Mitemcinal (Gm‐611), an Orally Active Motilin Receptor Agonist, Improves Delayed Gastric Emptying in a Canine Model of Diabetic Gastroparesis

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.

Emphysematous Cystitis in a Chemically-Induced Diabetic Dog

“…Glucosuria was suggested by the persistent hyperglycemia due to the STZ/ALX-induced diabetes. In STZ/ALX-induced diabetes model dogs, diabetic neuropathy in the vagal and tibial nerve has been observed in all model animals, including the present case 16 . Therefore, it is possible that diabetic neuropathy may affect urination and bring about bacterial infection of the urinary bladder.…”

Gastric emptying and postprandial glucose excursions in adolescents with type 1 diabetes

“…In dogs, it is reported to take 5 yr before delayed gastric emptying manifests after moderate hyperglycemia (25). Histopathologic examination of the dorsal vagal nerve revealed fewer fibers compared with controls, which was reported to the observed autonomic nerve dysfunction and delayed gastric emptying.…”

Spirocyclic Nucleosides in Medicinal Chemistry: An Overview

“…Mitemcinal (22) has successfully completed Phase-I trial by Chugai while Phase II trials in US are still running against diabetic reflux oesophagitis and idiopathic gastroparesis [35]. Phase-II trials of 22 against irritable bowel syndrome is also under process by Chugai Pharma.…”

“…Dalbavancin (33), a semi-synthetic derivative of the teicoplanin analogue A40926 (34), was discovered by Biosearch Italia and being developed by Pfizer for the treatment of bacterial infections [42]. Oritavancin (35), a derivative of chloroeremomycin (36) known to inhibit cell-wall biosynthesis was developed by Eli Lilly and acquired by InterMune in 2001. Later on in 2005 it was transferred to Targanta Therapeutics and in 2008, an NDA for 35 was submitted to the FDA that unfortunately couldn't be approved due to insufficient data.…”