PT  - JOURNAL ARTICLE
AU  - Luigino Calzetta
AU  - Mario Cazzola
AU  - Clive Page
AU  - Paola Rogliani
AU  - Francesco Facciolo
AU  - Maria Gabriella Matera
TI  - Interaction between RPL554 and glycopyrronium bromide in small human airways
DP  - 2014 Sep 01
TA  - European Respiratory Journal
PG  - P3337
VI  - 44
IP  - Suppl 58
4099  - http://erj.ersjournals.com/content/44/Suppl_58/P3337.short
4100  - http://erj.ersjournals.com/content/44/Suppl_58/P3337.full
SO  - Eur Respir J2014 Sep 01; 44
AB  - Background:The relaxant synergistic interaction between RPL554 and anticholinergic agents has been recently proved on human isolated segmental bronchi (Calzetta, L. et al. J Pharmacol Exp Ther. 2013;346:414-23).Aim:To investigate the interaction between RPL554 and glycopyrronium in human isolated bronchioles.Methods:Precision cut lung slices (PCLSs) from 6 patients were incubated in Krebs-Henseleit solution (37°C) aerated with O2/CO2 (95:5%). The concentration response to RPL554 and glycopyrronium, administered alone and in combination at isoeffective concentrations, was assessed at sub-maximal contraction (70% maximum, EC70) induced by carbachol (CCh). The relaxation of small bronchi (<1mm diameter) was expressed as % of maximal response (lumen area enhancement) induced by papaverine (Emax) and potency as negative logarithm of IC50 (pD2). Drug mixture effects were analyzed by Bliss Independence theory. Values (n=3) are mean±SEM.Results:Glycopyrronium induced a more potent concentration-dependent relaxation of bronchioles compared with RPL554 (pD2: glycopyrronium 9.2±0.4, RPL554 6.0±0.1, P<0.001) and both abolished the CCh-induced contraction. Glycopyrronium and RPL554 at low-to-middle concentrations (glycopyrronium 0.05nM–0.14 nM, RPL554 0.32µM–0.54µM) had a synergistic relaxant effect on small airway enhancing relaxation by +21.1±4.0%, compared with the expected response (P<0.05). Low concentrations (EC30) of glycopyrronium plus RPL554 induced significant (P<0.05) lumen area enhancement of 69.1±2.4%, compared with the expected response (51.0±5.4%).Conclusions:RPL554 and glycopyrronium had a synergistic interaction on the lumen area enhancement of bronchioles, mainly at low-to-middle concentrations.