Article

Mitemcinal (GM-611), an orally active motilin receptor agonist, improves delayed gastric emptying in a canine model of diabetic gastroparesis.

Fuji-Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd, Shizuoka, Japan.
Clinical and Experimental Pharmacology and Physiology (Impact Factor: 2.41). 08/2008; 35(7):788-96. DOI: 10.1111/j.1440-1681.2008.04924.x
Source: PubMed

ABSTRACT 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.

0 Bookmarks
 · 
182 Views
  • [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.
    Regulatory Peptides 02/2009; 155(1-3):145-9. · 2.06 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Gastroparesis is a chronic motility disorder of the stomach that involves delayed emptying of solids and liquids, without evidence of mechanical obstruction. Although no cause can be determined for the majority of cases, the disease often develops as a complication of abdominal surgeries or because of other underlying disorders, such as diabetes mellitus or scleroderma. The pathophysiology behind delayed gastric emptying is still not well-understood, but encompasses abnormalities at 3 levels--autonomic nervous system, smooth muscle cells, and enteric neurons. Patients will often cite nausea, vomiting, postprandial fullness, and early satiety as their most bothersome symptoms on history and physical examination. Those that present with severe disease may already have developed complications, such as the formation of bezoars or masses of undigested food. In patients suspected of gastroparesis, diagnostic evaluation requires an initial upper endoscopy to rule out mechanical causes, followed by a gastric-emptying scintigraphy for diagnosis. Other diagnostic alternatives would be wireless capsule motility, antroduodenal manometry, and breath testing. Once gastroparesis is diagnosed, dietary modifications, such as the recommendation of more frequent and more liquid-based meals, are encouraged. Promotility medications like erythromycin and antiemetics like prochlorperazine are offered for symptomatic relief. These agents may be frequently changed, as the right combination of effective medications will vary with each individual. In patients who are refractory to pharmacologic treatment, more invasive options, such as intrapyloric botulinum toxin injections, placement of a jejunostomy tube, or implantation of a gastric stimulator, are considered. Future areas of research are based on current findings from clinical studies. New medications, such as hemin therapy, are emerging because of a better understanding of the pathophysiology behind gastroparesis, and present treatment options, such as gastric electric stimulation, are evolving to be more effective. Regenerative medicine and stem cell-based therapies also hold promise for gastroparesis in the near future.
    Disease-a-month: DM 02/2011; 57(2):74-101. · 1.57 Impact Factor
  • [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.
    Pediatric Diabetes 09/2008; 9(6):561-6. · 2.08 Impact Factor