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(Circulation. 2000;102:2836.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Evidence for Possible Involvement of 5-HT2B Receptors in the Cardiac Valvulopathy Associated With Fenfluramine and Other Serotonergic Medications
From the Clinical Psychopharmacology Section, Division of Intramural Research, National Institute on Drug Abuse, NIH, Baltimore, Md (R.B.R., M.H.B.), and the Departments of Biochemistry (J.E.S., L.R., A.M., S.J.H., B.L.R.), Psychiatry (B.L.R.), Neurosciences (B.L.R.), and NIMH Psychoactive Drug Screening Program (J.E.S., L.R., A.M., S.J.H., B.L.R.), Case Western Reserve University, Cleveland, Ohio.
Background—Serotonergic medications with various mechanisms of action are used to treat psychiatric disorders and are being investigated as treatments for drug dependence. The occurrence of fenfluramine-associated valvular heart disease (VHD) has raised concerns that other serotonergic medications might also increase the risk of developing VHD. We hypothesized that fenfluramine or its metabolite norfenfluramine and other medications known to produce VHD have preferentially high affinities for a particular serotonin receptor subtype capable of stimulating mitogenesis.
Methods and Results—Medications known or suspected to cause VHD (positive controls) and medications not associated with VHD (negative controls) were screened for activity at 11 cloned serotonin receptor subtypes by use of ligand-binding methods and functional assays. The positive control drugs were (±)-fenfluramine; (+)-fenfluramine; (-)-fenfluramine; its metabolites (±)-norfenfluramine, (+)-norfenfluramine, and (-)-norfenfluramine; ergotamine; and methysergide and its metabolite methylergonovine. The negative control drugs were phentermine, fluoxetine, its metabolite norfluoxetine, and trazodone and its active metabolite m-chlorophenylpiperazine. (±)-, (+)-, and (-)-Norfenfluramine, ergotamine, and methylergonovine all had preferentially high affinities for the cloned human serotonin 5-HT2B receptor and were partial to full agonists at the 5-HT2B receptor.
Conclusions—Our data imply that activation of 5-HT2B receptors is necessary to produce VHD and that serotonergic medications that do not activate 5-HT2B receptors are unlikely to produce VHD. We suggest that all clinically available medications with serotonergic activity and their active metabolites be screened for agonist activity at 5-HT2B receptors and that clinicians should consider suspending their use of medications with significant activity at 5-HT2B receptors.
Key Words: valves • fenfluramine • norfenfluramine • receptors
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