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At least 19 recordsLinked to original sources
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↗
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↗
PubMed1977

The sympathomimetic activity of fenfluramine hydrochloride on rat vas deferens.

1. The peripheral, pharmacological effects of the anorexigenic agent, fenfluramine hydrochloride, have been investigated on rat isolated vas deferens. 2. Characteristic spiked contractions were observed within 2 to 3 min after exposure to fenfluramine; these contractions reached a rate of around 13 per min and were of variable height. 3. Pre-treatment of vasa with the indirectly acting sympathomimetic amine, tyramine, greatly reduced both the height and rate of contraction induced by fenfluramine. 4. The uptake inhibitor, desipramine, required a concentration in excess of 10 micronM to affect fenfluramine-induced contractions. Effects of desipramine on fenfluramine contractions were of equal magnitude whether desipramine was administered before fenfluramine or at the height of the fenfluramine-induced contractions. 5. Pre-treatment with debrisoquine (0.5 mM), reduced the contractions in response to fenfluramine over a period of time. 6. Fenfluramine, added to vasa from rats which had been injected intraperitoneally with 5 mg/kg reserpine 24 h and 48 h previously, failed to induce its characteristic contractions. 7. It is concluded that fenfluramine can be classed as an indirectly acting sympathomimetic amine on peripheral adrenergic nerve terminals.

Animals↗
PubMed1992

Releasing activities of d-fenfluramine and fluoxetine on rat hippocampal synaptosomes preloaded with [3H]serotonin.

Rat hippocampal synaptosomes preloaded with [3H]serotonin and maintained in a superfusion apparatus were exposed for 3 min to d-fenfluramine or fluoxetine. Both drugs evoked a tritium overflow which was reserpine-sensitive requiring the presence of intact synaptic vesicles. However the two drugs displayed different characteristics: 1) the overflow was immediate with d-fenfluramine whereas the releasing activity of fluoxetine showed a delay of about 2 min; 2) d-fenfluramine-induced overflow was already apparent at 0.15 mumol/l whereas the minimal effective concentration of fluoxetine was 2.5 mumol/l. Their concentration-effect curves were differently shaped, the effect of d-fenfluramine being saturable at 5-20 mumol/l (EC50 about 1 mumol/l) while no saturation was observed with fluoxetine up to 10 mumol/l; 3) only 19% of the tritium overflow evoked by fluoxetine (2.5-10 mumol/l) consisted of true [3H]serotonin, compared with 70% when 0.5 mumol/l d-fenfluramine was used; 4) the releasing action of 0.5 mumol/l d-fenfluramine was completely Ca(++)-dependent, while at higher d-fenfluramine concentrations the Ca(++)-independent overflow became more important. The fluoxetine induced overflow was mainly (70%) Ca(++)-independent; 5) the releasing activity of d-fenfluramine was mainly (80%) blocked by the serotonin uptake blockers indalpine, midalcipram and also fluoxetine whereas fluoxetine-induced overflow was insensitive to inhibition of the serotonin carrier. In conclusion, the releasing activity of d-fenfluramine is already present at a very low concentration (0.5 mumol/l) and at this concentration its mechanism of action was Ca(++)-dependent, together with the requirement of a functional serotonin carrier.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1975

Effect of fenfluramine on 5-hydroxytryptamine uptake and release by rat blood platelets.

