Article

The FDA's Assessment of Two Drugs for Chronic Weight Management

Food and Drug Administration, Silver Spring, MD, USA.
New England Journal of Medicine (Impact Factor: 55.87). 10/2012; 367(17):1577-9. DOI: 10.1056/NEJMp1211277
Source: PubMed

ABSTRACT

Owing to a complex interplay among genetic, environmental, and cultural factors, obesity has reached epidemic proportions in the United States. The adverse health consequences of obesity are manifold, potentially involving all major organ systems and contributing to reduced quality of life. The goal of all obesity therapies is negative energy balance. Drugs have long been used in an attempt to achieve this goal. However, numerous once-promising weight-loss drugs have been abandoned because of serious toxic effects: aminorex (which caused pulmonary hypertension), fenfluramine and dexfenfluramine (valvulopathy), phenylpropanolamine (stroke), rimonabant (suicidal ideation and behavior), and most recently sibutramine (myocardial infarction and stroke). . . .

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    • "In addition, Htr1b KO mice exhibited hyperphagia (Bouwknecht et al., 2001) and a selective HTR1B agonist induced hypophagia in mice (Halford and Blundell, 1996). Recently, lorcaserin ([1R]-8-Chloro-2,3,4,5- tetrahydro-1-methyl-1H-3-benzazepine), a selective HTR2C agonist, was approved for obesity treatment (Colman et al., 2012). Lorcaserin decreased body weight without influencing energy expenditure (Martin et al., 2010). "
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    ABSTRACT: Whole body energy balance is achieved through the coordinated regulation of energy intake and energy expenditure in various tissues including liver, muscle and adipose tissues. A positive energy imbalance by excessive energy intake or insufficient energy expenditure results in obesity and related metabolic diseases. Although there have been many obesity treatment trials aimed at the reduction of energy intake, these strategies have achieved only limited success because of their associated adverse effects. An ancient neurotransmitter, serotonin is among those traditional pharmacological targets for anti-obesity treatment because it exhibits strong anorectic effect in the brain. However, recent studies suggest the new functions of peripheral serotonin in energy homeostasis ranging from the endocrine regulation by gut-derived serotonin to the autocrine/paracrine regulation by adipocyte-derived serotonin. Here, we discuss the role of serotonin in the regulation of energy homeostasis and introduce peripheral serotonin as a possible target for anti-obesity treatment.
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    • "(1R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine [lorcaserin (Belviq ® ; Arena Pharmaceuticals, San Diego, CA)] (Smith et al., 2008) was recently approved by the U.S. Food and Drug Administration for treating obesity (Colman et al., 2012). The therapeutic effects of lorcaserin are thought to be due to agonist activity at serotonin (5-HT) 2C receptors. "
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    ABSTRACT: Lorcaserin is approved by the Food and Drug Administration for treating obesity and its therapeutic effects are thought to result from agonist activity at serotonin (5-HT)2C receptors. Lorcaserin has affinity for other 5-HT receptor subtypes, although its activity at those subtypes is not fully described. The current study compared the behavioral effects of lorcaserin (0.0032-32.0 mg/kg) to the effects of other 5-HT receptor selective agonists in rats (n=8). The 5-HT2C receptor selective agonist mCPP (0.032 - 1.0 mg/kg) and lorcaserin induced yawning that was attenuated by the 5-HT2C receptor selective antagonist SB 242084 (1.0 mg/kg). The 5-HT2A receptor selective agonist DOM (0.1-3.2 mg/kg) induced head twitching that was attenuated by the 5-HT2A receptor selective antagonist MDL 100907 (0.01 mg/kg), lorcaserin (3.2 mg/kg), and mCPP (3.2 mg/kg). In rats pretreated with 5-HT2C SB 242084 (1.0 mg/kg), lorcaserin also induced head twitching. At larger doses, lorcaserin produced forepaw treading that was attenuated by the 5-HT1A receptor selective antagonist WAY 100635 (0.178 mg/kg). While the behavioral effects of lorcaserin in rats are consistent with it having agonist activity at 5-HT2C receptors, these data suggest that, at larger doses, it also has agonist activity at 5-HT2A and possibly 5-HT1A receptors. Mounting evidence suggests that 5-HT2C receptor agonists might be effective for treating drug abuse. A more complete description of the activity of lorcaserin at 5-HT receptor subtypes will facilitate a better understanding of the mechanisms that mediate its therapeutic effects.
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    • "Clinical studies involving overweight and obese individuals with one obesity-related comorbidity have shown modest weight reduction of ~ 5% [95]. On the up side, the drug has shown a relatively good tolerability profile and the increased incidence of valvulopathy observed in rodents has not been borne out in humans thus far [94]. Phentermine, a central noradrenaline releasing drug and topiramate, is a licensed antiepileptic drug. "
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