Acomplia

Other names included commercial trade names:

• Rimonabant, SR141716, Acomplia, Bethin, Monaslim
• Remonabent, Riobant, Slimona, Rimoslim, Zimulti, Riomont

Chemical formula: C₂₂H₂₁Cl₃N_4O

Systematic (IUPAC) name: 5-(4-Chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide

Acomplia(Rimonabant) was the first selective central cannabinoid (CB1) receptor inverse agonist (Ki = 1.8 nM) to be developed as an appetite suppressant, anti-obesity drug¹. It is widely used as a tool to investigate CB receptor properties and the mechanisms by which CB agonists exert their pharmacological effects. In rodent models and clinical trials, rimonabant effectively induces lipolysis, reduces hepatomegaly, decreases body weight, and improves dyslipidemia by reducing triglyceride, free fatty acid, and total cholesterol levels and by increasing HDL/LDL ratios². However, rimonabant reportedly produces adverse psychiatric and neurological effects (e.g., depression or anxiety) and therefore is not approved by the FDA for use as a weight control medication².

Rimonabant elicits antiproliferative and immunomodulatory effects (e.g., cell cycle arrest, increased expression of IκB and phosphorylated Akt, and decreased expression of NF-κB, phosphorylated ERK1/2, COX-2, and iNOS) in vitro³.

Despite the FDA's issuing an approvable letter in February 2006 for the obesity indication and a non-approvable letter for smoking cessation, the drug did not enter the market in the United States in 2006. The French pharma firm Sanofi-Aventis disclosed that a complete response to the FDA's approvable letter was submitted on October 26, 2006, triggering a Class I (two-month) or Class II (six-month) review process. On June 13, 2007, FDA's Endocrine and Metabolic Drugs Advisory Committee (EMDAC) concluded that the French manufacturer Sanofi-Aventis failed to demonstrate the safety of rimonabant and voted against recommending the anti-obesity treatment for approval⁴. Subsequently, Sanofi-Aventis announced that it was suspending the new drug application (NDA) for rimonabant and that it would resubmit an application at some point in the future.

On 21 June 2006, the European Commission approved the sale of rimonabant in the then-25-member European Union. Sanofi announced that the first country in which Acomplia will be sold is the United Kingdom as a non-prescription drug. Sales began in July 2006. Sanofi also announced that it projects that the drug will be sold shortly thereafter in Denmark, Ireland, Germany, Finland, and Norway. It is expected in Belgium⁵ and Sweden in 2007. Ordinary obesity will, according to official medical recommendations, not be enough to acquire the prescription in Sweden; there are additional requirements concerning abnormal blood lipid levels⁶.

The EU's approval was not a blanket approval, nor did it approve Acomplia for non-obesity-related problems such as smoking cessation, although off-label use of the drug is still possible. The approval is in combination with diet and exercise for the treatment of obese patients (BMI greater than or equal to 30), or overweight patients (BMI greater than 27) with associated risk factors, such as type 2 diabetes or dyslipidaemia.

Paris, October, 23, 2008 - Sanofi-aventis announced today that the European Medicines Agency (EMEA) has recommended to the European Commission (EC) the temporary suspension of the marketing authorisation of Acomplia® (rimonabant) for the approved indication of overweight and obese patients.
Acomplia® has been marketed in 18 EU countries since 2006 and has provided significant clinical benefits to patients suffering from obesity and overweight with associated co-morbidities. Since the start of the commercialisation of Acomplia®, sanofi-aventis has been closely collaborating with both the regulatory authorities and healthcare providers to monitor on an ongoing basis the real life use of the product and to ensure its use in the right patient population. More than 700,000 patients have been treated with Acomplia® world-wide to date. In the postmarketing surveillance of Acomplia the safety profile of the product is aligned to the one
described in the current European SmPC for the product and is consistent with the one observed during the clinical development.

Acomplia(Rimonabant) Side-effects

Shortly after market introduction, press reports and independent studies suggest that side-effects occur stronger and more commonly than shown by the manufacturer in their clinical studies. Reports of severe depression are frequent. This is deemed to result from the drug's being active in the central nervous system, an area of human physiology so complex that the effects of a drug are extremely difficult to predict or anticipate⁸.

