Theophylline in Rhinitis
Condition: Rhinosinusitis; Asthma; Allergic Rhinitis
MeSH terms: Rhinitis; Rhinitis, Allergic
Study type: Interventional
Phase: Phase 2

Summary: 
      Allergic rhinitis and asthma are common respiratory diseases, which often coexist. The
      prevalence of allergic rhinitis in subjects with asthma is up to 80%, and the prevalence of
      asthma is 3-5 times greater in subjects with rhinitis than healthy controls. The mechanisms
      of the allergen response in both diseases are parallel to each other, with similar mediator
      and cellular responses to similar allergens. These observations have led to the suggestion
      that both diseases are different expressions of one airway disease.We wish to evaluate the
      effect of low dose theophylline in patients with asthma, given its effects as subtherapeutic
      concentrations and the propensity to develop adverse events at higher doses.
    

Detailed description: 
      The disease modifying treatments for asthma and rhinitis mirror each other. The first line
      therapy being the topical corticosteroids, for which there is good evidence of superiority
      over other therapies. They work by altering the transcription of genes involved in the
      inflammatory process, thereby favourably influencing the synthesis of inflammatory proteins
      and cytokines. They have been shown to reduce the numbers of inflammatory cells and their
      inflammatory action. Other disease modifying therapies such as anti-IgE antibodies improve
      allergic symptoms in both asthma and rhinitis. Theophylline has been used for many years as a
      treatment for asthma but has not been used to help patients with rhinitis.

      Theophylline has been considered a weak bronchodilator for many years. However relatively
      recently, it was shown to have anti-inflammatory effects in patients with asthma. It reduces
      eosinophil counts and eosinophilic cationic protein (ECP) concentration in induced sputum of
      asthmatic patients. The combination of low dose theophylline has greater effects on lung
      function and asthma severity than high dose inhaled corticosteroids.

      Aubier el al have shown, using a nasal allergen challenge model of rhinitis, that 3 weeks
      treatment with slow release oral theophylline reduced the increase in the concentration of
      eosinophilic cationic protein (ECP) and the percentage of eosinophils in nasal lavage
      following the challenge. Furthermore there was a significant reduction in nasal symptoms in
      those patients treated with theophylline. However theophylline has not previously been
      evaluated as a therapeutic option in patients with chronic rhinitis in the clinic setting.

      Cigarette smoking is a major cause of morbidity in patients with asthma and has been shown to
      be independently associated with impaired quality of life in asthmatic children. Recent
      evidence suggests that patients with asthma who smoke are relatively resistant to inhaled or
      oral corticosteroid therapy, with larger doses being required for clinical benefit. The
      actual mechanism for this observation is unknown however one hypothesis is that smoking has
      an effect on histone deacetylase. It is known that theophylline can active histone
      deacetylase and therefore improve the efficacy of corticosteroids.

      Theophylline causes significant adverse effects at high doses. Unfortunately the
      bronchodilator effect occurs at doses very close to those causing adverse effects. This low
      therapeutic index for bronchodilation means that therapeutic monitoring is required. However
      the anti-inflammatory effect of theophylline and the effect of theophylline on histone
      deacetylase activity occurs at concentrations lower therapeutic level for bronchodilation.

      Why have we chosen a dose of 200mg twice daily? In the study by Evans et al which compared
      low dose inhaled budesonide plus theophylline to high dose inhaled budesonide, greater
      effects with the theophylline combination were seen in terms of pulmonary function and
      hyperresponsiveness at serum concentrations of theophylline that were sub therapeutic
      (8.7mg/ml). Anti-inflammatory effects are seen in patients with chronic obstructive pulmonary
      disease at theophylline concentrations that are subtherapeutic. There have been studies in
      patients with asthma that have shown anti-inflammatory effects at in patients with asthma at
      doses of 250mg twice daily and 200mg twice daily. We wish therefore to evaluate the effect of
      low dose theophylline in patients with asthma, given its effects as subtherapeutic
      concentrations and the propensity to develop adverse events at higher doses.
    

Intervention name(s): Theophylline (Intervention Group); Placebo (Placebo Group)
Intervention type(s): Drug; Drug
Intervention description(s): 200 mg twice daily of slow release theophylline; 200 mg twice daily of placebo drug
Intervention MeSH terms: Theophylline
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Single (Participant)
Primary purpose: Treatment
Keywords: rhinosinusitis; asthma; allergic rhinitis; theophylline