Doxofylline: A “Novofylline”

doi:10.1016/j.pupt.2010.04.002

Pulmonary Pharmacology & Therapeutics

Volume 23, Issue 4, August 2010, Pages 231-234

https://doi.org/10.1016/j.pupt.2010.04.002 Get rights and content

Abstract

Xanthines such as theophylline have been used in the treatment of lung diseases since the early 1900's, but have a major drawback of a very narrow therapeutic window and many drug/drug interactions. With the increasing availability of other classes of drugs, this has limited the use of xanthnes. Doxofylline is a xanthine molecule that appears to be both bronchodilator and anti-inflammatory with an improved therapeutic window over conventional xanthines such as theophylline and the evidence supporting the effects of doxofylline in the treatment of lung diseases is discussed.

Section snippets

Xanthines

Since the first prescription of theophylline for the treatment of asthma in 1937, this drug and related xanthines have been widely used as an inexpensive oral treatment of both asthma and COPD [1]. Their clinical effectiveness has long been thought to be due primarily to bronchodilatation, although it is now known that these drugs also exhibit anti-inflammatory actions [2]. The predominant mechanism of action of theophylline has traditionally been ascribed to nonselective inhibition of

Doxofylline

Doxofylline is chemically designated as 7-(1,3 dioxolar-2-ylmethyl)-theophylline, a xanthine which has a dioxolone group in position 7 [14] (Fig. 1). Doxofylline has greatly decreased affinity towards adenosine A₁ and A₂ receptors when compared with theophylline [18], which may contribute to the better safety profile, since in a number of studies, doxofylline has been shown to have better efficacy with fewer side effects than theophylline (see Table 1, Table 2). Moreover, unlike theophylline,

Clinical effectiveness of doxofylline in the treatment of respiratory diseases

Various studies on the efficacy and safety of doxofylline have been undertaken and some of the major studies are summarized in Table 2. As seen from the table, doxofylline significantly improves spirometric parameters and reduces the need for rescue β₂-agonists. Most studies have also revealed that doxofylline is well tolerated with fewer dropout rates than theophylline.

However, it should be noted that most of these studies have involved adults with very few studies having been undertaken in

Conclusion

Doxofylline is a novel xanthine drug with similar efficacy to theophylline in the treatment of respiratory diseases, but with an improved tolerability profile compared to theophylline. Studies on the safety profile of doxofylline have found significant differences with regard to adverse events related to CNS, GIT and CVS and doxofylline would seem to provide a serious alternative to theophylline in the treatment of patients with respiratory disease, particularly in patients with GI intolerance.

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Cited by (46)

