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Orlistat
Packaging of orlistat (Xenical) 120 mg capsules, as sold in Canada. Systematic (IUPAC) name
(S)-((S)-1-((2S,3S)-3-hexyl-4-oxooxetan-2-yl)tridecan-2-yl) 2-formamido-4methylpentanoate
Pregnancy cat. B1(AU) B(US) Legal status Routes Pharmacist Only (S3) (AU) P (UK) OTC (US) Oral Pharmacokinetic data Bioavailability Negligible[1]
Protein binding >99% Metabolism Half-life Excretion In the GI tract 1 to 2 hours Fecal Identifiers CAS number ATC code PubChem DrugBank ChemSpider UNII KEGG ChEMBL 96829-58-2 A08AB01 CID 3034010 APRD00255 2298564 95M8R751W8 D04028 CHEMBL175247 Chemical data Formula Mol. mass SMILES C29H53NO5 495.735 g/mol eMolecules & PubChem
InChI[show]
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Orlistat (marketed as a prescription under the trade name Xenical by Roche in most countries, or over-the-counter as Alli[2] by GlaxoSmithKline in the United Kingdom and the United States), also known as tetrahydrolipstatin, is a drug designed to treat obesity.[3] Its primary function is preventing the absorption of fats from the human diet, thereby reducing caloric intake. It is intended for use in conjunction with a physician-supervised reducedcalorie diet. Orlistat is the saturated derivative of lipstatin, a potent natural inhibitor of pancreatic lipases isolated from the bacterium Streptomyces toxytricini.[4] However, due to simplicity and stability, orlistat rather than lipstatin was developed into an anti-obesity drug.
[5]
The effectiveness of orlistat in promoting weight loss is definite, though modest. Pooled data from clinical trials suggest that people given orlistat in addition to lifestyle modifications, such as diet and exercise, lose about 23 kilograms (4.46.6 lb) more than those not taking the drug over the course of a year.[6] Orlistat also modestly reduces blood pressure, and appears to prevent the onset of type 2 diabetes, whether due to weight loss itself or to other effects; in a large randomized controlled trial, orlistat was found to reduce the incidence of diabetes by nearly 40% in obese people.[7] Orlistat is notorious for its gastrointestinal side effects (sometimes referred to as treatment effects), which can include steatorrhea (oily, loose stools). These decrease with time, however, and are the most frequently reported adverse effects of the drug. In the United States, the European Union, and Australia, orlistat is available for sale without a prescription.
Over-the-counter approval was controversial in the United States, with consumer advocacy group Public Citizen repeatedly opposing it on safety and efficacy grounds.[8] Generics of orlistat are available in India.
Contents
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1 Medical uses 2 Contraindications 3 Side effects o 3.1 Long-term o 3.2 Precautions o 3.3 Interactions 4 Mechanism of action 5 Society and culture o 5.1 Legal status o 5.2 Criticism o 5.3 Counterfeit products 6 References 7 Further reading 8 External links
[edit] Contraindications
Orlistat is contraindicated in:[12]
Malabsorption Hypersensitivity to orlistat Reduced gallbladder function (e.g. after cholecystectomy) Pregnancy and breastfeeding Use caution with: obstructed bile duct, impaired liver function, and pancreatic disease
[edit] Long-term
Despite a higher incidence of breast cancer amongst those taking orlistat in early, pooled clinical trial datathe analysis of which delayed FDA review of orlistat[22]a two-year study published in 1999 found similar rates between orlistat and placebo (0.54% versus 0.51%), and evidence that tumors predated treatment in 3 of the 4 participants who had them.[23] There is evidence from an in vitro study to suggest that the introduction of specific varied preparations containing orlistat, namely the concurrent administration of orlistat and the monoclonal antibody trastuzumab, can actually induce cell death in breast cancer cells and block their growth.[24] A 2006 animal study linked orlistat with aberrant crypt foci (ACF), lesions found in the colon which are believed to be one of the earliest precursors of colon cancer.[25][26]
[edit] Precautions
Absorption of fat-soluble vitamins and other fat-soluble nutrients is inhibited by the use of orlistat. A multivitamin tablet containing vitamins A, D, E, K, and beta-carotene should be taken once a day, at bedtime, when using orlistat.[12] On June 4, 2009, the U.S. Food and Drug Administration released its quarterly list of drugs that are under investigation for potential safety issues or new safety information. Orlistat was included in the list as having a "Potential Signal of Serious Risk" of liver toxicity, meaning that a potential risk of liver toxicity was identified based on reports to the FDA Adverse Event Reporting System between October and December 2008.[27] Isolated cases of orlistatassociated liver problems have been reported before.[28] On August 24, the FDA reported that it would investigate 30 cases of liver damage reported between 1999 and October 2008 in patients taking orlistat, including six cases of liver failure.[29]
[edit] Interactions
Orlistat may reduce plasma levels of ciclosporin (also known as "cyclosporin" or "cyclosporine", trade names Sandimmune, Gengraf, Neoral, etc.), an immunosuppressive drug frequently used to prevent transplant rejection; the two drugs should therefore not be administered concomitantly.[12] Orlistat can also impair absorption of the antiarrhythmic amiodarone.[30]
Crystallographic structure of human fatty acid synthase (rainbow color, N-terminus = blue, C-terminus = red) inhibited by orlistat (space-filling model; white = grey, oxygen = red, nitrogen = blue).[31] Orlistat works by inhibiting gastric and pancreatic lipases, the enzymes that break down triglycerides in the intestine. When lipase activity is blocked, triglycerides from the diet are not hydrolyzed into absorbable free fatty acids, and are excreted undigested instead. Only trace amounts of orlistat are absorbed systemically; the primary effect is local lipase inhibition within the GI tract after an oral dose. The primary route of elimination is through the feces. At the standard prescription dose of 120 mg three times daily before meals, orlistat prevents approximately 30% of dietary fat from being absorbed,[32] and about 25% at the standard over-the-counter dose of 60 mg.[33][34] Higher doses do not produce more potent effects.[10]
and "a dangerous mistake" due to questionable benefits and possible adverse effects.[8] Public Citizen had already called for a ban of orlistat in April 2006.[43] Alli became available in the U.S. in June 2007. It is sold as 60 mg capsuleshalf the dosage of prescription orlistat.[8][42] [edit] European Union On January 21, 2009, the European Medicines Agency granted approval for the sale of orlistat without a prescription.[35][44] [edit] Generic formulations As of September 2009, no generic formulations of orlistat are legally available in the United States. U.S. patent protection for Xenical, originally to end on June 18, 2004, was extended by five years (until 2009) by the U.S. Patent and Trademark Office. The extension was granted on July 20, 2002,[45] and expired on June 18, 2009.[46] Generic orlistat is available in India, under the brands Olistat, Vyfat, Obelit, Orlica and Reeshape.[47]
[edit] Criticism
This section requires expansion. Glaxo was criticized for financing a documentary about eating.[48]