The discovery and status of sibutramine as an anti-obesity drug

Luque, Carla A.; Rey, José A

doi:10.1016/s0014-2999(02)01423-1

Cited by 123 publications

(76 citation statements)

References 50 publications

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“…39 Indeed, relative resistance to NE may contribute to the pathogenesis of obesity, because sibutramine-a pharmacological agent that prolongs adrenergic activity by inhibiting catecholamine reuptake-is a reasonably effective treatment for obesity. 40 When NE activity is decreased, hepatic NKT cell apoptosis is increased and restoring NE reduces apoptosis, even when leptin is absent. Thus, although leptin clearly has immunomodulatory actions, 7 NE is a more important viability factor for hepatic NKT cells.…”

Section: Discussionmentioning

confidence: 99%

Norepinephrine regulates hepatic innate immune system in leptin-deficient mice with nonalcoholic steatohepatitis

Oben

Yang

et al. 2004

Hepatology

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It is not known why natural killer T (NKT) cells, which modulate liver injury by regulating local cytokine production, are reduced in leptin-deficient ob/ob mice. NKT cells express adrenoceptors. Thus, we hypothesize that the low norepinephrine (NE) activity of ob/ob mice promotes depletion of liver NKT cells, thereby sensitizing ob/ob livers to lipopolysaccharide (LPS) toxicity. To evaluate this hypothesis, hepatic NKT cells were quantified in wild-type mice before and after treatment with NE inhibitors, and in dopamine ␤-hydroxylase knockout mice (which cannot synthesize NE) and ob/ob mice before and after 4 weeks of NE supplementation. Decreasing NE activity consistently reduces liver NKT cells, while increasing NE has the opposite effect. Analysis of hepatic and thymic NKT cells in mice of different ages demonstrate an age-related accumulation of hepatic NKT cells in normal mice, while liver NKT cells become depleted after birth in ob/ob mice, which have increased apoptosis of hepatic NKT cells. NE treatment inhibits apoptosis and restores hepatic NKT cells. In ob/ob mice with reduced hepatic NKT cells, hepatic T and NKT cells produce excessive T helper (Th)-1 proinflammatory cytokines and the liver is sensitized to LPS toxicity. NE treatment decreases Th-1 cytokines, increases production of Th-2 cytokines, and reduces hepatotoxicity. Studies of CD1d-deficient mice, which lack the receptor required for NKT cell development, demonstrate that they are also unusually sensitive to LPS hepatotoxicity. In conclusion, low NE activity increases hepatic NKT cell apoptosis and depletes liver NKT cells, promoting proinflammatory polarization of hepatic cytokine production that sensitizes the liver to LPS toxicity. (HEPATOLOGY 2004;40:434 -441.)

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Section: Discussionmentioning

confidence: 99%

Norepinephrine regulates hepatic innate immune system in leptin-deficient mice with nonalcoholic steatohepatitis

Oben

Yang

et al. 2004

Hepatology

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“…3,4 Anoretic agents, such as sibutramine and the combination of phentermine-fenfluramine are widely used around the world; however, they are associated with serious side effects, including increased blood pressure and effects in the central nervous system. 5 Inhibition of the digestion of dietary lipids is a reasonable target for pharmacological intervention because it does not involve a mechanism of action over a central nervous system reducing side effects. Inhibiting fat absorption is achieved by the inhibition of pancreatic lipase, a key enzyme for lipid breakdown that leads to the absorption of fatty acids.…”

