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1. The aim of the present study was to evaluate the effects of mitemcinal (GM-611), an orally active motilin receptor agonist, on delayed gastric emptying in a canine model of diabetic gastroparesis and to compare these effects with those of cisapride. 2. Moderate hyperglycaemia was induced by a single intravenous injection of a mixture of streptozotocin (30 mg/kg) and alloxan (50 mg/kg). Dogs that maintained moderate hyperglycaemia (fasting plasma glucose 200–300 mg/dL) without insulin treatment were selected and gastric emptying in these dogs was determined by the paracetamol method. 3. One year after the onset of diabetes, there was no difference in the gastric emptying of normal and diabetic dogs. However, after 5 years, the diabetic dogs showed delayed gastric emptying. The motor nerve conduction velocity of the tibial nerve was significantly lower in diabetic dogs comapred with normal dogs at both time points. 4. Histopathological examination at the end of the study showed that there were fewer nerve fibres in both dorsal vagal and tibial nerves of diabetic dogs comapred with normal dogs. The onset of delayed gastric emptying is thought to have occurred gradually, in parallel with abnormal autonomic nerve function induced by the long period of moderate hyperglycaemia. 5. Oral administration of mitemcinal (0.125, 0.25 or 0.5 mg/kg) dose-dependently accelerated delayed gastric emptying, significant at 0.5 mg/kg, in diabetic dogs, whereas cisapride (1, 3 or 10 mg/kg) had no significant effect. These results add to the existing evidence that mitemcinal is likely to be useful for treating diabetic gastroparesis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]