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Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications.
Circulation. 2000 Dec 05; 102(23):2836-41.Circ

Abstract

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-HT(2B) receptor and were partial to full agonists at the 5-HT(2B) receptor.

CONCLUSIONS

Our data imply that activation of 5-HT(2B) receptors is necessary to produce VHD and that serotonergic medications that do not activate 5-HT(2B) 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-HT(2B) receptors and that clinicians should consider suspending their use of medications with significant activity at 5-HT(2B) receptors.

Authors+Show Affiliations

Clinical Psychopharmacology Section, Division of Intramural Research, National Institute on Drug Abuse, NIH, Baltimore, MD 21224, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

11104741

Citation

Rothman, R B., et al. "Evidence for Possible Involvement of 5-HT(2B) Receptors in the Cardiac Valvulopathy Associated With Fenfluramine and Other Serotonergic Medications." Circulation, vol. 102, no. 23, 2000, pp. 2836-41.
Rothman RB, Baumann MH, Savage JE, et al. Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications. Circulation. 2000;102(23):2836-41.
Rothman, R. B., Baumann, M. H., Savage, J. E., Rauser, L., McBride, A., Hufeisen, S. J., & Roth, B. L. (2000). Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications. Circulation, 102(23), 2836-41.
Rothman RB, et al. Evidence for Possible Involvement of 5-HT(2B) Receptors in the Cardiac Valvulopathy Associated With Fenfluramine and Other Serotonergic Medications. Circulation. 2000 Dec 5;102(23):2836-41. PubMed PMID: 11104741.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications. AU - Rothman,R B, AU - Baumann,M H, AU - Savage,J E, AU - Rauser,L, AU - McBride,A, AU - Hufeisen,S J, AU - Roth,B L, PY - 2000/1/11/pubmed PY - 2001/2/28/medline PY - 2000/1/11/entrez SP - 2836 EP - 41 JF - Circulation JO - Circulation VL - 102 IS - 23 N2 - 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-HT(2B) receptor and were partial to full agonists at the 5-HT(2B) receptor. CONCLUSIONS: Our data imply that activation of 5-HT(2B) receptors is necessary to produce VHD and that serotonergic medications that do not activate 5-HT(2B) 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-HT(2B) receptors and that clinicians should consider suspending their use of medications with significant activity at 5-HT(2B) receptors. SN - 1524-4539 UR - https://www.unboundmedicine.com/medline/citation/11104741/Evidence_for_possible_involvement_of_5_HT_2B__receptors_in_the_cardiac_valvulopathy_associated_with_fenfluramine_and_other_serotonergic_medications_ L2 - https://www.ahajournals.org/doi/10.1161/01.cir.102.23.2836?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -