A comparison of the effects on central 5‐HT function of sibutramine hydrochloride and other weight‐modifying agents

Heal, DJ; Cheetham, Sharon C.; Prow, M. R.; Martin, Keith F.; Buckett, W. R.

doi:10.1038/sj.bjp.0702067

Cited by 95 publications

(69 citation statements)

References 31 publications

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“…It is suggested that the serotonergic effects of sibutramine on feeding and body weight may likely be ascribed to its primary and secondary amine metabolites, which are triple MRIs, rather than sibutramine per se (Heal et al, 1998;Glick et al, 2000;Nelson and Gehlert, 2006). As tesofensine and the bioactive metabolites of sibutramine are almost equipotent 5-HTT inhibitors in vitro (Heal et al, 1998;Glick et al, 2000;Lehr et al, 2008), this suggests that methodological differences may account for this discrepancy between tesofensine and sibutramine on acute food intake. The observation that the hypophagic effect of tesofensine was not sensitive to ritanserin co-administration may be ascribed to the observation that higher doses (0.1-1.0 mg/kg) have been used in studies on sibutramine-induced hypophagia (Jackson et al, 1997;Grignaschi et al, 1999).…”

Section: Discussionmentioning

confidence: 92%

“…For sibutramine, suppression of food intake could be partially reversed by simultaneous ritanserin or SB206553 administration, thus implicating 5-HT 2A/C or 5-HT 2B/C receptor activation (Jackson et al, 1997;Grignaschi et al, 1999;Balcioglu and Wurtman, 2000). It is suggested that the serotonergic effects of sibutramine on feeding and body weight may likely be ascribed to its primary and secondary amine metabolites, which are triple MRIs, rather than sibutramine per se (Heal et al, 1998;Glick et al, 2000;Nelson and Gehlert, 2006). As tesofensine and the bioactive metabolites of sibutramine are almost equipotent 5-HTT inhibitors in vitro (Heal et al, 1998;Glick et al, 2000;Lehr et al, 2008), this suggests that methodological differences may account for this discrepancy between tesofensine and sibutramine on acute food intake.…”

Section: Discussionmentioning

confidence: 99%

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Tesofensine, a Novel Triple Monoamine Reuptake Inhibitor, Induces Appetite Suppression by Indirect Stimulation of α1 Adrenoceptor and Dopamine D1 Receptor Pathways in the Diet-Induced Obese Rat

Axel

Mikkelsen

Hansen

2010

Neuropsychopharmacol

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Tesofensine is a novel monoamine reuptake inhibitor that inhibits both norepinephrine, 5-HT, and dopamine (DA) reuptake function. Tesofensine is currently in clinical development for the treatment of obesity, however, the pharmacological basis for its strong effect in obesity management is not clarified. Using a rat model of diet-induced obesity (DIO), we characterized the pharmacological mechanisms underlying the appetite suppressive effect of tesofensine. DIO rats treated with tesofensine (2.0 mg/kg, s.c.) for 16 days showed significantly lower body weights than vehicle-treated DIO rats, being reflected by a marked hypophagic response. Using an automatized food intake monitoring system during a 12 h nocturnal test period, tesofensine-induced hypophagia was investigated further by studying the acute interaction of a variety of monoamine receptor antagonists with tesofensine-induced hypophagia in the DIO rat. Tesofensine (0.5-3.0 mg/kg, s.c.) induced a dose-dependent and marked decline in food intake with an ED 50 of 1.3 mg/kg. The hypophagic response of tesofensine (1.5 mg/kg, s.c.) was almost completely reversed by co-administration of prazosin (1.0 mg/kg, a 1 adrenoceptor antagonist) and partially antagonized by co-administration of SCH23390 (0.03 mg/kg, DA D 1 receptor antagonist). In contrast, tesofensine-induced hypophagia was not affected by RX821002 (0.3 mg/kg, a 2 adrenoceptor antagonist), haloperidol (0.03 mg/kg, D 2 receptor antagonist), NGB2904 (0.1 mg/kg, D 3 receptor antagonist), or ritanserin (0.03 mg/kg, 5-HT 2A/C receptor antagonist). Hence, the mechanism underlying the suppression of feeding by tesofensine in the obese rat is dependent on the drug's ability to indirectly stimulate a 1 adrenoceptor and DA D 1 receptor function.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Tesofensine, a Novel Triple Monoamine Reuptake Inhibitor, Induces Appetite Suppression by Indirect Stimulation of α1 Adrenoceptor and Dopamine D1 Receptor Pathways in the Diet-Induced Obese Rat

