Orlistat, sold under the brand nameXenical among others, is amedication used to treatobesity. Its primary function is preventing the absorption of fats from the human diet by acting as alipase inhibitor, thereby reducingcaloric intake. It is intended for use in conjunction with a healthcare provider-supervisedreduced-calorie diet.[4]
The effectiveness of orlistat in promotingweight loss is definite but modest. Pooled data fromclinical trials suggest that people given orlistat in addition to lifestyle modifications, such as diet and exercise, lose about 2–3 kilograms (4–7 lb) more than those not taking the drug over the course of a year.[11] Orlistat also modestly reducesblood pressure and appears to prevent the onset oftype 2 diabetes, whether from the weight loss itself or other effects. It reduces the incidence of diabetes type II in people who are obese around the same amount that lifestyle changes do.[12]
Benefits aside, however, orlistat is noted for its gastrointestinalside effects (sometimes referred to astreatment effects), which can includesteatorrhea (oily, loose stools). They decrease with time, however, and are the most frequently reported adverse effects of the drug.[4] In Australia, the United States and the European Union, orlistat is available for salewithout a prescription.[13] Over-the-counter approval was controversial in the United States, withconsumer advocacy groupPublic Citizen repeatedly opposing it on safety and efficacy grounds.[14]Generic formulations of orlistat are available in some countries. In Australia it has been listed as an S3 medication, available from a pharmacist without a prescription, since 2000.[15]
Orlistat is used for the treatment ofobesity. The amount of weight loss achieved with orlistat varies. In one-yearclinical trials, between 35.5% and 54.8% of subjects achieved a 5% or greater decrease in body mass, although not all of this mass was necessarily fat. Between 16.4% and 24.8% achieved at least a 10% decrease in body fat.[4] After orlistat was stopped, asignificant number of subjects regained weight—up to 35% of the weight they had lost.[4] It reduces the incidence of diabetes type II in people who are obese around the same amount that lifestyle changes do.[12] Long-term use of orlistat also leads to a very modest reduction inblood pressure (mean reductions of 2.5 and 1.9mmHg insystolic anddiastolic blood pressure respectively).[16]
The primaryside effects of the drug are gastrointestinal-related, and includesteatorrhea (oily, loose stools with excessiveflatus due to unabsorbed fats reaching the large intestine),fecal incontinence and frequent or urgent bowel movements.[17] To minimize these effects, foods with high fat content should be avoided; the manufacturer advises consumers to follow a low-fat, reduced-calorie diet. Oily stools and flatulence can be controlled by reducing the dietary fat content to somewhere in the region of 15 grams per meal.[18] The manual for Alli makes it clear that orlistat treatment involvesaversion therapy, encouraging the user to associate eating fat with unpleasant treatment effects.[19]
Side effects are most severe when beginning therapy and may decrease in frequency with time;[4] It has also been suggested that the decrease in side effects over time may be associated with long-term compliance with alow-fat diet.[20]
On 26 May 2010, theU.S. Food and Drug Administration (FDA) approved a revised label for Xenical to include new safety information about cases of severe liver injury that have been reported rarely with the use of this medication.[21]
An analysis of over 900 orlistat users in Ontario showed that their rate ofacute kidney injury was more than triple that of non-users.[22]
A study from 2013 looked at 94,695 participants receiving orlistat in the UK between 1999 and 2011.[23] The study showed no evidence of an increased risk of liver injury during treatment.[23] They concluded:[23]
The incidence of acute liver injury was higher in the periods both immediately before and immediately after the start of orlistat treatment. This suggests that the observed increased risks of liver injury linked to the start of treatment may reflect changes in health status associated with the decision to begin treatment rather than any causal effect of the drug.
