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PubMed1995

Effects of dexfenfluramine on resting metabolic rate and thermogenesis in premenopausal obese women during therapeutic weight reduction.

To investigate whether a serotoninergic drug such as dexfenfluramine (dF) may have some beneficial effects on energy expenditure (EE) during therapeutic weight reduction, a 3-month study was conducted in a double-blind, placebo-controlled trial. Thirty-two obese, premenopausal women received either dF or placebo (P) in addition to a very-low-calorie diet (VLCD) prescription. All patients started--when hospitalized at the metabolic ward--with a 500-kcal regimen and fulfilled the 3-month trial on a +/- 760-kcal protein-sparing modified fast. Although not statistically significant, women receiving dF lost more weight (16.0 +/- 1.4 v 12.8 +/- 1.3 kg, P = .111) over the 3-month study period. Resting metabolic rate (RMR) decreased significantly by 5% in the dF group (4.79 to 4.53 kJ/min) and by 9% in the P group (5.09 to 4.63 kJ/min). When expressed per kilogram body weight, RMR significantly increased from 0.050 to 0.057 kJ/min/kg in the dF group (P < .001), versus 0.053 to 0.056 in the P group (NS). When expressed per kilogram fat-free mass (FFM), RMR remained stable in the dF group, whereas it significantly decreased in the P group (P = .024). No significant differences could be found between groups. Glucose-induced thermogenesis (GIT), expressed as percent increase above RMR, did not show significant differences between groups. When expressed per kilogram body weight, mean GIT increased in the dF group from 0.14% to 0.16% above RMR, with a significant decrease from 0.15% to 0.13% in the P group. Only during the first hour did GIT per kilogram body weight significantly (P = .038) increase in the dF group during the outpatient period (between day 16 and day 90). These results show that a serotoninergic drug seems capable of limiting the weight reduction-associated decrease in RMR and dietary-induced thermogenesis (DIT), certainly when expressed on a per-kilogram-weight basis.

Adolescent↗
PubMed1995

Effects of dexfenfluramine on free fatty acid turnover and oxidation in obese patients with type 2 diabetes mellitus.

To test the potential effects of dexfenfluramine (dF) on enhancing free fatty acid (FFA) turnover and oxidation rates, 11 obese female non-insulin-dependent diabetes mellitus (NIDDM) outpatients (age, 52.5 +/- 1.5 years; weight, 81.3 +/- 3.2 kg; height, 158 +/- 3.04 cm; body mass index, 32.4 +/- 0.7 kg/m2) received a primed-constant infusion of 1-14C-palmitate. The waist to hip ratio (WHR) was 0.91 +/- 0.04. Fat body mass and lean body mass, assessed by dual-energy x-ray densitometry, were 32.0 +/- 1.5 and 49.30 +/- 2.67 kg, respectively. All patients had an average hemoglobin A1 of 6.3% +/- 0.3% in the month preceding the study and had not received oral hypoglycemic agents. Gas exchange was measured both basally and during a ventilated-hood system, indirect-calorimetry session. The protocol was a randomized, placebo-controlled, single-blind design. Subjects received dF 30 mg acutely (n = 6) or a placebo (n = 5). A dose of dF 15 mg twice daily or placebo was then administered over 15 days (chronic). To obtain serum peak level of the drug, dF was administered 2 hours before starting palmitate infusion. A free diet was allowed throughout the study, and the group treated with dF lost approximately 0.5 kg body weight. Acute and chronic dF administration resulted in a significant increase in FFA oxidation, expressed as a percentage of the dose of radiocarbon (respectively, 11.47% +/- 0.46% v 9.50% +/- 0.46% [P < .01] and 12.06% +/- 0.71% v 9.88% +/- 0.62% [P < .01]). FFA turnover rate was higher after both acute and chronic dF administration (respectively, 10.71 +/- 2.18 v 7.79 +/- 1.48 mumol/kg/min [P < .05] and 11.92 +/- 2.74 v 8.43 +/- 1.86 mumol/kg/min [P < .05]). Serum FFA concentration during both acute and chronic dF administration increased, but not significantly. Mean serum glucose level decreased after acute dF from 114.3 +/- 8.6 to 86.5 +/- 5.1 mg/dL (P < .001) and after chronic dF from 120.3 +/- 7.3 to 89.8 +/- 5.8 mg/dL (P < .001). Serum insulin was not affected by dF administration. In conclusion, oral acute and chronic dF administration increase FFA turnover and oxidation rates in NIDDM obese patients. This may play an important role in weight reduction. In addition, dF shows a weight-independent effect on glucose metabolism, reducing serum glucose levels without acting on insulin secretion.

