An investigation of the serotonergic effects of fenfluramine, dexfenfluramine and dexnorfenfluramine using platelets as neuronal models.
The appetite-suppressant, fenfluramine (d,l-F) has been used for several decades to treat obesity. Dexfenfluramine (d-F), the d-enantiomer of d,l-F, was approved in 1996 for long-term administration. Subsequently, these drugs were voluntarily withdrawn due to reports of adverse effects on heart valves. So far, the evidence regarding the serotonergic action of d,l-F and d-F has relied on animal-based experiments. We used human platelets as neuronal models to assess the serotonergic action of both d,l-F, d-F and the main metabolite of d-F, d-norfenfluramine (d-norF). This was evaluated using a sensitive method that assesses platelet shape change (PSC) as expressed by an increase in median platelet volume (MPV). Human platelets increased their MPV in response to d-norF. This action was probably mediated via serotonin (subtype 2) receptors because a specific antagonist blocked it. This is the first demonstration, using human tissue, of the serotonergic action associated with the administration of d-F.
Department of Molecular Pathology and Clinical Biochemistry, Royal Free & University College Medical School (University of London), UK.
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Jagroop
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Mikhailidis
D000328:Adult; D001067:Appetite Depressants / Q000494:pharmacology; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects*; D048429:Cell Size / Q000187:drug effects; D020372:Dexfenfluramine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005277:Fenfluramine / Q000494:pharmacology; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D009642:Norfenfluramine / Q000494:pharmacology; D010627:Phenethylamines / Q000494:pharmacology*; D012701:Serotonin / Q000494:pharmacology; D018490:Serotonin Agents / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
D001067:Appetite Depressants; D010627:Phenethylamines; D018490:Serotonin Agents; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D009642:Norfenfluramine; D005277:Fenfluramine; D012701:Serotonin; D020372:Dexfenfluramine