苯氟雷司

苯氟雷司
临床资料
商品名（英语：Drug nomenclature）	Mediator
AHFS/Drugs.com	国际药品名称
给药途径	口服
ATC码	A10BX06 (WHO) ;
药物动力学数据
排泄途径	肾
识别信息
	IUPAC命名法 (RS)-2-({1-[3-(trifluoromethyl)phenyl]propan- 2-yl}amino)ethyl benzoate; ;
CAS号	23602-78-0
PubChem CID	2318;
DrugBank	DB09022 ;
ChemSpider	2228 ;
UNII	403FO0NQG3;
KEGG	D07192 ;
ChEMBL	ChEMBL400599 ;
CompTox Dashboard（英语：CompTox Chemicals Dashboard） (EPA)	DTXSID5048471 ;
ECHA InfoCard	100.041.601
化学信息
化学式	C19H20F3NO2
摩尔质量	351.37 g·mol−1
3D模型（JSmol（英语：JSmol））	交互式图像;
手性	Racemic mixture
	SMILES FC(F)(F)c1cccc(c1)CC(NCCOC(=O)c2ccccc2)C;
	InChI InChI=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 ; Key:CJAVTWRYCDNHSM-UHFFFAOYSA-N ;

苯氟雷司（英语：Benfluorex），商品名为Mediator，是一种在结构上与氟苯丙胺（一种苯丙胺替代物，也叫芬氟拉明）相关的厌食剂和降血脂剂。对于控制不佳的2型糖尿病患者，它可以改善血糖控制并降低胰岛素抵抗。^[1]^[2]

它于1976年至2009年间上市，据信已造成500至2,000人死亡。^[3]它获得专利并由法国制药公司施维雅制造。然而，施维雅被怀疑其所销售的苯氟雷司与药物的医疗特性不符。^[4]

2021年3月29日，法国法院裁定施维雅犯有欺骗和过失杀人罪，对其处以270万欧元（230万英镑）的罚款。^[5]

撤药

2009年12月18日，欧洲药品管理局建议在欧盟范围内停用所有含有苯氟雷司的药物，因为它们拥有风险，尤其是瓣膜性心脏病（类氟苯丙胺心血管副作用）的风险大于其益处。^[6]因此弗拉雄等人显示服用苯氟雷司的人患不明原因瓣膜性心脏病的几率更高。^[7]另外，威尔等人研究了超过100万糖尿病患者，结果表明服用苯氟雷司的患者因瓣膜性心脏病住院率更高。^[8]在法国，该药物已由施维雅以商品名Mediator作为辅助抗糖尿病药物销售。该药物于1976年至2009年间上市，据信已导致500至2,000人死亡。^[3]这种药物也在西班牙、葡萄牙和塞浦路斯等国使用。

2021年3月29日，法国法院裁定施维雅犯有欺骗和过失杀人罪，并处以270万欧元（230万英镑）的罚款，因为Mediator与多达2,000人的死亡有关。前高管让-菲利普·塞塔被判处四年有期徒刑，缓期执行。法国药品管理局被指控未能对有关该药物的警告采取足够快的行动，被罚款303,000欧元。该制药集团被判欺诈罪名不成立。^[9]

氟苯丙胺是一种相关药物，在出现心脏瓣膜病、^[10]^[11]肺动脉高压和心脏纤维化的报道后，于1997年退出市场。这种副作用是由心脏瓣膜5-HT_2B受体上的代谢物去甲氟苯丙胺介导的，^[12]导致三尖瓣上心脏成纤维细胞增殖后心力衰竭的特征模式。氟苯丙胺和苯氟雷司都形成去甲氟苯丙胺作为代谢物。这种副作用导致氟苯丙胺作为一种厌食药物在世界范围内被撤回，随后苯氟雷司也在欧洲被撤回。

