953 Electrical Stimulation Therapy (EST) of the Lower Esophageal Sphincter (LES) -an Effective Therapy for Refractory GERD -Interim Results of an International Multicenter Trial

Figure 1. Kaplan-Meier analysis of time to rejection by acid suppression exposure. Proton pump inhibitor use was associated with decreased acute or chronic rejection. 952 ONO-8539, a Novel Prostanoid EP1 Receptor Antagonist, Suppresses Transient Lower Esophageal Sphincter Relaxations in Monkeys Takashi Konemura, Ichiro Date, Hiroki Okada Background: Transient lower esophageal sphincter relaxation (TLESR) is the major cause of gastroesophageal reflux disease (GERD). TLESRs are considered to be triggered by postprandial gastric distension, and GABAB receptor agonists have been shown to inhibit TLESRs in animal models and in humans. It has demonstrated that prostaglandin E2 (PGE2) is involved in processing of pain hypersensitivity via the EP1 receptor; however, the contribution of the PGE2/EP1 receptor system to TLESRs is unknown. Aim: To investigate the effects of ONO-8539, a novel prostanoid EP1 receptor antagonist, on TLESRs in monkeys. Methods: This study was conducted as a crossover design using 4 female cynomolgus monkeys (age, 4 to 6 years). After fasting for 12 hours or more, the monkeys were placed in restraining chairs and a sensor catheter was positioned to enable pressure recordings in the proximal stomach, lower esophageal sphincter (LES) and the positions approximately 2, 3 and 6 cm above LES. TLESRs were induced by gastric infusion of an acidified (pH 3.0) liquid nutrient in a final volume of 80 mL, followed by air insufflations to maintain a gastric pressure at 20 mmHg. TLESRs were measured during a 45 minute period starting from nutrient infusion. TLESRs were defined by the following criteria; a rapid decrease in LES pressure (>0.5 mmHg/ s), a duration > 0.5 seconds and the relaxation not triggered by primary peristalsis. Vehicle (Control), ONO-8539 or baclofen (GABAB receptor agonist) were subcutaneously administered 30 minutes before the start of measurement. The expression of EP1 receptors in nodose ganglia and the brain stem, the source of vagal afferents and efferents, respectively, which initiate TLESRs, was measured by quantitative RT-PCR and Western blotting. Results: In the fasted state, TLESRs were very infrequently; however, they occurred after the nutrient infusion and air insufflations. ONO-8539 significantly reduced the number of TLESRs in a dose dependent manner without changing basal LES pressure compared to the control group. Baclofen also showed a significantly reduction of the number of TLESRs as well as an increase of basal LES pressure (45+/-19% vs control). EP1 mRNA and protein were detected in nodose ganglion and brain stem tissues. Conclusion: ONO-8539 has an inhibitory effect on TLESRs without the influence on the basal lower esophageal sphincter tone in monkeys, suggesting the involvement of EP1 receptors in the neural pathway underlying the triggering of TLESRs. ONO-8539 may therefore be a novel therapeutic option for reducing gastroesophageal reflux and thereby controlling GERD symptoms. Future studies are warranted to investigate the detailed mechanisms of action of ONO-8539 on TLESRs. The mean number of transient lower esophageal sphincter relaxation (TLESRs) during a 45min observation period after vehicle (control) or compound treatments

Figure 1: Statistically significant and sustained improvement in Esophageal Acid Exposure vs. baseline (p<0.01). No statistically significant difference between 3 and 6 months. Data: Medians (IQR).

953 Electrical Stimulation Therapy (EST) of the Lower Esophageal Sphincter (LES) - an Effective Therapy for Refractory GERD - Interim Results of an International Multicenter Trial Peter D. Siersema, Albert J. Bredenoord, José M. Conchillo, Jelle P. Ruurda, Nicole D. Bouvy, Mark I. van Berge Henegouwen, Philip W. Chiu, Michael Booth, Albis C. Hani, Duvvuru N. Reddy, Andreas J. Smout, Justin C. Wu, Alex Escalona

Figure 2: EndoStim® LES stimulator implant.

INTRODUCTION: A long-term single-center trial showed that LES-EST significantly improves esophageal acid exposure and symptoms in GERD patients (Endoscopy 2013; 45:595-604). AIMS: To establish safety and efficacy of LES-EST in refractory GERD patients in an international, multi-center setting. METHODS: We studied GERD patients partially responsive to proton pump inhibitors (PPI) with off-PPI GERD-HRQL >20 and >5 point

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AGA Abstracts

AGA Abstracts

improvement on-PPI, LES end-expiratory pressures of >5 mmHg, % 24 hour esophageal pH<4 for >5%, hiatal hernia <3cm and esophagitis