Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Ximelagatran: Difference between pages
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Saving copy of the {{drugbox}} taken from revid 447120827 of page Ximelagatran for the Chem/Drugbox validation project (updated: 'ChEMBL', 'CAS_number'). |
m Moving Category:AstraZeneca brands to Category:Drugs developed by AstraZeneca per Wikipedia:Categories for discussion/Log/2023 December 9#Category:AstraZeneca brands |
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{{Short description|Anticoagulant}} |
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{{ambox | text = This page contains a copy of the infobox ({{tl|drugbox}}) taken from revid [{{fullurl:Ximelagatran|oldid=447120827}} 447120827] of page [[Ximelagatran]] with values updated to verified values.}} |
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{{Drugbox |
{{Drugbox |
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| Verifiedfields = changed |
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| Watchedfields = changed |
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| image = Ximelagatran.svg |
| image = Ximelagatran.svg |
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| width = |
| width = 230 |
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<!--Clinical data--> |
<!--Clinical data--> |
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| tradename = |
| tradename = Exanta |
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| pregnancy_category = |
| pregnancy_category = Uncategorized |
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| legal_status = |
| legal_status = Withdrawn from market |
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| routes_of_administration = Oral |
| routes_of_administration = Oral ([[Tablet (pharmacy)|tablets]]) |
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<!--Pharmacokinetic data--> |
<!--Pharmacokinetic data--> |
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| bioavailability = 20% |
| bioavailability = 20% |
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| metabolism = |
| metabolism = to [[melagatran]] |
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| elimination_half-life = |
| elimination_half-life = 3–5 hours |
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| excretion = Renal (80%) |
| excretion = Renal (80%) |
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<!--Identifiers--> |
<!--Identifiers--> |
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| IUPHAR_ligand = 6381 |
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| CAS_number_Ref = {{cascite|changed|??}} |
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| ATC_prefix = B01 |
| ATC_prefix = B01 |
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| ATC_suffix = AE05 |
| ATC_suffix = AE05 |
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| ChEMBL_Ref = {{ebicite|correct|EBI}} |
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| ChEMBL = 522038 |
| ChEMBL = 522038 |
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| PubChem = 9574101 |
| PubChem = 9574101 |
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<!--Chemical data--> |
<!--Chemical data--> |
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| C=24 | H=35 | N=5 | O=5 |
| C=24 | H=35 | N=5 | O=5 |
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| molecular_weight_comment = (429 g/mol after conversion) |
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| smiles = O=C(NCc1ccc(C(=N\O)\N)cc1)[C@H]3N(C(=O)[C@H](NCC(=O)OCC)C2CCCCC2)CC3 |
| smiles = O=C(NCc1ccc(C(=N\O)\N)cc1)[C@H]3N(C(=O)[C@H](NCC(=O)OCC)C2CCCCC2)CC3 |
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| InChI = 1/C24H35N5O5/c1-2-34-20(30)15-26-21(17-6-4-3-5-7-17)24(32)29-13-12-19(29)23(31)27-14-16-8-10-18(11-9-16)22(25)28-33/h8-11,17,19,21,26,33H,2-7,12-15H2,1H3,(H2,25,28)(H,27,31)/t19-,21+/m0/s1 |
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| InChIKey = ZXIBCJHYVWYIKI-PZJWPPBQBO |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI = 1S/C24H35N5O5/c1-2-34-20(30)15-26-21(17-6-4-3-5-7-17)24(32)29-13-12-19(29)23(31)27-14-16-8-10-18(11-9-16)22(25)28-33/h8-11,17,19,21,26,33H,2-7,12-15H2,1H3,(H2,25,28)(H,27,31)/t19-,21+/m0/s1 |
| StdInChI = 1S/C24H35N5O5/c1-2-34-20(30)15-26-21(17-6-4-3-5-7-17)24(32)29-13-12-19(29)23(31)27-14-16-8-10-18(11-9-16)22(25)28-33/h8-11,17,19,21,26,33H,2-7,12-15H2,1H3,(H2,25,28)(H,27,31)/t19-,21+/m0/s1 |
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| StdInChIKey = ZXIBCJHYVWYIKI-PZJWPPBQSA-N |
| StdInChIKey = ZXIBCJHYVWYIKI-PZJWPPBQSA-N |
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}} |
}} |
