title: The novel, peripherally restricted GABAB receptor agonist lesogaberan (AZD3355) inhibits acid reflux and reduces esophageal acid exposure as measured with 24-h pHmetry in dogs.
abstract: While patients with symptoms of gastroesophageal reflux disease generally respond well to proton pump inhibitors, 20-30% continue to experience troublesome symptoms. In such cases, agents that target transient lower esophageal sphincter (LES) relaxation may be useful as add-on therapy to proton pump inhibitors. The GABAB receptor agonist baclofen inhibits transient LES relaxation but it is not an ideal agent due to central nervous system activity. Lesogaberan (AZD3355) is a peripherally restricted GABAB receptor agonist with limited central nervous system activity that inhibits transient LES relaxation in dogs. In the present study, the comparative effects of lesogaberan (7 micromol/kg) and baclofen (2.8 micromol/kg) on reflux were studied in dogs using 24-h pHmetry. Drugs (or vehicle control) were administered orally prior to the first meal of the day, and the number of reflux episodes (pH<4 for > or = 5 s) and acid exposure time were computed for the 24-h monitoring period. The mean (S.E.M.) number of reflux episodes/24 h was 4.6 (0.4) and 6.4 (0.6) for lesogaberan and baclofen, respectively, versus 10.7 (0.5) for control (P<0.0001 for both). Acid exposure time was 51.2 (4.5) min for control versus 23.6 (3.8) min for lesogaberan (P<0.0001) and 35.4 (6.5) min with baclofen (P=0.05). It is concluded that lesogaberan significantly reduces acid reflux in dogs, with comparable efficacy to baclofen.
authors.affiliation: AstraZeneca R&D, SE-431 83 Mölndal, Sweden.
authors.forename: Lena
authors.initials: L
authors.lastname: Brändén
authors.forename: Anita
authors.initials: A
authors.lastname: Fredriksson
authors.forename: Emelie
authors.initials: E
authors.lastname: Harring
authors.forename: Jörgen
authors.initials: J
authors.lastname: Jensen
authors.forename: Anders
authors.initials: A
authors.lastname: Lehmann
mesh_terms: D000818:Animals; D001418:Baclofen / Q000008:administration & dosage / Q000494:pharmacology; D004285:Dogs; D004947:Esophagus / Q000187:drug effects* / Q000502:physiology; D005260:Female; D018755:GABA Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D058786:GABA-B Receptor Agonists; D005744:Gastric Acid / Q000378:metabolism; D005764:Gastroesophageal Reflux / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control*; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D008297:Male; D008365:Manometry / Q000379:methods; D010721:Phosphinic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D010865:Pilot Projects; D011437:Propylamines / Q000494:pharmacology / Q000627:therapeutic use*; D018080:Receptors, GABA-B / Q000502:physiology; D013997:Time Factors
chemical_list: D018755:GABA Agonists; D058786:GABA-B Receptor Agonists; D010721:Phosphinic Acids; D011437:Propylamines; D018080:Receptors, GABA-B; C545087:lesogaberan; D001418:Baclofen