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At least 19 recordsLinked to original sources
PubMed1988

Effect of depletion of brain serotonin by repeated fenfluramine on neurochemical and anorectic effects of acute fenfluramine.

Fenfluramine is an anorectic agent in clinical use that is believed to act by enhancing 5-hydroxytryptamine (5-HT) neurotransmission. Tolerance to the anorectic properties of fenfluramine develops rapidly and long-lasting depletions of brain 5-HT have been reported to occur after repeated administration. It is possible that tolerance to fenfluramine may be related to the 5-HT depletions. Rats (n = 96), previously allowed to drink sweetened condensed milk during daily 15-min sessions, were treated with fenfluramine (6.25 mg/kg/12 hr x 4 days) or saline. Two or 8 weeks later rats were administered fenfluramine acutely (0, 1.25, 6.25 or 12.5 mg/kg; n = 6/group), tested for milk intake and sacrificed 2 hr later. Brains were removed and regions assayed for dopamine, 5-HT and metabolites. Acute administration of fenfluramine produced a dose-dependent decrease in milk intake and 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels in cortex, hypothalamus and hippocampus. Tolerance to the effects of acute fenfluramine on milk intake was observed in rats at 2 weeks (ED50 = 3.24 vs. 6.37 mg/kg; saline vs. fenfluramine pretreatment, respectively) and, to a lesser extent, at 8 weeks (ED50 = 2.99 vs. 4.04 mg/kg; saline vs. fenfluramine pretreatment) after the 4-day regimen of fenfluramine. Levels of 5-HT and 5-HIAA in somatosensory cortex, hypothalamus, striatum and hippocampus were depleted significantly 2 weeks after the last daily fenfluramine injection. The acute 5-HT depleting effect of fenfluramine was markedly attenuated in these regions 2 weeks after the 4-day regimen of fenfluramine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

p-Chloroamphetamine (PCA), 3,4-methylenedioxy-methamphetamine (MDMA) and d-fenfluramine pretreatment attenuates d-fenfluramine-evoked release of 5-HT in vivo.

Previous work has suggested that repeated treatment with substituted amphetamines including PCA, MDMA and d-fenfluramine produces a persistent neurodegeneration which is relatively selective for the fine serotoninergic terminals arising from the dorsal raphe nucleus. The aim of the present study was to investigate whether the acute releasing effect of d-fenfluramine might also be sensitive to lesions produced by PCA, MDMA and d-fenfluramine itself. Basal and 5-HT release evoked by d-fenfluramine or 100 mM KCl was measured by microdialysis in frontal or parietal cortex of rats 2 weeks after they had been treated with a neurodegenerative regime of PCA, MDMA, d-fenfluramine, or vehicle. In frontal cortex of vehicle controls, d-fenfluramine (10 mg/kg IP) and KCl (100 mM via microdialysis probe) evoked an increase in 5-HT of 1740% and 779% of basal, respectively. PCA pretreatment reduced d-fenfluramine-evoked 5-HT release by 90.9% while potassium-evoked release was reduced by only 66.8%. Similar results were obtained in parietal cortex. MDMA (20 mg/kg x 8) and d-fenfluramine (1.25 mg/kg x 8) pretreatment reduced d-fenfluramine-evoked release of 5-HT in frontal cortex by 45.2% and 72.0%, respectively. Overall, the present data are consistent with the hypothesis that the acute release of 5-HT evoked by d-fenfluramine occurs via those terminals destroyed by pretreatment with PCA, MDMA and d-fenfluramine, while KCl evokes release from both PCA-sensitive and PCA-insensitive terminals. The significance of these results for the interpretation of neuroendocrine data from d-fenfluramine challenge tests is discussed.

Amphetamines↗
PubMed1991

Differential effects of d-fenfluramine, l-fenfluramine and d-amphetamine on the microstructure of human eating behaviour.

An observational technique, demonstrated to provide reliable data under a variety of conditions, was used to evaluate the effects of d-fenfluramine, l-fenfluramine, d-amphetamine, and fenfluramine-amphetamine combinations on eating behaviour in human subjects. Following an overnight fast, subjects ate lunch from a dispenser allowing free access to a choice of ten sweet and savoury foods, of varying macronutrient composition. D-fenfluramine (30mg) and d-amphetamine (15mg) reduced food intake; l-fenfluramine (30mg) was essentially inactive. The net effects of d-fenfluramine and d-amphetamine on food intake were additive, but the behavioural mechanisms of action were different for the two drugs. D-amphetamine decreased the duration of the meal, as well as the time spent chewing or manipulating food and the number of bites, but had no effect on eating rate; by contrast, d-fenfluramine decreased the rate of eating, but had no effect on meal duration.