Section: Introductionmentioning

confidence: 99%

Effect of protamine in obesity induced by high-fat diets in rats

et al. 2009

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Objective: Protamine has been shown to have an inhibitory effect on protein lipase in vitro; the objective of this study was to evaluate the antiobesity activity effect of protamine in obese induced rats, and to evaluate the effect of protamine on postprandial hypertriacylglyceridemia in rats by intragastric administration of a lipid emulsion containing corn oil. Design: Two experiments were carried out: (1) In a parallel study in rats, we administered a lipid emulsion containing corn oil plus 0, 200 or 500 mg kg -1 of protamine intragastrically. (2) In a randomized parallel prospective rats experiment, rats were fed with a high-fat diet and 0, 200 or 500 mg of protamine per kg of animal weight during 5 weeks. Subjects: Male Sprague-Dawley rats. Measurements: In experiment 1, plasma triacylglycerol levels after oral administration of lipid emulsion were determined. In experiment 2, weight gain, concentrations of plasma triacylglycerol, plasma total cholesterol and albumin were determined, and the subcutaneous and visceral adipose tissues were weighed. Results: Plasma triacylglycerol concentration in rats administered with 200 or 500 mg kg -1 of protamine was significantly lower than that in rats in the control group (200 mg kg -1 of protamine, Po0.05 at 1, 2, 3 and 4 h; 500 mg kg -1 of protamine Po0.05 at 2, 3 and 4 h). In rats fed with a high-fat diet, and 200 and 500 mg kg -1 of protamine, there was a decreased body weight gain by 52 and 66 g, respectively, reduced visceral fat by 5 and 8 g, respectively and subcutaneous tissue weights by 12 and 15 g, respectively. Plasma triacylglycerol was 17 and 45 mg per 100 ml lower in rats fed with high-fat diet plus 200 and 500 mg kg -1 of protamine, respectively. And cholesterol concentrations were 18 and 22 mg per 100 ml lower in both protamine groups, respectively. Conclusion: Our study demonstrates that protamine reduce weight gain and body fat accumulation through the inhibition of dietary fat absorption.

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“…The serotonin and norepinephrine uptake inhibitor sibutramine is a widely used antiobesity drug. [5][6][7] Sibutramine mediates increased satiety, although a mild increase in energy expenditure may also contribute to weight loss. 8 Norepinephrine uptake inhibition with sibutramine in peripheral tissues could exacerbate arterial hypertension through an increase in synaptic norepinephrine concentrations.…”

Section: Introductionmentioning

confidence: 99%

Influence of Sibutramine on blood pressure: evidence from placebo-controlled trials

et al. 2005

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OBJECTIVE: Sibutramine, a serotonin and norepinephrine transporter inhibitor, is widely used as an adjunctive obesity treatment. There have been concerns that norepinephrine reuptake inhibition with sibutramine could exacerbate arterial hypertension. DESIGN: Combined analysis of two placebo-controlled trials. SUBJECTS: The combined data set consisted of 1336 patients. Of these patients, 966 were randomized to sibutramine and 370 were randomized to placebo. MEASUREMENTS: Body weight, blood pressure, heart rate (HR). RESULTS: Sibutramine reduced body weight regardless of basal blood pressure. In the complete set of patients, systolic blood pressure did not change with either intervention over the 48-week period (À0.1715.5 mmHg with sibutramine, À0.2715.2 mmHg with placebo, P ¼ 0.9). The change in diastolic blood pressure over the 48 week period was 0.379.5 mmHg with sibutramine and À0.879.2 mmHg with placebo (P ¼ 0.049). The blood pressure response was not exacerbated in patients with grade 1 or 2 hypertension or in patients with isolated systolic hypertension. Sibutramine treatment caused a slight increase in supine HR that was sustained throughout the studies. CONCLUSIONS: Sibutramine treatment is unlikely to elicit a critical increase in blood pressure even in hypertensive patients. However, blood pressure and HR should be monitored closely. In patients who experience a clinically significant and sustained increase in blood pressure, the drug should probably be discontinued.

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The discovery and status of sibutramine as an anti-obesity drug

Cited by 123 publications

References 50 publications

Norepinephrine regulates hepatic innate immune system in leptin-deficient mice with nonalcoholic steatohepatitis

Norepinephrine regulates hepatic innate immune system in leptin-deficient mice with nonalcoholic steatohepatitis

Effect of protamine in obesity induced by high-fat diets in rats

Influence of Sibutramine on blood pressure: evidence from placebo-controlled trials

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