title: Acotiamide, a new orally active acetylcholinesterase inhibitor, stimulates gastrointestinal motor activity in conscious dogs.
abstract: BACKGROUND Acotiamide hydrochloride (acotiamide), a novel selective acetylcholinesterase (AChE) inhibitor, has proven significantly effective in treating functional dyspepsia (FD) in clinical trials, particularly in alleviating meal-related symptoms. In the present study, we examined the gastrointestinal prokinetic effects of acotiamide administered orally or intraduodenally in conscious dogs and investigated in vivo and ex vivo anti-AChE activity of acotiamide to clarify its mechanism of prokinetic action.
  
  
  METHODS
  Gastrointestinal motility was measured in conscious dogs with chronically implanted force transducers.
  
  
  RESULTS
  Oral administration of acotiamide stimulated postprandial gastroduodenal and colonic motor activities. Measurement of gastrointestinal motility showed that acotiamide, like itopride and mosapride, enhanced gastric antral motility. Further, acotiamide markedly improved clonidine (an α(2) -adrenoceptor agonist)-induced hypomotility in a dog model of gastric motor dysfunction. The postprandial gastric antral motility enhanced by acotiamide was completely abolished on treatment with the muscarinic receptor antagonist atropine. Results of an in vivo experiment on anti-AChE activity showed clearly increased acetylcholine-induced gastric motility on intraduodenal administration of acotiamide, just as observed with the AChE inhibitor neostigmine. Further, in ex vivo experiment, intraduodenal administration of acotiamide significantly inhibited AChE activity in canine gastric antrum.
  
  
  CONCLUSIONS
  Our findings revealed that acotiamide administered through the alimentary tract exerts gastroprokinetic action via cholinergic pathways by inhibiting AChE activity. These results may also confirm the mechanism of action in clinical efficacy of acotiamide on FD.
authors.affiliation: Central Research Laboratories, Zeria Pharmaceutical Co., Ltd., Saitama, Japan. kenji-nagahama@zeria.co.jp
authors.forename: K
authors.initials: K
authors.lastname: Nagahama
authors.forename: Y
authors.initials: Y
authors.lastname: Matsunaga
authors.forename: M
authors.initials: M
authors.lastname: Kawachi
authors.forename: K
authors.initials: K
authors.lastname: Ito
authors.forename: T
authors.initials: T
authors.lastname: Tanaka
authors.forename: Y
authors.initials: Y
authors.lastname: Hori
authors.forename: H
authors.initials: H
authors.lastname: Oka
authors.forename: M
authors.initials: M
authors.lastname: Takei
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D003000:Clonidine / Q000494:pharmacology; D004285:Dogs; D005746:Gastric Emptying / Q000187:drug effects*; D005769:Gastrointestinal Motility / Q000187:drug effects*; D041981:Gastrointestinal Tract / Q000187:drug effects*; D008297:Male; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D001549:Benzamides; D002800:Cholinesterase Inhibitors; D013844:Thiazoles; C410959:Z 338; D003000:Clonidine