Ghrelin-Mimicking Peptides Anamorelin and Ipamorelin Reduce Chemotherapy-Induced Weight Loss — Anamorelin Also Stops Nausea When It Reaches the Brain

Both ghrelin mimetics — anamorelin and ipamorelin — inhibited cisplatin-induced weight loss by approximately 24% during the delayed phase (48-72 hours) when administered intraperitoneally. Neither reduced emesis via this route. However, anamorelin administered directly into the brain (intracerebroventricularly) reduced acute emesis by 60%, improved food and water consumption by 20-40% during the acute phase, and reduced weight loss by ~23% during the delayed phase. In isolated ileum, anamorelin inhibited contractions by 94.4% (IC50 = 14.0 µM) while ipamorelin achieved 54.4% (IC50 = 11.7 µM). The findings suggest brain penetration is critical for anamorelin's anti-emetic effect.

Ferrets were used as the animal model (standard for emesis research, as rodents cannot vomit). Anamorelin (1-3 mg/kg) or ipamorelin (1-3 mg/kg) were administered intraperitoneally 30 seconds before cisplatin (5 mg/kg) and then every 24 hours, with behavior recorded for 72 hours. Food and water consumption was measured every 24 hours. Separate experiments tested intracerebroventricular anamorelin (10 µg). Ex vivo experiments measured electrical field stimulation-induced contractions of isolated ferret ileum to assess peripheral gut effects.

Chemotherapy-induced nausea, vomiting, and weight loss (cachexia) are among the most distressing side effects of cancer treatment and major reasons patients discontinue therapy. Anamorelin, a ghrelin receptor agonist already approved in some countries for cancer cachexia, may have broader utility as an anti-emetic if formulated to cross the blood-brain barrier. This study provides mechanistic evidence for a dual role — appetite stimulation plus nausea reduction — through a central nervous system mechanism.

Anamorelin is already approved in Japan for cancer-related cachexia, and this study expands its potential utility to include anti-emetic effects — a dual benefit that could be transformative for patients undergoing chemotherapy. The finding that brain penetration is critical for the anti-emetic mechanism provides a clear engineering target: developing formulations that cross the blood-brain barrier could unlock a comprehensive supportive care drug that addresses both weight loss and nausea from a single mechanism.

Ferret studies, while the gold standard for emesis research, may not directly predict human responses. The intracerebroventricular route used to demonstrate anti-emetic effects is not clinically practical — whether a brain-penetrant formulation of anamorelin could achieve the same effect is unknown. Sample sizes per group are not reported in the abstract. Ipamorelin was not tested intracerebroventricularly, so it's unclear whether it would show similar central anti-emetic effects.