Fenfluramine Phentermine

Conelly, 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. The New England Journal of Medicine, 337, 581—588. 

Volmar, K.E. and Hutchins, G.M., Aortic and mitral fenfluramine-phentermine valvulopathy in 64 patients treated with anorectic agents, Arch. Pathol. Lab. Med., 125, 1555-1561, 2001. 

Kuitunen T, Karkkainen S, Ylitalo P. (1984). Comparison of the acute physical and mental effects of ephedrine, fenfluramine, phentermine and prolintane. Methods Find Exp Clin Pharmacol. 6(5) 265-70. 

Connolly HM, Crary JL, McGoon MD, et al. Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med 1997 337 581-588. 

The statistics of expenditure and NDA approvals can mask a major source of R D cost and frustration in the industry late-stage development and postmarketing failures. These types of failures attract significant unwanted publicity and only occur after hundreds of millions of dollars have been spent. Well-publicized examples have included the recent late-stage failure of torcetrapib (Tall et al., 2007) and the postmarketing withdrawals of fenfluramine-phentermine (Fen-Phen) and Vioxx (Embi et al., 2006). 

In the second phase of the study, all participants from the first phase received the fenfluramine-phentermine combination, either daily or intermittently, for a... 

These findings precipitated the widespread use of a fenfluramine-phentermine combination therapy that came to be known as Fen-Phen. The combined use of the two anorexigens had never been approved by the FDA, nor had the longterm safety of the therapy ever been established. Nevertheless, weight loss clinics specializing in Fen-Phen therapy were established throughout the country. In 1996, the FDA narrowly approved the more potent, less adverse-effect-prone (+)stereoisomer of fenfluramine, dexfenfluramine, for less-than-l-yr use in the treatment of obesity. The New York Times reported that in 1996, 18 million prescriptions had been written for fenfluramine alone or in combination with phentermine and that about 6 million Americans took the drug (37). 

Restrictive cardiomyopathy due to endocardial fibrosis occurred in a 35-year-old woman 5 months after she had started to take fenfluramine 10 mg tds and phentermine 15 mg/day (7). The endocardial findings strongly resembled the valvular lesions associated with the use of fenfluramine-phentermine. Endocardial and valvular fibrosis associated with anorectic drugs is strikingly similar to the plaque material found in patients with carcinoid syndrome and those exposed to methysergide, and all possibly arise from a common mechanism. 

Fowles RE, Cloward TV, YoweU RL. Endocardial fibrosis associated with fenfluramine-phentermine. N Engl 1 Med 1998 338(18) 1316. 

Mangion JR, Habboub AA, Kamat BR, Tam SK. Transesophageal echocardiography with pathological correlation in severe valvular disease associated with fenfluramine-phentermine. Echocardiography 1999 16(1) 27-30. 

Tovar EA, Landa DW, Borsari BE. Dose effect of fenfluramine-phentermine in the production of valvular heart disease. Ann Thorac Sing 1999 67(4) 1213-14. 

Garon CF, Oury JH, Duran CM. Virus-like particles in the mitral and tricuspid valves explanted from a patient treated with fenfluramine-phentermine. J Heart Valve Dis 1999 8(2) 232. 

Kancherla MK, Salti HI, Mulderink TA, Parker M, Bonow RO, Mehlman DJ. Exhocardiographic prevalence of mitral and/or aortic regurgitation in patients exposed to either fenfluramine-phentermine combination or to dexfenfluramine. Am J Cardiol 1999 84(ll) 1335-8. 

Bruce CJ, Connolly HM. Valvular heart disease, pulmonary hypertension and fenfluramine-phentermine use. Cardiol Rev 1998 15 17-19. 

The debate regarding the appropriateness of obesity pharmacotherapy remains heated, fueled by the recognized national need to treat a growing epidemic, the lack of longterm outcomes studies, and the medical and litigious fallout from the failed use of fen-phen (fenfluramine-phentermine) and dexfenfluramine (Redux). 

Food and Drug Administration. Fen-phen Safety Update Information fenfluramine, phentermine, dexfenfluramine. http //www.fda.gov/cder/ news/feninfo.htm, 2003. 

Kaddoumi, A. Kubota, A. Nakashima, M.N. Takahashi, M. Nakashima, K. High performance liquid chromatography with UV detection for the simultaneous determination of sympathomimetic amines using 4-(4,5-diphenyl-lH-imidazole-2-yl)benzoyl chloride as a label, Biomed.Chromatogr., 2001, 15, 379-388. [human rat plasma derivatization LOD 50-100 nM ephedrine norephedrine 2-phenylethylamine fenfluramine phentermine cyclohexylamine fluoxetine is internal standard pharmacokinetics]... 

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