tabimorelin and Body-Weight

The aim of the present study was to assess the safety, pharmacokinetics and pharmacodynamics (including specificity) of NN703 (tabimorelin), a growth hormone (GH) secretagogue, in healthy male subjects following treatment for 7 days once-daily. This was a randomized, double-blind and placebo-controlled study with four active dose levels: 1.71, 3.0, 4.5 and 6.86 mg/kg body weight. There was a dose-related increase for GH area under the curve (AUC) (0-12 h) and GH C(max)(0--12 h); these were significantly higher on both days 1 and 7 as compared with placebo treatment (P = 0.04 to P< 0.0001); however, an overall significant decrease in GH release was found from day 1 to day 7 (P< 0.001). Insulin-like growth factor-I (IGF-I) and IGF binding protein 3 (IGFBP-3) increased at all dose levels (including placebo); however, a significantly higher increase as compared with placebo treatment was observed at the three highest dose levels for IGF-I (P = 0.04--0.0006) and at the highest dose level for IGFBP-3 (P = 0.03). There was no statistically significant increase in AUC (0-5 h) for follicle-stimulating hormone, luteinizing hormone and cortisol between active and placebo treatment for day 1 or 7. On day 1 only, a statistically significant increase in AUC (0--5 h) was found for prolactin at 1.71 and 6.86 mg/kg (P< 0.05), for thyroid-stimulating hormone (TSH) at 3.0 mg/kg (P< 0.01) and for adrenocorticotrophic hormone (ACTH) at 4.5 mg/kg (P< 0.05); however, no dose--response relationship was observed for TSH or ACTH. In addition, a statistically significant decrease in AUC (0--5 h) for ACTH (3.0 and 6.86 mg/kg) and cortisol (1.71 mg/kg) was observed on day 7 (P< 0.05). Thus, NN703 is a promising candidate for treatment of absolute or relative GH deficiency.

Topics: Administration, Oral; Adrenocorticotropic Hormone; Adult; Area Under Curve; Body Weight; Dipeptides; Dose-Response Relationship, Drug; Double-Blind Method; Follicle Stimulating Hormone; Humans; Hydrocortisone; Luteinizing Hormone; Male; Placebos; Thyrotropin; Time Factors

The aim was to investigate the possible interactions of the two peripheral hormones, leptin and ghrelin, that regulate the energy balance in opposite directions.. Leptin-receptor mutated Zucker diabetic fatty (ZDF) and lean control rats were treated with the ghrelin-receptor ligand, tabimorelin (50 mg/kg p.o.) for 18 days, and the effects on body weight, food intake and body composition were investigated. The level of expression of anabolic and catabolic neuropeptides and their receptors in the hypothalamic area were analysed by in situ hybridization.. Tabimorelin treatment induced hyperphagia and adiposity (increased total fat mass and gain in body weight) in lean control rats, while these parameters were not increased in ZDF rats. Treatment with tabimorelin of lean control rats increased hypothalamic mRNA expression of the anabolic neuropeptide Y (NPY) mRNA and decreased hypothalamic expression of the catabolic peptide pro-opiomelanocortin (POMC) mRNA. In ZDF rats, the expression of POMC mRNA was not affected by treatment with tabimorelin, whereas NPY mRNA expression was increased in the hypothalamic arcuate nucleus.. This shows that tabimorelin-induced adiposity and hyperphagia in lean control rats are correlated with increased hypothalamic NPY mRNA and decreased POMC mRNA expression. The elimination of tabimorelin-induced adiposity and hyperphagia in ZDF rats may be due to lack of POMC mRNA downregulation. In conclusion, we suggest that ghrelin-receptor ligands exert their adipogenic and orexigenic effects via hypothalamic mechanisms that are dependent on intact leptin-receptor signalling.

Topics: Adipose Tissue; Animals; Body Composition; Body Weight; Dipeptides; Eating; Gene Expression; Hyperphagia; Hypothalamus; In Situ Hybridization; Mutation; Neuropeptide Y; Pro-Opiomelanocortin; Rats; Rats, Zucker; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Receptors, Ghrelin; Receptors, Leptin; RNA, Messenger; Signal Transduction