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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Dyspepsia is the medical term for difficult digestion. It consists of various symptoms in the upper abdomen, such as fullness, discomfort, early satiation, bloating, heartburn, belching, nausea, vomiting, or pain. The prevalence of dyspepsia in the western world is approximately 20% to 25%. Dyspepsia can be divided into 2 main categories: "organic" and "functional dyspepsia" (FD). Organic causes of dyspepsia are peptic ulcer, gastroesophageal reflux disease, gastric or esophageal cancer, pancreatic or biliary disorders, intolerance to food or drugs, and other infectious or systemic diseases. Pathophysiological mechanisms underlying FD are delayed gastric emptying, impaired gastric accommodation to a meal, hypersensitivity to gastric distension, altered duodenal sensitivity to lipids or acids, altered antroduodenojenunal motility and gastric electrical rhythm, unsuppressed postprandial phasic contractility in the proximal stomach, and autonomic nervous system-central nervous system dysregulation. Pathogenetic factors in FD are genetic predisposition, infection from Helicobacter pylori or other organisms, inflammation, and psychosocial factors. Diagnostic evaluation of dyspepsia includes upper gastrointestinal endoscopy, abdominal ultrasonography, gastric emptying testing (scintigraphy, breath test, ultrasonography, or magnetic resonance imaging), and gastric accommodation evaluation (magnetic resonance imaging, ultrasound, single-photon emission computed tomography, and barostat). Antroduodenal manometry can be used for the assessment of the myoelectrical activity of the stomach, whereas sensory function can be evaluated with the barostat, tensostat, and satiety test. Management of FD includes general measures, acid-suppressive drugs, eradication of H. pylori, prokinetic agents, fundus-relaxing drugs, antidepressants, and psychological interventions. This review presents an update on the diagnosis of patients presenting with dyspepsia, with an emphasis on the pathophysiological and pathogenetic mechanisms of FD and the differential diagnosis with organic causes of dyspepsia. The management of uninvestigated and FD, as well as the established and new pharmaceutical agents, is also discussed.
    Journal of clinical gastroenterology 03/2012; 46(3):175-90. · 2.21 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
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In addition to being valuable source of energy, carbohydrates, one of the main dietary components, are integral parts of the cell. As extra- & intracellular molecules they act as cell surface receptor and also as signaling molecules playing predominant role in molecular recognition and many other cellular processes. The clear understanding of their role in the various important biological events has led to the demand for easy access of diverse glycoconjugates for their complete chemical and biological investigations. Several carbohydrate-based molecules both of synthetic and natural origin are known for their wide range of pharmacological activities and even many of them are clinically used to treat different ailments. Due to their structural diversity in terms of functional groups, ring size and linkages they are valuable scaffolds in drug discovery processes. Because of the hydrophilic nature of monosaccharides they offer good water solubility, optimum pharmacokinetics and decreased toxicity. These naturally occurring molecules have therefore been extensively used to access diverse library of compounds with great chemotherapeutic importance. This review highlights an overview of development of carbohydrate-based molecules from others and our lab which have shown promising biological activity against front line diseases.
    Mini Reviews in Medicinal Chemistry 06/2012; · 2.87 Impact Factor