Abstract
Background: The acute relaxant synergistic interaction between RPL554 and anticholinergic agents has been recently proved on human isolated bronchi (Calzetta, L. et al. J Pharmacol Exp Ther. 2013; 346:414-23).
Aim: To investigate the long-lasting interaction between RPL554 and glycopyrronium in human isolated bronchi.
Methods: Bronchial rings from 6 patients were incubated in Krebs-Henseleit solution (37°C) aerated with O2/CO2 (95/5%) under 0.5–1.0 g tension. The duration of action (30% maximal relaxation, EC30) of RPL554 and glycopyrronium, alone or in combination, was studied in tissue contracted with 3-10-25 Hz electrical field stimulation (EFS). Bronchial tone was expressed as % of maximal response to papaverine (Emax) and the area under the curve (AUC) of the contractile response was assessed. Drug mixture effects were analyzed by Bliss Independence theory. Values (n=3) are mean±SEM.
Results: RPL554 and glycopyrronium administered alone induced the maximal relaxation at 160±20 min and 50±10 min, respectively, and the effect was detectable for 4 hrs. The maximal synergistic relaxant interaction was at ≅2 hrs (71.4±5.1%), during the washout period, and the combination of drugs extended the relaxant effect at 6 hrs, when the reduction of EFS-mediated contractile response was still 41.2±8.5%. The observed AUC (44.9±3.1%) was significantly lower than that expected (65.8±3.3%) during the 6 hrs of the study (P<0.001), with the main effectiveness for EFS at 3Hz (-35.8±2.5%, P<0.001).
Conclusions: RPL554 and glycopyrronium at low concentrations synergistically inhibited the contractile tone induced by EFS in human isolated bronchi and extended the ralaxant effect for 6 hrs.
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