Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Clozapine (CLZ) and metabolites norclozapine and clozapine-N-oxide were assayed with a new, sensitive (2 pmol), and selective method in 68 serum samples from 44 psychotic subjects, 20 to 54 years old, ill 16 years, and treated with CLZ for 2.2 years (currently at 294 mg, 3.4 mg/kg daily). CLZ levels averaged 239 ng/ml (0.73 microM; 92 ng/ml per mg/kg dose) or 48% of total analytes (norclozapine = 41% [91% of CLZ] and clozapine-N-oxide = 11%); metabolite and CLZ levels were highly correlated (rs = 0.9), and CLZ levels varied with daily dose (rs = 0.7). Sampling twice yielded similar within-subject analyte levels (r = 0.8 to 0.9; difference = 24% to 33%). Range and variance narrowed when levels were expressed per weight-corrected dose (ng/ml per mg/kg). Levels per dose were 40% higher in nonsmoking women than men, despite a 60% lower milligram per kilogram dose in women, and did not vary by diagnosis or age in this limited sample. Fluoxetine increased serum CLZ analytes by 60%; valproate had less effect. Patients rated treatment very positively; observer-assessed benefits typically were more moderate. Common late side effects were sialorrhea (80%), excess sedation (58%), obesity (55% > 200 lb), mild tachycardia (51%), constipation (32%), and enuresis (27%); there were no seizures or leukopenia. There was little evident relationship of drug dose or serum level to current clinical measures or side effect risks.
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PMID:Clozapine and metabolites: concentrations in serum and clinical findings during treatment of chronically psychotic patients. 819 52

Obesity is a risk factor of atherosclerosis. The TG content of a fat cell is determined by the balance of lipogenesis from plasma FFA and glucose and lipolysis by hormone-sensitive lipase (HSL). Plasma FFA is produced by TG lipolysis by lipoprotein lipase (LPL). Insulin stimulates LPL activity and inhibits HSL activity. Therefore, hyperinsulinemia stimulates TG accumulation in fat cells. Insulin also stimulates fat cell proliferation. Hyperinsulinemia is a major factor for obesity. Portal FFA stimulates VLDL synthesis and gluconeogenesis and inhibits insulin degradation in the liver. Therefore, visceral obesity is important as a risk factor of atherosclerosis. However the increase of total adipose tissue mass is more important for blood pressure and cardiac performance.
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PMID:[Atherosclerotic and hemodynamic effects of obesity]. 841 92

Evidence suggests that serotonin and neuropeptide Y neurons in the hypothalamus, which respectively inhibit and stimulate food intake, may interact to control energy homoeostasis. We therefore investigated the effects of fluoxetine, which inhibits serotonin reuptake, on food intake and the activity of the neuropeptide Yergic arcuato-paraventricular projection in lean Wistar and Zucker rats. We also studied its effects in obese Zucker rats, in which obesity is postulated to be due to overactivity of the arcuato-paraventricular projection. Fluoxetine significantly reduced food intake in lean and obese rats, both during continuous subcutaneous infusion and (10 mg/kg/day for seven days) and acutely after a single injection (10 mg/kg). Fluoxetine also significantly reduced neuropeptide Y levels in the paraventricular nucleus, a major site of neuropeptide Y release which is highly sensitive to the appetite-stimulating actions of neuropeptide Y. Push-pull sampling in lean and fatty Zucker rats showed that neuropeptide Y secretion in the paraventricular nucleus was significantly reduced after acute fluoxetine treatment. Furthermore, seven days fluoxetine treatment prevented the significant increases in hypothalamic neuropeptide Y messenger RNA which were induced in lean rats by food restriction which precisely matched the hypophagia induced by the drug. We conclude that fluoxetine inhibits various aspects of the activity of the neuropeptide Yergic arcuato-paraventricular neurons, and suggest that reduced neuropeptide Y release in the paraventricular nucleus may mediate, at least in part, the drug's hypophagic action. We further suggest that serotonin may influence food intake and energy balance by inhibiting the arcuato-paraventricular projection, and that the two neurotransmitters may act together to regulate feeding and energy homoeostasis.
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PMID:The serotonergic agent fluoxetine reduces neuropeptide Y levels and neuropeptide Y secretion in the hypothalamus of lean and obese rats. 873 24

