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PubMed2000

Prevalence and diagnostic value of precordial murmurs for valvular regurgitation in obese patients treated with dexfenfluramine.

Echocardiography is recommended for the detection of valvular regurgitation in asymptomatic users of anorexigens with a heart murmur. To determine the prevalence and diagnostic value of heart murmurs for valvular regurgitation, 223 patients receiving dexfenfluramine therapy for 6.9 months and 189 matched controls underwent history and cardiac auscultation by experienced noncardiologists unaware of echocardiography. Color Doppler echocardiograms were interpreted by 3 observers unaware of patients' clinical data. The frequency of at least mild regurgitation of any valve and abnormal regurgitation (moderate mitral or tricuspid or mild aortic regurgitation) were determined. Heart murmurs heard in 31 dexfenfluramine users (14%) and in 20 controls (11%) were all systolic and of grade I to II/VI intensity. Mild or worse regurgitation of any valve showed a trend in patients (18% vs 11.6% in controls, odds ratio [OR] 1.66, confidence interval [CI] 0.95 to 2.9, p = 0.08), but abnormal regurgitation (includes Food and Drug Administration grade regurgitation) was more common in patients (9% vs 3% in controls, OR 3.0, CI 1.18 to 7.65, p = 0.02). In dexfenfluramine users, heart murmurs were associated with at least mild or abnormal regurgitation (OR 3.1 and 3.05, 95% CI 1.34 to 7.13 and 1.1 to 8.67; p = 0.008 and 0.036, respectively), had a specificity of 89% and 88%, negative predictive value of 85% and 93%, but sensitivity of 37% and 30%, and positive predictive value of 35% and 19%, respectively. Most valves missed by cardiac auscultation had normal morphology and mild regurgitation. Finally, heart murmurs had better diagnostic value for either type of valvular regurgitation than heart murmurs and clinical variables or clinical variables alone. In summary, in dexfenfluramine users the prevalence of heart murmurs was low and their absence predicted absence of mild or worse regurgitation of any valve or abnormal valvular regurgitation. Therefore, cardiac auscultation should be the screening method of choice for detecting valvular regurgitation in users of anorexigens.

Case-Control Studies↗
PubMed2000

Comparative study of fluoxetine, sibutramine, sertraline and dexfenfluramine on the morphology of serotonergic nerve terminals using serotonin immunohistochemistry.

We compared the effects of treatment with high doses of fluoxetine, sibutramine, sertraline, and dexfenfluramine for 4 days on brain serotonergic nerve terminals in rats. Methylenedioxymethamphetamine (MDMA) and 5,7-dihydroxytryptamine (5,7-DHT) were used as positive controls because both compounds deplete brain serotonin. Food intake and body weight changes were also monitored and yoked, pair-fed animals were used to control for possible changes in morphology due to nutritional deficits. Fluoxetine, sibutramine, sertraline and dexfenfluramine all produced a significant reduction in body weight. Fluoxetine, sibutramine and sertraline treatment resulted in no depletion of brain serotonin but produced morphological abnormalities in the serotonergic immunoreactive nerve network. In contrast, dexfenfluramine and MDMA depleted brain serotonin and produced morphological changes in the serotonin nerve network. These results indicate that even though fluoxetine, sibutramine and sertraline do not deplete brain serotonin, they do produce morphological changes in several brain regions (as identified by serotonin immunohistochemistry). Dexfenfluramine and MDMA, on the other hand, markedly deplete brain serotonin and also produce morphological changes. Collectively, these results lend support to the concept that all compounds acting on brain serotonin systems, whether capable of producing serotonin depletion or not, could produce similar effects on the morphology of cerebral serotonin systems.

Animals↗
PubMed2001

Influence of the 5-HT(2C) receptor antagonist SB242,084 on behaviour produced by the 5-HT(2) agonist Ro60-0175 and the indirect 5-HT agonist dexfenfluramine.

