Mitemcinal (GM-611), an orally active motilin receptor agonist, accelerates colonic motility and bowel movement in conscious dogs

Abstract

The prokinetic effects of mitemcinal, an orally active motilin receptor agonist, on the lower gastrointestinal tracts were investigated in conscious dogs. Oral administration of mitemcinal (0.1-1 mg/kg) stimulated colonic motility, which was measured by chronically implanted force-transducers, as well as gastric motility in a dose-dependent manner. The gastrointestinal contractile activities induced by mitemcinal were inhibited by the continuous intravenous infusion of GM-109, a selective motilin receptor antagonist. Oral administration of mitemcinal (0.3-3 mg/kg) also accelerated bowel movement after feeding without inducing diarrhea in dogs. The results demonstrate that mitemcinal stimulates colonic motility via motilin receptors and the effect of mitemcinal on colonic motility may reflect bowel movement after feeding. Thus, mitemcinal could be a promising agent for treatment of not only the upper but also the lower gastrointestinal motility disorders.

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

“…14,15 It is being developed by Chugai Pharmaceutical Co., Ltd. as a treatment for gastric motility disorders, diabetic gastroparesis, 16 and colonic motility disorders. 18 The results of this study showed that mitemcinal caused proximal translocation of the GMC starting point and a statistically significant increase in the strength of the GMCs (the GMC index) during the 12-h period after administration. Mitemcinal increased the motor index of the ileum and the colon in parallel with its blood concentration, but it did not increase the motor index of the rectum.…”

“…Mitemcinal is an erythromycin derivative, and is the first acid‐resistant motilin receptor agonist ever described 14,15 . It is being developed by Chugai Pharmaceutical Co., Ltd. as a treatment for gastric motility disorders, diabetic gastroparesis, 16 and colonic motility disorders 18 …”

“…(K. Ozaki, unpublished data). Orally administered mitemcinal exhibits potent motility‐stimulating activity in the upper gastrointestinal tract of dogs and monkeys via the motilin receptor, 15,17 and it facilitates bowel movements in rabbits and dogs 18,19 . In a clinical trial, mitemcinal was shown to induce a significant response to treatment in diabetic gastroparesis, and patients who received mitemcinal experienced an increase in stool frequency in comparison with a placebo 16 …”

“…Orally administered mitemcinal exhibits potent motility-stimulating activity in the upper gastrointestinal tract of dogs and monkeys via the motilin receptor, 15,17 and it facilitates bowel movements in rabbits and dogs. 18,19 In a clinical trial, mitemcinal was shown to induce a significant response to treatment in diabetic gastroparesis, and patients who received mitemcinal experienced an increase in stool frequency in comparison with a placebo. 16 In the present study, we used mitemcinal to investigate the physiological role of motilin receptor agonists on colonic motility and assess the possibility of using mitemcinal for treatment of colonic motility disorders.…”

The Roles of Motilin and Ghrelin in Gastrointestinal Motility

“…Similarly to the case of motilin, intravenous administration of mitemcinal in dogs [54] stimulated interdigestive, as well as digestive, gastroduodenal motor activity, and its effect was blocked by the motilin-receptor antagonist GM-109. Colonic motility in dogs [55] could also be stimulated by mitemcinal given orally. Randomized controlled trials in 392 insulin-requiring diabetics revealed that symptoms attributable to gastroparesis could be ameliorated with 10 mg mitemcinal twice daily than with a placebo and without inducing significant adverse effects [56].…”