Fenfluramine pulmonary hypertension with

Common adverse reactions seen with phentermine use include heart palpitations, tachycardia, elevated blood pressure, stimulation, restlessness, dizziness, insomnia, euphoria, dysphoria, tremor, headache, dry mouth, constipation, and diarrhea. Phentermine should be avoided in patients with unstable cardiac status, hypertension, hyperthyroidism, agitated states, or glaucoma. In combination with fenfluramine or dexfenfluramine, pulmonary hypertension and valvular heart disease have been reported. The risk of developing either serious adverse effect cannot be ruled out with use of phentermine alone. Since phentermine is related to the amphetamines, the... 

Blanpain, C., Le Poul, E., Parma, J., Knoop, C., Detheux, M., Parmentier, M., Vassart, G. and Abramowicz, M.J. (2003) Serotonin 5-HT(2B) receptor loss of function mutation in a patient with fenfluramine-associated primary pulmonary hypertension. Cardiovascular Research, 60 (3), 518-528. 

Fenfluramine has not been systematically studied in the treatment of BN, but dexfenfluramine has been evaluated with disappointingly mixed results. Due to an association with the development of heart valve abnormalities and pulmonary hypertension, particularly when coadministered with phentermine (lonamin) in the so-called Fen-Phen strategy, these medications have recently been removed from the U.S. market. 

The amphetamines were replaced by amphetamine analogs—substances somewhat less potent than amphetamines. Fen-Phen, the combination of fenfluramine and phentermine, was a popular appetite suppressant in the 1990s, but was associated with severe health problems such as pulmonary hypertension, heart valve dysfunction, and nerve damage. As a result, both drugs were withdrawn from the market. 

Tomita T, Zhao Q. Autopsy findings of heart and lungs in a patient with primary pulmonary hypertension associated with use of fenfluramine and phentermine. Chest 2002 121 649-652. 

Mark EJ, Patalas ED, Chang HT, Evans RJ, Kessler SC. Fatal pulmonary hypertension associated with short-term use of fenfluramine and phentermine. N Engl... 

Strother J, Fedullo P, Yi ES, Masliah E. Complex vascular lesions at autopsy in a patient with phentermine-fenfluramine use and rapidly progressing pulmonary hypertension. Arch Pathol Lab Med 1999 123 539-540. 

Anorectic drugs, which are structurally related to the amphetamines, act mainly on the satiety centre in the hypothalamus and also increase general physical activity (1). All of them, except fenfluramine, stimulate the central nervous system and can cause restlessness, nervousness, irritabihty, and insomnia. Adverse effects also occur through sympathetic stimulation and gastrointestinal irritation. Drug interactions can occur with monoamine oxidase inhibitors. Dexamfetamine, phenmetrazine, and benzfetamine can cause dependence. Some of them have been associated with cardiac valvulopathy and primary pulmonary hypertension (2). 

The autopsy findings in the heart and lungs of a patient with pulmonary hypertension associated with fenfluramine and phentermine have been described (13). 

In 1996, in a case-control study, 95 patients from 35 centers in France, Belgium, the UK, and the Netherlands were compared with 355 age- and sex-matched controls (14). The use of anorexic drugs (mainly derivatives of fenfluramine) was associated with an increased risk of primary pulmonary hypertension. Association with recognized risk factors such as a family history of primary pulmonary hypertension, infection with HIV, or the use of intravenous drugs was also confirmed. The absolute risk for obese patients who took anorexic agents for more than 3 months was 30 times higher than in non-users. 

Pulmonary hypertension and multivalvular damage after prolonged use of fenfluramine with phentermine have been reported in a 70-year-old Israeh woman (61). 

Simonneau G, Fartoukh M, Sitbon O, Humbert M, Jagot JL, Herve P. Primary pulmonary hypertension associated with the use of fenfluramine derivatives. Chest 1998 114(Suppl. 3) 195S-9S. 

New pharmacological treatments have been developed for the treatment of obesity. These include the combination of phentermine and fenfluramine (phen-fen) and, alternatively, dexfenfluramine (Redux). Phentermine (Fastin, lonamin) is a stimulant and fenfluramine (Pondimin) is a serotonin agonist. In combination they have persistent appetite suppression and weight loss effects. These medications can cause anxiety and insomnia and must be used with extreme caution if taken with antidepressants, especially SSRIs. Dexfenfluramine works similarly, but avoids the side effect of increased anxiety, and instead tends to cause diarrhea, dry mouth, and somnolence. There have also been reports of pulmonary hypertension, a potentially fatal condition, especially when taken for longer than three months. Some researchers (Ricuarte et al. 1991 McCann et al. 1994) have expressed concern because rats given these medications showed evidence of neuronal toxicity. Thus, they are effective medications, but must be used with caution. 

