aminorex-fumarate and Hypertension--Pulmonary

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.

Topics: Aminorex; Fenfluramine; Hemodynamics; Humans; Hypertension, Pulmonary; Hypothyroidism; Hypoxia; Obesity; Risk Factors; Severity of Illness Index; Sleep Apnea Syndromes

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.

Topics: Altitude; Aminorex; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antidepressive Agents, Second-Generation; Appetite Depressants; Brassica; Comorbidity; Eisenmenger Complex; Fatty Acids, Monounsaturated; Female; Fenfluramine; Glycogen Storage Disease; Hematologic Diseases; HIV Infections; Humans; Hypertension, Portal; Hypertension, Pulmonary; Plant Oils; Pregnancy; Pregnancy Complications, Cardiovascular; Rapeseed Oil; Risk Factors; Smoking; Splenectomy; Telangiectasia, Hereditary Hemorrhagic; Thrombosis; Thyroid Diseases; Tryptophan

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.

Topics: Aminorex; Appetite Depressants; Dexfenfluramine; Echocardiography; Fenfluramine; Heart Valve Diseases; Humans; Hypertension, Pulmonary; Phentermine

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.

Topics: Alleles; Aminorex; Appetite Depressants; Cell Division; Clone Cells; Dexfenfluramine; Endothelium, Vascular; Female; Genetic Predisposition to Disease; Humans; Hypertension, Pulmonary; Lung; Middle Aged; Receptors, Androgen; X Chromosome

Selected cases of severe primary pulmonary arterial hypertension and associated pulmonary vascular disease have been related to the oral ingestion of aminorex fumarate, an anorexigen obviously responsible for an epidemic of primary pulmonary hypertension in Western Europe between 1967 and 1970. This report describes a fifteen year follow-up of a female patient with aminorex fumarate related pulmonary hypertension and the uncommon finding of the formation of an excessive fusiform pulmonary trunk aneurysm in the late stage of the disease process. The progressive clinical course was followed by serial chest x-ray films and repeat right heart catheterization. The diagnosis of a main stem pulmonary artery aneurysm was noninvasively established by two-dimensional echocardiography and confirmed by contrast-enhanced computed tomography and radionuclide blood pool imaging. The patient is alive, thus no histologic correlate of this entity is available at present.

Topics: Aminorex; Aneurysm; Appetite Depressants; Cardiac Catheterization; Echocardiography; Female; Follow-Up Studies; Heart; Humans; Hypertension, Pulmonary; Lung; Middle Aged; Oxazoles; Pulmonary Artery; Radionuclide Imaging; Time Factors; Tomography, X-Ray Computed

During the period 1967 to 1971 an increase in the incidence of pulmonary hypertension of vascular origin (PHVO) was observed in Austria, Federal Republic of Germany, and Switzerland. Most patients had been given aminorex fumarate and a possible link was suspected. We therefore investigated the possibility of genetically-determined drug hydroxylation deficiencies (debrisoquine or mephenytoin type) in these patients as an explanation for the development of PHVO. Seventeen patients took 10 mg debrisoquine and 100 mg mephenytoin orally. Sixteen PHVO patients were classified as extensive metabolizers of debrisoquine with logarithmic metabolic ratios of -0.35 +/- 0.11 (mean +/- SEM), whereas one patient was a poor metabolizer with a logarithmic metabolic ratio of 1.82. For the mephenytoin hydroxylation sixteen patients with PHVO were extensive metabolizers, with logarithmic hydroxylation indices of 0.27 +/- 0.05. One poor metabolizer of mephenytoin had a logarithmic hydroxylation index of 1.59. Deficient hydroxylation of debrisoquine and mephenytoin was found in two different patients. The prevalence of poor metabolizers among patients with PHVO after aminorex fumarate was therefore approximately 9% for both debrisoquine and mephenytoin. This corresponds closely to the data of our reference population study where genetic debrisoquine and mephenytoin hydroxylation deficiencies occurred independently, with a prevalence of 10% and 5% respectively. Thus, the normal prevalence of extensive drug hydroxylation phenotypes in patients with PHVO is not consistent with the hypothesis that the development of PHVO after aminorex fumarate might be related to a pharmacogenetically determined impairment of polymorphic drug oxidation.

