Wikipedia

Orlistat

(Redirected fromXenical)

Orlistat,sold under the brand nameXenicalamong others, is amedicationused to treatobesity.Its primary function is preventing the absorption of fats from the human diet by acting as alipase inhibitor,thereby reducingcaloricintake. It is intended for use in conjunction with a healthcare provider-supervisedreduced-calorie diet.[4]

Orlistat
Clinical data
Trade namesXenical, Alli
Other namestetrahydrolipstatin
AHFS/Drugs.comMonograph
MedlinePlusa601244
License data
Pregnancy
category
  • AU:B1
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokineticdata
BioavailabilityNegligible[8]
Protein binding>99%
MetabolismIn theGI tract
Eliminationhalf-life1 to 2 hours
ExcretionFecal
Identifiers
  • (S)-((S)-1-((2S,3S)-3-Hexyl-4-oxooxetan-2-yl)tridecan-2-yl) 2-formamido-4-methylpentanoate
CAS Number
PubChemCID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard(EPA)
ECHA InfoCard100.167.400Edit this at Wikidata
Chemical and physical data
FormulaC29H53NO5
Molar mass495.745g·mol−1
3D model (JSmol)
  • O=C(O[C@H](C[C@@H]1OC(=O)[C@H]1CCCCCC)CCCCCCCCCCC)[C@@H](NC=O)CC(C)C
  • InChI=1S/C29H53NO5/c1-5-7-9-11-12-13-14-15-16-18-24(34-29(33)26(30-22-31)20-23(3)4)21-27-25(28(32)35-27)19-17-10-8-6-2/h22-27H,5-21H2,1-4H3,(H,30,31)/t24-,25-,26-,27-/m0/s1checkY
  • Key:AHLBNYSZXLDEJQ-FWEHEUNISA-NcheckY
☒NcheckY(what is this?)(verify)

Orlistat is thesaturatedderivative oflipstatin,a potentnaturalinhibitor ofpancreatic lipasesisolated from thebacteriumStreptomyces toxytricini.[9]However, due to its relative simplicity and stability, orlistat was chosen over lipstatin for development as ananti-obesity drug.[10]

The effectiveness of orlistat in promotingweight lossis definite but modest. Pooled data fromclinical trialssuggest 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 pressureand 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 advocacygroupPublic Citizenrepeatedly opposing it on safety and efficacy grounds.[14]Genericformulations 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]

Medical uses

edit

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, asignificantnumber 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 1.9mmHginsystolicanddiastolicblood pressure respectively).[16]

Contraindications

edit

Orlistat iscontraindicatedin:[4]

Side effects

edit

The primaryside effectsof the drug are gastrointestinal-related, and includesteatorrhea(oily, loose stools with excessiveflatusdue to unabsorbed fats reaching the large intestine),fecal incontinenceand 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 injurywas 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.

Long-term

edit

Despite a higher incidence ofbreast canceramongst 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 vitrostudy to suggest that the introduction of specific varied preparations containing orlistat, namely the concurrent administration of orlistat and themonoclonal antibodytrastuzumab,can inducecell deathin breast cancer cells and block their growth.[26]

Fecal fat excretion promotescoloncarcinogenesis. 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-dimethylhydrazineproduced 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]

Precautions

edit

Absorption offat-solublevitaminsand other fat-soluble nutrients is inhibited by the use of orlistat.[4]

Interactions

edit

Orlistat may reduce plasma levels ofciclosporin(also known as "cyclosporin" or "cyclosporine", trade names Sandimmune, Gengraf, Neoral, etc.), animmunosuppressive drugfrequently used to preventtransplant rejection;the two drugs should therefore not be administered concomitantly.[4]Orlistat can also impair absorption of theantiarrhythmicamiodarone.[29]TheMedicines and Healthcare products Regulatory Agency(MHRA) has suggested the possibility that orlistat could reduce the absorption ofantiretroviralHIVmedications.[30]

Mechanism of action

edit
Crystallographic structureof humanfatty acid synthasethioesterase (rainbow color,N-terminus= blue,C-terminus= red) inhibited by orlistat (space-filling model;carbon = grey, oxygen = red, nitrogen = blue)[31]

Orlistat works by inhibiting gastric and pancreaticlipases,theenzymesthat break downtriglyceridesin theintestine.[32][33]When lipase activity is blocked, triglycerides from the diet are nothydrolyzedinto 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 tractafter 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 bruceiparasite.[35]

Orlistat prevents approximately 30% of dietary fat from being absorbed.[36]

edit

Orlistat is available both with andwithout a prescription.[37][4][5][38]

Australia and New Zealand

edit

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]

United States

edit

Orlistat was initially approved by theU.S. Food and Drug Administrationin 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 Citizenopposed 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]

European Union and Switzerland

edit

On 21 January 2009, theEuropean Medicines Agencygranted approval for the sale of orlistat without a prescription.[37][44]