参考资料

^ Moulin P, Andre M, Alawi H, dos Santos LC, Khalid AK, Koev D, et al. Efficacy of benfluorex in combination with sulfonylurea in type 2 diabetic patients: an 18-week, randomized, double-blind study. Diabetes Care. March 2006, 29 (3): 515–20. PMID 16505498. doi:10.2337/diacare.29.03.06.dc05-1439 .
^ Roger P, Auclair J, Drain P. 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. 1999, 13 (2): 62–7. PMID 10432168. doi:10.1016/S1056-8727(98)00004-X.
^ ^3.0 ^3.1 France braced for diabetic drug scandal report. BBC News. 2011-01-11 [2023-02-23]. （原始内容存档于2019-04-25）.
^ Mullard A. Mediator scandal rocks French medical community. Lancet. March 2011, 377 (9769): 890–2. PMID 21409784. S2CID 5325085. doi:10.1016/s0140-6736(11)60334-6 .
^ Mediator drug: French pharmaceutical firm fined over weight loss pill. BBC News. 29 March 2021 [2023-02-23]. （原始内容存档于2023-03-06）.
^ European Medicines Agency recommends withdrawal of benfluorex from the market in European Union (PDF). European Medicines Agency. 2009-12-18 [2015-01-12]. （原始内容 (PDF)存档于2009-12-22）.
^ Frachon I, Etienne Y, Jobic Y, Le Gal G, Humbert M, Leroyer C. Lexchin J , 编. Benfluorex and unexplained valvular heart disease: a case-control study. PLOS ONE. April 2010, 5 (4): e10128. Bibcode:2010PLoSO...510128F. PMC 2853566 . PMID 20405030. doi:10.1371/journal.pone.0010128 .
^ Weill A, Païta M, Tuppin P, Fagot JP, Neumann A, Simon D, et al. Benfluorex and valvular heart disease: a cohort study of a million people with diabetes mellitus. Pharmacoepidemiology and Drug Safety. December 2010, 19 (12): 1256–62. PMID 20945504. S2CID 15979457. doi:10.1002/pds.2044 .
^ French pharma firm found guilty over medical scandal in which up to 2,000 died. TheGuardian.com. 29 March 2021 [2023-02-23]. （原始内容存档于2023-03-08）.
^ Connolly HM, Crary JL, McGoon MD, Hensrud DD, Edwards BS, Edwards WD, Schaff HV. Valvular heart disease associated with fenfluramine-phentermine. The New England Journal of Medicine. August 1997, 337 (9): 581–8. PMID 9271479. doi:10.1056/NEJM199708283370901.
^ Weissman NJ. Appetite suppressants and valvular heart disease. The American Journal of the Medical Sciences. April 2001, 321 (4): 285–91. PMID 11307869. S2CID 46466276. doi:10.1097/00000441-200104000-00008.
^ Rothman RB, Baumann MH, Savage JE, Rauser L, McBride A, Hufeisen SJ, Roth BL. Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications. Circulation. December 2000, 102 (23): 2836–41. PMID 11104741. doi:10.1161/01.cir.102.23.2836 .

[1] Moulin P, Andre M, Alawi H, dos Santos LC, Khalid AK, Koev D, et al. Efficacy of benfluorex in combination with sulfonylurea in type 2 diabetic patients: an 18-week, randomized, double-blind study. Diabetes Care. March 2006, 29 (3): 515–20. PMID 16505498. doi:10.2337/diacare.29.03.06.dc05-1439 .

[2] Roger P, Auclair J, Drain P. 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. 1999, 13 (2): 62–7. PMID 10432168. doi:10.1016/S1056-8727(98)00004-X.

[BCC2011-3] 3.0 ^3.1 France braced for diabetic drug scandal report. BBC News. 2011-01-11 [2023-02-23]. （原始内容存档于2019-04-25）.

[4] Mullard A. Mediator scandal rocks French medical community. Lancet. March 2011, 377 (9769): 890–2. PMID 21409784. S2CID 5325085. doi:10.1016/s0140-6736(11)60334-6 .

[5] Mediator drug: French pharmaceutical firm fined over weight loss pill. BBC News. 29 March 2021 [2023-02-23]. （原始内容存档于2023-03-06）.

[6] European Medicines Agency recommends withdrawal of benfluorex from the market in European Union (PDF). European Medicines Agency. 2009-12-18 [2015-01-12]. （原始内容 (PDF)存档于2009-12-22）.

[7] Frachon I, Etienne Y, Jobic Y, Le Gal G, Humbert M, Leroyer C. Lexchin J , 编. Benfluorex and unexplained valvular heart disease: a case-control study. PLOS ONE. April 2010, 5 (4): e10128. Bibcode:2010PLoSO...510128F. PMC 2853566 . PMID 20405030. doi:10.1371/journal.pone.0010128 .

[8] Weill A, Païta M, Tuppin P, Fagot JP, Neumann A, Simon D, et al. Benfluorex and valvular heart disease: a cohort study of a million people with diabetes mellitus. Pharmacoepidemiology and Drug Safety. December 2010, 19 (12): 1256–62. PMID 20945504. S2CID 15979457. doi:10.1002/pds.2044 .

[9] French pharma firm found guilty over medical scandal in which up to 2,000 died. TheGuardian.com. 29 March 2021 [2023-02-23]. （原始内容存档于2023-03-08）.

[pmid9271479-10] Connolly HM, Crary JL, McGoon MD, Hensrud DD, Edwards BS, Edwards WD, Schaff HV. Valvular heart disease associated with fenfluramine-phentermine. The New England Journal of Medicine. August 1997, 337 (9): 581–8. PMID 9271479. doi:10.1056/NEJM199708283370901.

[pmid11307869-11] Weissman NJ. Appetite suppressants and valvular heart disease. The American Journal of the Medical Sciences. April 2001, 321 (4): 285–91. PMID 11307869. S2CID 46466276. doi:10.1097/00000441-200104000-00008.

[12] Rothman RB, Baumann MH, Savage JE, Rauser L, McBride A, Hufeisen SJ, Roth BL. Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications. Circulation. December 2000, 102 (23): 2836–41. PMID 11104741. doi:10.1161/01.cir.102.23.2836 .

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