Diabetes Mellitus, Type 2↗
PubMed1995

Depletion and time-course of recovery of brain serotonin after repeated subcutaneous dexfenfluramine in the mouse. A comparison with the rat.

The indole-depleting effects of repeated subcutaneous doses of dexfenfluramine (D-F) (2.5, 5, 10, 20 and 40 mg/kg/day, for four days) in mice were examined with regard to the initial response and time-course of recovery and related to the pharmacokinetics of D-F and its active metabolite dexnorfenfluramine (D-NF). Steady-state plasma and brain concentrations of D-F rose dose-dependently with a metabolite-to-drug ratio averaging 0.4 in brain. This confirmed that in mice D-NF contributes less than in other species to the effects of D-F. Regional serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) contents were decreased dose-dependently 4 hr after the last injection of D-F. However, two weeks after D-F (2.5-10 mg/kg/day) brain indoles had almost totally recovered, and the long-term effects of the 20 mg/kg/day dose were completely reversed by six weeks, when significant effects are still observable in rats. Although substantial recovery was evident even at 40 mg/kg/day, 5-HT but not 5-HIAA was still slightly reduced nine weeks later. Comparative studies in rats given 2.5-20 mg/kg/day D-F indicated much more severe initial indole depletions than in mice. Brain levels of D-F and D-NF were much higher in rats than in mice. The total active drug brain concentration (D-F + D-NF) was significantly correlated with 5-HT content in both species, with approx 20 nmol/g of total drug causing 50% reduction. These findings point to species differences in D-F kinetics as a main reason for differences in the neurochemical response, supporting the view that the recovery of indoles over time is related to the extent of initial depletion, which in turn depends on critical drug brain concentrations. In view of the qualitative and quantitative species differences in the pharmacodynamics and pharmacokinetics of D-F neither of these rodent species is a suitable model for predicting potential drug toxicity in humans.

Animals↗
PubMed1993

Adrenalectomy enhances the anorectic effect of dexfenfluramine: relation to mineralocorticoids and salt appetite.

A previous observation that adrenalectomized (ADX) rats were more anorectic and lost more weight than intact controls when treated with the serotonergic agent, d,l-fenfluramine, was confirmed using a high dose of the more selective d-enantiomer, dexfenfluramine (DFEN). However, ADX rats were not more anorectic than intact controls to a lower dose of DFEN. The extreme weight loss at high doses was accompanied by a loss of appetite for NaCl solution. The rapid deterioration of these animals may have been due to excessive loss of sodium ions and extracellular fluid volume, although this was not assessed directly. This interpretation was supported in a second study in which treatment of ADX rats with a selective mineralocorticoid, which eliminates both the need and appetite for NaCl, normalized weight loss during DFEN treatment. These data do not support the idea of an interactive role of glucocorticoids and brain serotonin in anorexia. The density of serotonin uptake sites in frontal cortex was reduced by DFEN in a dose-dependent manner, but did not differ between ADX and intact control groups.

Adrenal Glands↗
PubMed1993

Dexfenfluramine treatment influences plasma catecholamines and energy substrate metabolism in rats.

The effect of chronic intragastric administration of dexfenfluramine (FFL, 1 mg/kg, twice a day), a drug that increases serotonergic transmission, on peripheral energy substrate metabolism was investigated. Rats were provided with permanent cannulas, allowing stress-free intragastric treatment and blood sampling. Fenfluramine-treated and control animals were submitted to strenuous swimming at days -2, 1, 4, and 7 relative to the onset of FFL treatment at day 0. Blood samples were taken before, during, and after exercise. Thereafter, possible changes in catecholamine sensitivity were investigated during intravenous infusions of norepinephrine (NE) and epinephrine. Finally, energy expenditure, including resting respiratory quotient (RQ), and carbohydrate and fat utilization were measured under baseline conditions. It was found that chronic administration of FFL led to a transient reduction in the exercise-induced increase of blood glucose concentrations. Plasma norepinephrine responses to exercise gradually increased in the FFL-treated animals. Baseline RQ was markedly increased in the FFL-treated animals, indicating an increase of carbohydrate utilization and a decrease of fat combustion. Total energy expenditure remained unchanged. The increased RQ was accompanied by increased sensitivity for NE and significantly decreased baseline concentrations of plasma free fatty acids.

