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An anorectic drug, dexfenfluramine (dF) is commonly used in obesity treatment. The aim of our study was to investigate if dexfenfluramine used alone or together with alpha 2-adrenolitic yohimbine (Y), can change cardiovascular state in obese women.
We describe the use of dexfenfluramine (Redux) in six patients with mood disorders (bipolar disorder = 3; major depression = 3) who developed significant weight gain as a result of their psychotropics. All patients were females with an age range of 27-58 years. The duration of the trial varied from 3 to 20 weeks, with the dexfenfluramine dosage being 15 mg twice daily. Weight loss ranged from 2 to 23 pounds. None of the patients had any evidence of primary pulmonary hypertension or serotonin syndrome, despite being on serotonergic agents such as fluoxetine, paroxetine, and sertraline.
Increased visceral adipose tissue is thought to contribute to impaired glucose tolerance. We studied 10 men with non-insulin dependent diabetes (NIDDM) before and after a 12-week intervention study using dexfenfluramine. Subjects had a mean body mass index (BMI) of 26.4 +/- 1.7 kg/m2 and had an abdominal distribution of body fatness (waist-to hip ratio > 0.9). Anthropometric indices, biochemistry, macronutrient intake from 7-day food records as well as a euglycaemic glucose clamp and magnetic resonance imaging (MRI) were performed at week 0 and week 12. Abdominal adipose tissue area measured by MRI was reduced from 854 +/- 270 cm2 to 666 +/- 231 cm2 (p = 0.003) due mainly to a selective 32% reduction in visceral fat area from 484 +/- 230 cm2 to 333 +/- 72 cm2 (p = 0.002). Insulin sensitivity improved from 0.29 +/- 0.13 [min-1 (mU/L)] to 0.54 +/- 0.21 [min-1 (mU/L)] (p = 0.01) and C-peptide levels reduced from 0.77 +/- 0.24 mumol/L to 0.58 +/- 0.15 mumol/L (p = 0.002). The reductions in fasting glucose and glycated haemoglobin failed to achieve significance. Fasting total cholesterol and triglyceride levels significantly reduced (p = < 0.001 and p = 0.021 respectively). There was a reduction in total energy intake (p = 0.005) due to a significant reduction in calories obtained from fat (p < 0.001). Thus dexfenfluramine was shown to be a useful adjunct therapy for the reduction of visceral fat in abdominally-obese men with NIDDM with an associated improvement in insulin sensitivity.
Appetite suppressants, including aminorex and fenfluramine, have been associated with pulmonary hypertension ever since the well-known outbreak of primary pulmonary hypertension in Europe after treatment with aminorex. The usage of a new anorectic agent, dexfenfluramine, has recently increased dramatically in developed countries. We report 2 new cases of lethal pulmonary hypertension associated with the use of dexfenfluramine.
The effect of dexfenfluramine (dF) on body weight, blood pressure and noradrenergic activity were studied in 30 obese hypertensive patients randomly divided into two groups and treated for 3 months either with dF (30 mg daily; 16 subjects) or placebo (Pl; 14 subjects). 11 patients from the dF group and 9 patients given Pl completed the entire experimental protocol, including monthly visits for metabolic and hormonal measurements, as well as a bicycle exercise test with arterial catheterisation for haemodynamic and catecholamine measurements performed before and after 3 months of treatment. A progressive significant decrease in body weight, averaging 6.0 kg after 3 months was observed in the dF-treated group, whereas loss of weight in the placebo group (1.4 kg) was not significant. While blood pressure and noradrenergic activity, assessed as changes in the plasma levels and urinary excretion of norepinephrine, remained unaffected in the Pl group, a significant drop in the supine systolic and diastolic blood pressures, as well as in the resting venous norepinephrine level and in urinary norepinephrine excretion was found after the first month of dF administration. In addition, the exercise-induced rise in systolic and diastolic blood pressure, as well as in arterial plasma norepinephrine and epinephrine concentrations, was significantly reduced after 3 months of dF administration; there were no such changes in the Pl-treated group. The results of the present study indicate that, in addition to the weight-reducing effect of dexfenfluramine, its hypotensive effect may be mediated by a decrease in noradrenergic activity.
The purpose of the present study was to examine the effects of the 5-HT3 antagonists ondansetron and MDL72222, and the 5-HT releaser and reuptake inhibitor dexfenfluramine, on intravenous heroin self-administration by Wistar rats. Using separate squads of animals, two separate schedules of heroin reinforcement were used; a relatively low dose (0.03 mg/kg per infusion) made available under a FR5 schedule for 1 h each day, and a moderate heroin dose (0.1 mg/kg per infusion) available under a FR1 schedule for 2 h each day. Following the acquisition of stable levels of responding across days, both naloxone pretreatment (0.25 mg/kg SC) and halving the heroin infusion dose produced increases in operant responding for heroin at each concentration. Neither ondansetron (0.01-1 mg/kg SC) nor MDL72222 (0.1-3 mg/kg SC) pretreatment influenced heroin self-administration. Chronic treatment (5 day) of ondansetron (0.01-0.1 mg/kg) was similarly ineffective. However, dexfenfluramine (0.5-2.5 mg/kg IP) consistently reduced heroin self-administration at doses producing only modest decreases in food responding. These findings are in contrast to place conditioning studies, which show that 5-HT3 antagonists but not indirect 5-HT agonists block a morphine-induced place preference. Reasons for such discrepancies remain to be determined.
