Pituitary-adrenal responses to combined oral D-fenfluramine and intravenous naloxone in humans.
1. 1. Fenfluramine is an optically active 5-hydroxytryptamine (5-HT) releaser and re-uptake inhibitor. Increased brain 5-HT mediates appetite suppression, the D enantiomer being more active than L- or DL-fenfluramine. Fenfluramine also stimulates the hypothalamic-pituitary-adrenal (HPA) axis, leading to suggestions that this could act as a marker for its biological actions. However, the D enantiomer appears less active than a comparable DL racemate dose in animals, while effects of D-fenfluramine on the human HPA axis remain unproven. The aim of the present study was to clarify this. 2. Seven healthy human volunteers (three male, four female; 18-58 years) received 30 mg oral D-fenfluramine or placebo, followed by 125 micrograms/kg, i.v. naloxone or placebo, in randomized, double-blinded, placebo-controlled afternoon studies. We measured plasma adrenocorticotropic hormone (ACTH) and cortisol levels in samples taken at intervals throughout the study period. 3. In contrast to previous results with DL-fenfluramine, we found no dynamic responses to D-fenfluramine alone and no augmentation of responses to naloxone. 4. Central pathways to HPA axis activation are apparently not stimulated by D-fenfluramine at this dose in humans, in contrast with DL-fenfluramine, where the L enantiomer may be more selective for proposed corticotropin-releasing hormone-mediated, post-synaptic 5-HT2 or noradrenergic mechanisms. As previously reported, D-fenfluramine significantly blunted the circadian fall in basal plasma cortisol, providing in vivo evidence for serotonergic involvement in circadian regulation.
Grice
J E
JE
Neuroendocrine Research Unit, University of Queensland, Greenslopes Private Hospital, Australia.
Torpy
D J
DJ
Hockings
G I
GI
Walters
M M
MM
Crosbie
G V
GV
Jackson
R V
RV
D000293:Adolescent; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000328:Adult; D019540:Area Under Curve; D003346:Corticotropin-Releasing Hormone / Q000097:blood; D004311:Double-Blind Method; D005260:Female; D005277:Fenfluramine / Q000494:pharmacology*; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D009270:Naloxone / Q000008:administration & dosage / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D010913:Pituitary-Adrenal System / Q000187:drug effects*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D005277:Fenfluramine; D009270:Naloxone; D009292:Narcotic Antagonists; D017367:Selective Serotonin Reuptake Inhibitors