Axel

Mikkelsen

Hansen

2010

Neuropsychopharmacol

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“…In vitro release These experiments were performed using slices of hypothalamus preloaded with [ 3 H]5HT from male Wistar rats (150 -250 g) essentially as described by Heal et al 12 The accumulated efflux of tritium evoked by phentermine, dexfenfluramine or the two drugs in combination was calculated as a fraction of the total radioactivity initially present in the slices. Log-transformed data were statistically analysed using Williams' test.…”

Section: Methodsmentioning

confidence: 99%

“…12 Doses of drugs used were based on three times their oral ED 50 to inhibit food intake at 1 h. Post-injection levels of 5HT were expressed as a percentage of the mean basal level. Data were log-transformed and individual time-points were compared by two-way ANCOVA (baseline as covariate and treatment and experiment as factors) followed by post-hoc Dunnett's test.…”

Section: In Vivo Microdialysismentioning

confidence: 99%

Additive effects on rat brain 5HT release of combining phentermine with dexfenfluramine

et al. 2001

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OBJECTIVE AND DESIGN:This study examined the effects of the anti-obesity agents, phentermine and dexfenfluramine given alone or in combination, on in vitro and in vivo 5HT release from rat brain tissue. RESULTS: In vitro, phentermine was without effect on basal [ 3 H]5HT efflux from hypothalamic slices whereas dexfenfluramine (10 mM) evoked a 131% increase in [ 3 H]5HT release. In combination, the two drugs did not alter [ 3 H]5HT release beyond that caused by dexfenfluramine alone. At pharmacologically equivalent doses, phentermine (5.7 mg=kg, i.p.) caused a rapid, modest elevation, and dexfenfluramine (3 mg=kg, i.p.) a larger but equally rapid elevation of extracellular 5HT in the microdialysates from the rat anterior hypothalamus. In combination, the increase in extracellular 5HT evoked by these drugs was not significantly greater than the sum of their individual effects. CONCLUSIONS: This study provides evidence that phentermine's actions are not restricted to catecholamine systems and indicates that combining phentermine with dexfenfluramine results in an additive increase in neuronal 5HT release.

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“…, is a serotonin and noradrenalin reuptake inhibitor 5,6 currently used as an anti-obesity drug in the hydrochloride form. Sibutramine increases concentrations of HDL-cholesterol and lower triglycerides-levels, but can raise blood pressure and pulse rate.…”

Section: Sibutramine N-(1-(1-(4-chlorophenyl)-cyclobutyl)-3-methylbumentioning

confidence: 99%

Voltammetric determination of sibutramine in beverages and in pharmaceutical formulations

Carvalho¹,

Silva²,

Cunha³

et al. 2012

Quím. Nova

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Recebido em 6/10/11; aceito em 30/11/11; publicado na web em 23/1/12 A simple and sensitive method has been proposed for the determination of sibutramine-HCl in energy drinks, green tea and pharmaceutical formulations using differential pulse voltammetry performed on a hanging mercury drop electrode. In the chosen experimental condition (Mcllvaine pH 4.0 buffer, 50 mV pulse amplitude and 40 mV s -1 scan velocity), sibutramine-HCl presented a reversible behavior and a peak maximum at -80 mV. Detection limit was 0.4 mg L -1 and the working linear range extended up to 33.3 mg L -1 (r = 0.99). Analysis of real and fortified samples enabled recoveries between 91 and 102%. The electroanalytical method was compared with a HPLC method which indicated it accuracy.

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A comparison of the effects on central 5‐HT function of sibutramine hydrochloride and other weight‐modifying agents

Cited by 95 publications

References 31 publications

Tesofensine, a Novel Triple Monoamine Reuptake Inhibitor, Induces Appetite Suppression by Indirect Stimulation of α1 Adrenoceptor and Dopamine D1 Receptor Pathways in the Diet-Induced Obese Rat

Tesofensine, a Novel Triple Monoamine Reuptake Inhibitor, Induces Appetite Suppression by Indirect Stimulation of α1 Adrenoceptor and Dopamine D1 Receptor Pathways in the Diet-Induced Obese Rat

Additive effects on rat brain 5HT release of combining phentermine with dexfenfluramine

Voltammetric determination of sibutramine in beverages and in pharmaceutical formulations

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