Animals↗
PubMed1994

Tolerance to the anorectic effect of dexfenfluramine in rats: role of serotonin, cholecystokinin, and neuropeptide Y.

Tolerance to the anorectic effect of dexfenfluramine (DFEN) is shown in rats treated either chronically with low doses or once with a high dose of the agent. Rats given DFEN regimens that result in complete loss of DFEN anorexia showed no change in the anorexia caused by peripheral injection of cholecystokinin (CCK). The orexigenic effects of metergoline and neuropeptide Y were also unaltered as a function of DFEN pretreatment. Both the magnitude and duration of tolerance to a test dose of DFEN seemed to depend, in part, upon contingent (situational) factors, and were independent of whether brain serotonin (5-HT) measures were either unaffected or decreased by the DFEN pretreatment (low and high doses, respectively).

Animals↗
PubMed1995

Effect of dexfenfluramine on metabolic and neurochemical measures in restraint-stressed ob/ob mice.

Genetically obese (ob/ob) and lean C57BL/6J mice were subjected to 1 h acute restraint stress, and the effects on plasma glucose and corticosterone, and brain amines, were assessed relative to nonrestrained groups. Some mice were treated with dexfenfluramine (DFEN) prior to restraint. Compared with their lean counterparts, ob/ob mice had elevated basal plasma levels of both glucose and corticosterone. Both lean and ob/ob showed comparable absolute restraint-induced increments in these measures, but the fractional increase was much smaller in ob/ob. Metabolism of NE, DA and 5-HT was also assessed from the ratio of the metabolite-to-amine in various brain regions. Obese mice had smaller restraint-related increases in monoamine metabolism than lean their counterparts. Acute DFEN increased corticosterone, but tended to reduce the restraint-induced elevations in glucose and monoamine metabolism.

Animals↗
PubMed1988

Lipostatic and ischymetric mechanisms originate dexfenfluramine-induced anorexia.

Rats treated with physiological saline or dexfenfluramine (Isoméride, Laboratoires SERVIER, Neuilly, France) (dF), 1.75, 3.50, and 7.00 mg/kg, were studied in a computer-controlled open-circuit metabolic chamber, in which temperature was regulated at 24 degrees C. Total metabolic rate (TMR), respiratory quotient (RQ), locomotor activity (LA), energy cost of LA, and thus, locomotor free metabolic rate, were scanned at 10-second intervals throughout 22-hour uninterrupted recording sessions. The feeding pattern was also measured in relation to the dF-induced changes in the above parameters. It was found that dF induced a sustained decrease in TMR and RQ, while periodically enhancing the increase in TMR and RQ produced by the periods of LA. All phenomena occurred in a dose-dependent fashion. Anorexia was also increased as a function of the dF treatments and metabolic changes. It is concluded that dF-induced anorexia may be related to the enhanced release and utilisation of free fatty acids (lipostatic mechanism), and/or to the enhancement of metabolic rate during locomotor activity (ischymetric mechanism). In addition, it appeared that the increased prandial thermogenesis, previously reported from the measurement of changes in TMR, may be due to the dF-induced increase in the energy cost of LA, rather than to an effect of feeding per se. Indeed, in our experimental conditions, it was measured that the energetic cost of LA accounted for more than 60% of the periprandial increase in TMR.

Animals↗
PubMed1989

Effects of dexfenfluramine on the feeding behavior of rats foraging in the cold for palatable bait.

