Disease relevance of Dexfenfluramine

• Fatal pulmonary hypertension associated with short-term use of fenfluramine and phentermine [1].
• Valvular heart disease associated with dexfenfluramine [2].
• METHODS: We modified our randomized, double-blind, placebo-controlled study of dexfenfluramine to include echocardiographic examinations of 1072 overweight patients within a median of one month after the discontinuation of treatment [3].
• These analyses showed that aortic regurgitation of mild or greater severity occurred in 5.0 percent of the patients in the dexfenfluramine group, 5.8 percent of those in the sustained-release dexfenfluramine group, 5.4 percent of those in the two active-treatment groups combined, and 3.6 percent of those in the placebo group [3].
• CONCLUSIONS: The increased prevalence of aortic and mitral regurgitation in patients treated with dexfenfluramine was small, and the degree of regurgitation was usually classified as physiologic, trace, or mild [3].

Psychiatry related information on Dexfenfluramine

• Reduced prolactin responses to fenfluramine were correlated with history of suicide attempt in all patients but with clinician and self-reported ratings of impulsive aggression in patients with personality disorder only; there was no correlation with depression [4].
• Following m-CPP, but not fenfluramine or placebo, 55% (11/20) of the patients with obsessive-compulsive disorder experienced a transient exacerbation of obsessive-compulsive disorder [5].
• Controlling panic attacks with fenfluramine [6].
• RESULTS: From the group of 720 smokers who had originally participated in the smoking cessation therapy trial, 619 women were enrolled; data from 530 (276 in the fenfluramine group and 254 in the placebo group) were evaluable [7].
• There was a significant positive correlation between d-fenfluramine-evoked prolactin release and the overall positive symptom score and the hallucination and delusion subscores of the Scale for the Assessment of Positive Symptoms [8].

High impact information on Dexfenfluramine

• CONCLUSIONS: Obese patients who took fenfluramine and phentermine, dexfenfluramine alone, or dexfenfluramine and phentermine had a significantly higher prevalence of cardiac valvular insufficiency than a matched group of control subjects [9].
• CONCLUSIONS: The use of fenfluramine or dexfenfluramine, particularly for four months or longer, is associated with an increased risk of newly diagnosed cardiac-valve disorders, particularly aortic regurgitation [10].
• An assessment of heart-valve abnormalities in obese patients taking dexfenfluramine, sustained-release dexfenfluramine, or placebo. Sustained-Release Dexfenfluramine Study Group [3].
• BACKGROUND: Recently, a cluster of patients was observed in France in whom primary pulmonary hypertension developed in patients exposed to derivatives of fenfluramine in appetite suppressants (anorexic agents), which are used for weight control [11].
• RESULTS: The use of anorexic drugs (mainly derivatives of fenfluramine) was associated with an increased risk of primary pulmonary hypertension (odds ratio with any anorexic-drug use, 6.3; 95 percent confidence interval, 3.0 to 13.2) [11].

Chemical compound and disease context of Dexfenfluramine

• Serotonin depletion by fenfluramine in the carcinoid syndrome [12].
• To evaluate serotonergic (5-hydroxytryptamine) function in obsessive-compulsive disorder, behavioral and neuroendocrine responses to m-chlorophenylpiperazine (m-CPP; 0.5 mg/kg orally) and fenfluramine hydrochloride (60 mg orally) were examined in 20 patients and 10 healthy controls under double-blind, placebo-controlled conditions [5].
• Fluoxetine is a safer alternative to fenfluramine in the medical treatment of obesity [13].
• METHOD: The Life History of Aggression assessment scores of 24 subjects with personality disorders were compared with their lumbar CSF 5-HIAA concentrations and with their prolactin responses to d-fenfluramine challenge [14].
• Prolactin and cortisol responses to fenfluramine in Parkinson's disease [15].

Biological context of Dexfenfluramine

• Redox redux: the control of oxidative stress responses [16].
• Using the chronic-hypoxic-mouse model of pulmonary hypertension, we found that the hypoxia-dependent increase in pulmonary blood pressure and lung remodeling are associated with an increase in vascular proliferation, elastase activity and transforming growth factor-beta levels, and that these parameters are potentiated by dexfenfluramine treatment [17].
• Anorexic agents aminorex, fenfluramine, and dexfenfluramine inhibit potassium current in rat pulmonary vascular smooth muscle and cause pulmonary vasoconstriction [18].
• Neurobiology of an anorectic drug: fenfluramine [19].
• To test the hypothesis that stimulation of 5-HT1B receptors is required for the anorectic effect of fenfluramine, we assessed food intake in wild-type and 5-HT1B knock-out mice [20].

