Doxofylline [7-(1,3-dioxolan-2-ylmethyl)-3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione] is a xanthine derivative introduced in 1987. Preclinical studies suggest that it modulates cAMP-associated pathways, with limited affinity for adenosine receptors and a less defined role in PDE inhibition compared with theophylline (10,11). Structurally, it differs from theophylline by the presence of a dioxalane group at position 7 (Fig. 1), which contributes to its improved tolerability and reduced drug-drug interactions (12,13).

PDE enzymes are key to cell signaling, hydrolyzing cyclic nucleotides such as cAMP and cGMP. PDE2A hydrolyzes both cAMP and cGMP, and its activity is further stimulated by cGMP, leading to preferential hydrolysis of cAMP under conditions of elevated cGMP (14).

Doxofylline may interfere with PDE activity (including PDE2A1; Fig. 2), potentially contributing to its bronchodilator and anti-inflammatory effects (10). However, other investigations did not confirm this mechanism, indicating that the role of PDE inhibition remains uncertain and requires further clarification (11,15). In contrast, theophylline exhibits a broader inhibitory profile, affecting PDE2A1, PDE3A and PDE10A1, which may contribute to its wider range of side effects, including nausea, vomiting, gastroesophageal reflux, headache, insomnia, tremor and potentially severe cardiac arrhythmia (11,16). These targeted actions enhance its efficacy and safety profile in managing respiratory disease.

In the respiratory system, adenosine mediates bronchoconstriction and inflammatory responses through receptor activation. Theophylline serves as a non-selective antagonist of adenosine receptors, including the A_2A subtype, producing anti-inflammatory and bronchodilator effects (7). However, this non-selective antagonism is associated with adverse effects, such as CNS stimulation, cardiac arrhythmias (via A₁ receptor blockade), gastric hypersecretion, gastroesophageal reflux and diuresis. Additionally, paradoxical inhibition of adenosine A_2A receptor signaling may exacerbate inflammation (17).

Unlike theophylline, doxofylline demonstrates a low affinity for adenosine A₁ and A₂ receptors and does not antagonize calcium channel blockers, which may explain its decreased cardiac adverse effects (17). Selective inhibition of PDE, along with its unique chemical structure featuring the dioxalane group, may contribute to its improved safety profile. Studies indicate that its effect on the A₂A receptor decreases airway inflammation and promotes bronchial relaxation, thereby supporting its efficacy in treating BA and COPD (10,18) (Fig. 3).

β₂-adrenergic receptor agonists are widely used as bronchodilators in BA and COPD due to their role in G-protein-mediated smooth muscle relaxation in the bronchial tree, resulting in bronchodilation (19,20). While doxofylline does not act as a direct β₂-agonist, it may enhance bronchodilation by potentiating the effects of β₂-agonists via increased intracellular cAMP availability (10).

Theophylline enhances bronchodilation by potentiating the effects of β₂-agonists, increasing intracellular cAMP levels. This synergistic effect is beneficial in combination therapies for patients with severe BA or COPD. Inhaled bronchodilators, including β₂-agonists and antimuscarinics, are critical for managing COPD at all stages and are essential for BA treatment (21).

Doxofylline also enhances the bronchodilator effects of β₂-agonists. Studies highlight its lower side-effect profile compared with theophylline, positioning it as a safer option for long-term management (13,18). Doxofylline, in conjunction with β₂-agonists, achieves effective bronchodilation without the notable adverse effects associated with high-dose theophylline (10).

HDAC enzymes regulate gene transcription by remodeling chromatin structure. Decreased HDAC2 activity is associated with corticosteroid resistance in COPD and BA, underscoring the clinical relevance of this pathway (22,23).

Low-dose theophylline has been reported to restore HDAC2 activity, thereby enhancing the transcriptional suppression of pro-inflammatory genes and improving corticosteroid responsiveness (7).

Unlike theophylline, the role of doxofylline in HDAC pathways remains uncertain; its improved safety profile is attributed to the presence of the dioxalane group, which reduces interaction with PDEs and adenosine receptors while maintaining anti-inflammatory activity (10,24).

PKC is a family of enzymes that serves an essential role in cell processes, including proliferation, differentiation and inflammation. PKC inhibitors interfere with PKC activity, modulating these processes and offering therapeutic potential in inflammatory disease (25). Theophylline has demonstrated anti-inflammatory effects through PKC inhibition. By modulating inflammatory pathways, it decreases airway inflammation and improves respiratory function in patients with BA and COPD (7).

Doxofylline also exhibits PKC inhibitory properties. PKC inhibition potentiates its anti-inflammatory effects, making it a more specific and safer option compared with theophylline for the long-term management of chronic respiratory disease (18,24).