An alimentary/thermic conflict of motivation was used to explore the effects of very low doses of dexfenfluramine (dFF), an anorectic serotoninergic agonist, on the parameters of food motivation, drive and incentive (or palatability). Six rats trained to feed 2 hr/day, were given the possibility to feed on chow in a shelter (25 degrees C), and to get a snack of shortcake, a highly palatable bait, from a feeder placed 16 m away in a very cold environment (-15 degrees C). dFF at 0.6 or 1.25 mg/kg decreased neither the chow intake in the shelter, nor the mean duration of the snacks in the cold, which is the parameter believed to be the best indicator of incentive. In contrast, dFF reduced the number of trips to the bait in the cold as well as the total mass of palatable bait ingested and the mean amount ingested by snack. Such an effect was no longer observed after a food restriction had reduced the body weight of the rats to 90% of its initial value. It is concluded that, even at doses too small to reduce the consumption of basic food, dFF decreases the drive to get palatable food.

Animals↗
PubMed1991

Effects of dexfenfluramine and opioid peptides, alone or in combination, on food intake and brain serotonin turnover in rats.

Dexfenfluramine (d-FF) and opiate agonists both act on food intake but in opposite ways. Serotonin is known to be involved in the pharmacological action of both d-FF and opiates, but not necessarily in the feeding effect of the latter. In order to test this hypothesis, the effects of three opioid agonists, beta-endorphin, dynorphin and D-Ser2-Leu-Enk-Thr6 (DSLET) and of an antagonist, naltrexone, were investigated individually and in combination with d-FF on food intake and brain serotonin turnover. The opioid agonist-d-FF combinations generally produced a similar anorectic effect to that of d-FF alone, with the exception of DSLET which showed a reciprocal antagonism. The serotonergic effects varied according to the opioid tested, alone or in combination with d-FF. This does not allow to highlight a general pattern of serotonin involvement in the feeding effects of these peptides. However, all the treatments which decreased feeding (d-FF, naltrexone and the combinations dynorphin-d-FF and beta-endorphin-d-FF) displayed similar trends in hypothalamic serotonergic variations. This study evidences a role of serotonin in the feeding effect of opiates, although not similar for all of them. The use of d-FF provides a tool for assessing this involvement.

Animals↗
PubMed1992

Administration of dexfenfluramine in pregnant rats: effect on brain serotonin parameters in offspring.

Dexfenfluramine (DFEN) was infused SC at doses of either 6 or 12 mg/kg/day during the last week of pregnancy in rats. Compared with untreated controls, weight gain of dams was attenuated by DFEN without effect on the number or birth weight of offspring. Brain serotonin (5-HT) concentration and/or paroxetine binding to the 5-HT uptake carrier was reduced by 20% on the day after birth in one study but not in two other studies. No decreases in brain 5-HT parameters were observed on or after the sixth postnatal day. In contrast, mothers sustained large depletions of brain 5-HT when measured at least 3 weeks after giving birth. These data indicate that fetal brains either are protected from or recover rapidly from the 5-HT-depleting actions of high-dosage regimens of DFEN in rats.

Animals↗
PubMed1993

Stress and dexfenfluramine: effects on the immune response and energy balance in the rat.

The effects of stress, dexfenfluramine (d-Fen), and a combination of both were investigated on ingestive behavior, body weight, and the humoral immune response in the rat. Three-hundred and 84 male Sprague-Dawley rats were split into four groups of 96 animals. In a balanced design, each group was submitted or not to repeated intense stress for 20 consecutive days. Animals were also treated with 5 mg/kg/day d-Fen (IP, 1 ml/kg) or an equal volume of placebo (saline) for 28 days. The humoral immune response of rats to sheep red blood cells (50% solution, 1 ml IP at day 0) was assessed from the antibody titer on days 4, 8, 12, 16, 20, and 28. Antibodies were assayed by direct hemagglutination and by the Coombs' test. Plasma corticosterone was also measured on days 0 and 12. The effects of stress and d-Fen on ingestive behavior and body weight were consistent with previously published results. In addition, rats treated with d-Fen had a significantly reduced body weight (-20 g) 5 weeks after the end of the treatment, whereas the loss in body weight induced by stress had totally disappeared. Stress did not decrease animals' immune response despite a massive corticosterone secretion on day 0, with a marked response lasting for at least 12 days. d-Fen reduced the corticosterone levels determined on day 12. Antibody production was slightly but significantly reduced in rats receiving d-Fen.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Long-term administration of dexfenfluramine to genetically obese (ob/ob) and lean mice: body weight and brain serotonin changes.

