Stimulatory action of mitemcinal (GM‐611), an acid‐resistant non‐peptide motilin receptor agonist, on colonic motor activity and defecation: spontaneous and mitemcinal‐induced giant migrating contractions during defecation in dogs

Abstract

The aim of this study was to characterize giant migrating contractions (GMCs) during spontaneous defecation in dogs and to investigate the effect of mitemcinal (an orally active and highly acid-resistant motilin receptor agonist) on colonic motility to assess the possibility of using it for the treatment of colonic motility disorders. To assess colonic motility, strain-gauge force transducers were implanted on the gastrointestinal tract of five dogs, and the behaviour of the dogs was monitored with a noctovision-video camera system. The effect of mitemcinal (0, 3, 10 or 30 mg per dog) and sennoside (300 mg per dog) on colonic motility was assessed 24 h after oral administration. During a 39-day period, the starting point of most of the 140 GMCs was between the transverse colon and the descending colon, but some variation was observed. In the daytime, the GMCs originated from somewhat more proximal positions than at night. Mitemcinal caused an increase in the GMC-index (integration of contractile amplitude and duration) and proximal translocation of the GMC starting point, but did not cause an increase in the number of defecations 12 h after administration. Sennoside, however, caused a significant increase in the number of defecations, an increase in the GMC-index, and prolongation of the duration of GMCs. The GMC starting point in the canine colon varied during spontaneous defecation. Mitemcinal was a potent prokinetic drug to mimic a spontaneous defecation compared with sennoside. Mitemcinal evacuates more intestinal luminal contents during the defecation than does sennoside.

Elobixibat, an ileal bile acid transporter inhibitor, induces giant migrating contractions during natural defecation in conscious dogs

“…GI motility was recorded by means of chronically implanted strain gauge transducers (SGs), as previously reported . Each dog received a preoperative intramuscular administration of cefamezin (15 mg kg −1 , Astellas Pharma, Tokyo, Japan) and lepetan (0.01 mg kg −1 , Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan), followed by intramuscular administration of Ketalar (10 mg kg −1 , Daiichi Sankyo Co., Ltd., Tokyo, Japan) and Selactar (2 mg kg −1 Bayer Pharmaceutical Co., Ltd., Leverkusen, Germany).…”

“…The elobixibat dosage was selected as 3‐30 mg kg −1 because fecal weight increase was previously observed at 10 mg kg −1 in a canine constipation model, and the dose was estimated to be approximately 10 times higher than that in human dose (5‐15 mg) considering the difference between humans and dogs in terms of in vitro IBAT inhibition potency . The dose of sennoside was selected according to that previously reported to induce GMC in dogs . Water for injection, adjusted to a pH of 8.5 with NaOH, was used as the vehicle.…”

“…Elobixibat is a highly potent and selective inhibitor of human, murine, and canine IBAT and ameliorates meat‐induced constipation in dogs . As the colons of adult canines and humans are anatomically similar, canine digestive phenomena, such as colonic fermentation and water and electrolyte absorption, are comparable to processes observed in humans, and canine fecal properties and circadian rhythm are similar to those of humans . Thus, the dog is an appropriate animal model to investigate the pharmacological effects of elobixibat.…”

“…The aim of this study was to assess GI motility following single‐dose administration of elobixibat using a canine intestinal telemetry system. Sennoside was administered as a positive control in this model because it induces giant migrating contractions (GMCs), which are known as canine HAPCs …”

Intragastric Dai-Kenchu-To, a Japanese Herbal Medicine, Stimulates Colonic Motility via Transient Receptor Potential Cation Channel Subfamily V Member 1 in Dogs

“…Oral administration of magnesium citrate and olive oil increased the duration of contractile activity/hour later than 2 hours after the administration and induced defecations with the mean intervals at 7 ± 0.5 hours . The number of defecations increased within the first 2 hours and 4-8 hours after the administration of a motilin receptor agonist and sennoside, respectively, in conscious dogs (Hirabayashi et al 2009). These observations indicate that intragastric DKT may increase the number of defecations later than several hours after the administration.…”