Chronic administration of dexfenfluramine, at a relatively low daily dose, slowed the development of salt-induced elevation of blood pressure in salt-sensitive (Dahl DS and Rapp SS) rats. This effect could not be accounted for by drug-related anorexia alone. Elevated serotonin activity, possibly in the brain, may underlie this antihypertensive action of dexfenfluramine.
Dexfenfluramine, administered chronically either SC via osmotic minipump (3 mg/kg/day) or as daily IP injections (1.5 mg/kg) to rats, suppressed tail pinch-induced eating for up to 14 days. The minipump regimen also caused a reduction of intake of a palatable "dessert" for up to 9 days in heavy, adult rats, but was only transiently effective in young, rapidly growing rats. Nonetheless, the regimen produced decreased weight gain and insensitivity to a subsequent acute test dose of the agent. These results illustrate the sustained anorectic efficacy of dexfenfluramine in paradigms that do not involve restriction of diet, and these may be animal models of snacking or binging. The data also corroborate previous suggestions that the agent is more effective in older or more obese populations.
The effects of two indirect (dexfenfluramine and fluoxetine) and one direct (RU 24969) serotonergic agonists on diet selection over a 12-hr period were examined. Rats were habituated to eat, during the dark period, from two isoenergetic diets that differed in carbohydrate and protein content. Drugs were injected intraperitoneally at 1845 hr, 15 min prior to food access. The drugs exerted their effects mainly during the first hour of feeding (1900-2000 hr). At this time, a selective suppression in intake of the high carbohydrate-low protein diet was the most prominent characteristic of all three serotonergic agonists. This macronutrient specific effect was particularly strong at low dosages (dexfenfluramine, fluoxetine and RU 24969: 0.5, 2.0 and 1.0 mg/kg, respectively). With time, as the effect of drugs wore off, diet selection pattern became more variable. The fact that both indirect 5-HT agonists and a direct selective 5-HT receptor agonist share a specific behavioral effect provides additional support for the role of serotonin in the control of macronutrient specific appetites.
A method to determine the concentration of dexfenfluramine and its active metabolite nordexfenfluramine in human urine from healthy volunteers is described utilising a high-performance liquid chromatographic procedure with liquid-liquid extraction and ultraviolet detection. Analytes are measured after extraction of alkalinised urine with diethyl ether and subsequent back extraction with 0.5 M H2SO4 and with chromatography performed on a reversed-phase C18 column, using a mobile phase of acetonitrile-50 mM K2HPO4 (25:75, v/v) (flow-rate 1.3 ml/min) and ultraviolet detection at 210 nm. The sensitivity of the technique (10 ng/ml) is appropriate to measure both parent drug and metabolite in urine in humans for up to 5 days after a single 30-mg dose. The method is selective, reproducible (within- and between-day coefficient of variation ranged from 4.2 to 15%) and accurate (bias less than 8%) and thus suitable for dexfenfluramine pharmacokinetic investigations.
Dexfenfluramine (Redux), the dextro-rotatory (+) steroisomer of fenfluramine, was previously approved for the treatment of weight control in the United States. We report a case of acute dexfenfluramine ingestion characterized by coma, clonus, and respiratory failure.
A specific and useful method was developed for the determination of dexfenfluramine metabolism by microsomal systems utilising GC-MS. The synthesis of two metabolites 1-(3-trifluoromethylphenyl)propan-2-ol ('alcohol') and 1-(3-trifluoromethylphenyl)-1,2-propanediol ('diol') via straightforward routes, were confirmed by MS and NMR spectra. The conditions for extraction from alkalinised microsomal mixtures of the metabolites nordexfenfluramine, 1-(3-trifluoromethylphenyl)propan-2-one ('ketone'), alcohol and diol, their conversion to trifluoroacetate derivatives and analysis by GC-MS-SIM are described. Calibration curves were constructed between 48 and 9662 nM and fitted to quadratic equations (r2>0.999). The method precision was good over low (121 nM) medium (2415 nM) and above medium (9662 nM) concentrations for all metabolites; the within- and day-to-day coefficients of variation ranged between 2.5-12.4% and 6.7-17.5%, respectively. The accuracy, measured as bias, was very good both within- and day-to-day (range: -0.4-12.6%, 0.8-18.9%). For most metabolites, the C.V. for the assay and bias increased at 121 nM. Dexfenfluramine metabolism by rat liver microsomes was investigated using the assay method and showed a concentration dependent increase in nordexfenfluramine and ketone metabolites over the substrate range of 5-200 microM.
