benfluorex
{{Short description|Withdrawn diabetes drug}}
{{Drugbox
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 413885213
| IUPAC_name = (RS)-2-({1-[3-(trifluoromethyl)phenyl]propan- 2-yl}amino)ethyl benzoate
| image = Benfluorex.svg
| image_class = skin-invert-image
| width = 200
| chirality = Racemic mixture
| tradename = Mediator
| Drugs.com = {{drugs.com|international|benfluorex}}
| pregnancy_AU =
| pregnancy_US =
| pregnancy_category =
| legal_AU =
| legal_BR = C1
| legal_BR_comment = {{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-03-31 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=2023-08-03 |access-date=2023-08-16 |publisher=Diário Oficial da União |language=pt-BR |publication-date=2023-04-04}}
| legal_CA =
| legal_UK =
| legal_US =
| legal_status =
| routes_of_administration = By mouth
| bioavailability =
| protein_bound =
| metabolism =
| elimination_half-life =
| excretion = Kidney
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 23602-78-0
| ATC_prefix = A10
| ATC_suffix = BX06
| PubChem = 2318
| DrugBank_Ref = {{drugbankcite|changed|drugbank}}
| DrugBank = DB09022
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 2228
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 403FO0NQG3
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D07192
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 400599
| C=19 | H=20 | F=3 | N=1 | O=2
| smiles = FC(F)(F)c1cccc(c1)CC(NCCOC(=O)c2ccccc2)C
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C19H20F3NO2/c1-14(12-15-6-5-9-17(13-15)19(20,21)22)23-10-11-25-18(24)16-7-3-2-4-8-16/h2-9,13-14,23H,10-12H2,1H3
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = CJAVTWRYCDNHSM-UHFFFAOYSA-N
}}
Benfluorex, sold under the brand name Mediator, is an anorectic and hypolipidemic agent that is structurally related to fenfluramine (a substituted amphetamine). It may improve glycemic control and decrease insulin resistance in people with poorly controlled type-2 diabetes.{{cite journal | vauthors = Moulin P, Andre M, Alawi H, dos Santos LC, Khalid AK, Koev D, Moore R, Serban V, Picandet B, Francillard M | display-authors = 6 | title = Efficacy of benfluorex in combination with sulfonylurea in type 2 diabetic patients: an 18-week, randomized, double-blind study | journal = Diabetes Care | volume = 29 | issue = 3 | pages = 515–20 | date = March 2006 | pmid = 16505498 | doi = 10.2337/diacare.29.03.06.dc05-1439 | doi-access = free }}{{cite journal | vauthors = Roger P, Auclair J, Drain P | title = Addition of benfluorex to biguanide improves glycemic control in obese non-insulin-dependent diabetes: a double-blind study versus placebo | journal = Journal of Diabetes and Its Complications | volume = 13 | issue = 2 | pages = 62–7 | year = 1999 | pmid = 10432168 | doi = 10.1016/S1056-8727(98)00004-X }}
It was on the market between 1976 and 2009, and is thought to have caused between 500 and 2,000 deaths. It was patented and manufactured by the French pharmaceutical company Servier. However, Servier is suspected of having marketed benfluorex at odds with the drug's medical properties.{{cite journal | vauthors = Mullard A | title = Mediator scandal rocks French medical community | journal = Lancet | volume = 377 | issue = 9769 | pages = 890–2 | date = March 2011 | pmid = 21409784 | doi = 10.1016/s0140-6736(11)60334-6 | s2cid = 5325085 | doi-access = free }}
On March 29, 2021, a French court fined Servier €2.7m (£2.3m) after finding it guilty of deception and manslaughter.{{Cite news|url=https://www.bbc.co.uk/news/world-europe-56562909|title=Mediator drug: French pharmaceutical firm fined over weight loss pill|work=BBC News|date=29 March 2021}} On appeal, the former chief, Jean-Philippe Seta was additionally given 4 years (suspended), including 1 year of house arrest, and this is also being appealed. {{Cite web |title=Mediator° trial appeal: a judgement that better reflects the harm done |url=https://english.prescrire.org/en/81/168/68144/0/NewsDetails.aspx |access-date=2024-08-20 |website=english.prescrire.org}}
Drug withdrawn