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]

Generic formulations

edit

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

Society and culture

edit

Cost

edit

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]

Counterfeit products

edit

In January 2010, theU.S. Food and Drug Administrationissued 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]

References

edit
  1. ^"Xenical 120 mg hard capsules - Summary of Product Characteristics (SmPC)".(emc).18 May 2017.Archivedfrom the original on 8 March 2022.Retrieved19 September2022.
  2. ^"Beacita 120mg Capsules, hard - Summary of Product Characteristics (SmPC)".(emc).11 November 2020.Archivedfrom the original on 1 July 2022.Retrieved19 September2022.
  3. ^"alli 60 mg hard capsules - Summary of Product Characteristics (SmPC)".(emc).11 June 2021.Archivedfrom the original on 18 January 2022.Retrieved19 September2022.
  4. ^abcdefghij"Xenical- orlistat capsule".DailyMed.9 December 2021.Archivedfrom the original on 17 July 2022.Retrieved19 September2022.
  5. ^ab"Alli- orlistat capsule".DailyMed.9 November 2020.Archivedfrom the original on 30 November 2021.Retrieved19 September2022.
  6. ^"Xenical EPAR".European Medicines Agency.17 September 2018.Archivedfrom the original on 15 April 2021.Retrieved20 September2022.
  7. ^"Alli EPAR".European Medicines Agency.17 September 2018.Archivedfrom the original on 23 January 2022.Retrieved20 September2022.
  8. ^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.
  9. ^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.
  10. ^Pommier A, Pons M, Kocienski P (1995). "The first total synthesis of (−)-lipstatin".Journal of Organic Chemistry.60(22): 7334–7339.doi:10.1021/jo00127a045.
  11. ^Padwal R, Li SK, Lau DC (2004). Padwal RS (ed.)."Long-term pharmacotherapy for obesity and overweight".The Cochrane Database of Systematic Reviews.2003(3): CD004094.doi:10.1002/14651858.CD004094.pub2.PMC8078201.PMID15266516.
  12. ^abGillies CL, Abrams KR, Lambert PC, Cooper NJ, Sutton AJ, Hsu RT, Khunti K (February 2007)."Pharmacological and lifestyle interventions to prevent or delay type 2 diabetes in people with impaired glucose tolerance: systematic review and meta-analysis".BMJ.334(7588): 299.doi:10.1136/bmj.39063.689375.55.PMC1796695.PMID17237299.
  13. ^"POISONS STANDARD JUNE 2017".Federal Register of Legislation.Therapeutic Goods Administration. June 2017.Archivedfrom the original on 13 December 2020.Retrieved18 August2017.
  14. ^abcSchmid RE (9 February 2007)."FDA OKs First Nonprescription Diet Pill".USA Today.Archivedfrom the original on 25 October 2021.Retrieved9 June2009.
  15. ^ab"Orlistat 120mg capsule blister pack".TGA. 11 April 2000.Retrieved18 April2018.
  16. ^Siebenhofer A, Winterholer S, Jeitler K, Horvath K, Berghold A, Krenn C, Semlitsch T (January 2021)."Long-term effects of weight-reducing drugs in people with hypertension".The Cochrane Database of Systematic Reviews.1(1): CD007654.doi:10.1002/14651858.CD007654.pub5.PMC8094237.PMID33454957.
  17. ^"Treating Obesity".NHS.Archivedfrom the original on 13 October 2017.Retrieved13 July2013.
  18. ^"FDA Approves alli (orlistat 60 mg capsules) Over-The-Counter"(PDF)(Press release). PR Newswire. 7 February 2007. Archived fromthe original(PDF)on 24 August 2007.Retrieved8 April2007.
  19. ^From page 12 of theAlli Companion Guide,2007 edition: "They can be an incentive to keep from eating more fat than you really intend to."
  20. ^Mancini MC, Halpern A (April 2006)."Pharmacological treatment of obesity".Arquivos Brasileiros de Endocrinologia e Metabologia.50(2): 377–389.doi:10.1590/S0004-27302006000200024.PMID16767304.
  21. ^"FDA Drug Safety Communication: Completed safety review of Xenical/Alli (orlistat) and severe liver injury".U.S.Food and Drug Administration(FDA). 28 June 2019.Archivedfrom the original on 27 April 2022.Retrieved20 September2022.
  22. ^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.
  23. ^abcDouglas IJ, Langham J, Bhaskaran K, Brauer R, Smeeth L (April 2013)."Orlistat and the risk of acute liver injury: self controlled case series study in UK Clinical Practice Research Datalink".BMJ.346:f1936.doi:10.1136/bmj.f1936.PMC3624963.PMID23585064.
  24. ^Kolata G(20 January 1999)."Obesity Drug Can Lead to Modest Weight Loss, Study Finds".The New York Times.Archivedfrom the original on 13 August 2019.Retrieved11 December2007.
