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.
[Show abstract][Hide abstract] ABSTRACT: Natural product and natural product-derived compounds that are being evaluated in clinical trials or are in registration (as at 31st December 2007) have been reviewed, as well as natural product-derived compounds for which clinical trials have been halted or discontinued since 2005. Also discussed are natural product-derived drugs launched since 2005, new natural product templates and late-stage development candidates.
[Show abstract][Hide abstract] ABSTRACT: Because amylin is co-secreted with insulin from beta cells, patients with type 1 diabetes (T1DM) are deficient in both insulin and amylin. Amylin delays gastric emptying and suppresses glucagon in the postprandial period. Hence, we hypothesized that children with complication-naive T1DM have accelerated gastric emptying in response to a mixed meal because of amylin deficiency. Amylin, glucagon, insulin, glucose, and gastric emptying were measured in seven T1DM and in eight control subjects without diabetes. Subjects with T1DM had markedly elevated glucose concentrations when compared with controls (p < 0.0001). Amylin concentrations as predicted were lower in T1DM compared with those in controls (p < 0.0001). Insulin did not peak in the immediate postprandial period in T1DM when compared with controls (p < 0.0001). Glucagon concentrations did not significantly differ between groups. Interestingly, gastric velocity was delayed in patients with T1DM compared with controls (p < 0.01). In conclusion, subjects with T1DM do have amylin deficiency but this is not associated with accelerated gastric emptying as we had hypothesized but rather with delayed gastric emptying. Factors other than amylin play a role in control of gastric motility in T1DM. Subcutaneous insulin delivery fails to reach adequate concentrations in the postprandial period to curtail peak glucose concentration in T1DM.
[Show abstract][Hide abstract] ABSTRACT: To investigate the underlying mechanisms of Berberine-mediated antidiarrheal effects in thyroid hormone-induced diarrhea in rats, gastrointestinal peptides, such as motilin, gastrin, vasoactive intestinal peptide, and somatostatin from plasma and tissue of hyperthyroid diarrheic rats were measured using radioimmunoassay in healthy control, model, and treated model groups. The number and volume of goblet cells were also observed. Compared with healthy control, hyperthyroid diarrheic rats exhibited a significant reduction in body weight, and increase in plasma concentrations of tri-iodothyronine and free thyroxine along with the increase of wet stool. Both plasma motilin and gastrin were also elevated and reduced remarkably in Berberine-treated subgroup along with the body weight increased and wet stool reduced at the meantime. Significant changes in plasma vasoactive intestinal peptide and somatostatin were not seen. Gastrointestinal peptides trend in tissue samples were similar to those observed in plasma. Morphological data demonstrated an increase in number and/or volume of goblet cells to some extent in duodenum, jejunum, ileum, and colon, respectively and decreased by administration of Berberine. The possible underlying mechanisms of antidiarrheal effects of Berberine may be due in partially to the reduction of the number of goblet cells and the amount of mucous secretion through re-balancing gastrointestinal peptides.
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