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Antitussive effects of the peripherally restricted GABA(B) receptor agonist lesogaberan in guinea pigs: comparison to baclofen and other GABA(B) receptor-selective agonists
BACKGROUND: Gastroesophageal reflux disease (GERD) is a common cause of chronic cough. Both acid and nonacid reflux is thought to play a role in the initiation of coughing and cough hypersensitivity. The GABA(B) receptor agonist lesogaberan was developed as a peripherally restricted anti-reflux ther...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3520872/ https://www.ncbi.nlm.nih.gov/pubmed/23025757 http://dx.doi.org/10.1186/1745-9974-8-7 |
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author | Canning, Brendan J Mori, Nanako Lehmann, Anders |
author_facet | Canning, Brendan J Mori, Nanako Lehmann, Anders |
author_sort | Canning, Brendan J |
collection | PubMed |
description | BACKGROUND: Gastroesophageal reflux disease (GERD) is a common cause of chronic cough. Both acid and nonacid reflux is thought to play a role in the initiation of coughing and cough hypersensitivity. The GABA(B) receptor agonist lesogaberan was developed as a peripherally restricted anti-reflux therapy that reduces the frequency of transient lower esophageal sphincter relaxations (TLESR; the major cause of reflux) in animals and in patients with GERD. GABA(B) receptor agonists have also been shown to possess antitussive effects in patients and in animals independent of their effects on TLESR, suggesting that lesogaberan may be a promising treatment for chronic cough. METHODS: We have assessed the direct antitussive effects of lesogaberan (AZD3355). The effects of other GABA(B) receptor agonists were also determined. Coughing was evoked in awake guinea pigs using aerosol challenges with citric acid. RESULTS: Lesogaberan dose-dependently inhibited citric acid evoked coughing in guinea pigs. Comparable effects of the GABA(B) receptor agonists baclofen and 3-aminopropylphosphinic acid (3-APPiA) on cough were also observed. Baclofen produced obvious signs of sedation and respiratory depression. By contrast, both lesogaberan and 3-APPiA (both inactivated centrally by GABA transporters) were devoid of sedative effects and did not alter respiratory rate. CONCLUSIONS: Together, the data suggest that lesogaberan and related GABA(B) receptor agonists may hold promise as safe and effective antitussive agents largely devoid of CNS side effects. |
format | Online Article Text |
id | pubmed-3520872 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-35208722012-12-13 Antitussive effects of the peripherally restricted GABA(B) receptor agonist lesogaberan in guinea pigs: comparison to baclofen and other GABA(B) receptor-selective agonists Canning, Brendan J Mori, Nanako Lehmann, Anders Cough Research BACKGROUND: Gastroesophageal reflux disease (GERD) is a common cause of chronic cough. Both acid and nonacid reflux is thought to play a role in the initiation of coughing and cough hypersensitivity. The GABA(B) receptor agonist lesogaberan was developed as a peripherally restricted anti-reflux therapy that reduces the frequency of transient lower esophageal sphincter relaxations (TLESR; the major cause of reflux) in animals and in patients with GERD. GABA(B) receptor agonists have also been shown to possess antitussive effects in patients and in animals independent of their effects on TLESR, suggesting that lesogaberan may be a promising treatment for chronic cough. METHODS: We have assessed the direct antitussive effects of lesogaberan (AZD3355). The effects of other GABA(B) receptor agonists were also determined. Coughing was evoked in awake guinea pigs using aerosol challenges with citric acid. RESULTS: Lesogaberan dose-dependently inhibited citric acid evoked coughing in guinea pigs. Comparable effects of the GABA(B) receptor agonists baclofen and 3-aminopropylphosphinic acid (3-APPiA) on cough were also observed. Baclofen produced obvious signs of sedation and respiratory depression. By contrast, both lesogaberan and 3-APPiA (both inactivated centrally by GABA transporters) were devoid of sedative effects and did not alter respiratory rate. CONCLUSIONS: Together, the data suggest that lesogaberan and related GABA(B) receptor agonists may hold promise as safe and effective antitussive agents largely devoid of CNS side effects. BioMed Central 2012-10-01 /pmc/articles/PMC3520872/ /pubmed/23025757 http://dx.doi.org/10.1186/1745-9974-8-7 Text en Copyright ©2012 Canning et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Canning, Brendan J Mori, Nanako Lehmann, Anders Antitussive effects of the peripherally restricted GABA(B) receptor agonist lesogaberan in guinea pigs: comparison to baclofen and other GABA(B) receptor-selective agonists |
title | Antitussive effects of the peripherally restricted GABA(B) receptor agonist lesogaberan in guinea pigs: comparison to baclofen and other GABA(B) receptor-selective agonists |
title_full | Antitussive effects of the peripherally restricted GABA(B) receptor agonist lesogaberan in guinea pigs: comparison to baclofen and other GABA(B) receptor-selective agonists |
title_fullStr | Antitussive effects of the peripherally restricted GABA(B) receptor agonist lesogaberan in guinea pigs: comparison to baclofen and other GABA(B) receptor-selective agonists |
title_full_unstemmed | Antitussive effects of the peripherally restricted GABA(B) receptor agonist lesogaberan in guinea pigs: comparison to baclofen and other GABA(B) receptor-selective agonists |
title_short | Antitussive effects of the peripherally restricted GABA(B) receptor agonist lesogaberan in guinea pigs: comparison to baclofen and other GABA(B) receptor-selective agonists |
title_sort | antitussive effects of the peripherally restricted gaba(b) receptor agonist lesogaberan in guinea pigs: comparison to baclofen and other gaba(b) receptor-selective agonists |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3520872/ https://www.ncbi.nlm.nih.gov/pubmed/23025757 http://dx.doi.org/10.1186/1745-9974-8-7 |
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