumino, Kaharu</creatorcontrib><creatorcontrib>Wechsler, Michael E.</creatorcontrib><creatorcontrib>Wenzel, Sally</creatorcontrib><creatorcontrib>Israel, Elliot</creatorcontrib><creatorcontrib>AsthmaNet Investigators</creatorcontrib><title>Loss of bronchoprotection with ICS plus LABA treatment, β-receptor dynamics, and the effect of alendronate</title><title>Journal of allergy and clinical immunology</title><addtitle>J Allergy Clin Immunol</addtitle><description>Loss 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.
We sought to determine whether alendronate can reduce LABA-associated LOBP in inhaled corticosteroid (ICS)–treated patients.
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.
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.
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.</description><subject>Administration, Inhalation</subject><subject>Adrenal Cortex Hormones - administration & dosage</subject><subject>Adrenergic receptors</subject><subject>Adult</subject><subject>Alendronate - administration & dosage</subject><subject>Alendronic acid</subject><subject>Asthma</subject><subject>Asthma - drug therapy</subject><subject>Asthma - pathology</subject><subject>Asthma - physiopathology</subject><subject>bisphosphonate</subject><subject>Bisphosphonates</subject><subject>bronchoprotection</subject><subject>controller therapy</subject><subject>Corticosteroids</subject><subject>Cyclic AMP</subject><subject>Double-Blind Method</subject><subject>downregulation</subject><subject>Enzyme-linked immunosorbent assay</subject><subject>Female</subject><subject>Fluticasone</subject><subject>Fluticasone - administration & dosage</subject><subject>Humans</subject><subject>Inhalers</subject><subject>Kinases</subject><subject>loss of bronchoprotection</subject><subject>Lungs</subject><subject>Male</subject><subject>Methacholine</subject><subject>Peripheral blood mononuclear cells</subject><subject>Proof of Concept Study</subject><subject>Randomization</subject><subject>Receptors, Adrenergic, beta-2 - metabolism</subject><subject>Respiratory function</subject><subject>Salmeterol</subject><subject>Salmeterol Xinafoate - administration & dosage</subject><subject>Smooth muscle</subject><subject>Steroids</subject><subject>Studies</subject><subject>β2-Adrenergic receptor</subject><subject>β2-agonists</subject><issn>0091-6749</issn><issn>1097-6825</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc2KFDEUhYMoTs_oC7iQgNupMj9V-QERepr5gwYX6jqkklt2yu5KmUqPzGv5ID6TaXocxo2rcMm53z2cg9AbSmpKqHg_1IN1oWaE6prQmjT6GVpQomUlFGufowUhmlZCNvoEnc7zQMrMlX6JTjhRklEqFuj7Os4zjj3uUhzdJk4pZnA5xBH_DHmDb1ef8bTdz3i9vFjinMDmHYz5HP_-VSVwMOWYsL8f7S64-Rzb0eO8AQx9XygHrt3C6AvbZniFXvR2O8Prh_cMfb26_LK6qdafrm9Xy3XlGsVz1WlVPNMC6CzTFnoGSnkGmhPaSMrbTgBV0veOWwnMaasUYZ61De9AguRn6OORO-27HXhX_Ca7NVMKO5vuTbTB_Pszho35Fu-M0C2RQhTAuwdAij_2MGczxH0ai2fDWMlWtkrwomJHlUslwwT94wVKzKEgM5hDQeZQkCHUlILK0tun3h5X_jZSBB-OAigJ3QVIZnYBRgc-lLyz8TH8j_8HPXij-g</recordid><startdate>20190801</startdate><enddate>20190801</enddate><creator>Cardet, Juan Carlos</creator><creator>Jiang, Xiaofeng</creator><creator>Lu, Quan</creator><creator>Gerard, Norma</creator><creator>McIntire, Kristen</creator><creator>Boushey, Homer A.</creator><creator>Castro, Mario</creator><creator>Chinchilli, Vernon M.</creator><creator>Codispoti, Christopher D.</creator><creator>Dyer, Anne-Marie</creator><creator>Holguin, Fernando</creator><creator>Kraft, Monica</creator><creator>Lazarus, Stephen</creator><creator>Lemanske, Robert F.</creator><creator>Lugogo, Njira</creator><creator>Mauger, Dave</creator><creator>Moore, Wendy C.</creator><creator>Moy, James</creator><creator>Ortega, Victor E.</creator><creator>Peters, Stephen P.</creator><creator>Smith, Lewis J.</creator><creator>Solway, Julian</creator><creator>Sorkness, Christine A.