Topics: Adult; Aged; Aminorex; Animals; Appetite Depressants; Debrisoquin; Female; Humans; Hydantoins; Hydroxylation; Hypertension, Pulmonary; In Vitro Techniques; Isoquinolines; Male; Mephenytoin; Microsomes, Liver; Middle Aged; Oxazoles; Phenotype; Polymorphism, Genetic; Rats; Rats, Inbred Strains

There was an epidemic of chronic pulmonary hypertension in Austria, the Federal Republic of Germany and Switzerland, starting in 1967, peaking in 1968/69, and disappearing after 1972. The mechanism leading to pulmonary hypertension was chronic precapillary vascular obstruction due to plexogenic pulmonary arteriopathy. There was a close geographic as well as temporal relation of the epidemic to the marketing and intake of the appetite depressing drug aminorex fumarate (Menocil). 10 years after the epidemic, half of the patients have died, usually of right heart failure. Of those surviving, half present a definite regression of the pulmonary vascular obstruction. Average survival after the initial diagnosis was 3.5 years in those patients who died. Their PA pressure (+22%) and pulmonary arteriolar resistance (+40%) was higher at the onset of the observation period if compared with the corresponding values of the survivors; also the incidence of right heart failure was significantly higher (84 vs. 58%). Among the surviving patients, the only difference between those with an improved and those with a worsened haemodynamic situation was the age at the beginning of the weight-reducing treatment, those with a progression being 10 years older. The probability of survival after 10 years is considerably higher in chronic pulmonary hypertension of vascular origin (CPHVO) after aminorex than in "classical" primary pulmonary hypertension (CPHVO of unknown cause) and in CPHVO due to recurrent silent pulmonary thromboembolism. This difference in prognosis is an argument in favour of the identity of chronic pulmonary hypertension developing after the intake of the appetite depressing drug aminorex.

Topics: Adult; Aminorex; Appetite Depressants; Carbon Dioxide; Cardiac Catheterization; Europe; Female; Follow-Up Studies; Heart Failure; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Oxazoles; Oxygen

Over a period of up to 18 years, 24 patients (mean age: 33.8 years) with primary vascular pulmonary hypertension (PVPH) of unknown aetiology (group A) and 18 subjects (mean age: 45.3 years) with PVPH due to anorectic drug intake (group B) were comparatively studied. The following main tendencies became apparent: 1) The 10-year cumulative survival rate in group A (0.31) was lower than in group B (0.63). 2) Patients of group A showed more marked X-ray and ECG signs of pulmonary hypertension and right ventricular hypertrophy in comparison with group B. In contrast to group B, the ECG signs of hypertrophy in group A increased during the observation period. 3) Mean pulmonary artery pressure (PAP) significantly increased in group A (from 48.8 to 61.0 mmHg), while it decreased (from 47.6 to 33.3 mmHg) in group B. 4) The diameter of the descending branch of the right pulmonary artery increased with rising PAP only in group A, while the relationship between PAP and the Sokolow-Lyon index was significant only for the whole group of PVPH patients but not for the subgroups A and B. A regression of pulmonary hypertension in patients with anorectic drug intake was obvious, in contrast to the course in patients with PVPH of unknown aetiology.

Topics: Adolescent; Adult; Aged; Aminorex; Appetite Depressants; Child; Electrocardiography; Female; Fenfluramine; Follow-Up Studies; Humans; Hypertension, Pulmonary; Lung Volume Measurements; Male; Middle Aged; Oxazoles; Pulmonary Wedge Pressure; Radiography

1. The long-term follow-up of 22 patients with anorectic drug intake (aminorex fumarate) (AS) and PVPH is compared to 38 patients with PVPH of unknown etiology. 2. The 10-year cumulative survival rate is significantly higher for the AF-positive group (54 +/- 11%) than for the AF-negative patients (15 +/- 6%). 3. In terms of the hemodynamic parameters at the time of diagnosis, there were no differences between the two patient groups. 4. Hemodynamic serial controls in the AF-positive group often show a decrease in pulmonary pressure at rest, in contrast to the AF-negative group. However, in all but one of the patients with a pressure drop at rest there is a considerable increase in pulmonary pressure during exercise. 5. In neither group any correlation is to be found between pulmonary pressure and survival time.

Topics: Adolescent; Adult; Aged; Aminorex; Appetite Depressants; Child; Female; Follow-Up Studies; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Oxazoles; Pulmonary Artery; Pulmonary Circulation