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'''Ximelagatran''' ('''Exanta''' or '''Exarta''', H 376/95) is an [[anticoagulant]] that has been investigated extensively as a replacement for [[warfarin]]<ref>{{cite journal | vauthors = Hirsh J, O'Donnell M, Eikelboom JW | title = Beyond unfractionated heparin and warfarin: current and future advances | journal = Circulation | volume = 116 | issue = 5 | pages = 552–560 | date = July 2007 | pmid = 17664384 | doi = 10.1161/CIRCULATIONAHA.106.685974 | doi-access = free }}</ref> that would overcome the problematic [[Diet (nutrition)|dietary]], [[drug interaction]], and [[therapeutic drug monitoring|monitoring]] issues associated with warfarin therapy. In 2006, its manufacturer [[AstraZeneca]] announced that it would withdraw pending applications for marketing approval after reports of [[hepatotoxicity]] (liver damage) during trials, and discontinue its distribution in countries where the drug had been approved (Germany, Portugal, Sweden, Finland, Norway, Iceland, Austria, Denmark, France, Switzerland, Argentina and Brazil).<ref name="az">{{cite press release |
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|publisher=AstraZeneca |date=February 14, 2006 |
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|url=http://www.astrazeneca.com/Media/Press-releases/Article/20060214--AstraZeneca-Decides-to-Withdraw-Exanta |
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|title=AstraZeneca Decides to Withdraw Exanta |
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|access-date=2012-07-16 |
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}}</ref> |
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==Method of action== |
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Ximelagatran, a [[direct thrombin inhibitor]],<ref name="pmid17319469">{{cite journal | vauthors = Ho SJ, Brighton TA | title = Ximelagatran: direct thrombin inhibitor | journal = Vascular Health and Risk Management | volume = 2 | issue = 1 | pages = 49–58 | year = 2006 | pmid = 17319469 | pmc = 1993972 | doi = 10.2147/vhrm.2006.2.1.49 | doi-access = free }}</ref> was the first member of this class that can be taken orally. It acts solely by inhibiting the actions of [[thrombin]]. It is taken orally twice daily, and rapidly absorbed by the [[small intestine]]. Ximelagatran is a [[prodrug]], being converted ''[[in vivo]]'' to the active agent melagatran. This conversion takes place in the liver and many other tissues through [[hydrolysis]] and [[dehydroxylation]] (replacing the [[ethyl group|ethyl]] and [[hydroxyl]] groups with [[hydrogen]]). |
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[[File:Ximelagatran activation.svg|thumb|left|upright=1.5|The conversion of ximelagatran to melagatran. This conversion includes [[dealkylation]] and [[dehydroxylation]].]] |
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{{clear left}} |
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==Uses== |
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Ximelagatran was expected to replace [[warfarin]] and sometimes [[aspirin]] and [[heparin]] in many therapeutic settings, including [[deep venous thrombosis]], prevention of secondary venous [[thromboembolism]] and complications of [[atrial fibrillation]] such as stroke. The efficacy of ximelagatran for these indications had been well documented,<ref>{{cite journal | vauthors = Eriksson H, Wåhlander K, Gustafsson D, Welin LT, Frison L, Schulman S | collaboration = THRIVE Investigators | title = A randomized, controlled, dose-guiding study of the oral direct thrombin inhibitor ximelagatran compared with standard therapy for the treatment of acute deep vein thrombosis: THRIVE I | journal = Journal of Thrombosis and Haemostasis | volume = 1 | issue = 1 | pages = 41–47 | date = January 2003 | pmid = 12871538 | doi = 10.1046/j.1538-7836.2003.00034.x | s2cid = 20556829 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Francis CW, Berkowitz SD, Comp PC, Lieberman JR, Ginsberg JS, Paiement G, Peters GR, Roth AW, McElhattan J, Colwell CW | display-authors = 6 | title = Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement | journal = The New England Journal of Medicine | volume = 349 | issue = 18 | pages = 1703–1712 | date = October 2003 | pmid = 14585938 | doi = 10.1056/NEJMoa035162 | s2cid = 26026547 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Schulman S, Wåhlander K, Lundström T, Clason SB, Eriksson H | title = Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran | journal = The New England Journal of Medicine | volume = 349 | issue = 18 | pages = 1713–1721 | date = October 2003 | pmid = 14585939 | doi = 10.1056/NEJMoa030104 | doi-access = free }}</ref> except for non valvular atrial fibrillation. |
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An advantage, according to early reports by its manufacturer, was that it could be taken orally without any monitoring of its anticoagulant properties. This would have set it apart from [[warfarin]] and [[heparin]], which require monitoring of the [[international normalized ratio]] (INR) and the [[partial thromboplastin time]] (PTT), respectively. A disadvantage recognised early was the absence of an [[antidote]] in case acute bleeding develops, while warfarin can be antagonised by [[prothrombin complex concentrate]] and/or [[vitamin K]] and heparin by [[protamine sulfate]]. |
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==Side effects== |
