Pharmacological characterization of the interaction between the dual phosphodiesterase (PDE) 3/4 inhibitor RPL554 and glycopyrronium on human isolated bronchi and small airways

Background: The dual PDE3/4 inhibitor RPL 554 causes bronchodilation in patients with asthma or COPD and synergistically interacts with muscarinic receptor antagonists in relaxing human isolated bronchi in acute experimental settings. In the present study we investigated the long-lasting interaction between RPL554 and glycopyrronium by testing these drugs for their ability to relax both medium and small human isolated bronchi. Methods: The relaxant effect and duration of action of RPL554 and glycopyrronium, alone, or in combination, were studied on the contractile tone induced by electrical field stimulation (EFS) or carbachol in medium and small human isolated bronchi. Relaxation was expressed as percentage of maximal response and synergy analyzed by Bliss Independence theory. Results: Low concentrations of RPL554 and glycopyrronium induced maximal relaxation of medium bronchi at 160 +/- 20 min and 50 +/- 10 min, respectively, an effect detectable for at least 4 h. Maximal synergy was observed at similar or equal to 2 hrs (-71.4 +/- 5.1%), and the combination extended the relaxation to at least 6 hrs, when the contractile tone was -41.2 +/- 8.5% of the control responses. The combination induced the greatest effectiveness for EFS at 3 Hz and low-to-middle concentrations also produced significant synergism on small airways (21.1 +/- 4.0%,P < 0.05), compared with the additive response. The combination induced lumen area enhancement of 69.1 +/- 2.4% (P < 0.05), compared with the additive response (51.0 +/- 5.4%). Conclusions: RPL554 and glycopyrronium demonstrated a synergistic interaction in relaxing both human medium and small isolated bronchi, in terms of peak relaxation and an extended duration of action, suggesting that this combination may have a beneficial role in the treatment of asthma or COPD. (C) 2015 Elsevier Ltd. All rights reserved.