Taste sensor for detecting non-charged bitter substances: Xanthine derivatives of pharmaceutical applications
2024, Microchemical Journal
Novel taste sensors utilizing an allosteric mechanism for potentiometric measurement have demonstrated the ability to detect non-charged bitter substances, including caffeine. In this study, three xanthine derivatives commonly found in pharmaceuticals (i.e., etofylline, proxyphylline, and diprophylline) were detected by the sensor modified with 3-bromo-2,6-dihydroxybenzoic acid (3-Br-2,6-DHBA). The concentration-dependent experiments and selectivity tests revealed that the sensor exhibited remarkable sensitivity and selectivity for these materials. The sensory test results demonstrated a linear correlation with the measurements of the 3-Br-2,6-DHBA-modified taste sensor, particularly within the sample concentration range of 1 mM to 30 mM. Thus, this study provided an effective method to evaluate the bitterness of chemical substances with xanthine scaffold.
Phosphodiesterase inhibitors and lung diseases
2023, Advances in Pharmacology
Phosphodiesterase enzymes (PDE) have long been known as regulators of cAMP and cGMP, second messengers involved in various signaling pathways and expressed in a variety of cell types implicated in respiratory diseases such as airway smooth muscle and inflammatory cells making them a key target for the treatment of lung diseases as chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis, and pulmonary hypertension (PH). The first reported PDE inhibitor was the xanthine, theophylline, described as a non-specific PDE inhibitor and whilst this drug is effective, it also has a range of unwanted side effects. In an attempt to improve the therapeutic window of xanthines, a number of selective PDE inhibitors have been developed for the treatment of respiratory diseases with only the selective PDE 4 inhibitor, roflumilast, being approved for the treatment of severe COPD. However, roflumilast also has a very narrow therapeutic window due to a number of important doses limiting side effects, particularly in the gastrointestinal tract. However, there continues to be research carried out in this field to identify improved selective PDE inhibitors, both by targeting other PDE subtypes (e.g., PDE 7 found in a number of inflammatory and immune cells) and through development of selective PDE inhibitors for pulmonary administration to reduce systemic exposure and improve the side effect profile. This approach has been exemplified by the development of ensifentrine, a dual PDE 3-PDE 4 inhibitor, an inhaled drug that has recently completed two successful Phase III clinical trials in patients with COPD.
The solubility profile and apparent thermodynamic analysis of doxofylline in pure and mixed solvents
2020, Journal of Chemical Thermodynamics
Citation Excerpt :
Smoke, dust and other air pollutants are the most common aetiologic factor [1–5]. Doxofylline (7-(1,3-dioxalan-2-ylmethyl) theophylline, Fig. 1) is a new type of anti-bronchospasm drug, has recently drawn attention because of its better safety profile and similar efficacy over the most widely prescribed analogue [6,7]. The bronchodilating activities of doxofylline have been demonstrated in clinical trials involving patients with COPD [8,9].
Crystallization and purification is an important step in drug preparation. In this work, the solubility of doxofylline in some pure and mixed solvents at T = 273.15–313.15 K was experimentally determined under 101.2 kPa. Infrared spectroscopy (IR) was used to evaluate the crystal form of doxofylline, and no solvates or new form formation were observed during the whole experiment. In pure solvent, the solubility data increased with the increasing temperature. At 313.15 K, the solubility maximum value (mole fraction) was obtained in ethyl acetate (3.8552 × 10⁻²), followed by acetonitrile (2.8699 × 10⁻²), ethanol (1.7179 × 10⁻²), methanol (0.7069 × 10⁻²), isopropanol (0.4928 × 10⁻²) and n-propanol (0.1533 × 10⁻²), and similar trend was obtained at each temperature studied. In mixture of (isopropanol + ethyl acetate), the solubility increased monotonically with the increasing mass fraction of ethyl acetate at each temperature studied. The Apelblat equation and λh equation were applied to correlate the solubility data in selected pure solvents. All relative average deviation (RAD) values in the modified Apelblat equation are less than those in λh equation. Therefore, modified Apelblat is more suitable for correlating the solubility profile in selected pure solvents. In addition, Jouyban-Acree model was used to evaluate the results in mixed solvents, and the RAD value is 5.48%. During the dissolution process, the apparent dissolution standard enthalpy ( $Δ H_{sol}^{o}$ ), apparent molar standard Gibbs energy ( $Δ G_{sol}^{o}$ ) and apparent dissolution standard enthalpy ( $Δ S_{sol}^{o}$ ) were calculated. The values of $Δ H_{sol}^{o}$ and $Δ S_{sol}^{o}$ are all positive in this experiment, which indicates the dissolution process is not only endothermic but also entropy-driving. Moreover, the contribution of dissolution enthalpy, ( $% ξ_{H}$ ) is greater than entropy ( $% ξ_{TS}$ ) to the change of dissolution Gibbs energy in the dissolution process.
The effect of doxofylline in asthma and COPD
2020, Respiratory Medicine
Theophylline is still one of the most widely prescribed drugs for the treatment of asthma and COPD in developing countries because the majority of asthma and COPD medicines are largely unavailable and also because it is a cheap option. In any case, its anti-inflammatory effects and capacity to reverse corticosteroid resistance deserve consideration, but it can induce numerous side effects and drug-drug interactions and frequently requires measurement of drug levels in plasma. In order to overcome the problems posed by theophylline, other xanthines have been developed. Doxofylline is a newer generation xanthine with both bronchodilating and anti-inflammatory activities and for this reason it has been called “novofylline”. It differs substantially from theophylline at the pharmacological level. Clinical studies have shown substantial differences between doxofylline and theophylline. In particular, efficacy/safety profile of doxofylline is better than that of theophylline.
A long-term clinical trial on the efficacy and safety profile of doxofylline in Asthma: The LESDA study
2020, Pulmonary Pharmacology and Therapeutics
Doxofylline, an oral methylxanthine with bronchodilator and anti-inflammatory activities, offers a promising alternative to theophylline due to its superior efficacy/safety profile. No long-term studies on the efficacy and safety of doxofylline are currently available in asthma. The aim of the Long-term clinical trial on the Efficacy and Safety profile of Doxofylline in Asthma (LESDA) study was to investigate the safety and efficacy profile of doxofylline administered for one year in asthmatic patients. LESDA was a multicenter, open-label, Phase III, clinical trial in which adult asthmatic patients received the same treatment (oral doxofylline 400 mg t.i.d.) for one year. Efficacy was assessed through periodic pulmonary function tests and by having the subjects keep monthly records of asthma events rates and use of salbutamol as rescue medication. The rate of adverse events (AEs) was recorded during the study.
Three-hundred nine patients were screened and allocated in the study. Doxofylline significantly improved the change from baseline in forced expiratory volume in 1 s (FEV₁) (+16.90 ± 1.81%, P < 0.001 vs. baseline). Doxofylline also significantly improved the rate of asthma events (events/day: -0.57 ± 0.18, P < 0.05 vs. baseline) and the use of salbutamol as rescue medication (puffs/day: -1.48 ± 0.25, P < 0.01 vs. baseline). The most common AEs were nausea (14.56%), headache (14.24%), insomnia (10.68%), and dyspepsia (10.03%). There were neither serious AEs nor deaths during or shortly after the study. Concluding, doxofylline is effective and well tolerated when administered chronically in asthmatic patients.
Comparison of anti-inflammatory mechanisms between doxofylline and theophylline in human monocytes
2019, Pulmonary Pharmacology and Therapeutics
Methylxanthines are important pharmacological agents in the treatment of asthma and of chronic obstructive pulmonary diseases. The present study was designed to compare the ability of doxofylline and theophylline to modulate inflammatory pathways in human monocytes.
Monocytes isolated from healthy anonymous human buffy coats were treated with doxofylline or theophylline in the presence of phorbol 12-myristate 13-acetate (PMA) or lipopolysaccharide (LPS), and their phenotype, the oxidative burst, cytokine expression and release, cAMP production, and protein kinase C (PKC) activity were evaluated.
Doxofylline and theophylline did not have overlapping effects on human monocytes. While sharing some common characteristics, they differed significantly in their selectivity. Theophylline affected LPS- above PMA-induced cellular responsivity, while doxofylline behaved in the opposite manner. Furthermore, when testing PKC activity, we found an inhibitory effect of doxofylline but not of theophylline, at equimolar doses.
In conclusion, our data support the growing hypothesis that doxofylline does not have a superimposable mechanism of action compared to theophylline, and this may both explain some differences in the risk/benefit ratio and may direct studies to tailor therapy for patients.

