Endocrine effects of the novel ghrelin receptor inverse agonist PF-5190457: Results from a placebo-controlled human laboratory alcohol co-administration study in heavy drinkers. (15th June 2020)

• Record Type: Journal Article
• Authors: Lee, Mary R.; Farokhnia, Mehdi; Cobbina, Enoch; Saravanakumar, Anitha; Li, Xiaobai; Battista, Jillian T.; Farinelli, Lisa A.; Akhlaghi, Fatemeh; Leggio, Lorenzo
• Is Part Of: Neuropharmacology. Volume 170(2020)
• Publication Date: 2020-06-15
• Subjects: Ghrelin -- GHS-R1a -- PF-5190457 -- Alcohol -- Heavy drinking -- Alcohol use disorder -- Hormones -- Neuroendocrinology; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2019.107788
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: Both animal and human work suggests that the ghrelin system may be involved in the mechanisms that regulate the development and maintenance of alcohol use disorder. Previously, in a Phase 1b study, we tested pharmacological blockade of the growth hormone secretagogue receptor 1a (GHS-R1a, also known as the ghrelin receptor), in heavy drinking individuals with PF-5190457, an orally bioavailable, potent and selective GHS-R1a inverse agonist. We report here the effects of PF-5190457 on endocrine blood concentrations of amylin, gastric inhibitory polypeptide, glucagon-like peptide 1, insulin, leptin, pancreatic polypeptide, peptide YY, thyroid stimulating hormone, free triiodothyronine (T3), thyroxine (T4), cortisol, prolactin, and glucose during PF-5190457 dosing, as compared to placebo, in absence of alcohol as well as during an alcohol challenge when PF-5190457 was on steady-state. Blood hormone levels were largely unaffected by PF-5190457, both during dosing and in the context of alcohol challenge. The safety-related relevance of these findings to further develop PF-5190547 in alcohol use disorder is discussed. Clinicaltrials.gov: NCT02039349. This article is part of the special issue on 'Neuropeptides'. Highlights: We tested PF-5190457, a ghrelin receptor inverse agonist, in heavy drinkers. We assessed the effect of PF-5190457 on neuroendocrine hormones. Blood hormone levels were measured during dosing phase and alcohol administration. Neuroendocrine hormones remain largely unaffected by PF-5190457.