Despite a higher incidence ofbreast cancer amongst those taking orlistat in early, pooled clinical trial data—the analysis of which delayed FDA review of orlistat[24]—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.[25] There is evidence from anin vitro study to suggest that the introduction of specific varied preparations containing orlistat, namely the concurrent administration of orlistat and themonoclonal antibodytrastuzumab, can inducecell death in breast cancer cells and block their growth.[26]
Fecal fat excretion promotescolon carcinogenesis. In 2006 the results of 30-day study were published indicating that orlistat at a dosage of 200 mg/kg chow administered to rats consuming a high-fat chow and receiving two 25 mg/kg doses of the potent carcinogen1,2-dimethylhydrazine produced significantly higher numbers ofaberrant crypt foci (ACF) colon lesions than did the carcinogen plus high-fat chow without orlistat.[27] ACF lesions are believed to be one of the earliest precursors ofcolon cancer.[28]
Orlistat works by inhibiting gastric and pancreaticlipases, theenzymes that break downtriglycerides in theintestine.[32][33] When lipase activity is blocked, triglycerides from the diet are nothydrolyzed into absorbable freefatty acids, and instead are excreted unchanged. Only trace amounts of orlistat are absorbed systemically; the primary effect is local lipase inhibition within theGI tract after an oral dose. The primary route of elimination is through thefeces.
Orlistat was also found toinhibit the thioesterase domain of fatty acid synthase (FAS), an enzyme involved in the proliferation of cancer cells but not normal cells. However, potential side effects of orlistat, such as inhibition of other cellular off-targets or poor bioavailability, might hamper its application as an effective antitumor agent. One profiling study undertook a chemical proteomics approach to look for new cellular targets of orlistat, including its off-targets.[34] Orlistat also shows potential activity against theTrypanosoma brucei parasite.[35]
Orlistat prevents approximately 30% of dietary fat from being absorbed.[36]
In Australia and New Zealand, orlistat is available as a "Pharmacist Only Medicine".[15] In 2007, the Committee decided to keep orlistat as aSchedule 3 drug, but withdrew its authorization of direct-to-consumer Xenical advertising, stating this "increased pressure on pharmacists to provide orlistat to consumers...this in turn had the potential to result in inappropriate patterns of use".[39]
Orlistat was initially approved by theU.S. Food and Drug Administration in April 1999 as a prescription-only medication.[40] On 23 January 2006, an FDA advisory panel voted 11 to 3 to recommend the approval of an OTC formulation of orlistat, to be sold under the brand name Alli byGlaxoSmithKline.[41] Approval was granted on 7 February 2007,[42] and Alli became the first weight loss drug officially sanctioned by the U.S. government for over-the-counter use.[43]Consumer advocacy organizationPublic Citizen opposed over-the-counter approval for orlistat.[14]
Alli became available in the U.S. in June 2007. It is sold as 60 mg capsules—half the dosage of prescription orlistat.[14][43]
At least since September 2017, tablets with 60 mg orlistat can be freely sold in Swiss drugstores. Formulations with 120 mg per tablet require a prescription, but can be sold without one in pharmacies under an exemption rule, which is based on a list of easily diagnosable diseases.[45]
U.S. patent protection for Xenical, originally to end on 18 June 2004, was extended by five years (until 2009) by the U.S.Patent and Trademark Office. The extension was granted on 20 July 2002,[46] and expired on 18 June 2009.[47]
Generic orlistat is available in Iran under the brand Venustat manufactured by Aburaihan Pharmaceutical co., in India, under the brands Orlean (Eris), Vyfat, Olistat, Obelit, Orlica and Reeshape.[48] In Russia, orlistat is available under the brand names Xenical (Hoffmann–La Roche), Orsoten/Orsoten Slim (KRKA d. d.) and Xenalten (OBL-Pharm). In Austria, orlistat is available under the brand name Slimox. In Malaysia, orlistat is available under the brand name Cuvarlix and is marketed by Pharmaniaga. In the Philippines orlistat is available under the brand name RedoXfat Plus manufactured by ATC Healthcare
At times, such as in spring 2012, orlistat has come into short supply, with consequent price increases because of nonavailability of one of the drug's components.[49]
In January 2010, theU.S. Food and Drug Administration issued an alert stating that some counterfeit versions of Alli sold over the Internet contain no orlistat, and instead contain the weight-loss drugsibutramine. The concentration of sibutramine in these counterfeit products is at least twice the amount recommended for weight loss.[50]
^"Xenical EPAR".European Medicines Agency. 17 September 2018.Archived from the original on 15 April 2021. Retrieved20 September 2022.
^"Alli EPAR".European Medicines Agency. 17 September 2018.Archived from the original on 23 January 2022. Retrieved20 September 2022.
^Zhi J, Melia AT, Eggers H, Joly R, Patel IH (November 1995). "Review of limited systemic absorption of orlistat, a lipase inhibitor, in healthy human volunteers".Journal of Clinical Pharmacology.35 (11):1103–1108.doi:10.1002/j.1552-4604.1995.tb04034.x.PMID8626884.S2CID23618845.
