Aminorex associated with possible idiopathic pulmonary hypertension in a cocaine user.

The conversion of levamisole to aminorex in horses was first described in 2009 and, for the first time, confirmed in humans two years later by our laboratory. Aminorex and levamisole interfere with serotonin metabolism and both are proven cause of potentially fatal idiopathic pulmonary hypertension (IPH). Because most of the world's seizures of illicit cocaine is now contaminated with levamisole, this raises the possibility that users of levamisole adulterated cocaine users may be at risk for IPH. Here we describe the first case of IPH in a user of levamisole-contaminated cocaine. Levamisole and aminorex were both identified and quantified in hair and other biological specimens by means gas chromatography/mass spectrometry system (levamisole: urine, 75.05ng/mL; blood, 15.05ng/mL; brain, >0.15ng/g; liver, >0.15ng/g; hair, 12.15ngmg; aminorex: urine, 38.62ng/mL; blood, 8.92ng/mL, brain >0.15ng/g; liver, 0.15ng/g; hair 7.35ng/mg; cocaine, benzoylecgonine, morphine, 6-acetylmorphine, methadone, 2-ethylidine-1, 5-dimetil-3, 3 diphenylpyrrolidine were also detected). Moreover histological changes associated with IPH were observed in the lung. As IPH produces relatively non-specific symptoms in its early stages, this index case may serve as a harbinger of many more cases to come. It should also alert clinicians to the possibility that their patient may be suffering from this relatively rare disorder.

Idiopathic pulmonary arterial hypertension.

Idiopathic pulmonary arterial hypertension (IPAH), formerly called primary pulmonary hypertension, is a rare disease (incidence and prevalence rates of approximately one and six cases per million inhabitants, respectively) with different clinical phenotypes. A group of diverse conditions manifest pulmonary arterial hypertension (PAH) and share similar pathological and/or clinical findings with IPAH. By definition, IPAH is diagnosed only after alternative diagnoses have been ruled out. Extensive investigation is needed to determine if PAH is associated with thyroid diseases, infectious diseases, autoimmune conditions, exposure to certain drugs (particularly anorexigens), certain genetic mutations, and so on. The presence of genetic abnormalities and risk factors (such as specific drug exposures) reinforces the "multiple hit" concept for the development of pulmonary hypertension. Fortunately, within the past two decades, therapeutic options have become available for IPAH, resulting in improved survival and clinical outcomes. At least seven different compounds have been registered for PAH treatment. However, even with aggressive PAH-specific therapy, mortality rates remain high (∼40% at 5 years). Given the high mortality rates, the use of combinations of agents that work by different pathways has been advocated (either as "add-on" therapy or initial "up front" therapy). Further, new therapeutic agents and treatment strategies are on the near horizon, aiming to further improve survival from the remarkable progress already seen.

Temporal trends and drug exposures in pulmonary hypertension: an American experience.

BACKGROUND: Reports have linked anorexigen intake to an increased risk of pulmonary arterial hypertension (PAH). With the rise in anorexigen use in the latter half of the last decade, we established a surveillance network within the United States to monitor temporal trends in the number of reported cases of PAH. We also studied whether use of anorexigens and other drugs differed among patients with pulmonary hypertension of different etiologies. METHODS: Newly diagnosed subjects (N = 1335) at 13 tertiary pulmonary hypertension centers were enrolled between January 1998 and June 2001. Patient-reported medication use was obtained by a telephone interview. Patients were classified as to the type of pulmonary hypertension. Poisson regression models were fitted to monthly case counts, and logistic regression methods were used to assess the association between type of pulmonary hypertension and medication use. RESULTS: The average monthly number of reported cases of PAH and other categories of pulmonary hypertension did not change over the study period. Fenfluramine or dexfenfluramine use during the 5 years before the time of the interview was preferentially associated with PAH. Fenfluramine/dexfenfluramine use was particularly common in cases referred but found not to have pulmonary hypertension. CONCLUSIONS: No epidemic of anorexigen-related PAH was evident during the study period. As persons who had taken fenfluramine or dexfenfluramine were particularly likely to be referred for evaluation of pulmonary hypertension, it is unlikely that the failure to detect an anorexigen-induced rise in primary pulmonary hypertension was because of underascertainment. The association between fenfluramine derivatives and PAH is consistent with the risk elevations previously reported.

