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/CASE REPORTS/ The lesions of pulmonary muscular arteries of 9 female patients who died of pulmonary hypertensive disease between 9 and 17 years after intake of an anorexigenic drug, aminorex fumarate, have been examined by various methods (light microscopy, numeration of lesions, morphometry). The numeration of lesions showed the predominance of fibrotic and dilatation lesions, but also the presence of active lesions (intimal hyperplasia, plexiform lesions). Morphometry revealed an increase in mean thickness of the media, compared to that of the arteries of controls or those of a previous series, and a reduction in mean vascular volume. The existence of sclerotic lesions and reduction of vascular volume may explain the persistence of pulmonary hypertension, which fresh lesions helped to aggravate. It seems likely that functional and morphologic modifications due to the action of the drug had become self-perpetuating and may finally have induced the fatal outcome in these patients many years after intake of the slimming pill. /Aminorex fumarate/

/CASE REPORTS/ 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. /Aminorex fumarate/

/EPIDEMIOLOGY STUDIES/ 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. /The investigators/ 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. 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. 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.

/ALTERNATIVE and IN VITRO TESTS/ 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 fumarate/

/OTHER TOXICITY INFORMATION/ 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 hemodynamic 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 favor of the identity of chronic pulmonary hypertension developing after the intake of the appetite depressing drug aminorex. /Aminorex fumarate/

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ In an attempt to develop an experimental model of pulmonary hypertension, five mongrel dogs were treated with 1 mg/kg po and five with 1.5 mg/kg po of Aminorex base five days a week for two years. A control group was given empty capsules by months. The following effects of treatment with Aminorex were noted: 1. Anorexia and central stimulation, 2. Natriuresis, 3. an increase in respiration rate, heart rate and body temperature, 4. a tendency towards usually compensated metabolic acidosis, 5. an increase in pulmonary arterial pressure, total pulmonary resistance and right ventricular work, and, in the group given the higher dose, a slight increase in mean aortic pressure and peripheral resistance. 6. Only slight histopathological changes were detectable, e.g.: perivascular edema; increase in the number of muscle arteries, occasionally with hypertrophy of the tunica media and slight, focal fibro-elastoid thickening of the intima in some elastic arteries. These changes were present in about 60% of the treated dogs. Only one dog that died after 91 weeks' treatment also showed moderate, focal phlebosclerosis of large pulmonary veins and focal, fibro-elastoid thickening in the coronary artery. Serious morphological changes in the pulmonary vessels such as are observed in the human pulmonary hypertension were not seen in our laboratory animals. Two dogs in each dosage group died in the course of the experiment. The results of this experiment show that it is, in general, possible to induce pulmonary hypertension by administering Aminorex orally. In two dogs, however, pressure in the pulmonary artery (measured under anesthesia) was below 20 mm Hg (controls: 13.8 +/- 1.3 mm Hg). One possible pathogenetic mechanism underlying the pulmonary hypertension would appear to be precapillary vasoconstriction induced by Aminorex, which can lead to transient, persistent or, for some unknown reason, even permanent fixation of pulmonary resistance.

/LABORATORY ANIMALS: Neurotoxicity/ Acute and long-term neurochemical effects of aminorex, an appetite-suppressing drug related to amphetamine in chemical structure, and stereoisomers of its analogues were examined and compared with those of 3,4-methylenedioxymethylamphetamine (MDMA) and fenfluramine. Aminorex and its analogues, with exception of 4S, 5S-dimethylaminorex, did not cause the long-term neurotransmitter depletion in either the dopaminergic or 5-HT-ergic systems that was observed after MDMA or fenfluramine in CBA mice. These results are discussed in terms of possible structurally related mechanisms of neurotoxicity. The acute neurochemical effects showed that aminorex and analogues all produced increases in 5-hydroxytryptamine (5-HT) levels, unlike fenfluramine and MDMA in the present study or in published data. This suggests that inhibition of 5-HT metabolism, rather than direct 5-HT release, may be involved in their anorectic effect. The parallel study of acute dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) changes suggest that in CBA mice MDMA may be a better dopamine releaser and this may contribute to its dopaminergic neurotoxicity. However the ability to release dopamine or 5-HT, or both, may be important, but not the only factor involved in causing the long-term neurotoxicity observed with amphetamine derivatives.

While data specific to aminorex were not located(SRC, 2008), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2). Studies have indicated that several polar pharmaceutically active compounds can leach through soils(1).