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Rimonabant: a New Class of Drug to Fight Obesityobesity Molecules of the Millennium Rimonabant: A new class of drug to fight obesityobesity Obesity and tobacco abuse, widely recognised as serious induced by cannabinoid receptor agonists.[5] It powerfully health hazards, are increasing in prevalence. Obesity is reduces food intake and increases energy expenditure. It associated with numerous metabolic complications such as modulates the rewarding properties of food by inhibiting the dyslipidemia, type 2 diabetes and cardiovascular diseases.[1] action of endogenous cannabinoids at specific mesolimbic Smoking is a high risk factor for hypertension, lung carcinoma areas. It alters the variety of signals of peripheral origin (leptin, and various other health related problems.[2] The agents that ghrelin and adiponectin) which modulate the neurochemical have been used for the treatment of obesity include activation of hypothalamic neurons and the state of relative dexfenfluramine, phentermine, sibutramine and orlistat. energy balance. Rimonabant also inhibits the enzymes involved Currently, the options for smoking cessation are nicotine in lipogenesis.[6] Many rodent model studies have demonstrated patches, gum, lozenges and bupropion. As many of these drugs a memory enhancing effect due to rimonabant use.[7] Certainly, have serious adverse effects or are unsuitable for maintenance more information will become available as the drug completes therapy, the search for a novel drug continues. phase III trials. Rimonabant appears to be a promising drug in an entirely Preclinical trials new class called selective cannabinoid (CB1) receptor antagonists. Recent studies have demonstrated the beneficial A number of preclinical trials have been conducted on the effects of rimonabant in tackling obesity, smoking cessation effects of rimonabant in rodent models. The trials and metabolic syndrome. The drug may be approved for demonstrated that rimonabant treatment was associated with treatment of obesity and smoking cessation. Ongoing studies a reduction in intake of highly palatable as well as normal may provide information on its other clinical uses. foods in rats. Wiley et al [8] demonstrated that CB1 antagonist rimonabant dependently decreased food consumption at doses Chemistry which did not affect motor activity in mice. These trials Rimonabant (SR141716) is a neurokinin-3 antagonist and suggested that rimonabant may affect the actions of selective cannabinoid (CB1) receptor antagonist currently being endogenous cannabinoids in regulating appetite, or it may researched and developed under the proprietary name, directly affect feeding behaviour. In another study, rodents were Acomplia, by Sanofi-Aventis. The chemical name is N-piperino­ put on a high fat diet to develop obesity, increase energy intake 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3­ and insulin resistance. During a five- week treatment period, carboxamide.[3] rimonabant resulted in 48% reduction of food and 20% reduction in body weight. In addition, it helped in correcting Mechanism of action insulin resistance.[9] Rimonabant is the first in a new class of agents that act by Clinical trials selectively blocking the cannabinoid-1 receptors with resultant central and metabolic peripheral effects, thereby decreasing Some phase I/II clinical trials have been completed with food intake. Evidence currently exists for two types of rimonabant. However, limited information is available cannabinoid receptors: CB1 and CB2. CB1 receptors are regarding these trails. A randomised, double blind, placebo­ present both in the CNS as well as in certain peripheral tissues. controlled crossover study assessed the effect of rimonabant The areas in which CB1 receptors are most dense are thought on hunger, satiety, food consumption and body weight in obese to deal with cognition, motor function and movement.[4] humans and showed a reduction in their food intake and body Rimonabant is reported to possess a 1000-fold higher affinity weight.[10] for the CB1 receptor than CB2 receptor. It shows high affinity The results of phase III studies called RIO (Rimonabant in for the centrally located cannabinoid receptor, while displaying obesity)Europe, RIO-North America and RIO-Lipids, comparing low affinity for the peripherally located receptor. Additionally, rimonabant 5, 20 mg and placebo, have indicated significantly it has little or no affinity for non-cannabinoid receptors. more weight loss with rimonabant. (The studies were prospective, randomised, international, multicentre, double Pharmacokinetic parameters blind, placebo-controlled trials.) The RIO-Lipids and RIO- Rimonabant has demonstrated a long duration of action (8 Europe studies showed that the average loss of weight at 12 hours) and good oral bioavailability.