Ro60-0175 has been described as a selective agonist at the 5-HT(2C) receptor, yet it has only 10- fold higher affinity at the 5-HT(2C) compared to the 5-HT(2A) subtype, and equivalent affinity for the 5-HT(2B) receptor. The selective 5-HT(2C) receptor antagonist SB242,084 (0.5 mg kg(-1) i.p.), blocked the hypoactivity and penile grooming induced by Ro60-0175 (1 mg kg(-1) s.c.). The combination of SB242,084 (0.5 mg kg(-1) i.p.) and Ro60-0175 (3 - 10 mg kg(-1)) produced a completely different pattern of behaviours including wet-dog shakes, hyperactivity and back muscle contractions. These latter effects were blocked by the selective 5-HT(2A) receptor antagonist MDL100,907 (0.5 mg kg(-1) i.p.), but not the 5-HT(2B) receptor antagonist SB215,505 (3 mg kg(-1) p.o.). The indirect 5-HT releaser/reuptake inhibitor dexfenfluramine (1 - 10 mg kg(-1) i.p.) produced a mild increase in locomotor activity, penile grooming, and occasional back muscle contractions and wet-dog shakes. Pre-treatment with SB242,084 (0.5 mg kg(-1)), blocked the incidence of penile grooming, and markedly potentiated both the dexfenfluramine-induced hyperactivity, the incidence of back muscle contractions, and to a lesser extent wet-dog shakes. Some toxicity was also evident in animals treated with dexfenfluramine (10 mg kg(-1))/SB242,084 (0.5 mg kg(-1)), but not in any other treatment groups. The hyperactivity and toxicity produced by the dexfenfluramine (10 mg kg(-1))/SB242,084 (0.5 mg kg(-1)) combination was replicated in a further study, and hyperthermia was also recorded. Both hyperthermia and toxicity were blocked by MDL100,907 (0.5 mg kg(-1)) but not SB215,505 (3 mg kg(-1)). An attenuation of the hyperlocomotor response was also observed following MDL100,907. These findings suggest that 5-HT(2C) receptor activation can inhibit the expression of behaviours mediated through other 5-HT receptor subtypes.

Aminopyridines↗
PubMed1999

Use of dexfenfluramine, fenfluramine and phentermine and the risk of stroke.

AIMS: To estimate the incidence of newly diagnosed idiopathic stroke among users of fenfluramine, dexfenfluramine and phentermine compared to obese nonusers. METHODS: We conducted a cohort study with nested case-control analysis utilizing data from the General Practice Research Database in the UK. Eight thousand four hundred and twenty-three subjects aged 69 years or less at the start of follow-up were exposed to at least one of the three study drugs and 17 225 similarly obese subjects were not exposed to any of the study drugs. RESULTS: We identified 45 incident cases of idiopathic CVA in this cohort of subjects. The incidence of CVA among all current users of a diet drug was 1.3/1000 person-years (95% CI 0.5, 3.5). The incidence for current fenfluramine users (n=2) was 2.6/1000 person-years (95% CI 0.7, 9.6), for current dexfenfluramine users (n=1) 1.1/1000 person-years (95% CI 0.3, 3.8), and for current phentermine users 0/1000 person-years (95% CI 0.0, 12.9). The incidence in obese nonusers was 0.6/1000 person-years (95% CI 0.4, 0. 9). The adjusted matched odds ratio (OR) for thrombotic stroke from the case-control analysis comparing current use of a diet drug to nonuse was 2.4 (95% CI 0.6, 9.1). There was only one exposed subject among seven who had haemorrhagic stroke. CONCLUSIONS: The incidence of CVA in generally young obese subjects during use of fenfluramine, dexfenfluramine or phentermine is low. Although we found an OR of 2. 4 comparing users of any of the anorexiants with nonusers, this is based on only three exposed cases and the confidence limits are wide. We conclude that our study does not support a substantial increased risk of stroke attributable to the use of fenfluramine, dexfenfluramine or phentermine.