Doxofylline significantly decreases inflammatory response by blocking several inflammatory pathways, such as lipopolysaccharides (LPS)-induced thioredoxin-interacting protein/NOD-like receptor protein 3 (NLRP3) inflammasome activation, leading to decreased IL-1β and IL-18 release (26,27). In addition, it has been shown to reduce the need for steroid use in patients with bronchial inflammation by decreasing eosinophilic and neutrophilic infiltration in lung tissue, accompanied by inhibition of nitric oxide and prostaglandin E2 production (24,28).

Doxofylline decreases LPS-induced lung inflammation in mice (24) and inhibits NLRP3 inflammasome activation in human bronchial epithelial cells (26). Furthermore, rat models confirm that doxofylline may attenuate leukocyte adhesion to the vessel wall and migration of vascular endothelial cells via inhibition of IL-6 and tumor necrosis factor-α release, highlighting its potential role in managing inflammatory respiratory conditions (10,17).

The pharmacological and pharmacokinetic profiles of doxofylline and theophylline reveal notable differences in their mechanisms of action, indications and administration (Table I).

Doxofylline achieves effective bronchodilation at a dosage of 400 mg administered two to three times daily, whereas theophylline requires more variable dosing, typically 300-600 mg daily in 2-3 doses (29). In terms of pharmacokinetics, doxofylline shows high oral bioavailability of 90-100%, compared with 62-96% for theophylline (30), has been reported to reach therapeutic plasma concentrations of 8-20 µg/ml in chronic bronchitis, compared with theophylline's narrower therapeutic range of 5-15 µg/ml (31). However, unlike theophylline, doxofylline generally does not require routine plasma monitoring because of its more favorable pharmacokinetic stability and wider safety margin.

The time to peak concentration for doxofylline is 1.5-2.0 h, with a distribution half-life of about 1.5 h, compared with a longer elimination half-life for theophylline (8.7 h). Doxofylline exhibits moderate protein binding (~48%) and a relatively high volume of distribution (0.81 l/kg), compared with theophylline (40-60% and 0.3-0.7 l/kg, respectively) (30). Its metabolism occurs predominantly in the liver, with >90% of the administered dose metabolized primarily via cytochrome P450 3A4 (CYP3A4), producing inactive metabolites (30), whereas theophylline is metabolized primarily by CYP1A2 and CYP2E1, yielding active metabolites (31).

Renal excretion of doxofylline is minimal, with <4% of the dose excreted unchanged in urine, compared with 10-13% for theophylline. Doxofylline has a total body clearance of 5.4 l/h and an elimination half-life of ~6 h, whereas theophylline shows a clearance of ~0.65 l/h/kg (equivalent to ~2.6-3.0 l/h in adults) and an elimination half-life of approximately 8 h, which may be further prolonged in patients with hepatic or cardiac impairment (30,31).

COPD is a prevalent and debilitating respiratory condition that imposes a notable global burden. According to the Global Burden of Disease 2019 study, COPD was the third leading cause of death worldwide, responsible for 3.23 million deaths and affecting ~212 million people (32). This highlights the socio-economic and public health challenges associated with COPD. Effective management of COPD involves a combination of bronchodilators and anti-inflammatory medications aimed at improving lung function and enhancing the quality of life (QoL) in affected patients (32).

Theophylline has been a cornerstone in the treatment of COPD and BA since its introduction in 1937. However, due to its narrow therapeutic window and associated safety concerns, the GOLD Management Strategy guidelines (33) recommend its use only in patients who do not benefit from other bronchodilators or those unable to afford alternative treatments. In this context, doxofylline, a newer methylxanthine derivative, has emerged as a promising alternative (1). Unlike theophylline, doxofylline exhibits distinct pharmacological properties, including minimal effects on PDE isotypes, negligible antagonism at adenosine receptors and no impact on HDAC pathways. While not a direct β₂-agonist, doxofylline may potentiate β₂-adrenergic bronchodilation via increased intracellular cAMP (10,13).

In a clinical study involving 154 patients with COPD, doxofylline was compared with theophylline and demonstrated improvements in baseline spirometric parameters; doxofylline was better tolerated, with fewer side effects and lower dropout rates due to adverse events (34). A subset analysis of high-quality trials confirmed an improvement in FEV₁ of 239 ml (35). Grading of Recommendations Assessment, Development, and Evaluation analysis provided high-quality evidence for the impact of doxofylline on FEV₁ and moderate-quality evidence for its safety profile in COPD (35). Furthermore, an analysis of RCTs reported a significant increase in forced expiratory volume in 1 sec (FEV₁) of 8.2% and 324 ml from baseline with doxofylline (35).

Studies evaluating the effects of doxofylline in severe COPD have demonstrated its efficacy in decreasing respiratory symptoms such as dyspnea and cough and improving exercise tolerance (13,36,37). These findings underscore the rationale for using doxofylline in the treatment of COPD, with a superior efficacy-to-safety profile compared with theophylline (13,34,36).

