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

  • Original Article—Alimentary Tract
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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.

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Abbreviations

ATP:

Adenosine triphosphate

ANOVA:

Analysis of variance

AUC:

Area under the curve

BA:

Bile acid

ED:

Elemental diet

ECG:

Electrocardiography

FSSG:

Frequency scale for the symptoms of GERD

GERD:

Gastroesophageal reflux disease

GI:

Gastrointestinal

QOL:

Quality of life

GMP:

Good manufacturing practices

NSAID:

Nonsteroidal antiinflammatory drug

PGE2 :

Prostaglandin E2

PPIs:

Proton pump inhibitors

SEM:

Standard error of the mean

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Acknowledgements

We are grateful to Ms. Noriko Kamiya for excellent assistance. ONO-8539 and placebo tablets were produced by Ono Pharmaceutical Co., Ltd., in compliance with Good Manufacturing Practices.

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Authors and Affiliations

  1. Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan

    Takashi Kondo, Hiroo Sei, Takahisa Yamasaki, Toshihiko Tomita, Yoshio Ohda, Tadayuki Oshima, Hirokazu Fukui, Jiro Watari & Hiroto Miwa

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  1. Takashi Kondo
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  2. Hiroo Sei
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  3. Takahisa Yamasaki
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  4. Toshihiko Tomita
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  5. Yoshio Ohda
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  6. Tadayuki Oshima
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  7. Hirokazu Fukui
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  9. Hiroto Miwa
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Correspondence to Hiroto Miwa.

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The authors have no conflicts of interest.

Ethics approval

This trial was approved by the Ethics Committee of Hyogo College of Medicine (Approval Number: 1810) and was conducted in accordance with the principles governing human research in the Declaration of Helsinki.

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Kondo, T., Sei, H., Yamasaki, T. et al. A novel prostanoid EP1 receptor antagonist, ONO-8539, reduces acid-induced heartburn symptoms in healthy male volunteers: a randomized clinical trial. J Gastroenterol 52, 1081–1089 (2017). https://doi.org/10.1007/s00535-017-1308-3

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