Rimonabant A new class of drug to fight obesity Rimonabant A new

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					Molecules of the

  Millennium



                                                         obesity

                Rimonabant: A new class of drug to fight obesity

    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: salil_budhi@yahoo.com

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
                                                                         costs. United States 1995-1999.
    The results of early human trials with rimonabant treatment
                                                                    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
                                                                         Pharmacol Exp Ther 1996;277:586-94.
patients. The most frequently reported adverse effects are          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.
                                                                    10.	 Heshmati HM, Caplain H, Bellisle F. SR141716, a selective cannabinoid CB1
     metabolic syndrome.
                                                                         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 Congress, 2004 Nov 9 (online). [accessed
in weight loss, reduced waist circumference, improvement in              2005 Feb 10]. Available from: http://www.sanofi-synthelabo.us/index.html
                                                                    14.	 Boyd TS, Fremming BA. Rimonabant: a selective CB1 antagonist. Ann
lipid and glucose metabolism in obese people and may prevent
                                                                         Pharmacother 2005;39:684-90.
weight gain associated with smoking cessation. The positive         15.	 Rinaldi-Carmona M, Barth F, Heaulme M. Biochemical and pharmacological
effects may, in turn, improve cardiovascular and metabolic               characterization of SR141716A, the first potent and selective brain cannabinoid
risk factors. Future research and the results of ongoing clinical        receptor antagonist. Life Sci 1995;56:1941-7.




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                                                                               Indian J Pharmacol   | June 2006 |   Vol 38   |   Issue 3   |   220-21   221

				
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