Journal Article↗
PubMed1987

Fenfluramine treatment of autism: relationship of treatment response to blood levels of fenfluramine and norfenfluramine.

Nine children meeting DSM-III criteria for infantile autism were treated with fenfluramine hydrochloride or inactive placebo in a double-blind crossover trial that followed the protocol for the fenfluramine multicenter study. Parents of the two children who had had the highest fenfluramine blood levels wished to have their children continue on fenfluramine, although the improvement they saw could not be demonstrated on the various rating instruments employed. The results of the study, while providing minimal support in themselves for the effectiveness of fenfluramine, do raise the possibility that fenfluramine blood levels might be related to treatment response.

Adolescent↗
PubMed1992

Fenfluramine-induced increases in extracellular hippocampal serotonin are progressively attenuated in vivo during a four-day fenfluramine regimen in rats.

Rats were administered 8 injections of 12.5 mg/kg fenfluramine over a 4-day period. Extracellular hippocampal serotonin levels were monitored in vivo during the 4-day treatment period. Predrug baseline serotonin levels were 0.6 +/- 0.17 pg/5 microliters; 60 min after the first fenfluramine injection extracellular serotonin levels were increased to 28.06 +/- 5.2 pg/5 microliters. Fenfluramine-induced increases in serotonin were substantially reduced on the 2nd through 4th days of the regimen. Baseline serotonin levels were increased on days 2 through 4 of the treatment regimen. In a separate group of animals post-mortem tissue concentrations of serotonin were measured 2 weeks after 1,2,4, or 8 injections of 12.5 mg/kg fenfluramine. There were decreases in serotonin tissue concentrations which were related to the number of fenfluramine injections administered. The in vivo dialysis and post-mortem tissue assay results are consistent with the view that fenfluramine is neurotoxic.

Animals↗
PubMed1979

Bile acid, neutral sterol and faecal fat excretion in subjects treated with fenfluramine and its relationship to fenfluramine-induced diarrhoea.

Bile acid, neutral sterol and faecal fat excretion was studied over a period of 9 weeks in a group of 16 healthy subjects before, during and after administration of fenfluramine. Statistical analysis revealed a significant increase in bile acid excretion during the drug phase (P less than 0.02); and during recovery period of 3 weeks (P less than 0.05). Faecal neutral sterol, as the total of coprostanol and cholesterol elimination was also enhanced after fenfluramine. Coprostanol was replaced by cholesterol in 12 subjects. Faecal fat was studied in 6 subjects, the excretion increased during the drug phase (P less than 0.05), and remained elevated during the post-drug period (P less than 0.01). The composition of the bile acids remained unaltered in all the subjects except 3 who had a fenfluramine-induced watery diarrhoea; and these excreted chenodeoxy and cholic together with smaller amounts of secondary bile acids. A higher excretion of bile acids was found in the 8 overweight subjects (P less than 0.01) before ministration of fenfluramine. These results are discussed in an attempt to correlate the effect of fenfluramine with changes in bile acid and neutral sterol excretion, and its relationship to fenfluramine-induced diarrhoea.

Bile Acids and Salts↗
PubMed1975

Fenfluramine and 5-hydroxytryptamine?. Part 1: Is fenfluramine or norfenfluramine involved in the decrease of brain 5-hydroxytryptamine.

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.

Animals↗
PubMed1975

Fenfluramine and 5-hydroxytryptamine. Part 2: Involvement of brain 5-hydroxytryptamine in the anorectic activity of fenfluramine.

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).

Amides↗
PubMedDate not supplied

Acute fenfluramine administration reduces neuropeptide Y concentrations in specific hypothalamic regions of the rat: possible implications for the anorectic effect of fenfluramine.

Neuropeptide Y (NPY), a powerful central appetite stimulant, coexists in several hypothalamic areas with serotonin, which suppresses feeding. This study investigated the effect of acute administration of the serotonergic drug, fenfluramine, on NPY concentrations in microdissected hypothalamic nuclei. Adult male Wistar rats were given fenfluramine (10 mg/kg, n = 7) or saline (n = 7), intraperitoneally 1 h before darkness. Food was presented immediately before darkness and the rats were killed during the first 4 h of darkness. Fenfluramine injection significantly reduced food intake. In fenfluramine-injected animals, NPY levels in the ventromedial and dorsomedial nuclei and in the lateral hypothalamic and lateral preoptic areas were significantly lower than in saline-injected controls. The ventromedial and dorsomedial nuclei and the lateral hypothalamic area are sites which mediate the hyperphagic action of centrally injected NPY. Selective NPY changes in specific nuclei after fenfluramine injection suggest functional interaction between NPYergic and serotonergic systems, and may indicate that NPY is involved in mediating the anorectic effect of serotonergic agents.

