title: The mechanism of action of doxofylline is unrelated to HDAC inhibition, PDE inhibition or adenosine receptor antagonism.
abstract: 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 plasma levels have to be measured regularly 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 clear 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 some pharmacological activities of doxofylline in comparison with theophylline. Doxofylline does not directly inhibit any of the known HDAC enzymes, and did not inhibit any PDE enzyme sub types or act as an antagonist at any of the known adenosine receptors, except for PDE2A(1), and adenosine A(2A) and only at the highest tested concentration (10(-4) M). These results may explain the improved tolerability profile of doxofylline compared with theophylline.
authors.affiliation: Eurodrug Laboratories, The Hague, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: van Mastbergen
authors.forename: T
authors.initials: T
authors.lastname: Jolas
authors.forename: L
authors.initials: L
authors.lastname: Allegra
authors.forename: C P
authors.initials: CP
authors.lastname: Page
mesh_terms: D001993:Bronchodilator Agents / Q000494:pharmacology*; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000032:analysis / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000032:analysis / Q000378:metabolism; D058915:Purinergic P1 Receptor Antagonists / Q000494:pharmacology*; D043705:Receptor, Adenosine A2A / Q000187:drug effects / Q000378:metabolism; D012044:Regression Analysis; D015203:Reproducibility of Results; D013806:Theophylline / Q000031:analogs & derivatives* / Q000494:pharmacology; D014162:Transfection
chemical_list: D001993:Bronchodilator Agents; D056572:Histone Deacetylase Inhibitors; D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D058915:Purinergic P1 Receptor Antagonists; D043705:Receptor, Adenosine A2A; D013806:Theophylline; D010727:Phosphoric Diester Hydrolases; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2; C517275:PDE2A protein, human; D006655:Histone Deacetylases; C029797:doxofylline