title: A novel prostanoid EP1 receptor antagonist, ONO-8539, reduces acid-induced heartburn symptoms in healthy male volunteers: a randomized clinical trial.
abstract: 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 PGE2receptor, EP1, and investigated the effects of ONO-8539, a novel EP1 receptor antagonist, on heartburn symptoms in healthy male volunteers.
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.affiliation: Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kondo
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan.
authors.forename: Hiroo
authors.initials: H
authors.lastname: Sei
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Yamasaki
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Tomita
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Ohda
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan.
authors.forename: Tadayuki
authors.initials: T
authors.lastname: Oshima
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Fukui
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan.
authors.forename: Jiro
authors.initials: J
authors.lastname: Watari
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan. miwahgi@hyo-med.ac.jp.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Miwa
mesh_terms: D000328:Adult; D001565:Benzoates / Q000627:therapeutic use*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005764:Gastroesophageal Reflux / Q000188:drug therapy* / Q000473:pathology; D005765:Gastrointestinal Agents / Q000494:pharmacology*; D006356:Heartburn / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007192:Indenes / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D058306:Receptors, Prostaglandin E, EP1 Subtype / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013844:Thiazoles / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D001565:Benzoates; D005765:Gastrointestinal Agents; D007192:Indenes; D058306:Receptors, Prostaglandin E, EP1 Subtype; D013844:Thiazoles; C000629829:ONO-8539
keywords: EP1; GERD; Heartburn; ONO-8539; PGE2