| Revision as of 15:16, 15 November 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,081 edits Script assisted update of identifiers for the Chem/Drugbox validation project (updated: 'ChEMBL', 'CASNo').← Previous edit |
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{{Short description|Drug used to treat malaria}} |
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{{chembox |
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{{Use dmy dates|date=March 2024}} |
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{{cs1 config|name-list-style=vanc|display-authors=6}} |
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{{Drugbox |
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| Verifiedfields = changed |
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| verifiedrevid = 460786738 |
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| Watchedfields = changed |
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| image = Artenimol.svg |
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| verifiedrevid = 399897944 |
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| image_class = skin-invert-image |
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|ImageFile=Artenimol.png |
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| width = 150 |
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|ImageSize=200px |
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| alt = |
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|IUPACName=(3''R'',5a''S'',6''R'',8a''S'',9''R'',12''S'',12a''R'')-decahydro-3,6,9-trimethyl-3,12-epoxy-12''H''-pyrano-1,2-benzodioxepin-10-ol |
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| image2 = Dihydroartemisinin 3D balls.png |
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|OtherNames=DHA |
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| width2 = 180 |
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|Section1={{Chembox Identifiers |
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| alt2 = |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID = 96929 |
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<!-- Clinical data --> |
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| tradename = |
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| Drugs.com = {{drugs.com|international|artenimol}} |
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| pregnancy_category = |
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| routes_of_administration = ] |
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| ATC_prefix = P01 |
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| ATC_suffix = BE05 |
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| legal_status = Rx-only |
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<!--Pharmacokinetic data--> |
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| bioavailability = 12% |
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| metabolism = ] |
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| elimination_half-life = About 4–11 hours |
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| excretion = Mainly ] |
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<!--Identifiers--> |
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| CAS_number_Ref = {{cascite|correct|??}} |
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| CAS_number = 71939-50-9 |
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| PubChem = 107770 |
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
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| DrugBank = |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID = 2272104 |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| UNII = 6A9O50735X |
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| ChEMBL_Ref = {{ebicite|changed|EBI}} |
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| ChEMBL_Ref = {{ebicite|changed|EBI}} |
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| ChEMBL = <!-- blanked - oldvalue: 25164 --> |
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| ChEMBL = 25164 |
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| InChI = 1/C15H24O5/c1-8-4-5-11-9(2)12(16)17-13-15(11)10(8)6-7-14(3,18-13)19-20-15/h8-13,16H,4-7H2,1-3H3/t8-,9-,10+,11?,12+,13-,14?,15-/m1/s1 |
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<!--Chemical data--> |
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| InChIKey = BJDCWCLMFKKGEE-KWWHLYHABU |
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| IUPAC_name = (3''R'',5a''S'',6''R'',8a''S'',9''R'',12''S'',12a''R'')-Decahydro-3,6,9-trimethyl-3,12-epoxy-12''H''-pyrano-1,2-benzodioxepin-10-ol |
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| SMILES1 = O1(O)(C4CC(C)342OOC(O12)(C)CC3)C |
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| C=15 | H=24 | O=5 |
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| smiles = O1(O)(C4CC(C)342OOC(O12)(C)CC3)C |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI = 1S/C15H24O5/c1-8-4-5-11-9(2)12(16)17-13-15(11)10(8)6-7-14(3,18-13)19-20-15/h8-13,16H,4-7H2,1-3H3/t8-,9-,10+,11?,12+,13-,14?,15-/m1/s1 |
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| StdInChI = 1S/C15H24O5/c1-8-4-5-11-9(2)12(16)17-13-15(11)10(8)6-7-14(3,18-13)19-20-15/h8-13,16H,4-7H2,1-3H3/t8-,9-,10+,11?,12+,13-,14?,15-/m1/s1 |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChIKey = BJDCWCLMFKKGEE-KWWHLYHASA-N |
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| StdInChIKey = BJDCWCLMFKKGEE-KWWHLYHASA-N |
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| CASNo_Ref = {{cascite|correct|??}} |
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| CASNo = <!-- blanked - oldvalue: 71939-50-9 --> |
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| PubChem = 107770 |
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| Beilstein=4185848 |
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| UNII_Ref = {{fdacite|changed|FDA}} |
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| UNII = 6A9O50735X |
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| SMILES=C1CC2(C(O3241CC(O3)(OO4)C)O)C |
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}} |
