Aminorex, fenfluramine, and chlorphentermine are serotonin transporter substrates. Implications for primary pulmonary hypertension.
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BACKGROUND: Coadministration of phentermine and fenfluramine (phen/fen) effectively treats obesity and possibly addictive disorders. The association of fenfluramine and certain other anorexic agents with serious side effects, such as cardiac valvulopathy and primary pulmonary hypertension (PPH), limits the clinical utility of these drugs. Development of new medications that produce neurochemical effects like phen/fen without causing unwanted side effects would be a significant therapeutic breakthrough. METHODS AND RESULTS: We tested the hypothesis that fenfluramine (and other anorexic agents) might increase the risk of PPH through interactions with serotonin (5-HT) transporters. Because 5-HT transporter proteins in the lung and brain are identical, we examined, in rat brain, the effects of selected drugs on 5-HT efflux in vivo and monoamine transporters in vitro as a generalized index of transporter function. Our data show that drugs known or suspected to increase the risk of PPH (eg, aminorex, fenfluramine, and chlorphentermine) are 5-HT transporter substrates, whereas drugs that have not been shown to increase the risk of PPH are less potent in this regard. CONCLUSIONS: We speculate that medications that are 5-HT transporter substrates get translocated into pulmonary cells where, depending on the degree of drug retention, their intrinsic drug toxicity, and individual susceptibility, PPH could develop as a response to high levels of these drugs or metabolites. Emerging evidence suggests that it is possible to develop transporter substrates devoid of adverse side effects. Such medications could have therapeutic application in the management of obesity, drug dependence, depression, and other disorders. (+info)
Delayed onset of pulmonary hypertension associated with an appetite suppressant, mazindol: a case report.
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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. (+info)
Drug-induced pulmonary hypertension?
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Of 40 patients with obstructive pulmonary hypertension studied in Basle, Switzerland, during the period 1966-68, 32 had been taking an anorectic drug, aminorex fumarate. Rapidly progressing exertional dyspnoea, central chest pain, and syncope on effort were characteristic features. The absence of the usual causes of pulmonary vascular disease seems to suggest the possibility of drug-induced pulmonary hypertension. Further studies are necessary, however, to clarify the role of aminorex fumarate in this condition. (+info)
Anorexic agents aminorex, fenfluramine, and dexfenfluramine inhibit potassium current in rat pulmonary vascular smooth muscle and cause pulmonary vasoconstriction.
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BACKGROUND: The appetite suppressant aminorex fumarate is thought to have caused an epidemic of pulmonary hypertension in Europe in the 1960s. More recently, pulmonary hypertension has been described in some patients taking other amphetamine-like, anorexic agents: fenfluramine and its d-isomer, dexfenfluramine. No mechanism has been demonstrated that might account for the association between anorexic drugs and pulmonary hypertension. METHODS AND RESULTS: Using the whole-cell, patch-clamp technique, we found that aminorex, fenfluramine, and dexfenfluramine inhibit potassium current in smooth muscle cells taken from the small resistance pulmonary arteries of the rat lung. Dexfenfluramine causes reversible membrane depolarization in these cells. These actions are similar to those of hypoxia, which initiates pulmonary vasoconstriction by inhibiting a potassium current in pulmonary vascular smooth muscle. In the isolated, perfused rat lung, aminorex, fenfluramine, and dexfenfluramine induce a dose-related increase in perfusion pressure. When the production of endogenous NO is inhibited by N-nitro-L-arginine methyl ester, the pressor response to dexfenfluramine is greatly enhanced. CONCLUSIONS: These observations indicate that anorexic agents, like hypoxia, can inhibit potassium current, cause membrane depolarization, and stimulate pulmonary vasoconstriction. They suggest one mechanism that could be responsible for initiating pulmonary hypertension in susceptible individuals. It is possible that susceptibility is the result of the reduced production of an endogenous vasodilator, such as NO, but this remains speculative. (+info)