title: Xanthines and Phosphodiesterase Inhibitors.
abstract: Theophylline is an orally acting xanthine that has been used since 1937 for the treatment of respiratory diseases including asthma and chronic obstructive pulmonary disease (COPD). However, in most treatment guidelines, xanthines have now been consigned to third-line therapy because of their narrow therapeutic window and propensity for drug-drug interactions. However, lower than conventional doses of theophylline considered to be bronchodilator are now known to have anti-inflammatory actions of relevance to the treatment of respiratory disease. The molecular mechanism(s) of action of theophylline are not well understood, but several potential targets have been suggested including non-selective inhibition of phosphodiesterases (PDE), inhibition of phosphoinositide 3-kinase, adenosine receptor antagonism and increased activity of certain histone deacetylases. Although theophylline has a narrow therapeutic window, other xanthines are in clinical use that are claimed to have a better tolerability such as doxofylline and bamifylline. Nonetheless, xanthines still play an important role in the treatment of asthma and COPD as they can show clinical benefit in patients who are refractory to glucocorticosteroid therapy, and withdrawal of xanthines from patients causes worsening of disease, even in patients taking concomitant glucocorticosteroids.More recently the orally active selective PDE4 inhibitor, roflumilast, has been introduced into clinical practice for the treatment of severe COPD on top of gold standard treatment. This drug has been shown to improve lung function in patients with severe COPD and to reduce exacerbations, but is dose limited by a range side effect, particularly gastrointestinal side effects.
authors.affiliation: The Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, Franklin Wilkins Building, London, SE1 9NH, UK.
authors.forename: D
authors.initials: D
authors.lastname: Spina
authors.affiliation: The Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, Franklin Wilkins Building, London, SE1 9NH, UK. clive.page@kcl.ac.uk.
authors.forename: C P
authors.initials: CP
authors.lastname: Page
mesh_terms: D000818:Animals; D001249:Asthma / Q000188:drug therapy*; D000075202:Contraindications; D006801:Humans; D058988:Phosphodiesterase 4 Inhibitors / Q000627:therapeutic use; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy*; D013806:Theophylline / Q000494:pharmacology / Q000627:therapeutic use; D014970:Xanthines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D014970:Xanthines; D013806:Theophylline
keywords: Adenosine receptor antagonism; Bamifylline; Doxofylline; HDAC; PI3δ-kinase; Phosphodiesterases; Theophylline