1. (+)-Flenfluramine reduces the central stores of 5-hydroxytryptamine (5-HT) by a poorly understood mechanism. 2. Rat blood platelets have been used in this study as a simple model for serotoninergic nerve endings. 3. (+)-Fenfluramine shows a dual effect: it inhibits the uptake of (14C)-5-HT by platelets and it releases newly absorbed (14C)-5-HT from platelets. 4. The inhibition of (14C)-5-HT uptake induced by (+)-fenfluramine appears very rapidly, is concentration-dependent and seems not to be competitive. (+)-Fenfluramine is ten times less effective than chloroimipramine but tem times more effective than (+)-amphetamine; (+)-fenfluramine is more active than its (-)isomer or its metabolite norfenfluramine ((+)- or (-)-form). 5. The release of (14C)-5-HT from platelets induced by (+)-fenfluramine is concentration-dependent but increases wtih increased incubation time. Both chloroimipramine and (+)-amphetamine are in comparison very poor release inducers; (+)-fenfluramine is more active than its (-)-isomer or its metabolites. 6. The effect on (14C)-5-HT uptake exerted by (+)-fenfluramine and chloroimipramine in vitro could not be observed in vivo. 7. The observed effect on fenfluramine on the uptake and release of 5-HT may explain the lowering action of fenfluramine on the brain 5-HT level, an effect considered of importance for the anoretic effect on this drug.

Animals↗
PubMed1976

Peripheral effects of fenfluramine.

1 The peripheral cardiovascular effects of the centrally acting anorexigenic agent, fenfluramine hydrochloride, have been investigated in the rat. 2 After intravenous administration of fenfluramine, an immediate hypotensive response, followed by a reflex rise in blood pressure was recorded. This was followed by a prolonged fall in blood pressure which frequently failed to return to pre-drug levels. 3 The antagonists, propranolol and atropine, failed to inhibit this hypotensive effect of fenfluramine. 4 The effects of 5 mg/kg fenfluramine for 1h on the blood pressure responses to the sympathomimetic amines, tyramine, methoxamine and metaraminol were studied. 5 The responses to the indirectly acting tyramine were reduced by 50% following fenfluramine, while those to the directly acting methoxamine remained unaffected by the drug. Responses to metaraminol, an amine with both direct and indirect actions, were also unaffected to a significant degree by fenfluramine. 6 Studies on rat isolated vas deferens again showed that responses to tyramine are greatly reduced following fenfluramine. 7 In addition fenfluramine itself produced spontaneous contractions of the vas deferens. These contractions were blocked by the alpha-adrenoceptor blocking agents phentolamine and thymoxamine. 8 It is suggested that fenfluramine exerts an effect at the adrenergic nerve terminal, either by displacing noradrenaline stores or by inhibition of the amine uptake process.

Amines↗
PubMed1992

D-fenfluramine effects on hypothalamic monoamine activities and their hormonal correlates.

In order to test the hypothesis that the anorectic effects of D-fenfluramine involve mediation by increased serotonin (5-HT) activity we examined the effects of acute and chronic D-fenfluramine on the hypothalamic activities of 5-HT as well as the other major monoamine neurotransmitters noradrenaline (NA) and dopamine (DA). Precise and specific gas chromatograph/mass spectrometer analyses of NA, 5-HT and DA and their primary metabolites dihydroxphenylethyleneglycol (DHPG), 5-hydroxyindolacetic acid (5-HIAA) and dihydroxyphenylacetic acid (DOPAC), respectively, were made in combination with analysis of the hormonal correlates of the monoamines, glucose and adrenocorticotropin for NA, thyroid-stimulating hormone for 5-HT and prolactin for DA. Acute D-fenfluramine increased NA, while reducing 5-HT, functional activity. Chronic and acute after chronic, D-fenfluramine decreased both NA and 5-HT functional activity. The effect of acute D-fenfluramine on the DA system is consistent with a post-synaptic blockade which is compensated for by chronic treatment. Since chronic D-fenfluramine acted to depress noradrenergic tone, a further study was undertaken which showed that chronic D-fenfluramine does not impair the ability noradrenergic/sympathetic system to respond to stress. The results indicate that D-fenfluramine may not exert its anorectic and weight loss effects via serotonergic agonism and involvement of the NA and/or DA systems is likely.

Animals↗
PubMed1992

Effects of acute and chronic fenfluramine on self-stimulation and its facilitation by amphetamine.