1. The effects of the potent 5-hydroxytryptamine (5-HT) and noradrenaline reuptake inhibitor (serotonin-noradrenaline reuptake inhibitor, SNRI), sibutramine, on the cumulative food intake of freely-feeding male Sprague-Dawley rats during an 8 h dark period were investigated and compared to those of the selective 5-HT reuptake inhibitor (selective serotonin reuptake inhibitor, SSRI), fluoxetine; the selective noradrenaline reuptake inhibitor, nisoxetine; the 5-HT and noradrenaline reuptake inhibitors, venlafaxine and duloxetine; and the 5-HT releaser and 5-HT reuptake inhibitor, (+)-fenfluramine. 2. Sibutramine (3 and 10 mg kg-1, p.o.) and (+)-fenfluramine (1 and 3 mg kg-1, p.o.) produced a significant, dose-dependent decrease in food intake over the 8 h dark period. These responses became apparent within the first 2 h following drug administration. 3. Fluoxetine (3, 10 and 30 mg kg-1, p.o.), and nisoxetine (3, 10 and 30 mg kg-1, p.o.) had no significant effect on food intake during the 8 h dark period. However, a combination of fluoxetine and nisoxetine (30 mg kg-1, p.o., of each) significantly decreased food intake 2 and 8 h after drug administration. 4. Venlafaxine (100 and 300 mg kg-1, p.o.) and duloxetine (30 mg kg-1, p.o.) also significantly decreased food intake in the 2 and 8 h following drug administration. 5. The results of this study demonstrate that inhibition of 5-HT and noradrenaline reuptake by sibutramine, venlafaxine, duloxetine, or by a combination of fluoxetine and nisoxetine, markedly reduces food intake in freely-feeding rats and suggest that this may be a novel approach for the treatment of obesity.
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PMID:Comparison of the effects of sibutramine and other monoamine reuptake inhibitors on food intake in the rat. 928 14

Fluoxetine has been reported to suppress food intake in animal models of feeding. Fluoxetine increases extracellular serotonin in the brain. 5HT1A autoreceptors regulate synaptic levels of serotonin. A combination of a 5HT1A receptor antagonist and fluoxetine has been previously reported to enhance extracellular levels of serotonin over what is obtained with fluoxetine alone. Thus, a combination of fluoxetine and a 5HT1A antagonist could enhance the ability of fluoxetine to suppress appetite. Fluoxetine was tested in a model of feeding, in which CD-1 mice were trained to drink sweetened condensed milk. Fluoxetine was found to attenuate milk drinking, in a dose-dependent manner, at doses greater than 10 mg/kg, i.p. A 10 mg/kg dose of fluoxetine, which was ineffective by itself, was then combined either with 5-hydroxytryptophan (5HTP), a serotonin precursor, or with S(-) pindolol, a 5HT1A/beta adrenergic receptor antagonist or with LY206130, a more selective 5HT1A receptor antagonist. These treatment paradigms resulted in significant attenuation of the consumption of sweetened condensed milk. Since fluoxetine has been shown to be useful in the treatment of eating disorders and to promote weight loss in obese humans, although at doses greater than those required for the treatment of depression, a combination of fluoxetine with a 5HT1A receptor antagonist could be of clinical utility in the treatment of eating disorders and obesity.
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PMID:5HT1A receptor antagonists enhance the functional activity of fluoxetine in a mouse model of feeding. 950 85

Recent studies using melanocortin-4 receptor (MC4R) knockout mice and MC4R antagonists have shown that weakening of MC4R-ergic tone increases food intake and causes obesity. In this study, we used the newly discovered selective MC4R antagonist HS014 for increasing food intake in free-feeding rats and evaluated the effects of the NPY Y1 receptor antagonist 1229U91 and the selective serotonin uptake inhibitor fluoxetine on this increased feeding behavior. 1229U91 (12 nmol, i.c.v.), which alone does not affect food intake, significantly attenuated the orexigenic effects of HS014, whereas 1 and 3 nmol doses of 1229U91 were ineffective. Fluoxetine, which has been shown to inhibit NPY release, inhibited spontaneous food intake and completely blocked the stimulation of food intake by HS014. These data suggest that feeding induced by weakening of the MC4R-ergic tone may be mediated through activation of the NPY-ergic system. This is the first report showing that physiological feeding response evoked by MC4R blockage is influenced by NPY signalling.
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PMID:Evidence that orexigenic effects of melanocortin 4 receptor antagonist HS014 are mediated by neuropeptide Y. 967 21

