Steroid sparing effects of doxofylline

Abstract

Glucocorticosteroids are widely used in the treatment of asthma and chronic obstructive pulmonary disease (COPD). However, there are growing concerns about the side effect profile of this class of drug, particularly an increased risk of pneumonia. Over the last two decades there have been many attempts to find drugs to allow a reduction of glucocorticosteroids, including xanthines such as theophylline. Use of xanthines has been shown to lead to a reduction in the requirement for glucocorticosteroids, although xanthines also have a narrow therapeutic window limiting their wider use. Doxofylline is another xanthine that has been shown to be of clinical benefit in patients with asthma or COPD, but to have a wider therapeutic window than theophylline. In the present study we have demonstrated that doxofylline produces a clear steroid sparing effect in both an allergic and a non-allergic model of lung inflammation. Thus, we have shown that concomitant treatment with a low dose of doxofylline and a low dose of the glucocorticosteroid dexamethasone (that alone had no effect) significantly reduced both allergen-induced eosinophil infiltration into the lungs of allergic mice, and lipopolysaccharide (LPS)-induced neutrophil infiltration into the lung, equivalent to a higher dose of each drug. Our results suggest that doxofylline demonstrates significant anti-inflammatory activity in the lung which can result in significant steroid sparing activity.

The protective effect of doxofylline against lipopolysaccharides (LPS)-induced activation of NLRP3 inflammasome is mediated by SIRT1 in human pulmonary bronchial epithelial cells

“…In a rat model, doxofylline administration significantly improved cigarette smoke-induced COPD [13]. Several studies have shown that doxofylline administration has a significant anti-inflammatory effect in different lung diseases including bronchitis [14][15][16]. This evidence indicates that doxofylline is a favourable anti-inflammatory agent for the treatment of lung diseases.…”

Efficacy and safety profile of xanthines in COPD: a network meta-analysis

“…Given the pharmacological profile of doxofylline [49,50]; its significant anti-inflammatory activity that can result in significant steroid sparing activity, as documented at least in both an allergic and a nonallergic murine model of lung inflammation [54]; its documented clinical activity [12][13][14]; and, above all, the results of the present meta-analysis, there is a clear need to understand what is the room in the treatment of COPD for a xanthine that induces the same, if not even better, therapeutic effects of theophylline but with a totally different safety profile. Specifically, the rate of study withdrawal due to adverse events such as dyspepsia, epigastralgia, nausea and palpitation was approximately four-fold higher in COPD patients treated with theophylline than in those treated with doxofylline.…”

Efficacy and safety profile of xanthines in COPD: a network meta-analysis

“…Given the pharmacological profile of doxofylline [49,50]; its significant anti-inflammatory activity that can result in significant steroid sparing activity, as documented at least in both an allergic and a nonallergic murine model of lung inflammation [54]; its documented clinical activity [12][13][14]; and, above all, the results of the present meta-analysis, there is a clear need to understand what is the room in the treatment of COPD for a xanthine that induces the same, if not even better, therapeutic effects of theophylline but with a totally different safety profile. Specifically, the rate of study withdrawal due to adverse events such…”