The principal side effects of phentermine are insomnia, restlessness, and euphoria. Some patients rapidly develop toleranee to this agent, resulting in discontinuation of therapy. The combination of phentermine with fenfluramine or dexfenfluramine was as-soeiated with inereased incidences of both primary pulmonary hypertension (PPH) and ear-diae valvulopathy, but it is unlikely that phentermine alone causes these same problems. Phentermine, nonetheless, contains a warning label listing PPH and cardiac valve lesions as possible adverse events. 

The Fen-Phen combination regimen started in 1992 after the publication of an article that showed dramatic weight loss when both drugs were taken together. In 1995, the FDA was asked to approve a new diet drug, dexfenfluramine or Redux. Developed by Interneuron Pharmaceuticals Inc., a Massachusetts company, Redux is a purified form of fenfluramine. However, prior reports had linked fenfluramine use with primary pulmonary hypertension (PPH), a rare but potentially fatal cardiopulmonary disease. The FDA finally approved fenfluramine and Redux went on the market in April 1996. In July 1997, the Mayo Clinic released results from a study that found 24 cases of heart... 

The factors leading to the development of pulmonary hypertension are unclear, although associations with portal hypertension and pregnancy have been detected. Obesity by itself may double the risk of pulmonary hypertension. Additionally, the use of cocaine or oral contraceptives, infection with the human immunodeficiency virus (HIV), the use of anorexic agents, hepatic cirrhosis, genetic susceptibility, and female sex in the third to fourth decades of life also have been implicated as predisposing factors. Exposure of patients to fenfluramine or dexfenfluramine has been associated with 20% of all diagnosed cases of pulmonary hypertension. ... 

In a 12-year observational study, 62 patients with fenfluramine-associated pulmonary hypertension were compared with 125 sex-matched patients with pulmonary hypertension unrelated to the use of fenfluramine derivatives. In most of the cases (81%), fenfluramine derivatives were used for at least 3 months. The time frame between the initiation of the therapy and the onset of dyspnea ranged from 27 days to 23 years. Both the fenfluramine-associated pulmonary hypertension group and the control group had similar levels of New York Heart Association functional class and symptoms, as well as an overall survival rate of 50% in 3 years. ... 

In September 1997, the FDA requested the manufacturers of fenfluramine and dexfenfluramine to voluntarily withdraw their products from the market. This was done following case reports of valvular heart disease in patients taking either medication as monotherapy or in combination with another anorexic agent, phentermine. Because no association has been found between phentermine alone and valvular heart disease, it is still available. Isolated case reports of pulmonary hypertension and phentermine monotherapy have been reported, but present data do not support an association. Although fenfluramine and phentermine were both approved by the FDA to be used as anorectic agents, the combination therapy, fen-phen, was never approved. 

E. Prolonged use (usually 3 months or longer) of fenfluramine or dexfenflu-ramine in combination with phentermine ( fen-phen ) has been associated with an increased risk of pulmonary hypertension and of fibrotic valvular heart disease (primarily aortic, mitral, and tricuspid regurgitation). The pathology of the valvular disease is identical to that seen with carcinoid syndrome. 

Fenfluramine and dexfenfluramine have generally been withdrawn worldwide because of the occurrence of serious and sometimes fatal valvular heart disease (aortic, mitral, tricuspid or mixed valve disease). Pulmonary hypertension has also sometimes been seen. These serious adverse effects occurred when these drugs were taken alone, and when combined with phenter-mine as Fen-phen and Dexfen-phen, but not with phentermine alone. ... 

Conflicting evidence has been reported on the roles of anorexigens in pulmonary hypertension.53,5 It has been suggested that aminorex (XIII) may be Implicated in the development of pulmonary hypertension in dogs55,56 anj jp humans.57-61 On the other hand, 4,000 patients receiving aminorex showed no such side effect.62 in a series of studies that included treatment of obese patients with chronic chest diseases, with fenfluramine, no evidence of pulmonary hypertension was found.54 Therefore, to date no definite correlation can be made between appetite suppressants and the development of pulmonary hypertension. 

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