^Barbier P, Schneider F (1987). "Syntheses of tetrahydrolipstatin and absolute configuration of tetrahydrolipstatin and lipstatin".Helvetica Chimica Acta.70 (1):196–202.doi:10.1002/hlca.19870700124.
^"POISONS STANDARD JUNE 2017".Federal Register of Legislation. Therapeutic Goods Administration. June 2017.Archived from the original on 13 December 2020. Retrieved18 August 2017.
^Weir MA, Beyea MM, Gomes T, Juurlink DN, Mamdani M, Blake PG, et al. (April 2011). "Orlistat and acute kidney injury: an analysis of 953 patients".Archives of Internal Medicine.171 (7):703–704.doi:10.1001/archinternmed.2011.103.PMID21482850.
^Menendez JA, Vellon L, Lupu R (August 2005). "Antitumoral actions of the anti-obesity drug orlistat (XenicalTM) in breast cancer cells: blockade of cell cycle progression, promotion of apoptotic cell death and PEA3-mediated transcriptional repression of Her2/neu (erbB-2) oncogene".Annals of Oncology.16 (8):1253–1267.doi:10.1093/annonc/mdi239.PMID15870086.
^Garcia SB, Barros LT, Turatti A, Martinello F, Modiano P, Ribeiro-Silva A, et al. (August 2006). "The anti-obesity agent Orlistat is associated to increase in colonic preneoplastic markers in rats treated with a chemical carcinogen".Cancer Letters.240 (2):221–224.doi:10.1016/j.canlet.2005.09.011.PMID16377080.
^Zhi J, Moore R, Kanitra L, Mulligan TE (April 2003). "Effects of orlistat, a lipase inhibitor, on the pharmacokinetics of three highly lipophilic drugs (amiodarone, fluoxetine, and simvastatin) in healthy volunteers".Journal of Clinical Pharmacology.43 (4):428–435.doi:10.1177/0091270003252236.PMID12723464.S2CID24389189.
^PDB:2PX6;Pemble CW, Johnson LC, Kridel SJ, Lowther WT (August 2007). "Crystal structure of the thioesterase domain of human fatty acid synthase inhibited by Orlistat".Nature Structural & Molecular Biology.14 (8):704–709.doi:10.1038/nsmb1265.PMID17618296.S2CID2105534.
^"Orlistat".European Medicines Agency. 16 February 2012.Archived from the original on 5 December 2020. Retrieved19 September 2022.
^"Scheduling of orlistat" (Press release). Australian Therapeutic Goods Administration. 22 February 2007. Archived fromthe original on 29 December 2007.
^Jeanne Whalen (20 April 2012)."Glaxo Sells Bulk of Over-the-Counter Drugs".The Wall Street Journal.Archived from the original on 27 August 2016. Retrieved8 August 2017.Glaxo said the issue wasn't a lack of interested buyers, but manufacturing problems that have led to shortages of the diet pill and forced the company to delay the product's sale.
Boehm MF, McClurg MR, Pathirana C, Mangelsdorf D, White SK, Hebert J, et al. (February 1994). "Synthesis of high specific activity [3H]-9-cis-retinoic acid and its application for identifying retinoids with unusual binding properties".Journal of Medicinal Chemistry.37 (3):408–414.doi:10.1021/jm00029a013.PMID8308867.
Hanessian S, Tehim A, Chen P (1993). "Total synthesis of (−)-tetrahydrolipstatin".The Journal of Organic Chemistry.58 (27): 7768.doi:10.1021/jo00079a022.
Yang PY, Liu K, Ngai MH, Lear MJ, Wenk MR, Yao SQ (January 2010). "Activity-based proteome profiling of potential cellular targets of Orlistat--an FDA-approved drug with anti-tumor activities".Journal of the American Chemical Society.132 (2):656–666.doi:10.1021/ja907716f.PMID20028024.
Yang PY, Wang M, Liu K, Ngai MH, Sheriff O, Lear MJ, et al. (July 2012). "Parasite-based screening and proteome profiling reveal orlistat, an FDA-approved drug, as a potential anti Trypanosoma brucei agent".Chemistry: A European Journal.18 (27):8403–8413.doi:10.1002/chem.201200482.PMID22674877.
N
Y (what is this?) (verify)