  25. ^Davidson MH, Hauptman J, DiGirolamo M, Foreyt JP, Halsted CH, Heber D, et al. (January 1999)."Weight control and risk factor reduction in obese subjects treated for 2 years with orlistat: a randomized controlled trial".JAMA.281(3): 235–242.doi:10.1001/jama.281.3.235.PMID9918478.
  26. ^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.
  27. ^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.
  28. ^Takayama T, Katsuki S, Takahashi Y, Ohi M, Nojiri S, Sakamaki S, et al. (October 1998)."Aberrant crypt foci of the colon as precursors of adenoma and cancer".The New England Journal of Medicine.339(18): 1277–1284.doi:10.1056/NEJM199810293391803.PMID9791143.
  29. ^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.
  30. ^"Orlistat: theoretical interaction with antiretroviral HIV medicines".Medicines and Healthcare products Regulatory Agency(MHRA). 13 March 2014.Archivedfrom the original on 29 November 2014.Retrieved16 November2014.
  31. ^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.
  32. ^Heck AM, Yanovski JA, Calis KA (March 2000)."Orlistat, a new lipase inhibitor for the management of obesity".Pharmacotherapy.20(3): 270–279.doi:10.1592/phco.20.4.270.34882.PMC6145169.PMID10730683.
  33. ^Higham G (5 June 2020)."Orlistat & Xenical: Do Weight Loss Pills Work? | e-Surgery".e-surgery.Archivedfrom the original on 16 January 2021.Retrieved9 June2020.
  34. ^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.Archivedfrom the original on 25 October 2021.Retrieved19 April2019.
  35. ^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.Archivedfrom the original on 9 June 2020.Retrieved9 June2020.
  36. ^2006 Physicians' Desk Reference (PDR).Thomson PDR. 2006.ISBN978-1-56363-527-4.
  37. ^ab"Chemists to provide obesity pill".BBC News Online.21 January 2009.Archivedfrom the original on 23 January 2009.Retrieved22 January2009.
  38. ^"Orlistat".European Medicines Agency.Archivedfrom the original on 5 December 2020.Retrieved19 September2022.
  39. ^"Scheduling of orlistat"(Press release). Australian Therapeutic Goods Administration. 22 February 2007. Archived fromthe originalon 29 December 2007.
  40. ^Stolberg, Sheryl (27 April 1999)."F.D.A. Approves Fat-Blocking Anti-Obesity Drug".The New York Times.Retrieved20 April2023.
  41. ^"Panel Supports Offering Diet Pill Orlistat Over the Counter".The Washington Post.24 January 2006. pp. A02.Archivedfrom the original on 25 October 2021.Retrieved10 August2006.
  42. ^"FDA Approves Orlistat for Over-the-Counter Use"(Press release).U.S. Food and Drug Administration(FDA). 7 February 2007. Archived fromthe originalon 13 May 2009.Retrieved7 February2007.
  43. ^abSaul S (7 February 2007)."Weight-Loss Drug to Be Sold Over the Counter".The New York Times.Archivedfrom the original on 25 October 2021.Retrieved10 February2007.
  44. ^"GlaxoSmithKline receives European Commission approval to market alli (orlistat 60mg)"(Press release). GlaxoSmithKline. 21 January 2009. Archived fromthe originalon 27 January 2009.Retrieved22 January2009.
  45. ^http://www.compendium.chArchived10 October 2021 at theWayback Machine,directory of drugs approved in Switzerland
  46. ^Rogan JE(30 July 2002)."Certificate Extending Patent Term Under 35 U.S.C. § 156"(PDF).United States Patent and Trademark Office.Archived(PDF)from the original on 29 September 2006.Retrieved8 April2007.
  47. ^"Drug Patent Expirations in June 2009". DrugPatentWatch.com, in"Drug Patent Expirations in June 2009".Biotech Blog. 1 June 2009. Archived fromthe originalon 9 June 2009.Retrieved20 June2009.
  48. ^Devarajan U (1 March 2009)."Fatty issues".The Deccan Chronicle.Archived fromthe originalon 10 March 2009.Retrieved26 November2009.
  49. ^Jeanne Whalen (20 April 2012)."Glaxo Sells Bulk of Over-the-Counter Drugs".The Wall Street Journal.Archivedfrom the original on 27 August 2016.Retrieved8 August2017.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.
  50. ^"Fake Alli diet pills can pose health risks".CNN. 23 January 2010.Archivedfrom the original on 25 January 2010.Retrieved24 January2010.

Further reading

edit
  • 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.
edit
  • "Orlistat".Drug Information Portal.U.S. National Library of Medicine.
Retrieved from "https://en.wikipedia.org/w/index.php?title=Orlistat&oldid=1225095258"