Regional Analysis of Gastric Emptying Scintigraphy Provides Better Correlation of Dyspeptic Symptoms With Abnormal Gastric Emptying

Abstract

Ghrelin, a 28-amino acid peptide produced by the stomach, is the natural ligand for the GHS-1a receptor and may have the potential to treat clinical conditions associated with impaired gastric motility and energy balance. Administration of ghrelin promotes gastric motility in mice, rats, dogs and humans, and also increases body weight by increasing food intake, inducing positive energy balance, and increasing growth hormone secretion. RM131 (formerly reported as BIM-28131) is a novel pentapeptide that acts as a potent ghrelin agonist. The aim of the present study was to compare the gastroprokinetic effects of RM131with human ghrelin and small molecule GHS-1aR agonists including ipamorelin, anamorelin and MK-677, in a model of post-operative ileus. Male Sprague Dawley rats were fasted for 24 h with free access to water. Gastric ileus was induced by laparotomy under anesthesisa.. Abdominal muscles and skin were then closed with sutures and the animals were allowed to recover for 2.5 hours. At that time, to further worsen the symptoms of ileus, the animals were treated with morphine (4mg/kg, sc). Test compounds were administered by subcutaneous injection 30 min after morphine administration, and 15 minutes before receiving a phenol red-markedmeal by esophageal gavage. The effect on gastric emptyingwas determined by measuring the residual marked meal in the stomach after sacrifice. Laparotomy alone induced a 35% decrease in gastic emptying, while the additional administration of morphine further decreased gastric emptying to 61%, as compared with sham-operated, saline-injected controls. Administration of RM-131 resulted in a progressive, dose-related reversal of the laparotomy/morphine-induced ileus, reaching full restoration of gastric emptying by a dose of 0.3nmole/kg. Human ghrelin and anamorelin were also fully efficacious in restoring gastric emptying, but were 130and 100-fold less potent than RM-131, respectively. MK-677 and ipamorelin were only partially effective in restoring gastric emptying, even at doses as high as 100nmole/kg. These results demonstrate that RM-131, a potent agonist of the GHS-1a receptor, is highly efficacious in inducing increased gastric emptying in a model of gastric ileus induced by bothmorphine and laparatomy. RM-131 is being developed for the treatment of disorders of GI motility, including POI and diabetic gastroparesis by Rhythm Pharmaceuticals (Boston, MA).