Aged↗
PubMed1999

Possible thermogenesis with dexfenfluramine.

Fifty obese patients with a body mass index greater than 25 kg/m2 were randomized into 3 groups: control (C = 19), placebo (P = 18) and dexfenfluramine (D = 18). A behavioral modification program which included eating habits, exercise, attitudes, social relationships and six steps to lifetime weight control was taught every week. All patients strictly followed the food manual and recorded their behavior, physical activity and food intake every day through 12 weeks. Placebo and dexfenfluramine 30 mg/day were given in a double blind placebo controlled study. The results showed that all 3 groups had significant decreases in rest times and increased activity times (p < 0.05) and significant reductions of the average total daily energy, carbohydrate and fat intake (p < 0.05). They all lost weight. Mean +/- SEM cumulative weight loss was 8.3 +/- 0.7 kg in group D, 3.3 +/- 1 kg, in group P and 2.9 +/- 0.7 kg, in group C. The mean additional weight loss of 5 kg, and 5.4 kg seen with dexfenfluramine being highly significant (p < 0.001) from group P and C most likely due to increased thermogenesis. Significant (p < 0.05) and gradual reduction of biceps, triceps skinfold and per cent body fat were constantly observed only in the dexfenfluramine group. There were no significant differences among the 3 groups regarding blood pressure, heart rate, hematologic, lipids and biochemical profiles.

Adolescent↗
PubMed2000

Efficacy of dexfenfluramine in the treatment of alcohol dependence.

BACKGROUND: A substantial body of evidence supports a role for serotonin in modulating alcohol intake, which suggests that this neurotransmitter represents a promising target for pharmacotherapy development for alcohol use disorders. Dexfenfluramine. a serotonin releaser and reuptake inhibitor, decreases alcohol self-administration by rats. Its greater potency and several mechanisms of action suggest it should be more effective in treating alcohol dependence than drugs that only inhibit serotonin reuptake. METHODS: We conducted an 11 week, randomized, double-blind trial that compared oral placebo and dexfenfluramine 7.5, 15, 22.5, and 30 mg bid in 136 alcohol-dependent patients. A brief behavioral intervention was offered concurrently. RESULTS: The majority of subjects were male (72%), and the age of the group was 44 +/- 1 years (mean +/- SD). Both placebo- and drug-treated groups significantly reduced alcohol consumption compared with baseline (a 55% decrease in mean drinks per day; p < 0.01), but there were no significant differences between drug and placebo groups or dose effects for most outcome measures. CONCLUSIONS: Our results with dexfenfluramine are further evidence that serotonergic medications on their own do not significantly reduce alcohol consumption in alcohol-dependent individuals. Combination pharmacotherapy with agents that act on different receptors or neurotransmitter systems (e.g., naltrexone plus dexfenfluramine) may be one way to enhance serotonergic effects on drinking behavior and should be considered in future medication development clinical trials.

Adult↗
PubMed1995

Chronobiometric identification of disorders of hunger sensation in essential obesity: therapeutic effects of dexfenfluramine.

In human beings, hunger is a proprioceptive signal that shows intraday (circadian components) and within-day (ultradian components) recursivity. Both periodic components can be investigated by chronobiometric procedures by combining the Cosinor method with spectral analysis. A 24-hour profile of hunger sensation (HS) can be plotted on a 1-to-10 scale of intensity using self-rated scores performed every half-hour of the day. Circadian and ultradian components were studied in 60 patients affected by essential obesity (20 men and 40 women; mean age, 38.4 years; mean body weight, 101 kg) before and after treatment with dexfenfluramine (Isomeride; Servier, Orléans, France) 15 mg orally twice daily, for 30 days. The control group consisted of 30 clinically healthy subjects (15 men and 15 women; mean age, 37.5 years; mean body weight, 69 kg). Chronobiometric analysis shows three patterns in obese patients, which suggests that HS may be normal (eurectic obesity), exaggerated (hyperrectic obesity), or diminished (hyporectic obesity). After dexfenfluramine administration, HS was showed a substantial decrease in the daily mean level. The spectrum of resolution in circadian and ultradian components was found to be maintained in eurectic obesity and partially readjusted in hyperrectic and hyporectic obesities. This demonstrates that dexfenfluramine acts not only as an anorectic but also as a chronizer by interfering with the recursive components of HS. The anorectic and chronizing effects suggest that dexfenfluramine is a "chronoanorectic drug" that interacts with the chronobiologic properties of the serotoninergic system.