[Pulmonary hypertension and obesity]. / Hypertension artérielle pulmonaire et obésité

Obesity is a morbid condition with hemodynamic consequences affecting the systemic and pulmonary circulations leading to a risk of pulmonary hypertension. Data in the literature do not argue in favor of a direct relationship between pulmonary hypertension and obesity. These two conditions appear to be two distinct entities, the different co-morbidities observed in obesity favoring pulmonary hypertension. Certain co-morbidities, for instance use of anorexic agents, exhibit a clear relationship with pulmonary hypertension. There is also a possible relationship with left ventricular failure, hypoxemia, and other respiratory disorders (including obstructive sleep apnea), hypothyroidism, and thomboembolism.

Risk factors for pulmonary arterial hypertension.

The present limitations in knowledge of the potential risk factors for PPH undoubtedly are attributable to the facts that PPH is a rare disease with an unknown pathogenesis and lacking large case series. Moreover, definite epidemiologic data are rare and ideally should be obtained from epidemiologic surveys such as large case-control studies. The increased incidence of the disease in young women, the familial cases, the association with autoimmune disorders, and the recent discovery that mutation of the PPH1 gene may not be restricted to familial PPH support the hypothesis that the development of pulmonary hypertension likely implies an individual susceptibility or predisposition, which is probably genetically determined. It is also now commonly believed that the development of pulmonary hypertension in some of these predisposed individuals could be hastened or precipitated by various expression factors (some of them yet unrecognized), such as ingestion of certain drugs or diets, portal hypertension, or HIV infection.

[Drug induced pulmonary hypertension].

Primary pulmonary hypertension (PPH) is a rare, often fatal disease that tends to occur with particular frequency in woman. The factors leading to its development remain enigmatic. A variety of toxins and drugs have been implicated in the pathogenesis of pulmonary hypertension (PH). In the 1960s, the medical community was first alerted to the problem of an epidemic of PH in association with a particular anorexic agent, aminorex. Recent reports have indicated that anorexic drugs may have causative roles in PH. The International Primary Pulmonary Hypertension Study (IPPHS) showed a strong association between PPH and the use of appetite suppressants. But the mechanism by which these anorectic drugs cause PH is unknown.

Anorectic drugs and pulmonary hypertension from the bedside to the bench.

Anorectic drugs have been used for more than 30 years as an aid in weight reduction for obese persons. The use of aminorex, an amphetamine analog that increases norepinephrine levels in the central nervous system, led to an epidemic of primary pulmonary hypertension (PPH) in Europe in the late 1960s and early 1970s. The use of fenfluramine and later dexfenfluramine [drugs that inhibit 5-hydroxytryptamine (5-HT) release and reuptake and increases 5-HT and thus 5-HT secretion in the brain] was associated with a second epidemic of PPH. All of these drugs have been voluntarily withdrawn from the market. The pathogenesis of PPH in patients treated with these agents is uncertain, but recent evidence suggests that potassium channel abnormalities and vasoactive and proliferative properties of 5-HT may play a role. There is increasing experimental evidence suggesting that aminorex, fenfluramine and dexfenfluramine inhibit 4-aminopyridine-sensitive currents in potassium channels resulting in vasoconstriction in pulmonary resistance vessels and perhaps smooth muscle cell proliferation. 5-HT causes pulmonary artery vasoconstriction and smooth muscle cell proliferation. Its levels are known to be high in those with fenfluramine-induced PPH. However, a firm cause-and-effect relationship has not yet been established. One potentially beneficial effect of the epidemics of anorectic-related PPH is that it may have provided important insights into the causes of PPH unrelated to anorectic agents.