Because the drug has the opposite effects of cannabinoid receptor agonists such as tetrahydrocannabinol (THC, one of the substances found in marijuana), which is neuroprotective against excitotoxicity⁹, it can be theorized that Rimonabant promotes the development of neurodegenerative diseases of the central nervous system such as Multiple sclerosis, Alzheimer's disease, Amyotrophic lateral sclerosis (ALS), Parkinson's disease, and Huntington's disease in persons that are susceptible¹⁰. The reported development of previously clinically-silent multiple sclerosis in one patient taking Rimonabant suggests that any patients with an underlying neurological condition should not take Rimonabant, given the neuroprotective role of the endocannabinoid system in many experimental paradigms of neurological disease.

On June 15, 2007, BBC News reported¹¹ that a committee advising the U.S. FDA had voted not to recommend the drug's approval because of concerns over suicidality, depression, and other related side-effects associated with use of the drug.

Acomplia(Rimonabant) Other uses

• 
  

  Rimonabant and Smoking cessation

  
  Rimonabant may also be found to be effective in assisting some smokers to quit smoking. Sanofi-Aventis is currently conducting studies to determine the possible value of rimonabant in smoking-cessation therapy. The Studies with Rimonabant and Tobacco Use (STRATUS) Program involves more than 6,000 subjects. STRATUS is designed to explore two smoking-related therapies: first, to use rimonabant directly to aid in smoking cessation; second, to help prevent weight gain in former smokers. Initial results apparently suggest that rimonabant is effective for both uses. However, the FDA has explicitly stated to Sanofi-Aventis that, without additional studies, rimonabant cannot be approved in the United States for smoking cessation therapy. According to Cochrane review in 2007 Rimonabant "may increase the odds of quitting approximately 1(1/2)-fold¹².

• Rimonabant and Addiction

  
  Rimonabant reduced resumption of cocaine-seeking responses triggered by two of the three most common triggers of relapse in humans, priming and cues. It may also reduce ethanol- and opiate-seeking behavior¹³.
  
  

• Rimonabant and Memory

  
  Tetrahydrocannabinol(THC) is known to impair short-term memory. It was therefore hypothesised that Rimonabant may improve short-term memory. Indeed in animal studies it significantly improved the performance of rats to encode information in the short-term memory¹⁴.
  
  

• Rimonabant and Blockade of Cannabis effects

  
  Rimonabant blocks the psychoactive and some of the cardiovascular effects of Δ9-Tetrahydrocannabinol (THC) in humans without affecting the pharmacokinetics¹⁵
  
  

• Rimonabant and Effect on physical activity

  
  Rimonabant reduces voluntary wheel running in laboratory mice¹⁶. Apparently, the possibility of such effects in human beings has not been studied.
  
  

Related images:

*1 Rinaldi-Carmona, M., Barth, F., Héaulme, M., et al. SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett 350 240-244 (1994).

*2 Leite, C.E., Mocelin, C.A., Petersen, G.O., et al. Rimonabant: An antagonist drug of the endocannabinoid system for the treatment of obesity. Pharmacologiacal Reports 61 217-224 (2009).

*3 Malfitano, A.M., Laezza, C., Pisanti, S., et al. Rimonabant (SR141716) exerts anti-proliferative and immunomodulatory effects in human peripheral blood mononuclear cells. Brit J Pharmacol 153 1003-1010 (2009).

*4 Zimulti Acomplia Report - Diet Drug Acomplia / Zimulti Gets Thumbs Down From FDA Panel

*5 Article from the Belgian newspaper De Standaard

*6 Article from the Swedish TV station TV 4 website

*7 http://news.bbc.co.uk/2/hi/health/7687311.stm

*8 "Kassen müssen nicht für "Acomplia" zahlen". tagesschau.de. 2006-10-17. Retrieved on 2007-06-13.

*9 Neuroprotection by 9-Tetrahydrocannabinol, the Main Active Compound in Marijuana, against Ouabain-Induced In Vivo Excitotoxicity, M. van der Stelt, W. B. Veldhuis, P. R. Bär, G. A. Veldink1, J. F. G. Vliegenthart, and K. Nicolay, The Journal of Neuroscience, September 1, 2001

*10 Kim AH, Kerchner GA, and Choi DW. Blocking Excitotoxicity. Chapter 1 in CNS Neuroproteciton. Marcoux FW and Choi DW, editors. Springer, New York. 2002. Pages 3-36

*11 BBC NEWS | Health | Suicide risk fears over diet pill

information are getted from

• http://en.wikipedia.org/wiki/Acomplia
• http://www.acomplia.com/