The safety profile of doxofylline is a critical factor in the management of COPD, particularly given the disease association with significant declines in health-related (HRQoL). Improvements in HRQoL are key indicators of treatment success. Doxofylline is associated with HRQoL improvement (36), consistent with broader evidence on HRQoL determinants in COPD (38). Patients receiving 400 and 800 mg doses of doxofylline demonstrated significant decrease in symptom scores, including cough (77.35 and 97.43%. respectively), shortness of breath (77.60 and 95.90%. respectively) and chest tightness (86.29 and 98.40%. respectively) following 4 weeks of treatment (37). Consistent findings were observed in another study evaluating the combination of doxofylline with inhaled corticosteroids and long-acting bronchodilators, which resulted in significant improvements in QoL score and reductions in the frequency of exacerbation (36).

Doxofylline represents a promising therapeutic alternative for the long-term treatment of COPD. Its enhanced efficacy and safety profile, combined with better tolerability and improvement in lung function and QoL, position it as a safe and effective alternative to traditional therapies for COPD (34,39).

The literature supports doxofylline as an effective and safe methylxanthine for the treatment of BA, with a superior efficacy-to-safety profile compared with theophylline (13,36).

A meta-analysis demonstrated that doxofylline is more effective than theophylline in decreasing daily BA events and preventing adverse reactions (13). Similar findings were reported in other studies, which highlighted improvements in spirometric parameters, decreased consumption of salbutamol and fewer undesirable side effects or treatment dropouts (13,18). In patients with BA responsive to salbutamol, particularly those with features overlapping with COPD, increases in spirometric values-including slow and forced vital capacity (FVC), FEV₁, forced expiratory flow at 25-75%, and peak expiratory flow rate-have also been reported, consistent with evidence from bronchodilator response studies in BA and Asthma-COPD Overlap (ACO) (40).

Although a meta-analysis found no notable difference between doxofylline and theophylline in terms of FEV₁ improvement, doxofylline is superior in reducing the need for salbutamol as a rescue medication (13). Moreover, the LESDA long-term trial demonstrated that one year of doxofylline therapy in asthmatic patients significantly improved FEV₁, reduced daily asthma event rates, and decreased salbutamol usage, with a favorable safety profile (41).

Doxofylline has also proven to be a rapid and effective bronchodilator in mechanically ventilated patients with acute respiratory failure and airflow obstruction. It is associated with a decrease in respiratory resistance and intrinsic positive end-expiratory pressure, thereby improving the mechanical efficiency of respiratory muscles at lower lung volumes (42).

A meta-analysis involving 820 patients from 20 RCTs demonstrated that doxofylline significantly improves FEV₁, with fewer adverse events (35). Another meta-analysis examining the efficacy and safety of xanthines in BA reported that while doxofylline is no more effective than aminophylline or theophylline in improving baseline FEV₁, it is superior in alleviating dyspnea and significantly safer than both aminophylline and theophylline (13).

As with other methylxanthines, doxofylline is associated with potential drug interactions. Concomitant use of doxofylline with certain drugs such as erythromycin, troleandomycin, lincomycin, clindamycin, allopurinol, cimetidine, ranitidine, propranolol, is not recommended. These agents may decrease the hepatic clearance of xanthines, leading to elevated plasma levels of doxofylline (8,10,17). Additionally, doxofylline should not be co-administered with other xanthine derivatives to avoid competitive inhibition at enzymatic metabolization sites, which may further slow drug clearance (30).

Adverse effects associated with doxofylline are typically mild and may include gastrointestinal disturbances such as nausea and vomiting, as well as CNS symptoms such as headache and dizziness. Notably, doxofylline has a reduced incidence of cardiovascular side effects, including tachycardia and palpitations, compared with other xanthines (30).

In terms of drug interactions, doxofylline safety profile is favorable due to its limited interaction with CYP450 enzymes, reducing the likelihood of significant interactions with other medications metabolized via this pathway (8,10,17,30), although caution is advised when co-administering doxofylline with other xanthine derivatives to prevent potential additive effects.

Overall, improved therapeutic window and reduced adverse effect profile make doxofylline a safer alternative to traditional methylxanthines in the management of respiratory conditions.

COPD continues to represent a significant economic burden despite therapeutic advances, particularly in resource-limited regions. Doxofylline is a cost-effective option compared with other commonly used bronchodilators in the treatment of COPD and BA (Table II). For example, the average monthly price of doxofylline at usual doses (400 mg twice daily) is €5-15 (1,30). In comparison, tiotropium, a commonly used inhaled anticholinergic, has an estimated monthly cost of €45-65, while inhaled formoterol and budesonide-based inhaled combinations are €55-75/month (1,3). Salmeterol, either as monotherapy or in combination with fluticasone, incurs a monthly cost of €35-65, depending on dosage and formulation (1,4).

Despite being inexpensive (~€5/month), theophylline is limited by its narrow therapeutic window and increased risk of side effects, requiring close monitoring. In this context, doxofylline offers an advantageous balance between efficacy, superior safety profile and economic sustainability. Therefore, compared with riskier options (such as theophylline) and costly modern therapy, doxofylline represents a viable and affordable therapeutic alternative.