RT Journal Article SR Electronic T1 In vivo efficacy of CHF6001, an inhaled PDE4 inhibitor with a wide therapeutic window JF European Respiratory Journal JO Eur Respir J FD European Respiratory Society SP P1787 VO 44 IS Suppl 58 A1 Gino Villetti A1 Pier Tonino Bolzoni A1 Franco Bassani A1 Marco Bergamaschi A1 Paola Lorenza Caruso A1 Loredana Battipaglia A1 Angelo Sala A1 Fabrizio Facchinetti A1 Chiara Carnini A1 Maurizio Civelli YR 2014 UL http://erj.ersjournals.com/content/44/Suppl_58/P1787.abstract AB A strategy to overcome the side effect liabilities of oral phosphodiesterase 4 (PDE4) inhibitors has been to deliver the drugs by inhalation to improve their therapeutic index. We report the in vivo profile of CHF6001, a PDE4 inhibitor with biological and pharmacokinetic properties suitable for the inhaled delivery.CHF6001 therapeutic value was assessed in preclinical models of allergic asthma and COPD-models [lipopolysaccharide (LPS) and tobacco smoke-induced lung neutrophilia]. Gastrointestinal side-effects were investigated in a surrogate model of emesis in rats (reversal of ketamine/xylazine-induced anaesthesia) and in ferrets.Intratracheally (i.t.) administered as a dry powder, CHF6001 inhibits LPS-induced lung neutrophilia in rats (ED50 = 0.1 μmol/kg). In ovalbumin sensitised Brown Norway rats, CHF6001 is as potent as the PDE4 inhibitor GSK256066 and budesonide in suppressing eosinophilia (ED50= 0.03 μmol/kg i.t.) and shows a 24 hour duration of action at the ED50 × 3 dose, 0.09 μmol/kg.After 11 days of tobacco smoke exposure in mice, intranasal CHF-6001 inhibits neutrophilia both as prophylactic and interventional treatment at the lowest doses tested, 0.15 and 0.045 μmol/kg, respectively.CHF6001 is ineffective in reversing ketamine/xylazine-induced anaesthesia up to 5 μmol/kg i.t., a dose 50-150 fold higher than ED50 values obtained in inflammation models in rats. When given topically to ferrets, no emesis and nausea were evident up to 20 μmol/kg. GSK256066 induced nausea at 1 μmol/kg i.t.Upon topical treatment, CHF6001 showed potent and long-lasting anti-inflammatory effects combined with excellent tolerability. CHF6001 may represent a novel inhaled agent for COPD treatment.