Does inhaled anticholinergic treatment improve airway inflammation in asthma?

Study to investigate anti-inflammatory effects of Glycopyrronium in asthma

Current treatment for patients with asthma includes inhaled corticosteroids (ICS) and long-acting β2-agonists (LABA). The long-acting muscarinic antagonist (LAMA) tiotropium has recently been registered for the treatment of asthma. Clinical trials have shown beneficial effects on lung function by addition of tiotropium to standard treatment in moderate and severe asthma. In addition, treatment with tiotropium reduces the number of severe exacerbations, suggesting that anticholinergics might exert anti-inflammatory effects in these patients.

Anti-inflammatory effects of anticholinergics have been observed in in vitro and in vivo studies using various experimental models. In vitro, anticholinergics exert direct anti-inflammatory effects on T cells, macrophages, epithelial cells, and on airway smooth muscle cells. Moreover, in vivo animal models have demonstrated inhibitory effects of tiotropium or muscarinic M3 receptor knock-out on ovalbumin-induced inflammation, the anti-inflammatory effects of tiotropium being comparable to those of the corticosteroid budesonide.

The effects of the combination of anticholinergics with ICS/LABA on airway inflammation are currently largely unknown. In vitro, it has been shown that the anticholinergic glycopyrronium acts synergistically with budesonide in inhibiting TNF-α release from isolated monocytes, suggesting that the combination of anticholinergics and corticosteroids might be more effective than the monotherapies in vivo. In addition, it was recently demonstrated that the combination of the anticholinergic tiotropium with the corticosteroid ciclesonide is more effective than either compound alone in inhibiting allergen-induced airway inflammation and remodelling in a guinea pig model of chronic asthma. It is currently unknown whether treatment with anticholinergics added to ICS/LABA has anti-inflammatory effects in patients with asthma.

The purpose of this study is to:

  1. Assess the anti-inflammatory effects of glycopyrronium on top of mometasone and indacaterol/mometasone on the allergen-induced late asthmatic response in patients with asthma.
  2. Assess whether nasal epithelial gene and microRNA expression is useful as a biomarker to determine a) treatment responsiveness to anticholinergic therapy in asthma and b) to Th2 related inflammatory responses after allergen provocation. A better easy-to-use biomarker to measure the presence/extent of the allergic inflammatory response is highly needed as this may have therapeutic implication for treatment with anti-allergic or anti-inflammatory therapies.

 

Summary
The effects of the combination of anticholinergics with ICS/LABA on airway inflammation are currently largely unknown. In vitro, it has been shown that the anticholinergic glycopyrronium acts synergistically with budesonide in inhibiting TNF-α release from isolated monocytes, suggesting that the combination of anticholinergics and corticosteroids might be more effective than the monotherapies in vivo. In addition, it was recently demonstrated that the combination of the anticholinergic tiotropium with the corticosteroid ciclesonide is more effective than either compound alone in inhibiting allergen-induced airway inflammation and remodelling in a guinea pig model of chronic asthma. It is currently unknown whether treatment with anticholinergics added to ICS/LABA has anti-inflammatory effects in patients with asthma.
Technology Readiness Level (TRL)
3 - 3
Time period
48 months
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