Oral mitemcinal (GM-611), an erythromycin-derived prokinetic, accelerates normal and experimentally delayed gastric emptying in conscious dogs.
1. We examined effects of orally administered mitemcinal, an erythromycin-derived motilin agonist, on gastric emptying and antroduodenal motility in conscious normal dogs and conscious dogs with experimentally delayed gastric emptying. For comparison, we also examined the effects of orally administered cisapride. 2. Gastric emptying was assessed by adding paracetamol to the test meal and determining three of its pharmacokinetic parameters as indices of gastric emptying. Antroduodenal motility was assessed from the output of force transducers chronically implanted in the gastric antrum and duodenum. 3. In normal dogs, mitemcinal (0.25, 0.5 and 1 mg/kg) dose-dependently accelerated gastric emptying, significantly increasing all three indices at doses of 0.5 and 1 mg/kg; cisapride (1, 3 and 10 mg/kg) had no significant effect. Mitemcinal also dose-dependently stimulated antroduodenal motility in the interdigestive and digestive states. Cisapride, at 100-fold the dose, produced similar effects in the interdigestive state, but mixed results in the digestive state. 4. In dogs with delayed gastric emptying induced by subcutaneous clonidine (0.03 mg/kg), mitemcinal (0.25, 0.5 and 1 mg/kg) dose-dependently improved delayed gastric emptying, significantly increasing two of three indices at a dose of 1 mg/kg. Cisapride (1, 3 and 10 mg/kg) caused non-significant increases in the indices of gastric emptying, with roughly bell-shaped dose-response curves. The highest dose of mitemcinal (1 mg/kg) also stimulated antroduodenal motility. 5. In dogs with delayed gastric emptying induced by vagotomy, mitemcinal (0.125, 0.25 and 0.5 mg/kg) dose-dependently improved delayed gastric emptying, significantly increasing all three indices at doses of 0.25 and 0.5 mg/kg. Cisapride (3 mg/kg) restored the indices to roughly prevagotomy levels, but none of the increases was significant. Mitemcinal, at a dose of 0.25 mg/kg, also stimulated antroduodenal motility. 6. Because delayed gastric emptying is the basic characteristic of gastroparesis, the fact that mitemcinal accelerated gastric emptying in dogs with normal and delayed gastric emptying much more robustly than cisapride adds to the evidence that mitemcinal is likely to be useful for the treatment of patients with gastroparesis.
Fuji-Gotemba Research Laboratories, Chugai Pharmaceutical Co. Ltd, Gotemba, Shizuoka, Japan.
Mitsu
M
Onoma
Kenji
K
Yogo
Ken-Ichi
K
Ozaki
Kenshi
K
Kamei
Michitaka
M
Akima
Hiroshi
H
Koga
Zen
Z
Itoh
Satoshi
S
Omura
Hisanori
H
Takanashi
D000082:Acetaminophen / Q000493:pharmacokinetics; D000284:Administration, Oral; D000818:Animals; D020117:Cisapride / Q000008:administration & dosage*; D003000:Clonidine; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004386:Duodenum / Q000187:drug effects* / Q000294:innervation / Q000378:metabolism / Q000503:physiopathology; D004917:Erythromycin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D005746:Gastric Emptying / Q000187:drug effects*; D005753:Gastric Mucosa / Q000378:metabolism; D005765:Gastrointestinal Agents / Q000008:administration & dosage*; D005769:Gastrointestinal Motility / Q000187:drug effects*; D018589:Gastroparesis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D019518:Postprandial Period; D011964:Receptors, Gastrointestinal Hormone / Q000819:agonists / Q000378:metabolism; D018013:Receptors, Neuropeptide / Q000819:agonists / Q000378:metabolism; D013270:Stomach / Q000187:drug effects* / Q000294:innervation / Q000503:physiopathology; D013997:Time Factors; D014628:Vagotomy
D005765:Gastrointestinal Agents; D011964:Receptors, Gastrointestinal Hormone; D018013:Receptors, Neuropeptide; C050802:motilin receptor; D000082:Acetaminophen; D004917:Erythromycin; C103741:mitemcinal; D003000:Clonidine; D020117:Cisapride