Anatomical context of Dexfenfluramine

• Life and death in germinal centers (redux) [21].
• Myelin repair: developmental myelination redux [22]?
• Action of fenfluramine on voltage-gated K+ channels in human pulmonary-artery smooth-muscle cells [23].
• A positive correlation was found between cerebrospinal fluid 5-hydroxyindoleacetic acid and the maximal prolactin response to fenfluramine but not with platelet serotonin2 receptor indexes [24].
• However, young adult BDNF(+/-) mice show a blunted c-fos induction by the specific serotonin releaser-uptake inhibitor dexfenfluramine and alterations in the expression of several 5-HT receptors in the cortex, hippocampus, and hypothalamus [25].

Associations of Dexfenfluramine with other chemical compounds

• Although the combination has not been approved by the FDA, in 1996 the total number of prescriptions in the United States for fenfluramine and phentermine exceeded 18 million [26].
• Brain serotonin neurotoxicity and primary pulmonary hypertension from fenfluramine and dexfenfluramine. A systematic review of the evidence [27].
• The three psychostimulants, as well as fenfluramine, imipramine, and tyramine, reduced the pH gradient, resulting in reduced uptake and increased release of neurotransmitter [28].
• This study examines the prolactin response to fenfluramine hydrochloride challenge in young boys who show clinically significant aggressive behavior or who are raised in a social environment that is conducive to the development of chronic aggression [29].
• Peripheral glucose disposal, reflecting measured skeletal muscle changes, was reduced by fat feeding (from 23.5 +/- 1.0 to 13.8 +/- 0.6 mg.kg-1.min-1) but was improved by d-fenfluramine (16.9 +/- 0.5, P less than .05 vs. fat fed) [30].

Gene context of Dexfenfluramine

• METHODS: Prolactin (PRL) and cortisol (CORT) responses to the serotonergic agonist d-fenfluramine (D-fen), clinical psychobehavioral changes, and psychometric measures were evaluated 3 weeks and then 12 months after MDMA discontinuation [31].
• Administration of m-chlorophenylpiperazine and fenfluramine, both of which induce anorexic effects via 5-HT2C receptors and/or 5-HT1B receptors, suppressed food intake in 5- and 8-wk-old A(y) mice, whereas the anorexic effects were attenuated in food-restricted A(y) mice [32].
• Yeast-expressed recombinant human CYP2D6 metabolized dexfenfluramine with high affinity (Km 1.6 microM, Vmax 0.18 nmol min(-1) nmol P450(-1)) to nordexfenfluramine which was the sole product observed [33].
• We were able to identify CYP2D6 (high affinity) and CYP1A2 (low affinity) as the major enzymes catalysing the N-dealkylation of dexfenfluramine in human liver microsomes [33].
• CONCLUSION(S): The lower PRL response to fenfluramine in the stress-sensitive animals suggests that stress-sensitive individuals have decreased activity in central serotonergic neurons [34].

Analytical, diagnostic and therapeutic context of Dexfenfluramine

• Follow-up time from discontinuation of drug to follow-up echocardiogram for 371 dexfenfluramine patients was 17.5 months (range, 13-26 months) and for 340 phentermine/fenfluramine patients was 18.7 months (range, 13-26 months) after discontinuation of drug therapy [35].
• OBJECTIVE: To evaluate cardiovascular status and the prevalence of valvular abnormalities, as assessed by clinical cardiovascular parameters and echocardiography, in patients treated for obesity with dexfenfluramine or phentermine/fenfluramine [36].
• In a randomised, placebo-controlled, double-blind study, 822 obese patients of both sexes were given either dexfenfluramine (dF), 15 mg twice daily (404), or placebo (418) in addition to a calorie-restricted diet for 1 year [37].
• In the isolated, perfused rat lung, aminorex, fenfluramine, and dexfenfluramine induce a dose-related increase in perfusion pressure [18].
• METHODS AND RESULTS: Using the whole-cell, patch-clamp technique, we found that aminorex, fenfluramine, and dexfenfluramine inhibit potassium current in smooth muscle cells taken from the small resistance pulmonary arteries of the rat lung [18].

References