Managing Cardiometabolic Risk

Rimonabant

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Mechanism of action
The ability of Cannabis sativa (marijuana) to stimulate appetite generated interest in the endogenous cannabinoid (or endocannabinoid) system as a target for weight-related disorders. The endocannabinoid system has two major receptors (CB1 and CB2) and two major endogenous ligands (anandamide and 2-arachidonoyl-glycerol (2-AG)) (36, 37). Endocannabinoids are polyunsaturated phospholipid-derived eicosanoids produced on demand from arachidonic acid that elicit many biological responses, including counteracting stressful stimuli such as food deprivation, aversive memories, and pain (37). The CB1 receptor is a G-protein coupled receptor that is extensively expressed in the central nervous system (CNS), including in areas involved in food intake (38). Endocannabinoids interact with several anorexic and orexigenic pathways within the CNS, increasing motivation to eat and stimulating food intake (38).

Rimonabant, the first CB1-receptor blocker, has been approved by the European Agency for the Evaluation of Medicinal Products (EMEA). As of August 2007, it is now approved for clinical use in 42 countries. Rimonabant is a potent, selective CB1 antagonist (39). The drug is metabolized in the liver and excreted in bile.

Rimonabant produces a dose-dependent reduction in food intake, body weight, and fat accretion in various rodent models (40-42). In addition, unlike other weight-reducing drugs, rimonabant improves the metabolic profile beyond what can be explained by weight loss alone, as suggested by pair feeding studies in rodents (43). This can be explained by the fact that the CB1 receptor can also be expressed outside the CNS in several peripheral tissues, including adipose tissue, liver, gut, and skeletal muscle (43, 44). Animal studies have suggested there are several peripheral mechanisms responsible for rimonabant’s food intake-independent benefits. These include enhanced thermogenesis via increased oxygen consumption in skeletal muscle (45), diminished hepatic (46) and adipocyte lipogenesis (43), promotion of vagally-mediated cholecystokinin-induced satiety (38, 47), inhibition of preadipocyte proliferation coupled with increased adipocyte maturation without lipid accumulation (48), and increased circulating adiponectin levels via enhanced adipose tissue expression (49). Modulation of adiponectin levels by rimonabant is of particular interest given the insulin-sensitizing properties of this adipokine (50), as is the drug’s anti-lipogenic effects, which can reduce both fat cell hypertrophy and hepatic steatosis. Most of the individual mechanisms by which rimonabant acts on peripheral metabolism (as suggested by animal studies) await confirmation in humans.

Reference

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36. Lambert DM and Fowler CJ. The endocannabinoid system: drug targets, lead compounds, and potential therapeutic applications. J Med Chem 2005; 48: 5059-87.

37. Di Marzo V, Bifulco M and De Petrocellis L. The endocannabinoid system and its therapeutic exploitation. Nat Rev Drug Discov 2004; 3: 771-84.

38. Di Marzo V and Matias I. Endocannabinoid control of food intake and energy balance. Nat Neurosci 2005; 8: 585-9.

39. Rinaldi-Carmona M, Barth F, Heaulme M, et al. SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett 1994; 350: 240-4.

40. Carai MA, Colombo G and Gessa GL. Rimonabant: the first therapeutically relevant cannabinoid antagonist. Life Sci 2005; 77: 2339-50.

41. Boyd ST and Fremming BA. Rimonabant--a selective CB1 antagonist. Ann Pharmacother 2005; 39: 684-90.

42. Doyon C, Denis RG, Baraboi ED, et al. Effects of rimonabant (SR141716) on fasting-induced hypothalamic-pituitary-adrenal axis and neuronal activation in lean and obese Zucker rats. Diabetes 2006; 55: 3403-10.

43. Cota D, Marsicano G, Tschop M, et al. The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. J Clin Invest 2003; 112: 423-31.

44. Pertwee RG. Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Ther 1997; 74: 129-80.

45. Liu YL, Connoley IP, Wilson CA, et al. Effects of the cannabinoid CB1 receptor antagonist SR141716 on oxygen consumption and soleus muscle glucose uptake in Lep(ob)/Lep(ob) mice. Int J Obes (Lond) 2005; 29: 183-7.

46. Osei-Hyiaman D, DePetrillo M, Pacher P, et al. Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest 2005; 115: 1298-305.

47. Gomez R, Navarro M, Ferrer B, et al. A peripheral mechanism for CB1 cannabinoid receptor-dependent modulation of feeding. J Neurosci 2002; 22: 9612-7.

48. Gary-Bobo M, Elachouri G, Scatton B, et al. The cannabinoid CB1 receptor antagonist rimonabant (SR141716) inhibits cell proliferation and increases markers of adipocyte maturation in cultured mouse 3T3 F442A preadipocytes. Mol Pharmacol 2006; 69: 471-8.

49. Després JP, Golay A and Sjostrom L. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med 2005; 353: 2121-34.

50. Trujillo ME and Scherer PE. Adiponectin--journey from an adipocyte secretory protein to biomarker of the metabolic syndrome. J Intern Med 2005; 257: 167-75.

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