The weight-reducing and brain 5-HT-depleting properties of dexfenfluramine (DFEN) or dexnorfenfluramine (DNOR) were measured in genetically obese (ob/ob) and lean mice. These agents were infused for 14 days via osmotic minipumps to mice fed either a low fat or a moderate fat diet. Weight loss was observed in only the obese mice, with DNOR more potent than DFEN. At the end of 14 days, neither agent caused a consistent change in either plasma glucose or corticosterone concentrations, although some effects of diet and differences between batches of mice were apparent. The levels of brain 5-HT, or of paroxetine binding that correlates with 5-HT level, were reduced by 24 mg DFEN/kg/day, a decline that persisted for at least 14 days after the end of treatment. Plasma and brain concentrations of DFEN and DNOR were measured on the last day of pump function. DNOR accounted for about 30% of the total drug + metabolite content, a ratio comparable to that in human plasma. Brain concentrations exceeded plasma by 10-fold at 6 mg DFEN/kg/day and by 17-fold at 24 mg DFEN/kg/day. The levels were higher in mice fed the moderate-fat compared with the low-fat diet. Depletions in brain 5-HT parameters were found only in the high-dose groups, and at brain total levels above about 20 microM.

Animals↗
PubMed1996

Changes in energy metabolism and metabolite patterns of obese rats after application of dexfenfluramine.

Serotonergic neuronal networks are important for food intake and body weight regulation. Dexfenfluramine (dF), a serotonin releaser and reuptake inhibitor, was used to investigate changes in food intake, body weight development, energy expenditure, respiratory quotient, and substrate oxidation rates for 12 days. Rats, which had been made obese by early postnatal overfeeding, received an energy-controlled mash diet and water ad lib and were intraperitoneally injected daily with either saline, 5 or 10 mg dF/kg. Compared to controls, food intake, body weight development, and energy expenditure were decreased in a dose-dependent manner, especially during the first 6 days. Lipid oxidation was increased while oxidation of carbohydrates was decreased. Pair-feeding experiments over 2 days revealed that this was not solely a result of diminished food intake but also an additional metabolic effect of dF, different from its anorectic effect. At the end of these experiments, plasma glucose and liver glycogen were unchanged after dF, but plasma free fatty acids were significantly decreased. Insulin-sensitivity was probably improved, indicated by decreased insulin levels and increases in muscle glycogen contents and activities of muscle pyruvate kinase. Liver-glutamine and contents of valine, leucine, and isoleucine in the muscle were significantly decreased after dF-treatment, the latter indicating a diminished proteolysis. The plasma tryptophan/large neutral amino acids ratio of the dF-rats was unchanged but that of the paired-fed rats was changed, despite similar changes in food intake. It is concluded that both increased oxidation of endogenous fat and reduced food intake could mediate the body weight reducing effect of dF.

Animals↗
PubMed1994

Cholecystokinin- and dexfenfluramine-induced anorexia compared using devazepide and c-fos expression in the rat brain.

It has been proposed that there might be a link between the anorectic actions of cholecystokinin (CCK) and serotonin (5HT). The present study compared the patterns of c-fos protein-like immunoreactivity (FLI) induced in rat brain by CCK and the indirect 5HT agonist dexfenfluramine (DFEN), as well as the ability for devazepide, a CCK-A receptor antagonist, to antagonize both anorexia and FLI induced by these agents. Devazepide reversed the anorectic effect of CCK but not that of DFEN in food deprived rats. The FLI induced by CCK and DFEN occurred in similar brain regions, but in different subdivisions. Such regions included the bed nucleus of the stria terminalis (BST), the lateral central nucleus of the amygdala (CeL), and the lateral parabrachial nucleus (LPB). Devazepide abolished the FLI induced by CCK in most of these brain regions, but had no effect on FLI induced by DFEN. These results suggest that the LPB-CeL/BST pathway might be responsible for the anorectic effects of both CCK and DFEN, but different parts or neuronal populations in these structures might be differentially engaged by CCK and DFEN. The putative interaction between CCK and 5HT might happen along this pathway, rather than in the periphery.