Adult↗
PubMed1990

Reversal of a feeding-reward system by dexfenfluramine: neurochemical involvement.

In addition to its anorectic properties, dexfenfluramine may inhibit some manifestations of feeding-related reward. We attempted to verify this effect by measuring paw-lick latency on the hot plate test in rats conditioned to expect a palatable food. The involvement of variations in beta-endorphinergic, dopaminergic and serotonergic systems was assessed. Despite an inherent effect of increasing paw-lick latency, dexfenfluramine (1.5 mg/kg IP) partly reversed the expectancy-induced increase in this latency. Saline-treated "expectant" rats displayed elevated plasma beta-endorphin levels and reduced hypothalamic 5-HIAA/5-HT and DOPAC/DA ratios. Only the decrease in the DOPAC/DA ratio was reversed by dexfenfluramine, suggesting an involvement of the dopaminergic system in this dexfenfluramine-sensitive reward system.

Animals↗
PubMed1998

Acute and chronic effects of dexfenfluramine on the porcine pulmonary artery.

1. Studies were designed to investigate the responses of isolated pulmonary arteries from control pigs or pigs chronically treated with dexfenfluramine (7.2 mg/kg per day orally for 4 weeks). 2. Rings with and without endothelium were suspended in organ chambers for recording of isometric tension. 3. Dexfenfluramine (10[-9] to 10[-6] M) did not affect vascular tone, but at higher concentrations caused contractions that were not affected by indomethacin, methiothepin, the presence of endothelium or by the chronic treatment. 4. Chronic treatment augmented the endothelium-dependent relaxations to serotonin and aggregating platelets but not those to adenosine diphosphate. It did not affect the contraction or rings without endothelium evoked by platelets, nor the relaxation to SIN-1, a nitric oxide donor. The maximal contraction to endothelin-1 (but not that of norepinephrine) was impaired in treated pigs. 5. These results show that dexfenfluramine causes contraction of isolated porcine pulmonary arteries only at concentrations higher than 3 x 10(-6) M, and that chronic treatment with dexfenfluramine potentiates the endothelium-dependent relaxations to serotonin and aggregating platelets in the porcine pulmonary artery without affecting their direct effect on the smooth muscle.

Animals↗
PubMed1997

Measurement of liver fat by MRI and its reduction by dexfenfluramine in NIDDM.

