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.

Assessment of the Airway Smooth Muscle Relaxant Effect of Drotaverine

“…Theophylline was equipotent against the constrictor mediators, and was also a weak inhibitor of the constrictor mediator-induced contractions. These results also support the relatively weak bronchodilator effect of PDE inhibitory methylxanthines [34, 35]. Based on our experimental data, drotaverine shares the characteristics of both a PDE inhibitor and an L-VOCC blocker with respect to airway smooth muscle relaxation and/or decreasing the constrictor response of smooth muscle constrictors (Fig.…”

Modeling asthma: Pitfalls, promises, and the road ahead

“…Interestingly, Salter prescribed black coffee, a beverage with relatively high levels of the xanthine alkaloid, theobromine. Both theobromine and the related compound, theophylline, which reduce ASM contraction in part by inhibiting phosphodiesterases, thus increasing intracellular cAMP, were first‐line therapy for asthma until relatively recently …”

“…by inhibiting phosphodiesterases, thus increasing intracellular cAMP, were first-line therapy for asthma until relatively recently. 17 Sir William Osler (1849-1919) further defined the pathological and clinical features of asthma, and reported increased mucus in the airways, specialized inflammation of the bronchioles, and a familial predisposition. He was also the first to recognize the association of asthma with allergy (e.g.…”

Roles of roflumilast, a selective phosphodiesterase 4 inhibitor, in airway diseases

“…Roflumilast is recommended for being added on therapy to ICS/LABA or LAMA in COPD with frequent exacerbations. However, the roles of theophylline for CODP are limited due to relatively narrow therapeutic window and the availability of the effective inhaled bronchodilators (76)(77)(78). Despite that theophylline enhancing histone deacetylase (HDAC) activity and improving corticosteroid sensitivity were recognized (79).…”

“…Low-dose theophylline increases corticosteroid sensitivity, as its molecular mechanism enhances HDAC activity in PBMCs in cases of severe asthma and COPD (79,85). However, the effects of roflumilast on HDAC activation and reversal corticosteroid resistance in COPD require further investigation (78,86). Despite that roflumilast was approved for COPD, its potential beyond inflammatory lung diseases such as bronchiectasis, pulmonary fibrosis and ACOS is promising.…”