TY - JOUR T1 - Late-breaking abstract: Further studies on the mechanism of action of doxofylline JF - European Respiratory Journal JO - Eur Respir J VL - 38 IS - Suppl 55 SP - 3414 AU - Thierry Jolas AU - Clive Page AU - Luigi Allegra Y1 - 2011/09/01 UR - http://erj.ersjournals.com/content/38/Suppl_55/3414.abstract N2 - Xanthines such as theophylline have been used in the treatment of lung diseases since the early 1900's, but have a major drawback of a very narrow therapeutic window and many drug/drug interactions. This means that regular plasma levels often have to be obtained and can make the use of theophylline problematic. With the increasing availability of other classes of drugs for the treatment of respiratory diseases, this has limited the use of xanthines, despite their clean clinical benefit in the treatment of patients with asthma and COPD. Doxofylline is a xanthine molecule having both bronchodilator and anti-inflammatory activity, with an improved therapeutic window over conventional xanthines such as theophylline. However, the mechanistic basis of this improved therapeutic window is not understood. The present study has investigated the ability of doxofylline to inhibit human recombinant PDE and HDAC enzymes, and bind to adenosine receptor assays in vitro in comparison with theophylline. Theophylline had a significant effect on adenosine receptor binding that was not shared by doxofylline. Our results suggest that doxofylline may have a wider therapeutic window than theophylline due to a lack of adenosine receptor antagonism. Neither drug had any significant inhibitory effect on HDAC enzymes over a wide range.Additionally, in contrast to doxofylline, theophylline showed a significant effect on PDE3. It has been suggested that the ability of theophylline to inhibit PDE3 may contribute to the unwanted cardiovascular effects observed at higher serum concentrations. The lack of effect of doxofylline on PDE3 may also help explain its improved tolerability profile on the cardiovascular system. ER -