Antitussive effects of the peripherally restricted GABAB receptor agonist lesogaberan in guinea pigs: comparison to baclofen and other GABAB receptor-selective agonists

Cough

Anders Lehmann²  Nanako Mori¹  Brendan J Canning¹ 

[1] Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, Maryland, 21224, USA;AstraZeneca R&D Mölndal, SE-431 83, Mölndal, Sweden

关键词: Lesogaberan;    TRPV1;    C-fiber;    LES relaxation;    Esophagus;    Gastroesophageal reflux;   

Others  :  809288
DOI  :  10.1186/1745-9974-8-7

 received in 2012-03-23, accepted in 2012-09-07,  发布年份 2012

【 摘 要 】

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.

【 授权许可】

   
2012 Canning et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

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