Animals↗
PubMed1987

From fenfluramine racemate to d-fenfluramine. Specificity and potency of the effects on the serotoninergic system and food intake.

Experiments using the binding of various ligands for monoamines to rat brain membranes and synaptosomal preparations for studying monoamine uptake and release have shown that d-fenfluramine is more potent than the l isomer in inhibiting 5-HT uptake, whereas d-norfenfluramine preferentially releases 5-HT from a reserpine-insensitive compartment. Studies on brain monoamine metabolism in intact animals have shown that the d and l isomers of fenfluramine at relatively low doses have a specific action on brain 5-HT and catecholamines, respectively. Based on the different ability of metergoline and ritanserin to displace 5-HT2 binding to rat brain membranes and to antagonize d-fenfluramine's anorexia, evidence has been provided that d-fenfluramine preferentially uses 5-HT1 sites in the rat brain to cause anorexia in this animal species. Finally, characteristics, regional distribution, and pharmacological characterization of a high-affinity [3H]d-fenfluramine binding to rat brain membranes have been described. This binding appears to be different from 5-HT uptake sites ([3H]imipramine binding) and 5-HT receptors and is not regionally related to the endogenous levels of 5-HT in the rat brain. It is, however, preferentially displaced by some agents using 5-HT to cause anorexia in rats, raising the possibility that it is somewhat related to 5-HT mechanisms involved in feeding control.

Amines↗
PubMed2001

In vitro reaction of formaldehyde with fenfluramine: conversion to N-methyl fenfluramine.

Embalming is common, and it can create problems for the forensic scientist if a drug has been the cause death and this drug is also reactive toward the embalming fluid. Previous studies have focused on the tricyclic amines nortriptyline and desipramine. In the presence of formaldehyde, a typical component of embalming fluid, either of these two compounds can be rapidly converted to their methylated derivatives amitriptyline and imipramine, respectively. We have begun a larger project designed to determine the reactivity and reactions of a wide range of drugs with formaldehyde. We report here our results from fenfluramine, which, like the tricyclic amines, is reactive towards formaldehyde and is converted into its N-methyl derivative. The rate of conversion is dependent upon pH and formaldehyde concentration. Up to 100% conversion in 24 h was observed. In addition, we have also devised a simplified procedure for monitoring this process that may be useful for others working in this area. Finally, we note that the reactions of fenfluramine studied here and of amines in general with formaldehyde need to be considered when performing postmortem/postembalming forensic analysis.

Embalming↗
PubMed1992

Effects of fenfluramine on the metabolism of calcium and phosphorus in the rat: fenfluramine effects on Ca and P metabolism.

Daily administration of 2, 5, 10, 15 and 20mg of fenfluramine/kg body weight to adult rats for four weeks resulted in dose dependent decrease in calcium and phosphorus absorption with an inverse correlation of r = -0.94 for calcium and r = -0.93 for phosphorus. Significant (P less than 0.05) increase in the total faecal lipids and moderate decline in plasma calcium levels were also observed in the rats. Adult rats made obese by dietary methods when treated with 10mg and 15 mg of fenfluramine/kg body weight/day for 10 weeks showed a significant reduction (p less than 0.001) in the intestinal absorption of both calcium and phosphorus. The reduction at 15mg/kg drug dose was 10.7 pc for calcium and 9.5 pc for phosphorus. Analyses of the long bones as well as carcasses of the obese rats showed significant decrease (p less than 0.001) in the content of these minerals. Plasma calcium and phosphorus levels were also significantly (p less than 0.001) reduced in the obese-treated rats. However, fenfluramine treatment significantly reduced the plasma calcium but not the phosphorus levels in the non-obese rats. These studies have demonstrated that chronic administration of fenfluramine (greater than or equal to 10mg/kg body weight) to rats, obese or non-obese, impairs calcium and phosphorus metabolism in the body.

Animals↗
PubMed1985

Pharmacokinetics of fenfluramine and norfenfluramine in volunteers given D- and DL-fenfluramine for 15 days.

The kinetics of accumulation and elimination of d- and l-fenfluramine (F) and norfenfluramine (NF) have been studied in 8 young healthy volunteers given daily doses of 60 mg of sugar-coated tablets of 20 mg dl-F hydrochloride (dl-F) t.i.d. and capsules of 15 mg d-F hydrochloride (d-F) b.i.d. for 15 days. Repeated doses of d-F plus l-F gave the same values for the parameters measured as did d-F administered alone. Steady-state concentrations of all compounds were achieved within 4-8 days. The predicted mean steady-state concentrations of d-F and elimination half-lives calculated from the results of a previous single dose study were similar to those measured at steady state in this study, confirming the lack of effect of the drug on hepatic microsomal enzymes and on kinetics after repeated dosing. d-NF concentrations were approximately half those of the parent drug and the half-life was almost twice as long. Steady state concentrations both of L-f and l-NF were consistently about 40-50% higher than of the d-isomers and there was a comparable in the half-life.