OBJECTIVE: To validate a variation of a well-established magnetic resonance imaging (MRI) technique to detect liver fat and use it to monitor liver fat changes after treatment with dexfenfluramine in men with non-insulin dependent diabetes mellitus (NIDDM). DESIGN: (a) Simple correlation study of MRI Liver Fat Index with liver biopsy results; (b) Open Study of 10 men with NIDDM treated with dexfenfluramine for 12 weeks in addition to their 'usual' therapy. SUBJECTS: (a) 19 patients (3F; 16M) with abnormal liver function tests undergoing liver biopsy; (b) 10 men, Body Mass Index (BMI) < 30, Waist to hip ratio (WHR) > 0.90 with poorly controlled NIDDM despite oral sulphonylurea therapy. MEASUREMENTS: (a) MRI liver fat; standard liver biopsy; (b) MRI visceral fat, MRI liver fat, euglycaemic clamp, plasma lipids, fasting glucose and c-peptide levels. RESULTS: In the validation group, there was a strong relationship between the MRI Liver Fat Index and histopathological assessment of the liver biopsies (r = 0.87, < 0.0001). During treatment with dexfenfluramine the mean Liver Fat Index reduced from 10.6 +/- 3.4 to 6.6 +/- 2.8 (P = 0.05). The reduction in Liver Fat Index correlated with the reduction in visceral fat (r = 0.84, P = 0.001) as well as with the improvement in insulin sensitivity (r = 0.62, P = 0.05). Using partial correlation analysis, the relationship between the change in visceral adipose tissue and the improvement in insulin sensitivity was weaker if the Liver Fat Index was kept constant (r = 0.76 decreased to r = 0.56). CONCLUSIONS: In this group of subjects MRI Liver Fat Index correlated well with liver fat as seen on biopsy. The Liver Fat Index reduced after 12 weeks therapy with dexfenfluramine suggesting a role for hepatic steatosis in the complex interaction between visceral adipose tissue and insulin sensitivity.

Adult↗
PubMed1990

Dexfenfluramine. Its place in weight control.

Dexfenfluramine, the dextrostereoisomer of fenfluramine, is a pure serotonin (5-hydroxytryptamine) agonist, apparently devoid of any additional antidopaminergic or sympathomimetic effects. The drug is approximately twice as effective as its racemic predecessor in reducing food intake in animals, and at a dose of 30 mg/day dexfenfluramine substantially modifies eating behaviour in man. Thus, a reduction in the motivation to eat and fewer snacking episodes were seen in volunteers treated with the drug, while total caloric and carbohydrate (but not protein) intakes were reduced in obese carbohydrate cravers. In clinical studies in obesity, dexfenfluramine combined with dietary support has produced mean weight reductions superior to those achieved with placebo over 3-month treatment periods. Importantly, the drug appears to maintain its weight-reducing effects for at least 12 months, without serious adverse effects. Dexfenfluramine appears to possess many of the properties of an 'ideal' pharmacotherapeutic agent for obesity. However, further long term clinical studies are required to confirm the promising efficacy and safety data obtained to date, and to further define the most appropriate indications for its use. Ideally, the drug should be used as adjunctive treatment in the clinical management of more severe cases of obesity, which are refractory to simpler supportive measures such as dietary or psychological counseling.

Animals↗
PubMed1992

Dexfenfluramine and appetite in humans.

Dexfenfluramine has been demonstrated to produce decreases in daily energy intake varying between 13 and 25% depending on the time for which the drug has been administered. This reduction in energy intake is achieved by a decrease in the size of meals (11-40% depending on the dose) and by a decrease in the frequency of snacks consumed between meals. These objective adjustments are accompanied by a decrease in the level of perceived hunger, particularly apparent in the postprandial period. Taken together these changes can be interpreted as an action of dexfenfluramine to intensify the satiating power of food. This effect is consistent with the proposed role of serotonin systems in the mediation of satiety. The effect of dexfenfluramine on eating parameters leads to an overall modulation of the pattern of eating and the profile of motivation to eat. The reduction in energy intake achieved by this modulation is consistent with the weight losses recorded following several months of treatment. This restraint over the expression of appetite exerted by dexfenfluramine appears to be present even after 12 months of continuous treatment. These demonstrated actions should help overweight people to achieve a better management of their appetite in order to assist weight loss and to prevent weight regain.

Appetite↗
PubMed1988

Effect of 6 months therapy with dexfenfluramine in obese patients: studies in the United Kingdom.