Animals↗
PubMed1996

Effects of dexfenfluramine or 5,7-dihydroxytryptamine on tryptophan hydroxylase and serotonin transporter mRNAS in rat dorsal raphe.

Dexfenfluramine (DF), given in high doses, can produce long-lasting decreases in brain levels of serotonin (5-HT) and 5-HT transporter (5-HTT) protein. The purpose of this study was to determine if DF-induced decreases in 5-HT and 5-HTT in rat forebrain are correlated with compensatory changes in the expression of the genes for tryptophan hydroxylase (TPH) and 5-HTT in the dorsal raphe nucleus. Gene transcripts were measured by quantitative reverse transcription-polymerase chain reaction (RT-PCR). Rats were treated with either one or eight injections of DF at either high (10 mg/kg) or low (2 mg/kg) doses. A positive control group for 5-HT cell loss received a single cerebroventricular injection of 5,7-dihydroxytryptamine (DHT). Rats were killed either 5, 15 or 30 days after their last treatment. Paroxetine binding to the 5-HTT protein in frontal cortex was, as expected, reduced in all of the treated groups relative to vehicle controls. TPH mRNA levels in the dorsal raphe of animals that received DHT were significantly higher than those measured in all other treatment groups 15 days following treatment. By 30 days, the amount of TPH mRNA in DHT-treated rats had fallen to well below control levels. None of the DF regimens significantly affected TPH mRNA levels. Unlike the TPH mRNA changes in DHT-treated rats, the 5-HTT mRNA levels in the dorsal raphe declined progressively throughout the 30 day survival period. None of the DF regimens significantly affected 5-HTT mRNA levels. The significance of these data are discussed in terms of whether loss of forebrain markers for 5-HT reflects either the loss of fine caliber 5-HT axon terminals or a decrease in the expression of these markers in the somata of these cells which are located in the dorsal raphe.

5,7-Dihydroxytryptamine↗
PubMed1996

Dexfenfluramine lacks amphetamine-like abuse potential.

1. The amphetamine-like abuse potential of dexfenfluramine (dFEN) was evaluated using drug discrimination and self-administration procedures. 2. Male Fischer rats were trained to discriminate either dFEN (1.0 mg/kg) or d-amphetamine (dAMP; 1.0 mg/kg) from saline in a two-choice discrete-trial avoidance paradigm. 3. In dAMP-trained rats, dFEN (0.5-4.0 mg/kg) engendered almost exclusively saline-appropriate responding. In dFEN-trained rats, dAMP (1.0-4.0 mg/kg) engendered entirely saline-appropriate responding in 3 of 6 rats and intermediate levels of dFEN-appropriate responding in the remaining animals. 4. Potential reinforcing effects of dFEN were also evaluated in 3 male rhesus monkeys trained to self-administer cocaine (i.v.) during daily 60 min sessions under a fixed-ratio (FR)-10 schedule. 5. Various doses of dFEN (30-1000 micrograms/kg/infusion) and dAMP (10 micrograms/kg/infusion) were substituted for cocaine in 4 consecutive daily sessions. In all subjects, dFEN maintained rates of self-administration within the range of rates maintained by saline and considerably below those maintained by cocaine and dAMP. Furthermore, the within-session distribution of responding with dFEN resembled that produced by saline. 6. Taken together, these results strongly suggest that dFEN will not have amphetamine-like abuse potential in humans.

Amphetamine↗
PubMed1993

Dexfenfluramine induces Fos-like immunoreactivity in discrete brain regions in rats.

Administration of the anorectic agent, dexfenfluramine (DFEN) to rats induced dose- and time-dependent expression of Fos-like immunoreactivity in several discrete brain regions of rats. At moderate doses, the regions showing the most intense Fos immunostaining included the bed nucleus of the stria terminalis, the lateral part of the central amygdala, midline thalamic nuclei, habenular nuclei, lateral parabrachial nucleus, and nucleus of the solitary tract. It is suggested that these nuclei, many of which are known to receive gustatory or visceral input, may form part of a functional circuit via which DFEN modulates food intake. Rats that were made hungry by either food deprivation or administration of insulin also showed induction of Fos in several brain regions, but only that in the supramamillary/ventral tegmental area was suppressed by pretreatment with an anorectic dose of DFEN. The functional significance of these sites requires further investigation.

Animals↗