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ReviewDoxofylline: A “Novofylline”

Abstract

Section snippets

Xanthines

Doxofylline

Clinical effectiveness of doxofylline in the treatment of respiratory diseases

Conclusion

Lancet

J Allergy Clin Immunol

Lancet

Eur J Pharmacol

Theophylline: new perspectives for an old drug

Am J Respir Crit Care Med

Inhibitors of cyclic nucleotide phosphodiesterase isoenzymes – their potential utility in the therapy of asthma

Pulm Pharmacol

A molecular mechanism of action of theophylline: induction of histone deacetylase activity to decrease inflammatory gene expression

Proc Natl Acad Sci U S A

Caffeine suppresses TNF-α production via activation of the cyclic AMP/protein kinase A pathway

Int Immunopharmacol

Comparison of high dose inhaled steroids, low dose inhaled steroids plus low dose theophylline, and low dose inhaled steroids alone in chronic asthma in general practice

Thorax

Comparison of addition of theophylline to inhaled steroid with doubling of the dose of inhaled steroid in asthma

Eur Respir J

Executive summary

Comparison of patients compliance with prescribed oral and inhaled asthma medications

Arch Intern Med

Theophylline induces neutrophil apoptosis through adenosine A2A receptor antagonism

J Leukoc Biol

Comparative effects of bamifylline and theophylline on allergic bronchospasm induced by the proactive inhalation test: a double blind cross over study

Poumon Coeur

Acebrofylline: an airway regulator and anti-inflammatory agent

Monaldi Arch Chest Dis

Doxofylline: a new generation xanthine bronchodilator derived and major cardiovascular side effects

Curr Med Res Opin

Roflumilast in moderate to severe chronic obstructive pulmonary disease treated with long acting bronchodilators: two randomized trials

Lancet

Doxofylline, an anti-asthmatic drug lacking afficnity for adenosine receptors

Arch Int de Pharmacodynamic et Therapie

Review
Doxofylline: A “Novofylline”