Pulmonary hypertension and fenfluramine

Douglas, Janice G.; Munro, James; Kitchin, A. H.; Muir, A L; Proudfoot, A. T.

doi:10.1136/bmj.283.6296.881

Cited by 160 publications

(37 citation statements)

References 7 publications

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“…In the early 1980s, the first descriptions of a possible relationship between the use of fenfluramine derivatives and PAH were published [8]. Following this, a retrospective study [9] reinforced the possible role of fenfluramine derivatives as risk factors for PAH development and the results of the International Primary Pulmonary…”

mentioning

confidence: 99%

“…The fact that the epidemic started 2 yrs after aminorex fumarate became commercially available and disappeared 2 yrs after the drug was withdrawn, allowed the recognition of temporal and geographic relationships between the use of the drug and PAH development [6]. Although this clearly indicated a role as a risk factor, the clinical course of aminorex-associated PAH was not conclusively different from idiopathic PAH (IPAH, formerly known as primary pulmonary hypertension), despite later results suggesting a better survival in the first group [7].In the early 1980s, the first descriptions of a possible relationship between the use of fenfluramine derivatives and PAH were published [8]. Following this, a retrospective study [9] reinforced the possible role of fenfluramine derivatives as risk factors for PAH development and the results of the International Primary Pulmonary…”

mentioning

confidence: 99%

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Pulmonary arterial hypertension associated with fenfluramine exposure: report of 109 cases

Souza

Humbert²,

Sztrymf³

et al. 2008

European Respiratory Journal

111

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The aim of the present study was to describe a large cohort of fenfluramineassociated pulmonary arterial hypertension (fen-PAH) and its possible prognostic markers.The records of all patients with a diagnosis of fen-PAH evaluated at the present authors' centre from 1986-2004 were retrospectively studied. Baseline clinical and haemodynamic data were collected, as well as survival times.The median duration of fenfluramine exposure was 6 months, with a median of 4.5 yrs between exposure and onset of symptoms. Nine (22.5%) out of 40 patients evaluated resulted positive for the presence of germline bone morphogenetic protein receptor (BMPR) type 2 mutations. In these patients, the duration of exposure to fenfluramine was significantly lower than in patients without mutation. The median survival was 6.4 yrs, without significant difference between fen-PAH and a control group of idiopathic and familial pulmonary arterial hypertension patients referred to the present authors' centre during the same time frame and treated identically. Duration of fenfluramine exposure showed no relation to survival, while cardiac index was the only independent predictor of multivariate analysis.Fenfluramine-associated pulmonary arterial hypertension shares clinical, functional, haemodynamic and genetic features with idiopathic pulmonary arterial hypertension, as well as overall survival rates. Therefore, the present authors conclude that fenfluramine exposure characterises a potent trigger for pulmonary arterial hypertension without influencing its clinical course.KEYWORDS: Bone morphogenetic protein receptor type 2, fenfluramine derivatives, idiopathic pulmonary arterial hypertension, pulmonary arterial hypertension, survival P ulmonary arterial hypertension (PAH) is a rare condition in which the main feature is the presence of increased pulmonary vascular resistance resulting in right heart failure and, ultimately, death [1]. In recent years, the understanding of PAH pathophysiology has allowed the recognition of multiple risk factors and associated conditions that trigger and/or worsen the progression of the disease [2,3]. Germline mutations of the gene encoding bone morphogenetic protein receptor (BMPR) type 2 are certainly clear examples of established risk factors for PAH development [4].In the late 1960s, an increased incidence of severe PAH cases took place in Austria, Germany and Switzerland. Of newly diagnosed patients, .60% had a history of intake of the anorexigen aminorex fumarate [5]. The fact that the epidemic started 2 yrs after aminorex fumarate became commercially available and disappeared 2 yrs after the drug was withdrawn, allowed the recognition of temporal and geographic relationships between the use of the drug and PAH development [6]. Although this clearly indicated a role as a risk factor, the clinical course of aminorex-associated PAH was not conclusively different from idiopathic PAH (IPAH, formerly known as primary pulmonary hypertension), despite later results suggesting a better survival in the firs...