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Ximelagatran was generally well tolerated in the trial populations, but a small proportion (5–6%) developed elevated [[liver enzyme]] levels, which prompted the [[U.S. Food and Drug Administration|FDA]] to reject an initial application for approval in 2004. The further development was discontinued in 2006 following reports of hepatotoxicity. Subsequent analysis of Phase 2 clinical study data using [[extreme value theory|extreme value modelling]] showed that the elevated [[liver enzyme]] levels observed in Phase 3 clinical studies could have been predicted; if this had been known at the time, it might have affected decisions on future development of the compound.<ref name="Southworth 2014">{{cite journal | vauthors = Southworth H | title = Predicting potential liver toxicity from phase 2 data: a case study with ximelagatran | journal = Statistics in Medicine | volume = 33 | issue = 17 | pages = 2914–2923 | date = July 2014 | pmid = 24623062 | doi = 10.1002/sim.6142 | ref = Southworth 2014 | s2cid = 36324117 }}</ref> |
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A chemically different but pharmacologically similar substance, [[AZD-0837]], was developed by AstraZeneca for similar indications.<ref name="az" /> It is a prodrug of a potent, competitive, reversible inhibitor of free and fibrin-bound thrombin called [[ARH0637]].<ref name=Ahrens>{{cite journal | vauthors = Ahrens I, Peter K, Lip GY, Bode C | title = Development and clinical applications of novel oral anticoagulants. Part II. Drugs under clinical investigation | journal = Discovery Medicine | volume = 13 | issue = 73 | pages = 445–450 | date = June 2012 | pmid = 22742650 }}</ref> The development of AZD-0837 has been discontinued. Due to a limitation identified in long-term stability of the extended-release AZD-0837 drug product, a follow-up study from ASSURE on stroke prevention in patients with non-valvular atrial fibrillation, was prematurely closed in 2010 after 2 years. There was also a numerically higher mortality against warfarin.<ref>{{cite web|url=http://www.astrazenecaclinicaltrials.com/other-drug-products/in_development_drugs/AZD0837/ |title=AZD0837 |publisher=Astrazenecaclinicaltrials.com |access-date=2012-10-16}}</ref><ref>{{cite web | work = Clinical Study Report Synopsis | publisher = AstraZeneca | date = 21 January 2010 | title = Long-term treatment with the oral direct thrombin inhibitor AZD0837, compared to Vitamin-K antagonists, as stroke prevention in patients with non-valvular atrial fibrillation and one or more risk factors for stroke and systemic embolic events. A 5-year follow-up study study | id = Trial D1250C0004221 | url = http://www.astrazenecaclinicaltrials.com/_mshost800325/content/clinical-trials/resources/pdf/D1250C00042 | archive-url = https://web.archive.org/web/20131110014536/http://www.astrazenecaclinicaltrials.com/_mshost800325/content/clinical-trials/resources/pdf/D1250C00042 | archive-date = 10 November 2013 }}</ref><ref>{{cite journal | vauthors = Eikelboom JW, Weitz JI | title = New anticoagulants | journal = Circulation | volume = 121 | issue = 13 | pages = 1523–1532 | date = April 2010 | pmid = 20368532 | doi = 10.1161/CIRCULATIONAHA.109.853119 | doi-access = free }}</ref> In a Phase 2 trial for AF the mean serum creatinine concentration increased by about 10% from baseline in patients treated with AZD-0837, which returned to baseline after cessation of therapy.<ref name="pmid19690349">{{cite journal | vauthors = Lip GY, Rasmussen LH, Olsson SB, Jensen EC, Persson AL, Eriksson U, Wåhlander KF | title = Oral direct thrombin inhibitor AZD0837 for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation: a randomized dose-guiding, safety, and tolerability study of four doses of AZD0837 vs. vitamin K antagonists | journal = European Heart Journal | volume = 30 | issue = 23 | pages = 2897–2907 | date = December 2009 | pmid = 19690349 | pmc = 2785945 | doi = 10.1093/eurheartj/ehp318 }}</ref> |
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== References == |
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{{reflist}} |
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== External links == |
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* {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/ximelagatran | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Ximelagatran }} |
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{{Antithrombotics}} |
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{{AstraZeneca}} |
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{{Portal bar | Medicine}} |
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[[Category:Direct thrombin inhibitors]] |
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[[Category:Abandoned drugs]] |
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[[Category:Prodrugs]] |
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[[Category:Hepatotoxins]] |
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[[Category:Drugs developed by AstraZeneca]] |
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[[Category:Azetidines]] |