Montelukast in the treatment of duodenal eosinophilia in children with dyspepsia: Effect on eosinophil density and activation in relation to pharmacokinetics

Abstract

BackgroundWe have previously demonstrated the clinical efficacy of montelukast in a randomized double-blind controlled cross-over trial in patients with dyspepsia in association with duodenal eosinophilia. The mechanism of this clinical response is unknown but could involve a decrease in eosinophil density or activation.MethodsTwenty-four dyspeptic patients 8–17 years of age underwent initial blood sampling and endoscopy with biopsy. Eighteen of these patients had elevated duodenal eosinophil density and underwent repeat blood sampling and endoscopy following 21 days of therapy with montelukast (10 mg/day). The following were determined: global clinical response on a 5-point Lickert-type scale, eosinophil density utilizing H & E staining, eosinophil activation determined by degranulation indices on electron microscopy, and serum cytokine concentrations. On day 21, pharmacokinetics and duodenal mucosal drug concentrations were determined.ResultsEighty-three percent of the patients had a positive clinical response to montelukast with regard to relief of pain with 50% having a complete or nearly complete clinical response. The response was unrelated to systemic drug exposure or to mucosal drug concentration. Other than a mild decrease in eosinophil density in the second portion of the duodenum, there were no significant changes in eosinophil density, eosinophil activation, or serum cytokine concentrations following treatment with montelukast. Pre-treatment TNF-α concentration was negatively correlated with clinical response.ConclusionThe short-term clinical response to montelukast does not appear to result from changes in eosinophil density or activation. Whether the effect is mediated through specific mediators or non-inflammatory cells such as enteric nerves remains to be determined.Trial RegistrationClinicalTrials.gov; NCT00148603

The Gastric and Duodenal Eosinophilia in Functional Dyspepsia

“…Few papers show that the gastric and duodenal eosinophil density was increased in children with functional GI disorders. 4,5 This article showed similar results in pediatric patients with functional GI disorders, however, the diagnosis was based on the Rome III criteria, and excluded food allergy, asthma, atropic dermatitis, and rhinitis before the diagnosis. H. pylori infection group showed high eosinophils in the stomach and duodenum, but no statistical significance.…”

Functional dyspepsia

“…New treatment options are emerging based on these concepts, including anti-inflammatory drugs (at least in paediatric functional dyspepsia, montelukast (a cysteinyl leukotriene receptor 1 antagonist) has yielded promising results) 233 and non-absorbable antibiotics, such as rifaximin 234 . New data support the role of low-dose tricyclic antidepressants in functional dyspepsia, although the mechanism of action is unclear 200 .…”

Editorial: the diminishing returns of normalisation of the oesophageal mucosa

“…Anti-inflammatory agents and drugs aimed at decreasing allergic reactions are already being studied in functional dyspepsia. 9,10 Observational studies, while confirming the original observation of duodenal eosinophilia, need to give way to mechanistic studies that help us understand the pathogenesis of duodenal eosinophilia. Future studies will help determine if treating the eosinophilia, much as we treat eosinophilic oesophagitis, or restricting the diet will alleviate dyspeptic symptoms.…”