On 18 December 2009, the European Medicines Agency recommended the withdrawal of all medicines containing benfluorex in the European Union, because their risks, particularly the risk of heart valve disease (fenfluramine-like cardiovascular side effects), are greater than their benefits.{{ cite web | title = European Medicines Agency recommends withdrawal of benfluorex from the market in European Union | url = http://www.emea.europa.eu/pdfs/human/referral/benfluorex/Benfluorex_81503309en.pdf | publisher = European Medicines Agency | date = 2009-12-18 | access-date = 2015-01-12 | archive-url = https://web.archive.org/web/20091222213737/http://www.emea.europa.eu/pdfs/human/referral/benfluorex/Benfluorex_81503309en.pdf | archive-date = 2009-12-22 | url-status = dead }} Thus Frachon et al. showed a higher rate of unexplained valvular heart disease in people taking benfluorex.{{cite journal | vauthors = Frachon I, Etienne Y, Jobic Y, Le Gal G, Humbert M, Leroyer C | title = Benfluorex and unexplained valvular heart disease: a case-control study | journal = PLOS ONE | volume = 5 | issue = 4 | pages = e10128 | date = April 2010 | pmid = 20405030 | pmc = 2853566 | doi = 10.1371/journal.pone.0010128 | editor1-last = Lexchin | bibcode = 2010PLoSO...510128F | editor1-first = J. | doi-access = free }} Weill et al. looked at over 1 million people with diabetes demonstrating a higher hospitalization rate in benfluorex takers for valvular heart disease.{{cite journal | vauthors = Weill A, Païta M, Tuppin P, Fagot JP, Neumann A, Simon D, Ricordeau P, Montastruc JL, Allemand H | display-authors = 6 | title = Benfluorex and valvular heart disease: a cohort study of a million people with diabetes mellitus | journal = Pharmacoepidemiology and Drug Safety | volume = 19 | issue = 12 | pages = 1256–62 | date = December 2010 | pmid = 20945504 | doi = 10.1002/pds.2044 | s2cid = 15979457 | doi-access = free }}
In France, the medication had been marketed by Servier as an adjuvant antidiabetic under the name Mediator. The drug was on the market between 1976 and 2009, and is thought to have caused between 500 and 2,000 deaths.{{ cite web | url = https://www.bbc.co.uk/news/world-europe-12155639 | title = France braced for diabetic drug scandal report | work = BBC News | date = 2011-01-11 }} The drug was also used in Spain, Portugal, and Cyprus.
On March 29, 2021, a French court fined Servier €2.7m (£2.3m) after finding it guilty of deception and manslaughter, with Mediator linked to the deaths of up to 2,000 people. The former executive Jean-Philippe Seta was sentenced to a suspended jail sentence of four years. The French medicines agency, accused of failing to act quickly enough on warnings about the drug, was fined €303,000.{{Cite web|url=https://www.theguardian.com/world/2021/mar/29/french-pharma-firm-found-guilty-over-medical-scandal-in-which-up-to-2000-died|title=French pharma firm found guilty over medical scandal in which up to 2,000 died|website=TheGuardian.com|date=29 March 2021}} The pharmaceutical group was later additionally convicted of charges of fraud.
Fenfluramine, a related drug, had been withdrawn from the market in 1997 after reports of heart valve disease,{{cite journal | vauthors = Connolly HM, Crary JL, McGoon MD, Hensrud DD, Edwards BS, Edwards WD, Schaff HV | title = Valvular heart disease associated with fenfluramine-phentermine | journal = The New England Journal of Medicine | volume = 337 | issue = 9 | pages = 581–8 | date = August 1997 | pmid = 9271479 | doi = 10.1056/NEJM199708283370901 | doi-access = free }}{{cite journal | vauthors = Weissman NJ | title = Appetite suppressants and valvular heart disease | journal = The American Journal of the Medical Sciences | volume = 321 | issue = 4 | pages = 285–91 | date = April 2001 | pmid = 11307869 | doi = 10.1097/00000441-200104000-00008 | s2cid = 46466276 }} pulmonary hypertension, and development of cardiac fibrosis. This side effect is mediated by the metabolite norfenfluramine on 5HT2B receptors of heart valves,{{cite journal|author7-link=Bryan Roth | vauthors = Rothman RB, Baumann MH, Savage JE, Rauser L, McBride A, Hufeisen SJ, Roth BL | title = Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications | journal = Circulation | volume = 102 | issue = 23 | pages = 2836–41 | date = December 2000 | pmid = 11104741 | doi = 10.1161/01.cir.102.23.2836 | doi-access = free }} leading to a characteristic pattern of heart failure following proliferation of cardiac fibroblasts on the tricuspid valve. Both fenfluramine and benfluorex form norfenfluramine as a metabolite. This side effect led to the withdrawal of fenfluramine as an anorectic drug worldwide, and later to the withdrawal of benfluorex in Europe.
References
{{Reflist}}
{{Anorectics}}
{{Oral hypoglycemics and insulin analogs}}
{{Lipid modifying agents}}
{{Monoamine releasing agents}}
{{Serotonin receptor modulators}}
{{Phenethylamines}}
Category:Experimental anti-obesity drugs
Category:Monoamine releasing agents
Category:Serotonin receptor agonists
Category:Substituted amphetamines