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confidence: 99%

mentioning

confidence: 99%

Pulmonary arterial hypertension associated with fenfluramine exposure: report of 109 cases

Souza

Humbert²,

Sztrymf³

et al. 2008

European Respiratory Journal

111

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“…It has been clearly demonstrated that the risk of developing PAH is increased after exposure to anorexigens, such as aminorex and fenfluramine derivatives [12,[39][40][41][42]. For example, SOUZA et al [40] have shown that fenfluramineassociated PAH shares similar clinical, functional, haemodynamic and genetic characteristics with idiopathic PAH.…”

Section: Toxic and Tobacco Exposurementioning

confidence: 99%

Pulmonary veno-occlusive disease

Montani¹,

Price²,

Dorfmüller³

et al. 2009

European Respiratory Journal

269

250

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Pulmonary veno-occlusive disease (PVOD) is currently classified as a subgroup of pulmonary arterial hypertension (PAH) and accounts for 5-10% of cases initially considered to be idiopathic PAH. PVOD has been described as idiopathic or complicating other conditions, including connective tissue diseases, HIV infection, bone marrow transplantation, sarcoidosis and pulmonary Langerhans cell granulomatosis. PVOD shares broadly similar clinical presentation, genetic background and haemodynamic characteristics with PAH. Compared to PAH, PVOD is characterised by a higher male/female ratio, higher tobacco exposure, lower arterial oxygen tension at rest, lower diffusing capacity of the lung for carbon monoxide, and lower oxygen saturation nadir during the 6-min walk test. High-resolution computed tomography (HRCT) of the chest can be suggestive of PVOD in the presence of centrilobular ground-glass opacities, septal lines and lymph node enlargement. Similarly, occult alveolar haemorrhage is associated with PVOD. A noninvasive diagnostic approach using HRCT of the chest, arterial blood gases, pulmonary function tests and bronchoalveolar lavage could be helpful for the detection of PVOD patients and in avoiding high-risk surgical lung biopsy for histological confirmation. PVOD is characterised by a poor prognosis and the possibility of developing severe pulmonary oedema with specific PAH therapy. Lung transplantation is the treatment of choice. Cautious use of specific PAH therapy can, however, be helpful in some patients.KEYWORDS: Alveolar haemorrhage, BMPR2, computed tomography, diffusing capacity of the lung for carbon monoxide, pulmonary arterial hypertension, pulmonary veno-occlusive disease P ulmonary arterial hypertension (PAH) is a severe condition characterised by elevated pulmonary artery pressure leading to right heart failure and death [1,2]. Pulmonary veno-occlusive disease (PVOD) is classified as a subgroup of PAH and accounts for 5-10% of histological forms of cases initially considered to be idiopathic PAH. Even though the first welldocumented case of PVOD was described .70 yrs ago, the characteristics and pathophysiology of this disease remain poorly understood [3,4]. While pulmonary vascular pathology of idiopathic or familial PAH is characterised by a major remodelling of small pre-capillary pulmonary arteries with typical plexiform and/or thrombotic lesions, PVOD preferentially affects the post-capillary venous pulmonary vessels [5,6]. Despite this anatomical histological difference, PVOD has a very similar clinical presentation to PAH but is characterised by a worse prognosis and the possibility that severe pulmonary oedema can develop with specific PAH therapy, justifying the importance of diagnosing this disease. A definitive diagnosis of PVOD requires histological analysis of a lung sample [7,8]; however, surgical lung biopsy is a high-risk procedure in these patients and the development of a less invasive diagnostic approach would be preferable [9][10][11]. The present manuscript will summa...

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“…In the 1960's, PPH was linked to the use of the appetite suppressant aminorex. 13,28 More recently, PPH has been reported to be linked to the chronic use of dexfen and fen¯ura-mine 10,11,14,15,29 Moreover, exposure to phentermine alone has resulted in reported cases of PPH. 30 ± 32 Serotonin has long been thought to play a role in the development of PPH.…”

Section: Primary Pulmonary Hypertensionmentioning

confidence: 99%

Synergistic interactions between Fenfluramine and Phentermine

Wellman

Maher

1999

Int J Obes

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Fen-phen' refers to the off-label combination of the appetite suppressants fen¯uramine and phentermine. The rationale for the fen-phen combination was that the two drugs exerted independent actions on brain satiety mechanisms so that it was possible to use lower doses of each drug and yet retain a common action on suppressing appetite while minimizing adverse drug effects. The focus of the present review is to consider whether fen¯uramine and phentermine exert actions that are additive in nature or whether these two drugs exhibit drug-drug synergism. The fen-phen combination results in synergism for the suppression of appetite and body weight, the reduction of brain serotonin levels, pulmonary vasoconstriction and valve disease. Fen-phen synergism may re¯ect changes in the pharmacokinetics of drug distribution, common actions on membrane ion currents, or interactions between neuronal release and reuptake mechanisms with MAO-mediated transmitter degradation. The synergism between fen¯uramine and phentermine highlights the need to more completely understand the pharmacology and neurochemistry of appetite suppressants prior to use in combination pharmacotherapy for the treatment of obesity.

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Pulmonary hypertension and fenfluramine

Cited by 160 publications

References 7 publications

Pulmonary arterial hypertension associated with fenfluramine exposure: report of 109 cases

Pulmonary arterial hypertension associated with fenfluramine exposure: report of 109 cases

Pulmonary veno-occlusive disease

Synergistic interactions between Fenfluramine and Phentermine

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