</creator><creator>Sumino, Kaharu</creator><creator>Wechsler, Michael E.</creator><creator>Wenzel, Sally</creator><creator>Israel, Elliot</creator><general>Elsevier Inc</general><general>Elsevier Limited</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7SS</scope><scope>7T5</scope><scope>H94</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>5PM</scope></search><sort><creationdate>20190801</creationdate><title>Loss of bronchoprotection with ICS plus LABA treatment, β-receptor dynamics, and the effect of alendronate</title><author>Cardet, Juan Carlos ; Jiang, Xiaofeng ; Lu, Quan ; Gerard, Norma ; McIntire, Kristen ; Boushey, Homer A. ; Castro, Mario ; Chinchilli, Vernon M. ; Codispoti, Christopher D. ; Dyer, Anne-Marie ; Holguin, Fernando ; Kraft, Monica ; Lazarus, Stephen ; Lemanske, Robert F. ; Lugogo, Njira ; Mauger, Dave ; Moore, Wendy C. ; Moy, James ; Ortega, Victor E. ; Peters, Stephen P. ; Smith, Lewis J. ; Solway, Julian ; Sorkness, Christine A. ; Sumino, Kaharu ; Wechsler, Michael E. ; Wenzel, Sally ; Israel, Elliot</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c483t-b986741fecba29aef2e88d2e930147135b6e187dfc3a7e2c9a8802d2543be7e73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Administration, Inhalation</topic><topic>Adrenal Cortex Hormones - 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LOBP has been attributed to β2-adrenergic receptor (B2AR) downregulation, a process requiring farnesylation, which is inhibited by alendronate.
We sought to determine whether alendronate can reduce LABA-associated LOBP in inhaled corticosteroid (ICS)–treated patients.
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.
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.
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.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>30872116</pmid><doi>10.1016/j.jaci.2019.01.049</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0091-6749 |
| ispartof | Journal of allergy and clinical immunology, 2019-08, Vol.144 (2), p.416-425.e7 |
| issn | 0091-6749 1097-6825 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6950766 |
| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Administration, Inhalation Adrenal Cortex Hormones - administration & dosage Adrenergic receptors Adult Alendronate - administration & dosage Alendronic acid Asthma Asthma - drug therapy Asthma - pathology Asthma - physiopathology bisphosphonate Bisphosphonates bronchoprotection controller therapy Corticosteroids Cyclic AMP Double-Blind Method downregulation Enzyme-linked immunosorbent assay Female Fluticasone Fluticasone - administration & dosage Humans Inhalers Kinases loss of bronchoprotection Lungs Male Methacholine Peripheral blood mononuclear cells Proof of Concept Study Randomization Receptors, Adrenergic, beta-2 - metabolism Respiratory function Salmeterol Salmeterol Xinafoate - administration & dosage Smooth muscle Steroids Studies β2-Adrenergic receptor β2-agonists |
| title | Loss of bronchoprotection with ICS plus LABA treatment, β-receptor dynamics, and the effect of alendronate |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-04T16%3A58%3A40IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Loss%20of%20bronchoprotection%20with%20ICS%20plus%20LABA%20treatment,%20%CE%B2-receptor%20dynamics,%20and%20the%20effect%20of%20alendronate&rft.jtitle=Journal%20of%20allergy%20and%20clinical%20immunology&rft.au=Cardet,%20Juan%20Carlos&rft.aucorp=AsthmaNet%20Investigators&rft.date=2019-08-01&rft.volume=144&rft.issue=2&rft.spage=416&rft.epage=425.e7&rft.pages=416-425.e7&rft.issn=0091-6749&rft.eissn=1097-6825&rft_id=info:doi/10.1016/j.jaci.2019.01.049&rft_dat=%3Cproquest_pubme%3E2268275863%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2268275863&rft_id=info:pmid/30872116&rft_els_id=S0091674919303471&rfr_iscdi=true |