In Vivo Correlates of Central Serotonin Function after High‐Dose Fenfluramine Administration
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High doses of fenfluramine (FEN) are known to deplete central serotonin (5-HT) in animals, but functional impairments associated with such 5-HT depletion have been difficult to identify. In the present work, we examined neuroendocrine responsiveness in rats exposed to repeated high-dose FEN treatment. Male rats fitted with indwelling catheters received FEN (20 mg/kg, subcutaneously, twice a day) or saline for 4 days. At 1 and 2 weeks after treatment, rats were challenged with intravenous FEN (1.5 & 3 mg/kg) or saline. Repeated blood samples were drawn, and plasma was assayed for prolactin and corticosterone by radioimmunoassay. Acute FEN challenge caused dose-dependent elevations of plasma prolactin and corticosterone in all rats. However, the FEN-induced hormone responses were significantly blunted (p < 0.01) in rats previously exposed to FEN. The repeated FEN dosing regimen dramatically reduced (> 50%) postmortem 5-HT levels in the mediobasal hypothalamus, basolateral amygdala, and hippocampus, while the lateral hypothalamus was unaffected. These data suggest that high-dose FEN causes alterations in central 5-HT systems involved with pituitary hormone secretion. The relevance of the present data to the clinical use of FEN is unclear. Because the neuroendocrine challenge paradigm is able to identify functional 5-HT deficits in rats, we propose that similar experiments should be performed in humans. Neuroendocrine challenge tests represent a reliable method to test the existence of FEN-induced neurotoxicity in human patients undergoing long-term FEN treatment.Keywords:
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Both fenfluramine and de-ethylated fenfluramine decrease the brain stores of 5-hydroxytryptamine (5-HT). As the fenfluramine metabolite is present in the brain of the rat after fenfluramine injection, it could be suggested that the depletion of brain 5-HT elicited by fenfluramine is mediated by its metabolite. Comparative studies on 5-HT lowering effects and drug brain levels, indicate a primary effect of fenfluramine, following by the rising involvement of the de-ethylated compound in the sustained effect.
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Pulmonary hypertension developed in two women who had been taking fenfluramine for over eight months for weight reduction. On withdrawing the drug symptoms and electrocardiographic evidence of pulmonary hypertension disappeared in both cases. In one patient, however, the evidence recurred after rechallenge with fenfluramine. These findings are strong evidence that fenfluramine may cause pulmonary hypertension. Hence any patient taking the drug should report immediately any deterioration in exercise tolerance.
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As it is well-known, fenfluramine produces anorexia and decrease in brain 5-hydroxytryptamine (5-HT). As it has been suggested that the anorectic effect of fenfluramine may be due to a release of brain 5-HT, we have examined the influence of several drugs active on 5-HT mechanisms and metabolism, on the anorexigenic activity of fenfluramine. These studies were made in relationship with the depletion of 5-HT levels and the concentration of brain fenfluramine or m-trifluoromethyl-isopropylamine. The results have confirmed the involvement of a tryptaminergic mechanism in fenfluramine anorexia and suggest the hypothesis that fenfluramine itself can interfere with the serotoninergic system in the brain (stimulation of tryptaminergic neurons directly).
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The reports of hyperserotonaemia in chronic schizophrenics and the indications that fenfluramine, a serotonin-releasing drug, may be of therapeutic value in hyperserotonaemic autistic children, were the rationale for this clinical trial. Fenfluramine was administered to 4 treatment-resistant chronic schizophrenic in-patients. They were studied for 14 weeks: 2 baseline weeks, 8 on fenfluramine (maximal dose 120 mg/day for 4 weeks) and 4 post-fenfluramine. Plasma levels of fenfluramine and nor-fenfluramine indicated good compliance. Platelet serotonin concentration decreased in all 4 subjects, weight loss was noted in 2. Clinical changes (assessed by rating psychiatric symptoms and ward behaviour) were observed in 3: moderate sustained improvement in 1, a shortlived activation followed by a slight improvement in another, and a brief amelioration with subsequent worsening in the third. The time and pattern of these changes suggest that they were due to fenfluramine.
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T combination of phentermine and fenfluramine hydrochloride is widely used for the treatment of exogenous obesity even though there has been only 1 full published study.1The therapy is cheap, highly successful, and well tolerated. Nevertheless, experience in Europe suggests that there is a grave risk of primary pulmonary hypertension (PPH) from fenfluramine, whether dispensed as the racemic mixture or the pure D-isomer.2Even though the risk for PPH is small, the mortality is high, the results of treatment are uncertain, and there is no proven screening method. I have treated 557 patients with a variation of the "phen-fen" combination, in which fenfluramine was replaced with fluoxetine hydrochloride. The chemical structure of fluoxetine is similar to that of fenfluramine; both drugs are serotonin-promoting agents, and fluoxetine acts on the cerebral appestat as well as fenfluramine. My patients have lost 3645 kg in 2 years. Only 7 patients failed
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