Xanthine Derivatives and Phosphodiesterase Inhibitors

Xanthine derivatives, which include theophylline and its salt, aminophylline, are very effective in treating obstructive airways disease. However, the means by which these agents induce airway smooth muscle relaxation remains unclear. The primary mechanisms proposed include: (1) inhibition of phosphodiesterase, the enzyme responsible for metabolism of the intracellular messenger, cyclic adenosine 3',5'-monophosphate (cAMP) [39] and (2) antagonism of receptors for adenosine, an agent that is proinflammatory and induces airway smooth muscle contraction in asthmatics [40]. It has become clear that several phosphodiesterase (PDE) isozymes (or subtypes) exist in the airways [42]. PDE3 and PDE4 are important in regulating cAMP levels in airway smooth muscle, and theophylline likely induces bronchodilation as a nonselective inhibitor of both isozymes [39]. PDE4 appears to be the primary cAMP-metabolizing enzyme in inflammatory (e.g., mast cells) and immune cells [41]. Consistent with these observations are the documented anti-inflammatory effects of recently developed inhibitors of PDE4 [41]. Xanthine derivatives are administered to the systemic circulation via the intravenous or oral routes of administration. Cardiovascular and central nervous system side effects represent a concern with the use of these agents because of their relatively narrow therapeutic index; i.e., side effects begin to manifest at the upper limits of therapeutic doses. Several pharmaceutical companies are developing isozyme-selective inhibitors with the hope of maintaining anti-inflammatory activity (PDE4 inhibition) to treat airways disease and diminishing side effects associated caused by inhibition of other isozymes, e.g., cardiovascular effects caused by PDE3 inhibition [41,42]. Several PDE4 inhibitors are advancing through early clinical studies [43], with cilomilast demonstrating beneficial effects in patients with chronic obstructive pulmonary disease [44]. Limited studies evaluating the activity of aerosolized xanthines have been conducted and have shown these compounds to induce bronchodila-tion, albeit less effectively than aerosolized b2-adrenoceptor agonists [45,46]. Currently in trials, PDE4 inhibitors are administered orally, with nausea and gastrointestinal side effects representing the most common adverse events [41,44]. It remains to be seen whether administration by inhalation could be used to reduce these systemic side effects.

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