A novel prostanoid EP1 receptor antagonist, ONO-8539, reduces acid-induced heartburn symptoms in healthy male volunteers: a randomized clinical trial.

Abstract

BACKGROUND:

Patients with proton pump inhibitor (PPI)-refractory gastroesophageal reflux disease (GERD) have unmet clinical needs. Recently, we reported that esophageal prostaglandin E2 (PGE2) plays a crucial role in the generation of heartburn. In the present study, we focused on the PGE2 receptor, EP1, and investigated the effects of ONO-8539, a novel EP1 receptor antagonist, on heartburn symptoms in healthy male volunteers.

METHODS:

This prospective, double-blind, placebo-controlled, two-period crossover study was performed in 20 healthy male subjects. The novel prostanoid EP1 receptor antagonist, ONO-8539 (450 mg), was administered once 4 h prior to acid perfusion test. During the test, hydrochloric acid (0.15 mol l-1) was perfused into the lower esophagus for 30 min. Acid perception threshold was quantified by the time to first sensation of heartburn and intensity of GI symptoms determined using a validated categorical rating scale, and the area under the curve (AUC) as the total symptom score.

RESULTS:

ONO-8539 significantly reduced a total heartburn symptom score, not other upper GI symptom scores, during acid perfusion compared with placebo (AUC for heartburn, 85.0 ± 10.6 for placebo and 56.5 ± 7.2 for ONO-8539; P < 0.01), and significantly extended the time to first sensation of heartburn compared with placebo (5.7 ± 4.3 min for placebo and 9.7 ± 7.2 min for ONO-8539; P < 0.05).

CONCLUSIONS:

ONO-8539 attenuated acid-induced heartburn in healthy male subjects, suggesting that EP1 receptors play a role in generation of heartburn symptoms. ONO-8539 is a potential novel therapeutic option for controlling heartburn symptoms in GERD patients. Clinical Trials Registry No: UMIN000015753.

• Authors: Takashi Kondo, Hiroo Sei, Takahisa Yamasaki, Toshihiko Tomita, Yoshio Ohda, Tadayuki Oshima, Hirokazu Fukui, Jiro Watari, Hiroto Miwa
• Journal: Journal of gastroenterology (J Gastroenterol) Vol. 52 Issue 10 Pg. 1081-1089 (10 2017) ISSN: 1435-5922 [Electronic] Japan
• PMID: 28120127 (Publication Type: Journal Article, Randomized Controlled Trial)

Chemical References

• Benzoates
• Gastrointestinal Agents
• Indenes
• Receptors, Prostaglandin E, EP1 Subtype
• Thiazoles
• ONO-8539

Topics

• Adult
• Benzoates (therapeutic use)
• Cross-Over Studies
• Double-Blind Method
• Gastroesophageal Reflux (drug therapy, pathology)
• Gastrointestinal Agents (pharmacology)
• Heartburn (drug therapy, pathology)
• Humans
• Indenes (therapeutic use)
• Male
• Middle Aged
• Prospective Studies
• Receptors, Prostaglandin E, EP1 Subtype (antagonists & inhibitors, metabolism)
• Thiazoles (therapeutic use)
• Time Factors
• Treatment Outcome
• Young Adult