OBJECTIVE: Hyperactivity of the HPA axis is a possible mechanism underlying abdominal obesity. We aimed to evaluate in premenopausal women with abdominal obesity, (i) the hypothalamic-pituitary-adrenal (HPA) axis responses to direct pituitary stimulation with corticotrophin releasing hormone (CRH) and to opioid blockade with naloxone, and (ii) the interaction between short-term serotoninergic activation with dexfenfluramine (dF), a serotonin-release agonist, and these responses. DESIGN AND SUBJECTS: Eight obese women (mean BMI, 35 kg/m2) with waist to hip ratio (WHR) > 0.85 were tested with CRH (1 microgram/kg i.v.) and naloxone (125 micrograms/kg i.v.) before and at the end of two treatment periods with dF (15 mg twice daily for 7 days) and placebo (washout 7 days) in a cross-over design. Eight normal weight control women were tested with CRH and naloxone. RESULTS: Prior to treatment, ACTH and cortisol responses to naloxone (areas under the curve) were significantly higher in obese women then in control women (P = 0.027 and P = 0.035 respectively) dF treatment resulted in significant (P < 0.05) reduction of ACTH and cortisol increments. In contrast, ACTH and cortisol responses to CRH were not significantly different in obese and control subjects and were unaffected by dF treatment. CONCLUSION: We conclude that women with abdominal obesity have hyperreactivity of the HPA axis to opiod blockage and that dexfenfluramine treatment reduces this hyperactivity.
This randomized, placebo-controlled, double-blind study was designed to evaluate the safety and efficacy of dexfenfluramine (Dfen). Dfen 15 mg BID, and placebo were administered for 12 weeks to 337 moderately obese patients on calorically restricted diets. Patients were monitored for an additional 4 weeks. Efficacy was evaluated in 321 patients who were an average of 52% in excess of ideal body weight. Dfen-treated patients lost significantly more weight than did those treated with placebo (p less-than-or-equal 0.001). Small nonsignificant fluctuations in body weight were observed during the 4-week posttreatment period in both groups. The most common drug-related side effects were diarrhea, asthenia, dry mouth, and thirst (p less-than-or-equal 0.05 compared with placebo). Dexfenfluramine may become a valuable addition to weight loss and weight management programs.
At very low doses dexfenfluramine, a serotonin agonist, is a potent inhibitor of hoarding behavior. The dose able to suppress 40% of this food motivated response (ED 40) is approximately 0.3 mg/kg. The action of dexfenfluramine is mediated through serotoninergic receptors because it is suppressed by a pretreatment with metergoline, a selective serotonin-receptor blocker, but is not modified by haloperidol, a dopamine antagonist.
The authors report a case of severe pulmonary hypertension after long-term dexfenfluramine treatment in a 48 year old man with no previous medical history. Dexfenfluramine, which has previously been reported to cause pulmonary hypertension, is an amphetamine-like anorexic agent, a pharmacological group known to predispose to this type of side effect. The possibility of this complication should be born in mind before prescribing the drug. In particular, it would seem to be particularly important not to exceed the recommended length of treatment especially as potential reversibility of pulmonary hypertension on withdrawal of the drug has been reported in one case.
In depressive disorders an association between basal pre-treatment plasma ratios of tryptophan (Trp) and tyrosine (Tyr) to other large neutral amino acids (LNAA) and the clinical efficacy of serotonergic acting drugs have been established. In order to clarify whether a similar relation exists in obesity and to elucidate the long-term effect of dexfenfluramine (dF) on plasma amino acid profiles and macronutrient selection, we examined 29 obese patients participating in a 12 months double-blind weight loss trial with either dexfenfluramine (dF) (30 mg/day) or placebo (PL) in conjunction with 4.2-5.0 MJ/d diet. Maximum weight loss was obtained after 6 months (dF 12.8 +/- 5.4 kg; PL 13.8 +/- 9.2 kg, x +/- s.d., ns). Plasma Trp/LNAA and Tyr/LNAA were found to be lower than in normal weight controls and were further reduced during treatment (p < 0.05), but without differences between dF and PL groups. Macronutrient selection was not affected by the dF treatment. In the placebo group weight loss was associated with a high pre-treatment energy intake and a high carbohydrate-protein ratio (p < 0.05). A decrease in dietary fat and increase in protein intake (%) and age was found to explain 82% of the variation in weight loss (p < 0.0005), whereas no correlation could be shown in the dF group. Pre-treatment plasma Trp/LNAA or Tyr/LNAA and weight loss were not correlated. In conclusion, neither food selection nor basal plasma amino acid profiles were predictors of weight loss during long-term treatment with dF as an adjuvant to energy restriction, and they were not affected by the drug treatment.
The effect of dexfenfluramine, the new serotoninergic appetite suppressor, was tested in 20 women. The drug was administered 3 months, 15 mg twice a day. A selected reduction of carbohydrate and of fat intake was observed. The body weight decreased mainly due to fat loss in the abdominal region. An important decrease of blood lipids was recorded, while insulinemia and OGTT remained unchanged. Serum alkaline phosphatase increased and ALT decreased. Other liver tests did not change. During the treatment the level of cortisol, TSH, T3 and 17-ketosteroids were not affected. T4 decreased and GH increased. These metabolic and hormonal effects were discussed. The treatment with dexfenfluramine was well tolerated and was found to have several favourable effects.