View source for Rimonabant

Rimonabant (also known as [[SR141716]]; trade name Acomplia) is an anorectic antiobesity drug that has been withdrawn from the market due to potentially serious side effects. It was approved for use in Europe and other countries, but never approved in the United States. Rimonabant is an inverse agonist for the [[cannabinoid receptor CB1]]. Its main effect is reduction in appetite.


== History ==

Rimonabant was the first selective CB1 receptor blocker to be approved for use anywhere in the world. In Europe, it was indicated for use in conjunction with diet and exercise for patients with a body mass index (BMI) greater than 30 kg/m², or patients with a BMI greater than 27 kg/m² with associated risk factors, such as type 2 diabetes or dyslipidaemia. In the UK, it was available beginning in July 2006. As of 2008, the drug was available in 56 countries.


On 21 June 2006, the European Commission approved the sale of rimonabant in the then-25-member European Union. Pharmaceutical company Sanofi-Aventis, (which changed its name to Sanofi in 2011) announced the first country in which Acomplia would be sold was the United Kingdom as a prescription drug. Sales began in July 2006. Sanofi-Aventis also projected that the drug would be sold shortly thereafter in Denmark, Ireland, Germany, Finland, and Norway. It was expected in Belgium and Sweden in 2007. Ordinary obesity would, according to official medical recommendations, not be enough to acquire the prescription in Sweden; there would be additional requirements concerning abnormal blood lipid levels.


Rimonabant was submitted to the Food and Drug Administration (FDA) for approval in the United States. However, in 2007, the FDA's Endocrine and Metabolic Drugs Advisory Committee (EMDAC) concluded the French manufacturer Sanofi-Aventis failed to demonstrate the safety of rimonabant and voted against recommending the anti-obesity treatment for approval. Subsequently, Sanofi-Aventis announced it was suspending the new drug application (NDA) for rimonabant, and that it would resubmit an application at some point in the future.


The EU's approval was not a blanket approval, nor did it approve Acomplia for nonobesity-related problems, such as smoking cessation, although off-label use of the drug was still possible. The approval was, 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.


In October 2008, the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) had determined that the risks of Acomplia outweighed its benefits. The Agency subsequently recommended that the product be suspended from the UK market, and that doctors not prescribe the drug due to the risk of serious psychiatric problems, and even suicide. Sanofi-Aventis then suspended sale of the drug. Approval of the drug was officially withdrawn by the European Medicines Agency on 16 January 2009.


India has prohibited the manufacture and sale of the drug.


== Uses/potential uses ==

'''Obesity'''

In a 2006 (2 year) study reported in JAMA, "Compared with the placebo group, the 20 mg of rimonabant group produced greater mean (SEM) reductions in weight (-6.3 [0.2] kg vs -1.6 [0.2] kg; P<.001), waist circumference (-6.1 [0.2] cm vs -2.5 [0.3] cm; P<.001), and level of triglycerides (percentage change, -5.3 [1.2] vs 7.9 [2.0]; P<.001) and a greater increase in level of high-density lipoprotein cholesterol (percentage change, 12.6 [0.5] vs 5.4 [0.7]; P<.001)." 


'''Smoking cessation'''

Rimonabant may also be found to be effective in assisting some smokers to quit smoking. Sanofi 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 rimonabant is effective for both uses. However, the FDA has explicitly stated to Sanofi that, without additional studies, rimonabant cannot be approved in the United States for smoking cessation therapy. According to a Cochrane Collaboration review in 2007, rimonabant "may increase the odds of quitting approximately 11/2-fold".


'''Addiction behaviors'''

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 behavior.


'''Short-term memory'''

Tetrahydrocannabinol ([[THC]]) is known to impair short-term memory. It was therefore hypothesised that rimonabant may reduce or inhibit the atrophic effects of cannabinoids. Indeed, in animal studies, it significantly improved the ability of rats to encode information into short-term memory.


'''Blockage of cannabis effects'''

Rimonabant blocks the psychoactive and some of the cardiovascular effects of Δ9-tetrahydrocannabinol (THC) in humans without affecting the pharmacokinetics. Rimonabant has been described colloquially as "reverse [[marijuana]]", having a depressing effect on appetite inverse to the increased appetite created by [[cannabinoids]].


== Other effects ==

Rimonabant reduces voluntary wheel running in laboratory mice.


Rimonabant significantly increased human sperm motility and viability in vitro.


== Negative side effects ==

Shortly after market introduction, press reports and independent studies suggested that side effects occurred more intensely and more commonly than had been found by the manufacturer in their clinical studies. Reports of severe depression and suicidal thoughts were frequent. As the drug's target CB1 receptors are fairly ubiquitous throughout the central nervous system, it is not currently understood where the inverse agonist is acting to cause these side-effects.


In 2007, it was reported that the 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.


== Preparation ==

The chemical synthesis of rimonabant is described as follows:



== Brand names ==

Brand names for rimonabant include Acomplia, Bethin, Monaslim, Remonabent, Riobant, Slimona, Rimoslim and Redufast. The proposed brand name if it had been approved for use in the United States was Zimulti.