[15] Currently, limited months was 6.9 and 8.6 kg, respectively, with rimonabant 20 information has been published regarding rimonabant’s mg/day; 3.1 and 4.8 kg, respectively, with rimonabant 5 mg/ pharmacokinetic parameters. day.[11,12] The RIO-North America trial was a two-year study Functional in vitro and in vivo studies showed that that enrolled 3040 obese people throughout USA and Canada. rimonabant is able to antagonise the pharmacologic effects The investigators found that those who received the highest 220 Indian J Pharmacol | June 2006 | Vol 38 | Issue 3 | 220-21 Molecules of the Millennium dose of rimonabant (20 mg) lost >5% of their body weight, trials of this exciting drug are required to establish its long­ while one-third of them lost >10% of their body weight.[13] term therapeutic implications. The results also showed an increase in HDL-C levels with a decrease in atherogenic LDL-C levels. The incidence of J. Singh, S. Budhiraja metabolic syndrome decreased by nearly one-third and insulin Department of Pharmacology, sensitivity was reported as greatly improved. Pt. B. D. Sharma PGIMS, Rimonabant’s role in smoking cessation will be evaluated Rohtak - 124001, Haryana. India in STRATUS-US, STRATUS-EU, STRATUS-WW (prospective, E-mail: [email protected] randomised, multicentre, double blind, placebo-controlled) trials.[14] Preliminary results of these trials showed that treatment with rimonabant greatly increases the likelihood of References quitting smoking. 1. Bray GA, Bounchard C, James WPT, editors. Handbook of Obesity. New York: Marcel Dekker; 1998. Adverse effects 2. Annual smoking attributable mortality, years of potential life lost, and economic The results of early human trials with rimonabant treatment costs. United States 1995-1999. 3. Iversen L. Cannabis and the brain. Brain 2003;126:1252-70. showed an excellent tolerance among patients, except for some 4. Howlett AC, Barth F, Bonner TI. International union of pharmacology. XXVII. mild gastrointestinal adverse effects at the highest dose Classification of cannabinoid receptors. Pharmacol Rev 2002;54:161-202. administered. Safety data from the preliminary results of the 5. Compton DR, Aceto MD, Lowe J, Martin BR. In vivo characterization of a spe­ RIO-Lipids, RIO-Europe, RIO-North America and STRATUS-US cific cannabinoid receptor antagonist (SR141716): inhibition of delta-9­ trials revealed that rimonabant is well tolerated among tetrahydro-cannabinol induced responses and apparent agonist activity. J patients. The most frequently reported adverse effects are Pharmacol Exp Ther 1996;277:586-94. 6. Cota D, Marsicano G, Tschop M. The endogenous cannabinoid system af­ nausea, dizziness and upper respiratory infections. Diarrhoea fects energy balance via central orexigenic drive and peripheral lipogenesis. J was seen most commonly in the RIO-Europe trial (2.3%, 5.8% Clin Inves 2003;112:423-31. and 7% for placebo, rimonabant 5 mg/day and 20 mg/day, 7. Coizet V, Cassel JC, Kelche C. Effects of the selective CB1 cannabinoid respectively). receptor antagonist, SR141716, on cognitive performance in intact, brain-dam­ aged and scopolamine-treated rats. Behav Pharmacol 1998;9:25. Advantages 8. Wiley JL, Burston JJ, Leggett DC. CB1 cannabinoid receptor-mediated modu­ lation of food intake in mice. Br J Pharmacol 2005;145:293-300. � Rimonabant is reported to increase HDL-C and decrease 9. Trillou CR, Arnone M, Delgorge C. Anti-obesity effect of SR141716, a CB1 atherogenic LDL-C levels. The unique property of this drug receptor antagonist, in diet-induced obese mice. Am J Physiol Regul Integr may, in turn, improve cardiovascular risk factors and Comjp Physiol 2003;284:345-53. metabolic syndrome. 10. Heshmati HM, Caplain H, Bellisle F. SR141716, a selective cannabinoid CB1 receptor antagonist, reduces hunger, caloric intake, and body weight in over­ � In addition to weight loss, rimonabant is reported to weight or obese men. Obes Res 2001;9:70. produce improvement in HbA1C levels and may be helpful 11. Van Gaal L. RIO-Europe: A randomized, double-blind study of weight reduc­ in diabetes. ing effect and safety of rimonabant in obese patients with or without comorbidity. � It also prevents weight gain in persons who are quitting Program and abstracts from the European Society of Cardiology Congress smoking. 2004, Aug 28-Sep1; Munich, Germany; 2004. 12. Press release. [accessed 2004 Nov 9]. Available from: http://en.sanofi­ Conclusion aventis.com/press/p_press_2004.asp 13. Results from the RIO-North America trial show that first year improvements in Rimonabant, the selective blocker of CB1 receptors, may cardiovascular risk factors are maintained in the second year of treatment. normalise the activity of the endocannabinoid system, resulting American Society of Cardiology
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