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• W4383499118 abstract "STRUCTURE: Fezolinetant, 4-fluorophenyl [(8R)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro [1,2,4] triazolo [4,3-a] pyrazin-7(8H)-yl] methanone, belongs to the drug class of N-acyl-triazolopiperazine neurokinin 3 receptor (NK3R) antagonists. The molecular formula of fezolinetant is C16H15FN6OS and its molecular weight is 358.39 g/mol. MECHANISM OF ACTION: A high percentage of postmenopausal patients experience vasomotor symptoms (VMS), characterized by hot flashes and/or nocturnal sweats. VMS are produced by an alteration of the thermoregulatory mechanisms that originate through the physiological decline of estrogen levels occurring at climacteric. The hypothalamus participates in the homeostatic regulation of body temperature. In this brain region, several neuronal populations integrate direct thermal stimuli, nervous afferences, and endocrine signals to activate heat conservation or dissipation mechanisms (1 in the diagram). Kisspeptin neurons are located in the arcuate nucleus of the hypothalamus (ARC); in addition to their regulatory action on gonadotropin-releasing hormone neurons and the hypothalamus–pituitary–gonadal axis, they are also part of this thermoregulatory system. In particular, kisspeptin neurons project to the thermoregulatory centers located in the median preoptic nucleus (MnPO), activating downstream nervous afferences of the autonomic nervous system to maintain thermal balance (2). Kisspeptin neurons are stimulated by neurokinin B (NKB) and inhibited by estradiol as part of the neuroendocrine mechanisms controlling reproductive function but also thermal homeostasis (3). The drop in estradiol levels during menopause alters this equilibrium (4), triggering neuronal activity and, as a consequence, increasing the heat dissipation effectors (e.g., sweating and cutaneous vasodilation) (5). Fezolinetant acts on the NK3Rs expressed in kisspeptin neurons (6) and glutamatergic MnPO neurons (7) that receive projections from the kisspeptin neurons. This targeted mechanism allows fezolinetant to address the underlying neuroendocrine and thermoregulatory dysregulation associated with VMS, providing a focused therapeutic approach. Antagonism of the NKB effects inhibits both kisspeptin neuronal action and the activation of the MnPO neurons, ameliorating the VMS (8). Fezolinetant (also known as ESN364); brand name is VEOZAH. Fezolinetant is the first NK3R antagonist approved by the FDA to treat moderate to severe hot flashes from menopause. Fezolinetant application was designated for Priority Review by the FDA. Fezolinetant is approved for patients with moderate to severe hot flashes due to menopause. As a prerequisite for initiating treatment with fezolinetant, baseline bloodwork is recommended to evaluate for hepatic function and injury [including serum alanine aminotransferase (ALT), serum aspartate aminotransferase (AST), and serum bilirubin (total and direct)]. Treatment should not start if the concentration of ALT or AST is equal to or exceeds twice the upper limit of normal (ULN) or if the total bilirubin is elevated (equal to or exceeds twice the ULN) for the evaluating laboratory, otherwise, treatment can be started. Once fezolinetant treatment starts, follow-up bloodwork should be performed to control liver injury. The recommended dosage is 45 mg of fezolinetant orally once daily with or without food. Astellas Pharma USA The most common adverse reactions with fezolinetant are abdominal pain (4.3%), diarrhea (3.9%), insomnia (3.9%), back pain (3.0%), hot flush (2.5%), and hepatic transaminase elevation (2.3%). Transaminase levels returned to pretreatment levels without sequelae with dose continuation and upon dose interruption or discontinuation. 2018–2023: Phase 1 trials (NCT03436849, NCT04476849, NCT04482270, NCT04277624, NCT04793204, NCT04641260). 2017–2023: Phase 2 trials (NCT03192176, NCT05419908, NCT05034042). 2019–2023: Phase 3 trials (NCT04003155, NCT04003142, NCT04003389, NCT04234204, NCT05033886, NCT04451226). May 2023: FDA approval for VEOZAHTM (fezolinetant; https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216578s000lbl.pdf). Funded by the Ministerio de Ciencia e Innovación of Spain, cofunded by the Fondo Europeo de Desarrollo Regional (FEDER) Program of the EU (PID2021-128145NB-I00 and PDC2022-133958-I00 to M.L.). I.G-G. is supported by a Ramón y Cajal Award (RYC2021-031225-I) from the Ministerio de Ciencia e Innovación of Spain. The authors declare no competing interests." @default.
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• W4383499118 date "2023-09-01" @default.
• W4383499118 modified "2023-10-18" @default.
• W4383499118 title "Fezolinetant for menopausal hot flashes and night sweats" @default.
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• W4383499118 doi "https://doi.org/10.1016/j.tips.2023.06.003" @default.
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