Mo1091 A Study of the Mechanisms Underlying the Potential Usefulness of STW 5 in Reflux Esophagitis

Abstract

Proton pump inhibitor (PPI) therapy is the most effective medical treatment for symptom relief in gastro-esophageal reflux disease (GERD). However, up to 40% of patients do not achieve adequate symptom relief, especially those suffering from non-erosive reflux disease (NERD) which does not respond well to PPIs. Therefore, the search continues for other treatment options. STW 5, a multi-component herbal preparation, was shown to relieve heartburn and concomitant reflux symptoms in patients with functional dyspepsia and to prevent inflammation in an acute model of reflux esophagitis (RE), without affecting the pH of the refluxate. The present study assesses the efficacy of STW 5 in a more chronic model of RE, and the underlying mechanisms both In-Vivo and in-vitro. Rats were pretreated for 7 d with STW 5 or omeprazole (as reference drug) before surgical induction of esophagitis. RE was achieved by ligation of the fore-stomach and covering the duodenum near the pylorus with a piece of Nelaton catheter. After recovery, rats were treated for a further 10 d with the drugs and then sacrificed, their esophagi excised, weighed and evaluated macroscopically. Tissue homogenates were used for semi-quantitative determination of cytokines using a cytokine array. Both, STW 5 and omeprazole, improved body weight, tissue damage score and esophageal weight index to similar extents. However, STW 5 had a much more pronounced anti-inflammatory effect. As shown in the cytokine array (fig. 1), STW 5 inhibited the majority of the measured pro-inflammatory cytokines induced by surgical reflux, suggesting a direct anti-inflammatory and/or mucosal protecting action. Since recent evidence indicates that the mucosal damage observed in GERD is due to release of inflammatory mediators from mucosal and sub-mucosal cells in response to bile salts and other substances in the gastric refluxate, the effects of STW 5 on cytokine release from the normal human esophageal cell-line HET-1A in response to stimulation with chenodeoxycholic acid (CDCA) was assessed. Incubation of cells with CDCA caused marked release of CD40ligand, IFN-γ, IL-1ra, IL-6, IL-8 and IL-23, which were all inhibited by co-incubation with STW 5 (0,3 10 μl/ml) as assessed semi-quantitatively (cytokine array, fig.2) and confirmed quantitatively (ELISA), without affecting cell viability. Similar effects were observed when cells were incubated with capsaicin as TRPV1 agonist (shown to be the main receptor involved in acid induced cytokine release from HET-1A cells), which evoked the release of CD40-ligand and IL-23. The present findings suggest that multi-target anti-inflammatory drugs like STW 5 might present an alternative/additional treatment option for GERD patients not responding adequately to PPIs. Further elucidation of its exact mechanism of action might pave the way for a new class of anti-reflux agents.