The efficacy of dexfenfluramine in inducing weight loss and its clinical acceptability were assessed in two studies carried out in a hospital obesity clinic and general practitioner's office. Seventeen patients who had gained an average of 0.7 +/- 1.9 kg during 12 weeks treatment with diet and placebo lost a mean of 2.9 +/- 0.5 kg after 12 weeks sequential treatment with dexfenfluramine 15 mg twice daily (p less than 0.001). In a second trial, 29 patients treated for 24 weeks with dexfenfluramine showed significantly increased, and continuing, weight loss after 24 weeks (7.0 +/- 0.8 kg) compared to that after 12 weeks of treatment (5.7 +/- 0.1 kg; p = 0.05). The incidence of side effects in both trials was lower than that reported in previous studies of racemic dl-fenfluramine. The clinically significant weight loss and low incidence of unwanted effects suggest that dexfenfluramine has a role in the treatment of refractory obesity.

Clinical Trials as Topic↗
PubMed1988

Metabolic and hormonal effects of dexfenfluramine on stress situations.

Chronic treatment of rats with dexfenfluramine decreased the concentrations of circulating corticosterone, fatty acid, glycerol, and triacylglycerol after feeding a test load of fructose. It also decreased the rise in adrenalin in the blood of rats that were anaesthetized with urethane. These effects of dexfenfluramine probably result from changes in the metabolism of 5-HT in the CNS and consequent alterations in hormonal balance. It is proposed that the long-term metabolic effects of dexfenfluramine could be explained by a decrease in the effectiveness of stress hormones (e.g., glucocorticoids, corticotropin, catecholamines, glucagon) in regulating metabolism since these hormones antagonize many of the actions of insulin. This hypothesis also identifies the possibility that the ability of dexfenfluramine to decrease an exaggerate stress response could alleviate some of the potential risk factors associated with atherosclerosis including obesity and maturity onset diabetes.

Adipose Tissue↗
PubMedDate not supplied

Prolonged weight loss with dexfenfluramine treatment in obese patients.

17 patients with refractory obesity, who had gained an average of 0.7 +/- 1.9 kg during 12 weeks treatment with diet and placebo, lost a mean of 2.9 +/- 0.5 kg after 12 weeks sequential treatment with dexfenfluramine 15 mg twice daily (p less than 0.001). In a second trial, 29 patients were treated for 24 weeks with dexfenfluramine; average cumulative weight loss after 12 weeks in these patients (5.7 +/- 0.1 kg) was significantly greater than in the patients who had been treated initially with placebo. After 24 weeks of dexfenfluramine treatment there was a further significant increase in cumulative weight loss (7.0 +/- 0.8 kg; p = 0.05). The incidence of side effects in both trials was lower than that reported in previous studies of racemic dlfenfluramine. The clinically significant weight loss, and low incidence of unwanted effects, suggest that dexfenfluramine has a role in the treatment of refractory obesity.

Adult↗
PubMed1999

Measurement of human brain dexfenfluramine concentration by 19F magnetic resonance spectroscopy.

OBJECTIVE: The goals of this study were to quantitate the brain concentration of the anorectic drug dexfenfluramine (DF) in human subjects receiving clinical doses of DF and to determine whether human brain DF concentrations approach those reported to cause irreversible neurochemical changes in animals. Each subject's brain DF concentration was measured several times over an extended period of DF treatment to determine whether drug accumulation in the brain would plateau or continue to increase throughout the treatment period. DESIGN: Fluorine magnetic resonance spectroscopy (19F-MRS) was used to directly detect and quantitate brain levels of the fluorinated drug dexfenfluramine and its active metabolite dex-norfenfluramine (dNF). Patients received 15 mg dexfenfluramine BID for 90 days. 19F-MRS measurements were performed at baseline and at three times during the treatment period. PARTICIPANTS: Twelve women (age 38-54 years) who were obese, with body mass indices of 28. 4-37.4, but otherwise healthy. RESULTS: The combined concentration of DF and nDF reached steady-state in the human brain after approximately 10 days of treatment. The steady-state brain concentration averaged approximately 4 microM and did not tend to increase significantly during the 90 day treatment period. CONCLUSIONS: These results demonstrate that fluorinated drugs can be quantified using 19F MRS at concentrations below 10 microM in the human brain. The time-course data suggest that brain DF concentrations parallel DF plasma pharmacokinetics in humans. Measured brain dexfenfluramine/nor-dexfenfluramine concentrations were well below levels previously found to cause irreversible brain alterations in animals.

