title: Pharmacological characterization of the interaction between the dual phosphodiesterase (PDE) 3/4 inhibitor RPL554 and glycopyrronium on human isolated bronchi and small airways.
abstract: 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 ≃ 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.
authors.affiliation: Department of Systems Medicine, University of Rome 'Tor Vergata', Rome, Italy. Electronic address: luigicalz@gmail.com.
authors.forename: Luigino
authors.initials: L
authors.lastname: Calzetta
authors.affiliation: Department of Systems Medicine, University of Rome 'Tor Vergata', Rome, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Cazzola
authors.affiliation: Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, London, UK.
authors.forename: Clive P
authors.initials: CP
authors.lastname: Page
authors.affiliation: Department of Systems Medicine, University of Rome 'Tor Vergata', Rome, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Rogliani
authors.affiliation: Thoracic Surgery, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Facciolo
authors.affiliation: Department of Experimental Medicine, Second University of Naples, Naples, Italy.
authors.forename: Maria Gabriella
authors.initials: MG
authors.lastname: Matera
mesh_terms: D000368:Aged; D001980:Bronchi / Q000187:drug effects* / Q000378:metabolism; D004357:Drug Synergism; D004558:Electric Stimulation; D005260:Female; D006024:Glycopyrrolate / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D007546:Isoquinolines / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects*; D058987:Phosphodiesterase 3 Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D058988:Phosphodiesterase 4 Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D011744:Pyrimidinones / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D007546:Isoquinolines; D018727:Muscarinic Antagonists; D058987:Phosphodiesterase 3 Inhibitors; D058988:Phosphodiesterase 4 Inhibitors; D011744:Pyrimidinones; C512996:ensifentrine; D006024:Glycopyrrolate
keywords: Airway smooth muscle; Asthma; COPD; Glycopyrronium; Human isolated bronchi; RPL554; Relaxant response; Small airways; Synergistic interaction