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Benfluorex

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Benfluorex

Benfluorex
Systematic (IUPAC) name
(RS)-2-({1-[3-(trifluoromethyl)phenyl]propan- 2-yl}amino)ethyl benzoate
Clinical data
AHFS/Drugs.com
Legal status
?
Routes Oral
Pharmacokinetic data
Excretion Renal
Identifiers
CAS number  YesY
ATC code A10
PubChem
ChemSpider  YesY
UNII  YesY
KEGG  YesY
ChEMBL  YesY
Chemical data
Formula C19H20F3NO2 
Mol. mass 351.363 g/mol
 YesY   

Benfluorex is an anorectic and hypolipidemic agent that is structurally related to fenfluramine patented and manufactured by a French pharmaceutical company Servier. Two clinical studies have shown it may improve glycemic control and decrease insulin resistance in people with poorly controlled type 2 diabetes.[1][2] However, Servier is suspected of having marketed Mediator (benfluorex) at odds with the drug's medical properties.[3]

Drug withdrawn

On 18 December 2009, the European Medicines Agency (EMEA) 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.[4] Thus Frachon et al. showed a significantly higher prevalence of unexplained valvular heart disease in patients taking benfluorex compared to controls.[5] and Weill et al. looked at over 1 million diabetic patients demonstrating a higher hospitalization rate in benfluorex takers for valvular heart disease.[6]

In France the medication had been marketed as 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 – 2,000 deaths.[7] The drug was also used in Spain (trade name, Modulator), Portugal and Cyprus.

Fenfluramine, a related drug, had been withdrawn from the market in 1997 after reports of heart valve disease,[8][9] pulmonary hypertension, and development of cardiac fibrosis. This side effect is mediated by the metabolite norfenfluramine on 5HT2B receptors of heart valves (Rothman et al., Circulation 2000), 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

  1. ^ Moulin, P.; Andre, M.; Alawi, H.; dos Santos, L. C.; Khalid, A. K.; Koev, D.; Moore, R.; Serban, V. et al. (2006). "Efficacy of Benfluorex in Combination with Sulfonylurea in Type 2 Diabetic Patients: An 18-Week, Randomized, Double-Blind Study". Diabetes Care 29 (3): 515–520.  
  2. ^ Roger, P.; Auclair, J.; Drain, P. (1999). "Addition of Benfluorex to Biguanide Improves Glycemic Control in Obese Non-Insulin-Dependent Diabetes: A Double-Blind Study versus Placebo". Journal of Diabetes and its Complications 13 (2): 62–67.  
  3. ^ Mullard, A. (2011). "Mediator Scandal Rocks French Medical Community" (pdf). Lancet 377 (9769): 890–892.  
  4. ^ "European Medicines Agency recommends withdrawal of benfluorex from the market in European Union" (pdf). European Medicines Agency. 2009-12-18. 
  5. ^ Frachon, I. N.; Etienne, Y.; Jobic, Y.; Le Gal, G. G.; Humbert, M.; Leroyer, C.; Lexchin, J. (2010). Lexchin, J., ed. "Benfluorex and Unexplained Valvular Heart Disease: A Case-Control Study". PLoS ONE 5 (4): e10128.  
  6. ^ Weill, A.; Païta, M.; Tuppin, P.; Fagot, J. P.; Neumann, A.; Simon, D.; Ricordeau, P.; Montastruc, J. L.; Allemand, H. (2010). "Benfluorex and Valvular Heart Disease: A Cohort Study of a Million People with Diabetes Mellitus". Pharmacoepidemiology and Drug Safety 19 (12): 1256–1262.  
  7. ^ "France braced for diabetic drug scandal report". BBC News. 2011-01-11. 
  8. ^ Connolly, H. M.; Crary, J. L.; McGoon, M. D.; Hensrud, D. D.; Edwards, B. S.; Edwards, W. D.; Schaff, H. V. (1997). "Valvular Heart Disease Associated with Fenfluramine-Phentermine". New England Journal of Medicine 337 (9): 581–588.  
  9. ^ Weissman, N. J. (2001). "Appetite Suppressants and Valvular Heart Disease". American Journal of the Medical Sciences 321 (4): 285–291.  

10. Rothman RB, Baumann MH, Savage JE, Rauser L, McBride A, Hufeisen SJ, Roth BL.(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. PMID 11104741

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