Adult↗
PubMed2001

The effect of (R)-HA966 or ACEA 1021 on dexfenfluramine or (S)-MDMA-induced changes in temperature, activity, and neurotoxicity.

The glycine site-specific N-methyl-D-aspartate (NMDA) antagonist 5-nitro-6,7-dichloro-2,3-quinoxalinedione (ACEA 1021, 4x30 mg/kg, i.p.) given 30 min before dexfenfluramine (4x15 mg/kg, i.p., every 2 h) was unable to prevent dexfenfluramine-induced depletion of 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA) content, and 5-HT transporter (5-HTT) density. Another glycine site-specific NMDA antagonist, R(+)-3-aminohydroxypyrrolidin-2-one [(R)-HA 966] (2x30 mg/kg, ip), given 30 min before dexfenfluramine (2x10 mg/kg, ip, 2 hourly) was also unable to prevent regional depletion of 5-HT, 5-HIAA, and 5-HTT density. However, ACEA 1021 (4x30 mg/kg, i.p.) given 30 min before (S)-3,4-methylenedioxymethamphetamine (MDMA, 4x10 mg/kg, 2 hourly, ip) attenuated the regional depletion of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), 5-HT, 5-HIAA content, and 5-HTT density. ACEA 1021 combined with (S)-MDMA also prevented (S)-MDMA-induced hyperthermia without causing hypothermia or preventing an (S)-MDMA-induced increase in locomotor activity.

Animals↗
PubMed2000

In obese individuals dexfenfluramine corrects molecular derangements reflecting insulin resistance.

BACKGROUND: Circulating lymphocytes of obese individuals with and without type 2 diabetes have derangements of pyruvate dehydrogenase (PDH) that are described as reflecting a disorder underlying systemic insulin resistance, namely basal activity below normal and, in vitro, unresponsiveness to insulin at 33 pmol/l and activation at 330 pmol/l instead of activation and inhibition as in controls. OBJECTIVE: To explore whether the above enzyme derangements are overcome in obese individuals on dexfenfluramine treatment, known to improve poor peripheral insulin sensitivity. METHODS: Fifteen obese diabetic patients and 15 age-matched euglycaemic obese subjects with normal glucose tolerance were enrolled for a trial composed of two 21-day periods; in the first (D-21-D0), participants received a placebo, and in the second (D0-D21), dexfenfluramine (30 mg/day). At D-21, D0 and D21 participants were evaluated for weight, BMI, fasting glycaemia (FG), fasting insulinaemia (FI), fasting insulin resistance index (FIRI), area under the glycaemic (G-AUC) and insulinaemic (I-AUC) curves from an OGT test, and for PDH activity assayed in their circulating lymphocytes before (basal activity) and after incubation with 33 or 330 pmol/l insulin. At D2, basal PDH activity and clinical parameters were assayed. RESULTS: In both groups of participants at D0 all parameters tested were constant with respect to D-21; at D2, only basal PDH activity rose significantly; at D21, basal and insulin stimulated PDH activities were normalized and weight decreased significantly, as did FG, FI, FIRI and G-AUC in the diabetic, and FI, FIRI, G-AUC and I-AUC in the non-diabetic participants. CONCLUSION: In obese, non-diabetic and diabetic individuals on dexfenfluramine treatment, amelioration of clinical parameters and indexes of poor insulin sensitivity of blood glucose homeostasis are preceded by correction, in their circulating lymphocytes, of PDH derangements described as reflecting a disorder underlying insulin resistance.

Adult↗