DL-Fenfluramine (20 mg/kg) releasing serotonin and amphetamine (2 mg/kg) releasing dopamine were given to adult rats trained to bar press for electrical stimulation to the medial forebrain bundle. Amphetamine treatment enhanced lever-pressing for 1-2 h. A single fenfluramine treatment rapidly suppressed self-stimulation with slow recovery in 5-7 days to a rate below the initial basal rate. A second treatment a week later again suppressed response rate and rates returned to a still lower baseline. Combined fenfluramine-amphetamine treatment at this time transiently abolished lever pressing for 1-3 h followed by 9-11 h of enhanced responding. The serotonin antagonist, ketanserine (0.1 mg/kg), but not cyproheptadine (0.1 mg/kg i.p.), partially protected against the effects of fenfluramine. The serotonin agonist, quipazine (0.5 mg/kg), but not dimethoxyiodophenylisopropylamine (DOI) (2.2 mg/kg), partially substituted for fenfluramine in the combined treatment. Fenfluramine markedly depleted serotonin and 5-hydroxyindoleacetic acid in frontal cortex, hippocampus, and caudate putamen. Ventral and midline midbrain regions were less affected. Combined fenfluramine and amphetamine treatment elevated dopamine levels in frontal cortex, hippocampus and caudate-putamen, but not in midbrain. These findings support a serotonin-dopamine interaction in self-stimulation behavior and suggest that repeated fenfluramine treatment results in chronic low level serotonergic stimulation and diminished serotonin storage capacity.

Amphetamine↗
PubMed1992

Long-term weight control study. III (weeks 104 to 156). An open-label study of dose adjustment of fenfluramine and phentermine.

Between weeks 104 and 156 we attempted to optimize response by adjusting the doses of fenfluramine and phentermine. Dosing changes were based on an algorithm that aimed to achieve 120% of ideal body weight (IBW) while minimizing adverse effects. The dose groups were as follows: stage I, 30 mg fenfluramine plus 15 mg phentermine in the morning; stage II--continuous or targeted intermittent, 60 mg fenfluramine plus 15 mg phentermine in the morning; stage III, 60 mg fenfluramine plus 30 mg phentermine in the morning; stage IV, 60 mg fenfluramine plus 30 mg phentermine in the morning and 30 mg fenfluramine in the evening; and stage V, 60 mg fenfluramine plus 30 mg phentermine in the morning and 60 mg fenfluramine in the evening. Seventy-seven participants began this segment of the study and 59 completed to week 156. Completers of this segment of the study gained an average of 2.7 +/- 0.5 kg between weeks 104 and 156 but remained 9.4 +/- 0.8 kg (10.5%) below baseline. On average, weight loss from baseline by group was as follows: for stage I (n = 2), 14.1 +/- 6.8 kg; for stage II continuous (n = 14), 10.9 +/- 0.7 kg; for stage II targeted intermittent (n = 7), 8.8 +/- 2.4 kg; for stage III (n = 9), 7.7 +/- 2.6 kg; for stage IV (n = 8), 10.5 +/- 2.6 kg; and for stage V (n = 19), 8.4 +/- 2.4 kg. Upward dose adjustment (n = 36) resulted in further weight loss in 11 and no gain in six participants.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Feeding pattern studies suggest that d-fenfluramine and sertraline specifically enhance the state of satiety in rats.

The effects of d-fenfluramine (1.5 mg/kg) and sertraline (10 mg/kg), administered intraperitoneally once daily for seven days were studied on feeding parameters of rats over various periods. On the first day of treatment both drugs markedly reduced meal size and meal duration during the first hour and, to a lesser extent, the first 4 h. No effects were seen later. The size and duration of eating bouts were also markedly reduced by both drugs in the first hour. There was no significant effect of either drug on meal frequency in any period. Only d-fenfluramine significantly reduced the rate of eating within 4 h from the start of testing. Sertraline, but not d-fenfluramine, markedly increased locomotor activity in the first 4 h after the start of testing. The d-fenfluramine effect on eating rate disappeared by the second day whereas total intake and meal size were still reduced on day five. By days six and seven however the d-fenfluramine-treated rats did not differ from the controls. During the seven-day treatment sertraline always reduced total food eaten and meal size but caused only transient changes of locomotor activity and eating rate. Since the effects of d-fenfluramine and sertraline on meal size and food intake could be separated from the effects on eating rate and arousal, it appears that at appropriate doses these drugs specifically increase the satiating effect of food. Tolerance to this effect appears to develop more rapidly for d-fenfluramine than for sertraline.