Fluoxetine is one of the most widely used antidepressants and nowadays it is also being used to manage obesity problems. In our laboratory we demonstrated that the drug inhibited sugar absorption (Monteiro et al. 1993). The aim of the present work was to determine the effect of fluoxetine on intestinal leucine absorption. Using a procedure of successive absorptions in vivo the drug diminished amino acid absorption by 30% (P < 0.001). Experiments in vitro in isolated jejunum also revealed a reduction in leucine uptake of 37% (P < 0.001). In both cases fluoxetine only affected mediated transport without altering diffusion. In a preparation enriched in basolateral membrane, fluoxetine inhibited the Na+,K(+)-ATPase (EC 3.6.1.37) activity (55%; P < 0.001) in a non-competitive manner with an inhibition constant (Ki) value of 0.92 mM. Leucine uptake by brush-border membrane vesicles was diminished by the drug (a reduction of 48% was observed at 30s, P < 0.001); only the apical Na(+)-dependent transport system of the amino acid was modified and the inhibition was non-competitive. Leucine uptake in the presence of lysine indicated that transporter B was involved. These results suggest that fluoxetine reduces leucine absorption by its action on the basolateral and apical membrane of the enterocyte; the nutritional status of the patients under drug treatment may be affected as neutral amino acid absorption is decreased.
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PMID:Drug-nutrient interactions: inhibition of amino acid intestinal absorption by fluoxetine. 968 63

Fluoxetine is used in the treatment of a variety of clinical disorders including depression and obesity, and of cocaine detoxification or alcoholism. It is generally believed that fluoxetine exerts its clinical effects because it selectively blocks 5-hydroxytryptamine (5HT) reuptake into nerve terminals. In here we describe that fluoxetine antagonized the neuronal homomeric alpha 7 nicotinic acetylcholine receptors (nAChR) expressed in Xenopus oocytes, with an IC50 of 43 microM, when fluoxetine was coapplied with ACh, and of 1.6 microM when the oocytes were pretreated briefly with fluoxetine. A similar block occurred in oocytes expressing L247T alpha 7 mutant nAChR. Furthermore, blockage of mutant alpha 7 receptors appeared non-competitive and was stronger with cell membrane hyperpolarization. Cell-attached single channel recordings in oocytes expressing L247T alpha 7 mutant nAChR showed that the voltage-dependence of the blockage by fluoxetine could be due to a drastic decrease in channel opening frequency accompanied by marked channel flickering and reduced channel conductance. We conclude that fluoxetine behaves as a reversible blocker of both wild and mutant alpha 7 receptors; and that the Leu-247T mutation in the channel domain renders the blockage of alpha 7 nAChR by fluoxetine voltage-dependent. These effects of fluoxetine on alpha 7 receptors may be clinically important.
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PMID:Effects of fluoxetine on wild and mutant neuronal alpha 7 nicotinic receptors. 970 46

To evaluate the weight reducing effect of fluoxetine on steroid-induced obesity, we conducted an open, clinical intervention study of 20-40 mg/day fluoxetine, 24 weeks duration. Thirteen myasthenia gravis, overweight, long-term steroid-treated patients [age: 31-59, body mass index (BMI): 29-54 kg/m2] were included. Measurements of weight, BMI, and routine laboratory tests, were undertaken at baseline, 12 and 24 weeks. Muscle strength and fatigue parameters were assessed at 4 week intervals. Fluoxetine induced mean weight loss of 7.7+/-2.6 kg and 10.3+/-2.9 kg over a period of 12 and 24 weeks respectively, (P<0.05). Mean BMI decreased from 35.8 to 32.2 kg/m2 over the study period. No significant side effects were noted. We conclude that patients suffering from steroid-induced obesity respond to fluoxetine treatment of overweight by significant weight loss.
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PMID:Fluoxetine treatment for weight reduction in steroid-induced obesity: a pilot study in myasthenia gravis patients. 1008 36

The effects of fluoxetine on food intake, body weight, and mood of obese individuals was examined in a 16-week inpatient/outpatient study. Six male and eight female obese volunteers began the study (four male and five females completed all phases of the study). They lived in a residential laboratory during three one-week inpatient periods separated by a 5-week and an 8-week outpatient period. Following an initial 4-day placebo baseline, participants were maintained on fluoxetine (60 mg/day) for the remainder of the study. Food intake parameters (total daily energy intake, macronutrient intake, mean number of eating bouts, interbout interval), body weight, subjective effects, and task performance were measured several times during the day during inpatient periods; food intake questionnaires were completed daily during the outpatient periods. Fluoxetine significantly reduced daily energy intake derived from fat, carbohydrate, and protein by decreasing the mean number of eating bouts per day throughout the study. No other food intake parameter was affected. Body weight was significantly reduced after 7 weeks, but not after 16 weeks of daily fluoxetine administration. These results indicate that fluoxetine reduced food intake for at least 16 weeks in nondepressed obese individuals without specifically affecting carbohydrate intake. Weight that was lost during the first few weeks of daily fluoxetine administration was subsequently regained even though food intake remained reduced. Therefore, fluoxetine maintenance does not appear promising as a sole long-term therapy for obesity.
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PMID:Fluoxetine-maintained obese humans: effect on food intake and body weight. 1040 10


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