Recreational use of aminorex and pulmonary hypertension.

Pulmonary hypertension has been associated with ingestion of the appetite suppressant aminorex. A similar compound, 4-methyl-aminorex (street names, "U-4-E-uh" [pronounced euphoria] or "ice"), is a "designer" drug with central stimulant activity. This drug was discovered on the property of three individuals with diagnoses of pulmonary hypertension. The association between "recreational" aminorex manufacture and ingestion and the development of pulmonary hypertension is described.

[Obesity: principles of drug therapy]. / Adipositas: Grundlagen--medikamentöse Therapie.

Obesity is a major global public health problem. In many instances, a combination of diet modification, increased physical activity and behavior therapy fail or are insufficient for sustained weight loss. In these situations, drug therapy may be helpful. However, drug treatment of obesity resulted in unexpected devastating events in recent years. In the late sixties, aminorex caused an epidemic of pulmonary hypertension with high mortality rates. Dexfenfluramine and phentermine were also associated with the development of pulmonary hypertension and with alarming reports of cardiac valvular abnormalities. Therefore, these drugs were withdrawn from the market. Newer drugs, like sibutramine, a serotonin and norepinephrine reuptake inhibitor, and orlistat, a specific lipase inhibitor, reduce body weight significantly compared to placebo. In combination with a hypocaloric diet, weight loss of three to ten kilos can be achieved. Pharmacotherapy is limited to patients with a body mass index greater than 30 kg/m2, if non-pharmacological treatment programs have failed. The drugs should be prescribed under strict medical surveillance only.

Delayed onset of pulmonary hypertension associated with an appetite suppressant, mazindol: a case report.

The use of the appetite suppressant agents aminorex and fenfluramine derivatives has been reported as a risk factor for the development of pulmonary hypertension. A 29-year-old female developed pulmonary hypertension suspected to be due to an amphetamine-like appetite suppressant agent, mazindol ((+/-)-5-(p-chlorophenyl)-2,5-dihydro-3H-imidazo [2,1-a] isoindol-5-ol). She was admitted to Sapporo Medical University Hospital with dyspnea due to severe pulmonary hypertension. Twelve months prior to admission, she had taken mazindol continuously for a period of 10 weeks. As yet, her pulmonary hypertension has not completely improved. This is the first reported case of mazindol-associated pulmonary hypertension, which developed after a long latent interval, and it suggests that mazindol is also a risk factor for the development of pulmonary hypertension, making long-term follow-up necessary for patients taking this anorectic agent.

Anorexigen-related cardiopulmonary toxicity.

Three years after the withdrawal of fenfluramine and dexfenfluramine from the market, the magnitude and prevalence of their deleterious cardiopulmonary effects remain undetermined. The links between these anorexigens and valvular heart disease and primary pulmonary hypertension, however, are clearly established. Because some evidence indicates that the valvular lesions may regress with cessation of the drug, management guidelines are still in flux. Patient reassurance and close surveillance, including serial echocardiography in selected cases, are warranted.

Monoclonal endothelial cells in appetite suppressant-associated pulmonary hypertension.

Anorexigens such as aminorex fumarate and dexfenfluramine are associated with the development of severe pulmonary hypertension (PH), which clinically and histopathologically is considered indistinguishable from idiopathic or primary pulmonary hypertension (PPH). For the current study, we asked whether anorexigen-associated PH is characterized by monoclonal pulmonary endothelial cell proliferation (such as in PPH) or, alternatively, is associated with a polyclonal endothelial cell proliferation as found in secondary PH. Analysis of clonality by the human androgen receptor assay was performed in microdissected endothelial cells of plexiform lesions of two patients with anorexigen-associated PH. The four plexiform lesions of Patient 1 and the six of Patient 2 with anorexigen-associated PH exhibited a monoclonal expansion of pulmonary endothelial cells, with a mean clonality ratio of 0.03 +/- 0.01 SE. Our results indicate that appetite suppressant-associated PH is identical to PPH not only in clinical and histopathologic features but also, at a molecular level, in terms of the monoclonal nature of the endothelial cell proliferation. The anorexigens may accelerate the growth of pulmonary endothelial cells in patients with predisposition to develop PPH.

