mitemcinal and Gastroparesis

Mitemcinal (GM-611) is a macrolide motilin receptor agonist with acid-resistance and without antibiotic activity. Since ABT-229 (a first generation of motilin receptor agonist) had failed to demonstrate symptomatic relief in functional dyspepsia and diabetic gastroparesis, there is a controversy for which of prokinetics or relaxants is clinically beneficial. Currently, oral mitemcinal has been focused on diabetic gastroparesis under clinical development. It showed to accelerate gastric-emptying in diabetic animals and in patients with gastroparesis. The latest double-blind, placebo-controlled study demonstrated to be effective at improving diabetes-related gastroparesis symptoms. A sub-group analysis, which included patients with BMI < 35 kg/m2 and hemoglobin A1c < 10%, there were significantly more symptomatic relieves in the 10 mg mitemcinal group than in the placebo group. The frequency of adverse events did not differ between groups. Mitemcinal shows promise in the subset of patients who should be confirmed in future studies.

Topics: Animals; Diabetes Complications; Dogs; Erythromycin; Gastric Emptying; Gastrointestinal Agents; Gastroparesis; Humans; Molecular Structure; Randomized Controlled Trials as Topic

Mitemcinal is an orally active motilin agonist that could potentially improve gastric emptying.. To investigate the effect of mitemcinal on gastric emptying in patients with idiopathic and diabetic gastroparesis.. In a randomized, double-blind design, 106 patients were randomized into four dosing regimens (22 to placebo and 21 each to mitemcinal 10 mg, 20 mg, 30 mg bid or 20 mg tid) for 28 days. A standardized scintigraphic gastric emptying test was performed at screening and again after completing the 4-week protocol.. All doses of mitemcinal showed prokinetic activity. A significant improvement in meal retention at 240 min was noted even in the lowest dose group with the greatest improvement observed with 30 mg bid group (75% vs. 10% in placebo group). Diabetic patients responded better than the idiopathic subgroup. In diabetic patients, blood glucose at 1 h after a meal showed dose-dependent elevation. Although gastroparetic symptoms improved with both mitemcinal and placebo, the prominent placebo effect was not statistically exceeded by mitemcinal. Baseline scintigraphy results exhibited no clear correlation between the severity of gastroparetic symptoms and the status of gastric emptying.. Mitemcinal is capable of accelerating gastric emptying in both diabetic and idiopathic patients with gastroparesis.

Topics: Adolescent; Adult; Aged; Blood Glucose; Diabetes Mellitus; Dose-Response Relationship, Drug; Double-Blind Method; Erythromycin; Female; Gastric Emptying; Gastrointestinal Agents; Gastroparesis; Humans; Male; Middle Aged; Motilin; Placebos; Treatment Outcome

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.

Topics: Acetaminophen; Administration, Oral; Animals; Cisapride; Clonidine; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Duodenum; Erythromycin; Gastric Emptying; Gastric Mucosa; Gastrointestinal Agents; Gastrointestinal Motility; Gastroparesis; Postprandial Period; Receptors, Gastrointestinal Hormone; Receptors, Neuropeptide; Stomach; Time Factors; Vagotomy

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 compared 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 compared 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.

Topics: Administration, Oral; Animals; Diabetes Mellitus, Experimental; Disease Models, Animal; Dogs; Erythromycin; Female; Gastric Emptying; Gastroparesis; Receptors, Gastrointestinal Hormone; Receptors, Neuropeptide