Doxofylline: Efficacy/Safety in COPD and Superiority to Theophylline

Doxofylline is used to treat and prevent symptoms of asthma and chronic obstructive pulmonary disorder (a lung disorder in which flow of air to the lung is blocked). It helps in relaxing the muscles of the air passages, thus widening it and making it easier to breathe. Doxofylline can be taken with the food in the evening. Take it in the exact dose and duration as prescribed by your doctor. The dose and how often should take it may depend on what you are taking it for. Take it for as long as it is prescribed for you. In case you missed a dose, take it as soon as you remember it. It does not work immediately or prevent the already started breathing trouble, hence always carry your medical inhaler with you for an emergency. Doxofylline helps the airways in your lungs stay open. It relaxes the muscles of these airways. This makes it easier for air to get in and out. It will relieve symptoms such as tightness in your chest, shortness of breath, wheezing and coughing and help you carry out your daily activities more easily. This medicine is safe and effective. It usually starts to work within a few minutes and the effects can last up to several hours.

The effect of doxofylline in asthma and COPD

Although both Global Initiative for Chronic Obstructive Lung Disease (GOLD) and Global Initiative for Asthma (GINA) strategies do not recommend the use of theophylline because its small therapeutic index and the evidence that most of benefits occurs only when near-toxic doses are given, but also because there are more efficient medications, theophylline is still prescribed worldwide in milder forms of chronic obstructive pulmonary disease (COPD) and asthma and also as supplementary treatment of patients with COPD or as ‘last choice’ treatment in uncontrolled asthmatics with severe disease. Doxofylline (7-(1,3-dioxolan-2-ylmethyl)-3,7-dihydro-l, 3 dimethyl-lH-purine-2,6-dione) is a newer generation xanthine with both bronchodilating and anti-inflammatory activities and for this reason it has been called “novofylline”. The presence of the dioxalane group at position 7 and also a distinct pharmacological profile differentiate doxofylline from theophylline. It inhibits the lipopolysaccharide (LPS)-induced inflammatory response in the mouse lung and regulates leukocyte migration in vivo and in vitro, effects that suggest an important activity of this drug on leukocyte diapedesis. As already mentioned, also theophylline has anti-inflammatory properties, but the specificity of the anti-inflammatory action of the two drugs is not superimposable. From a mechanistic viewpoint, protein kinase C (PKC) has been identified as a differentiating target as it is solely affected by doxofylline.[1]

A pooled analysis of two large RCTs, DOxofylline compaRed tO THEOphylline (DOROTHEO 1 and DOROTHEO 2), showed that after 12 weeks of treatment both doxofylline 400 mg and theophylline 250 mg significantly (P < 0.001) increased 2-h postdose FEV1, and reduced the rate of asthma events compared to baseline. Furthermore, they reduced the use of salbutamol compared to baseline, and also improved the change from baseline in asthma events rate vs. placebo, and reduced the use of rescue medication vs. placebo during the study period.The evidence generated by large preclinical studies indicated that it must be understood as a xanthine completely different from theophylline. Clinical studies have also shown a substantial difference between doxofylline and theophylline. The most solid evidence comes from the meta-analyses that were performed as a method for pooling (aggregating) results from multiple trials to produce a combined estimate. It now accepted that meta-analysis of a body of evidence combines a larger sample size and more events than any individual study, leading to greater precision of estimates, and facilitating confident decision making.

The Efficacy and Safety of Doxophylline

As of 2011, 235-300 million people worldwide were affected by asthma leading to approximately 250,000 deaths per year. Asthma is thought to be caused by a combination of genetic and environmental factors. These factors influence how severe asthma is and how well it responds to medication.Theophylline, a PDE inhibitor has been used in asthma for its anti-inflammatory effect in the concentration range of 5- 20 μg/ml but with a variety of side effects above >20 μg/ml. A new methylxanthine derivative Doxophylline with similar efficacy but has significantly less side effects, may immensely benefit the patients. Studies in both animals as well as in human adults have shown doxofylline to be safe and effective. This better safety profile of doxofylline is better explained by its decreased affinity towards A1 and A2 adenosine receptors. Asthma is a non communicable chronic disease prevalent all over the world. Two commonly used methylxanthines, theophylline and doxofylline were compared in the study in stable asthmatic patients at recommended doses by various spirometric lung function tests with forced expiratory volume at second one (FEVI) between 50 to 80% of predicted FEVI.[2]

A total of 100 patients were divided in two groups. Group I was administered 300 mg theophylline twice a day and Group II was administered doxofylline 400 mg twice a day orally for six weeks. Spirometric variables symptom score, and adverse effects were recorded at the baseline level and after six weeks of therapy. Data was compared and analysed statistically. Doxophylline is known to cause less of these side effects than theophylline because of more specificity and less of interference with calcium channels in cardiac cells Moreover, it does not affect sleep rhythm, gastric secretions, heart rate and rhythm and CNS functioning. The fact that serum toxicity levels overlap therapeutic levels explains the high incidence of toxic side effects. The risk of such adverse events can be reduced by monitoring the drug’s plasma levels and reducing the dose accordingly. Doxofylline produces stable serum concentrations; hence plasma monitoring is required only in patients with hepatic insufficiency and intolerance to xanthine drugs. In the study it was concluded that both theophylline and doxofylline improved the lung function tests and symptoms in patients of mild Bronchial Asthma, but doxofylline has a better profile in terms of safety.

Doxofylline: A "Novofylline"

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. 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. 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 it would seem to provide a serious alternative to theophylline in the treatment of patients with respiratory disease, particularly in patients with GI intolerance.[3]

However, it should be noted that most of these studies have involved adults with very few studies having been undertaken in children with respiratory disease. Moreover, doxofylline has largely been administered as an add-on therapy to glucocorticosteroids or other maintenance drugs and not as a stand alone drug in many of these studies.Doxofylline would appear to be both a bronchodilator and an anti-inflammatory drug with a wider therapeutic window than other xanthines. The recent availability of a novel once a day formulation of doxofylline should improve the usefulness of this drug clinically still further.

References

[1]Cazzola M, Matera MG. The effect of doxofylline in asthma and COPD. Respir Med. 2020 Apr;164:105904. doi: 10.1016/j.rmed.2020.105904. Epub 2020 Feb 19. PMID: 32094104.

[2]Margay SM, Farhat S, Kaur S, Teli HA. To study the efficacy and safety of doxophylline and theophylline in bronchial asthma. J Clin Diagn Res. 2015 Apr;9(4):FC05-8. doi: 10.7860/JCDR/2015/12438.5743. Epub 2015 Apr 1. PMID: 26023566; PMCID: PMC4437080.

[3]Page CP. Doxofylline: a "novofylline". Pulm Pharmacol Ther. 2010 Aug;23(4):231-4. doi: 10.1016/j.pupt.2010.04.002. Epub 2010 Apr 7. PMID: 20380886.

You may like