1-Naphthylamine↗
PubMed1992

Disparate effects of fenfluramine on thermogenesis in brown adipose tissue in the rat.

It has been suggested that fenfluramine, a clinically used appetite suppressant, can also promote weight loss by augmenting energy expenditure, as indicated by increased whole-body O2 consumption (VO2) and mitochondrial GDP binding in brown adipose tissue (BAT) of fenfluramine-treated rats. To further investigate a possible involvement of BAT in the drug's metabolic effects, 113Sn-labelled microspheres were injected into the left cardiac ventricle of conscious rats 70-80 min after intraperitoneal delivery of 20 mg/kg fenfluramine (DL-mixture) or saline vehicle. At 28 degrees C ambient temperature, fenfluramine augmented resting whole-body VO2 and increased the microsphere entrapment in BAT, indicating enhanced blood flow and metabolism. At 20 degrees C ambient temperature, the expected increase in BAT blood flow associated with nonshivering thermogenesis was observed in control rats, but in fenfluramine-treated rats the increase in BAT blood flow was severely attenuated, and VO2 and body temperature were reduced. The stimulatory effect of fenfluramine on BAT metabolism was not prevented by urethane anesthesia but did not occur if the tissue was denervated. These blood flow measurements corroborate previous reports, based on GDP-binding assays, that fenfluramine treatment can augment thermogenesis in BAT by effects mediated through the innervation of the tissue. However, the data also indicate that this calorigenic effect is dependent on ambient temperature being near thermoneutrality and that in a cool environment the drug inhibits BAT thermogenesis.

Adipose Tissue, Brown↗
PubMed1977

Actions of fenfluramine on glucose uptake in vitro and in vivo.

Fenfluramine stimulates the glucose uptake of the isolated hemidiaphragm from normal and streptozotocin diabetic rats in the presence of insulin. The drug does not cause an increased storage of glycogen. During hind leg perfusion of the dog fenfluramine stimulated peripheral glucose uptake. No increase in lactate or in free fatty acids release was observed during prolonged infusions of the drug. Fenfluramine caused an improvement of glucose tolerance in normal glucose-primed rats. A single dose of fenfluramine significantly lowered the blood glucose levels in streptozotocin diabetic rats and in diabetic dogs treated with insulin. Prolonged treatment with fenfluramine of streptozotocin diabetic rats had no significant effect on blood glucose levels. Additional treatment for one week of insulin dependent diabetic dogs with small non-anorexic doses of fenfluramine resulted in slightly decreased blood glucose levels. The dogs could not be maintained on fenfluramine alone (without insulin).

Animals↗
PubMed1992

Role of 5-HT receptors in the effect of d-fenfluramine on feeding patterns in the rat.

The effect of d-fenfluramine, 1.5 mg/kg i.p., on meal patterns was studied in rats treated i.p. with 1 mg/kg metergoline or 0.5 mg/kg ritanserin or s.c. with 3 mg/kg (+/-)cyanopindolol. d-Fenfluramine significantly reduced eating rate, meal size and total intake in the first 4 h of testing and the effects were antagonized by metergoline. (+/-)Cyanopindolol reduced total intake and the effect of d-fenfluramine on this measure; the effect of d-fenfluramine on meal size (but not on eating rate) was also reduced by (+/-)cyanopindolol. Ritanserin only reduced the rate of eating and the effect of d-fenfluramine on this measure. The results suggest that 5-HT1 receptors, possibly of the 5-HT1B type, are involved in the ability of d-fenfluramine to cause satiety in freely feeding rats.

Animals↗