Adult↗
PubMedDate not supplied

Elevations in plasmatic titers of corticosterone and aldosterone, in the absence of changes in ACTH, testosterone, or glial fibrillary acidic protein, 72 h following D,L-fenfluramine or D-fenfluramine administration to rats.

Studies in both humans and animals demonstrate that D,L- and D-fenfluramine (D,L-FEN and D-FEN, respectively) can activate the hypothalamic-pituitary-adrenal axis following an acute dose. No data exist showing a prolonged effect of either drug, although two studies have hinted at increased adrenal activity. There are also considerable differences in the literature pertaining to the neurotoxic effects of D,L- and D-FEN. Some possible explanations for these differences include: activation of different neurotransmitter systems, the temperature at which the animals were maintained during exposure, or the substance sampled in each study. We investigated the effects of either D,L-FEN or D-FEN on pituitary, adrenal, and gonadal hormones 72 h after drug exposure. Furthermore, using a dosing regimen adapted from studies on methamphetamine (e.g., four times every 2 h in a single day) known to produce elevations in glial fibrillary acidic protein (GFAP) under hyperthermic conditions, we examined the effects of D- and D,L-FEN (15 mg/kg, four times) on GFAP content when the animals were dosed at ambient temperatures of 21 or 32 degrees C. Approximately fivefold increases of corticosterone and threefold increases of aldosterone were found 72 h later under resting conditions following both D- and D,L-FEN. Nonetheless, when animals were dosed with D-FEN at 32 degrees C, no significant elevation in corticosterone was detected. No effect was observed for ACTH, testosterone, or GFAP following D- or D,L-FEN treatment. These data suggest that: (1) FEN treatment causes prolonged elevations in adrenal cortical hormones; (2) FEN-treated animals displayed hormonal characteristics similar to animals undergoing a chronic stressor as suggested by no difference in ACTH titers; (3) D,L-FEN treatment or D-FEN treatment (as reported previously) is not similar to other substituted amphetamines in that it does not increase GFAP, even under hyperthermic conditions.

Adrenocorticotropic Hormone↗
PubMed1998

Fenfluramine and norfenfluramine levels in brain microdialysate, brain tissue and plasma of rats administered doses of d-fenfluramine known to deplete 5-hydroxytryptamine levels in brain.

The relationship between dose, frontal cortex (brain) microdialysate and brain tissue levels of fenfluramine (FEN) and norfenfluramine (NF), as well as the effect that these levels have on body temperature, was determined after systemic d-FEN. FEN and NF levels were monitored continuously in the microdialysate of adult male Sprague-Dawley rats dosed with 3 x 5 mg/kg s.c. (spaced 2 hr apart), 1 x 2 mg/kg s.c. or 1 x 10 mg/kg i.p. d-FEN (at ambient temperatures of either 23 degrees C or 27 degrees C). Drug concentrations in plasma and brain regions were also determined 1 hr after one or three doses of 5 mg/kg of d-FEN and 1 and 8 hr after 10 mg/kg d-FEN, and the levels of 5-hydroxytryptamine and 5-hydroxyindole acetic acid in the frontal cortex of FEN and controls were determined 4 days after dosing. Peak microdialysate FEN levels, occurring between 40 and 60 min after the first dose, were 0.24 +/- 0.07 microM after 2 mg/kg, 0.33 +/- 0.04 microM after 5 mg/kg and 1.65 microM after 10 mg/kg. After multiple doses of 5 mg/kg FEN the time-to-peak level was greater than 80 min with peaks of 0.68 +/- 0.04 microM after the second dose and 1.20 +/- 0.07 microM after the third dose. There was a positive correlation between combined (FEN + NF) peak levels in microdialysate and the increase in body temperature after 10 mg/kg d-FEN at 27 degrees C; however, the group mean and peak levels of FEN and NF in microdialysate were statistically the same at either 23 degrees C or 27 degrees C. The indole-depleting effect of d-FEN at 4 days after dosing was exacerbated at 27 degrees C when hyperthermia occurred. Thus, hyperthermia does not affect the pharmacokinetics of d-FEN but pharmacokinetics can influence the degree of hyperthermia in a 27 degrees C environment. Plasma levels, brain extracellular and brain levels of approximately 1 microM, 2.5 microM and 50 microM FEN (respectively), or greater, result from 5-hydroxytryptamine-depleting doses of 5 mg/kg s.c. FEN.

Animals↗