Pharmacodynamic hormonal effects of anamorelin, a novel oral ghrelin mimetic and growth hormone secretagogue in healthy volunteers.

OBJECTIVE: Activation of ghrelin receptors stimulates GH secretion and appetite, increasing lean body mass and body weight. However, clinical use of ghrelin is limited because it has a short half-life and must be administered parenterally. Anamorelin is a novel, orally active, non-peptidic ghrelin mimetic and growth hormone secretagogue. Our objective was to evaluate its hormonal effects in healthy subjects. DESIGN: A double-blind, randomized, placebo-controlled study evaluated the short-term effects of anamorelin on GH, insulin-like growth factor-1 (IGF-1), insulin-like growth factor binding protein 3 (IGFBP-3), prolactin, ACTH, LH, FSH, TSH, cortisol, insulin and glucose. Normal healthy volunteers (n=32) recruited from the general population were administered escalating doses of anamorelin (25, 50, and 75 mg daily) vs. placebo. RESULTS: Anamorelin significantly increased GH levels at all doses (p

Effect on body weight and safety of RC-1291, a novel, orally available ghrelin mimetic and growth hormone secretagogue: results of a phase I, randomized, placebo-controlled, multiple-dose study in healthy volunteers.

PURPOSE: RC-1291 is a novel, oral ghrelin mimetic and growth hormone (GH) secretagogue being developed to increase appetite and lean muscle mass in patients with cancer-associated anorexia/cachexia. This randomized, double-blind, placebo-controlled, multiple-dose, dose-escalation phase I study in healthy volunteers evaluated RC-1291 once daily (qd) and twice daily (bid) for effect on body weight and safety. METHODS: The study was conducted with three sequential groups of volunteers. Panel A subjects (n = 8) received placebo or RC-1291, 25 mg qd, for 5 days. Panel B subjects received RC-1291, 25 mg bid or 50 mg qd, for 6 days then crossed over to the other dosage for 5 days (n = 12); three subjects received placebo for all 11 doses to maintain double-blinding. Panel C subjects (n = 9) received placebo or RC-1291, 75 mg qd, for 6 days. RESULTS: Subjects who received RC-1291, 50 or 75 mg, had significant dose-related weight gain after 6 days versus placebo, with the greatest increases seen with daily dosing. The mean increase in weight from baseline after 50 mg qd was 1.25 +/- 0.725 kg (p = .0022 versus placebo), and after 75 mg qd it was 1.16 +/- 0.651 kg (p = .0022 versus placebo). One subject in the 50 mg qd group had moderate transient elevation in aspartate aminotransferase and alanine aminotransferase levels. No other laboratory or clinical adverse events of consequence were reported. CONCLUSIONS: Results indicate that RC-1291 produces dose-related increases in body weight with no dose-limiting adverse effects, and may be an effective treatment for anorexia/cachexia.

The significance of glucose, insulin and potassium for immunology and oncology: a new model of immunity.

BACKGROUND: A recent development in critical care medicine makes it urgent that research into the effect of hormones on immunity be pursued aggressively. Studies have demonstrated a large reduction in mortality as a result of infusion with glucose, insulin and potassium. Our work in the oncology setting has led us to propose that the principal reason for such an effect is that GIK stimulates lymphocytes to proliferate and attack pathogens, sparing the patient the stress of infection. That suggestion is based on a new model of immunity that describes the effect of hormones on lymphocytes. We hypothesized that the application of glucose, insulin, thyroid and potassium would awaken inert tumor infiltrating lymphocytes to destroy the tumor. METHODS: The antitumor effect of a thyroxine, glucose, insulin, and potassium (TGIK) combination was studied in a series of controlled experiments in murine models of tumor progression to assess the biologic activity of the formulation, the effect of route of administration, the effect on tumor type, and the requirement for insulin in the TGIK formulation. RESULTS: Melanoma and colon tumors inoculated with TGIK were significantly reduced in size or retarded in growth compared to controls injected with saline. I.P. and I.M. injections showed that the formulation had no effect systemically at the doses administered. CONCLUSION: We conclude that TGIK has anti-tumor activity when administered intratumorally, probably by stimulating lymphocytes to attack tumors. This is similar to the effect of GIK on reducing sepsis in critical care patients. We suggest that when GIK is administered exogenously, it restores immune competence to the critically ill or cancer patient and causes destruction of pathogens or tumors, while endogenous resources are devoted to repair. This implies that hormonal therapy may be useful in treating various other pathologies involving immune suppression, as well as malignancies. We also propose research that could bring resolution of the controversy over mechanism and point the way to new therapeutic strategies for numerous diseases including chronic infections and auto-immune diseases.

Gastrokinetic effect of ghrelin analog RC-1139 in the rat. Effect on post-operative and on morphine induced ileus.

We aimed to confirm the gastrokinetic effect of ghrelin analog, RC-1139, in the presence of opiates. Gastric emptying was verified in rats by counting stomach residue 15 min after gavage of methylcellulose. Normal rats: RC-1139 (0, 0.25, 1.0, 2.5 mg/kg i.v.) decreased methylcellulose left in stomach (47, 36, 12, 10% of ingested solution). Post-operative ileus (post-op. ileus) ileus: gastric residue decreased from 88 to 66, 53, 51% with RC-1139 0, 1.0, 2.5, 10 mg/kg. Morphine in post-op. ileus: gastroparesis was corrected at 10 mg/kg (54%). Ghrelin analog RC-1139 is a potent gastrokinetic in rat; it reversed gastric post-op. ileus, even in the presence of opiates.