title: Adverse effects of benfluorex on heart valves and pulmonary circulation.
abstract: Benfluorex is responsible for the development of restrictive valvular regurgitation due to one of its metabolites, norfenfluramine. The 5-HT2B receptor, expressed on heart valves, acts as culprit receptor for drug-induced valvular heart disease (VHD). Stimulation of this receptor leads to the upregulation of target genes involved in the proliferation and stimulation of valvular interstitial cells through different intracellular pathways. Valve lesions essentially involve the mitral and/or aortic valves. The randomised prospective REGULATE trial shows a threefold increase in the incidence of valvular regurgitation in patients exposed to benfluorex. A cross-sectional trial shows that about 7% of patients without a history of VHD previously exposed to benfluorex present echocardiographic features of drug-induced VHD. The excess risks of hospitalisation for cardiac valvular insufficiency and of valvular replacement surgery were respectively estimated to 0.5 per 1000 and 0.2 per 1000 exposed patients per year. Recent data strongly suggest an aetiological link between benfluorex exposure and pulmonary arterial hypertension (PAH). The PAH development may be explained by serotonin, which creates a pulmonary vasoconstriction through potassium-channel blockade. Further studies should be conducted to determine the subsequent course of benfluorex-induced VHD and PAH, and to identify genetic, biological and clinical factors that determine individual susceptibility to developing such adverse effects.
authors.affiliation: Department of Cardiology, INSERM, U1088, Amiens University Hospital, Amiens, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Szymanski
authors.forename: Michel
authors.initials: M
authors.lastname: Andréjak
authors.forename: Marcel
authors.initials: M
authors.lastname: Peltier
authors.forename: Sylvestre
authors.initials: S
authors.lastname: Maréchaux
authors.forename: Christophe
authors.initials: C
authors.lastname: Tribouilloy
mesh_terms: D004452:Echocardiography; D005277:Fenfluramine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000378:metabolism; D006349:Heart Valve Diseases / Q000139:chemically induced* / Q000453:epidemiology / Q000503:physiopathology; D006351:Heart Valves / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000139:chemically induced* / Q000453:epidemiology / Q000503:physiopathology; D000960:Hypolipidemic Agents / Q000009:adverse effects; D009642:Norfenfluramine / Q000009:adverse effects / Q000378:metabolism; D011652:Pulmonary Circulation / Q000187:drug effects; D016032:Randomized Controlled Trials as Topic; D044403:Receptor, Serotonin, 5-HT2B / Q000187:drug effects / Q000378:metabolism
chemical_list: D000960:Hypolipidemic Agents; D044403:Receptor, Serotonin, 5-HT2B; D009642:Norfenfluramine; D005277:Fenfluramine; C001584:benfluorex
keywords: appetite suppressant; benfluorex; pharmacoepidemiology; pulmonary arterial hypertension; valvular heart disease; valvular regurgitation