Aminorex, dexfenfluramine, and primary pulmonary hypertension.

BACKGROUND: In the late 1960s, an epidemic of primary pulmonary hypertension (PPH) occurred in Europe shortly after the introduction of aminorex fumarate, a potent anorexigen. A recently published case-control study from Europe reported that use of other anorexigens (the most prevalent of which was dexfenfluramine) was also associated with an increased risk of PPH. This led to warnings of a repeat epidemic, especially after the introduction of dexfenfluramine on the North American market. OBJECTIVE: To compare the epidemiologic associations of PPH with aminorex and dexfenfluramine, both with respect to strength of association (estimate of relative risk) and public health impact (etiologic fraction) and thus to assess the potential for a new epidemic of PPH. METHODS: We constructed a "synthetic" case-control study for aminorex based on reported case series from Berne and Basel, Switzerland, and a random population sample from Hanover, Germany, and compared the results with those recently reported for dexfenfluramine. Control rates of exposure were used to estimate population exposure prevalences and, hence, etiologic fractions. RESULTS: The estimated odds ratio (and 95% confidence interval) for the association between PPH and any exposure to aminorex was 97.8 (78.9-121.3), with a corresponding etiologic fraction of 77%. The corresponding figures for dexfenfluramine were 3.7 (1.9-7.2) and 17%, respectively. CONCLUSION: The strong association between aminorex and PPH probably led to a 5-fold increase in PPH incidence, and thus a very noticeable epidemic. The association with dexfenfluramine would result in an increase in incidence of only 20%. Based on the available evidence, a repeat PPH epidemic seems unlikely.

The effect of anticoagulant therapy in primary and anorectic drug-induced pulmonary hypertension.

In a retrospective study, we tested the hypothesis that anticoagulant therapy with warfarin sodium (Coumadin) has a beneficial influence on the long-term prognosis in patients with primary pulmonary hypertension (PPH) and aminorex-induced plexogenic pulmonary hypertension. The study included a total of 173 patients from two European cities. One hundred four of these patients took the anorectic drug aminorex (Menocil), which was available in some European countries almost 30 years ago; 69 patients had pulmonary hypertension of unexplained etiology, ie, PPH. Fifty-six of the 104 aminorex-treated patients and 24 patients in the PPH group received warfarin after diagnosis was established. For analysis, patients were divided into four groups according to their history of aminorex intake and anticoagulant therapy. Survival time, changes in hemodynamics (pulmonary arterial pressure), and improvement in quality of life (scored by the New York Heart Association [NYHA] classification) were compared and analyzed. We found that aminorex-treated patients had a better long-term prognosis than those with PPH (7.5 vs 3.9 years; p < or = 0.001). The best mean survival time of 8.3 years was found in anticoagulated aminorex-treated patients, compared to 6.1 years in nonanticoagulated aminorex-treated patients. Moreover, aminorex-treated patients who received anticoagulant therapy soon after the onset of symptoms showed significantly better prognosis (10.9 years) than those who commenced treatment 2 years thereafter (5.9 years) (p < or = 0.05). In patients with PPH, systolic pulmonary pressure was shown to influence survival time significantly (p < or = 0.0005); however, this correlation was not found in aminorex-treated patients. An improvement of symptoms like dyspnea on exertion was seen in 44.8% of the anticoagulated aminorex-treated patients, while deterioration was evident in 72.2% of the nonanticoagulated aminorex-treated patients. In conclusion, our study has shown that anticoagulant therapy had a positive influence on long-term survival and a significant improvement in quality of life in patients with PPH, in particular in patients with a history of anorectic drug intake.