Efficacy of ipamorelin, a ghrelin mimetic, on gastric dysmotility in a rodent model of postoperative ileus

Summary

Rodent study, not a human trial. It tested whether ipamorelin, a synthetic ghrelin-receptor agonist, speeds gastric emptying in rats after laparotomy and intestinal manipulation, a model of postoperative ileus. Rats received intravenous ipamorelin or vehicle after surgery. In a separate group, strips of stomach muscle were tested in an organ bath. The authors conclude that ipamorelin accelerated gastric emptying by stimulating gastric contractility through a ghrelin receptor-mediated mechanism involving cholinergic excitatory neurons. Ipamorelin was also tested for postoperative ileus in people, in a separate phase 2 randomized, placebo-controlled trial in bowel resection patients (Beck et al. 2014, International Journal of Colorectal Disease). That trial found no significant difference from placebo on its key efficacy endpoint, time to tolerating a solid meal; see 25331030-prospective-randomized-controlled-proof-of-concept-study-o.

Key Findings

• Abdominal surgery delayed gastric emptying: 78% ± 5% of the meal remained in the stomach in vehicle-treated rats, compared with 44% ± 6% in non-surgical controls
• Ipamorelin at 0.014 µmol/kg IV significantly accelerated gastric emptying (P < 0.05 vs vehicle), with 52% ± 11% of the meal remaining
• After surgery, isolated gastric smooth muscle showed marked inhibition of contractions induced by acetylcholine and electrical field stimulation; ipamorelin and ghrelin reversed this
• The proposed mechanism is ghrelin-receptor activation acting through cholinergic excitatory neurons

Methodology

Fasted adult male rats underwent laparotomy and intestinal manipulation, then received ipamorelin (0.014-0.14 µmol/kg) or vehicle intravenously. Gastric emptying was measured as the percentage of recovered radioactivity left in the stomach 15 minutes after gavage of 1.5 mL of technetium-99m sulfur colloid in 0.5% methylcellulose. In a separate group of operated rats, gastric fundus strips were suspended in an organ bath to test ipamorelin (1 µM) on contractions induced by acetylcholine and electrical field stimulation. The abstract does not report the number of animals.

Limitations

• Rat model only; it does not show benefit in people
• Single intravenous doses with gastric emptying measured over 15 minutes; no subcutaneous dosing and no longer-term outcomes
• Number of animals not reported in the abstract
• Measures gastric emptying, one part of postoperative ileus, rather than overall recovery of bowel function

Relevance to Content

Shows that ipamorelin has prokinetic effects on the stomach through the ghrelin receptor in rats, a use distinct from its GH-releasing effect. It should not be cited as evidence that ipamorelin treats postoperative ileus in humans, because the phase 2 human trial did not show a significant benefit over placebo.

See Also

• Parent compound: Ipamorelin
• 25331030-prospective-randomized-controlled-proof-of-concept-study-o