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|Section2={{Chembox Properties |
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| C=15|H=24|O=5 |
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| Appearance= |
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| Density= |
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| Solubility= |
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}} |
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|Section3={{Chembox Hazards |
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| MainHazards= |
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| FlashPt= |
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| Autoignition= |
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}} |
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}} |
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}} |
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'''Dihydroartemisinin''' (or '''dihydroqinghaosu''' or '''artenimol''') is a drug used to treat ]. Dihydroartemisinin is the active metabolite of all ] compounds (artemisinin, ], ], etc.) and is also available as a drug in itself. It is a semi-synthetic derivative of ] and is widely used as an intermediate in the preparation of other artemisinin-derived antimalarial drugs.<ref>{{cite journal | author = Soon Hyung Woo, Michael H. Parker, Poonsakdi Ploypradith, John Northrop and ] |title= Direct conversion of pyranose anomeric OH→F→R in the artemisinin family of antimalarial trioxanes |journal = Tetrahedron Letters |volume =39 |issue= 12 |year=1998| pages= 1533–1536| doi=10.1016/S0040-4039(98)00132-4 |url= http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6THS-3SHKHRD-P&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=30b29298d7f7d7c8f81b87e3491376ae}}</ref>It is sold commercially in combination with ] and has been shown to be equivalent to ].<ref name="Arinaitwe2009">{{cite journal|author=Arinaitwe E, Sandison TG, Wanzira H, ''et al.''|title=Artemether‐lumefantrine versus dihydroartemisinin‐piperaquine for falciparum malaria: A longitudinal, randomized trial in young Ugandan children|journal=Clin Infect Dis|year=2009|volume=49|issue=11|pages=1629–1637|doi=10.1086/647946|pmid=19877969}}</ref> |
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'''Dihydroartemisinin''' (also known as '''dihydroqinghaosu''', '''artenimol''' or '''DHA''') is a drug used to treat ]. Dihydroartemisinin is the active metabolite of all ] compounds (artemisinin, ], ], etc.) and is also available as a drug in itself. It is a semi-synthetic derivative of ] and is widely used as an intermediate in the preparation of other artemisinin-derived antimalarial drugs.<ref>{{cite journal | vauthors = Woo SH, Parker MH, Ploypradith P, Northrop J, Posner GH |doi=10.1016/S0040-4039(98)00132-4 |title=Direct conversion of pyranose anomeric OH→F→R in the artemisinin family of antimalarial trioxanes |year=1998 |journal=Tetrahedron Letters |volume=39 |issue=12 |pages=1533–6|doi-access=free }}</ref> It is sold commercially in combination with ] and has been shown to be equivalent to ].<ref name="Arinaitwe2009">{{cite journal | vauthors = Arinaitwe E, Sandison TG, Wanzira H, Kakuru A, Homsy J, Kalamya J, Kamya MR, Vora N, Greenhouse B, Rosenthal PJ, Tappero J, Dorsey G | title = Artemether-lumefantrine versus dihydroartemisinin-piperaquine for falciparum malaria: a longitudinal, randomized trial in young Ugandan children | journal = Clinical Infectious Diseases | volume = 49 | issue = 11 | pages = 1629–1637 | date = December 2009 | pmid = 19877969 | doi = 10.1086/647946 | doi-access = free }}</ref> |
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==Medical use== |
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Dihydroartemisinin is used to treat ], generally as a ] with ].<ref>{{cite journal | vauthors = Tilley L, Straimer J, Gnädig NF, Ralph SA, Fidock DA | title = Artemisinin Action and Resistance in Plasmodium falciparum | journal = Trends in Parasitology | volume = 32 | issue = 9 | pages = 682–696 | date = September 2016 | pmid = 27289273 | pmc = 5007624 | doi = 10.1016/j.pt.2016.05.010 | author-link5 = David A. Fidock }}</ref> |
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In a systematic review of randomized controlled trials, both dihydroartemisinin-piperaquine and artemether-lumefantrine are very effective at treating ] (high quality evidence). However, dihydroartemisinin-piperaquine cures slightly more patients than artemether-lumefantrine, and it also prevents further malaria infections for longer after treatment (high quality evidence). Dihydroartemisinin-piperaquine and artemether-lumefantrine probably have similar side effects (moderate quality evidence). The studies were all conducted in Africa. In studies of people living in Asia, dihydroartemisinin-piperaquine is as effective as artesunate plus mefloquine at treating malaria (moderate quality evidence). Artesunate plus mefloquine probably causes more nausea, vomiting, dizziness, sleeplessness, and palpitations than dihydroartemisinin-piperaquine (moderate quality evidence).<ref>{{cite journal | vauthors = Zani B, Gathu M, Donegan S, Olliaro PL, Sinclair D | title = Dihydroartemisinin-piperaquine for treating uncomplicated Plasmodium falciparum malaria | journal = The Cochrane Database of Systematic Reviews | volume = 2014 | issue = 1 | pages = CD010927 | date = January 2014 | pmid = 24443033 | pmc = 4470355 | doi = 10.1002/14651858.CD010927 }}</ref> |
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==Pharmacology and mechanism== |
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The proposed ] of artemisinin involves cleavage of endoperoxide bridges by iron, producing ] (] iron-oxo species, ], ], and ] compounds) which damage biological macromolecules causing ] in the cells of the parasite.<ref>{{cite book | vauthors = Cumming JN, Ploypradith P, Posner GH | title = Antimalarial activity of artemisinin (Qinghaosu) and related trioxanes: Mechanism(s) of action | series = Advances in Pharmacology | volume = 37 | pages = 253–297 | date = 1996 | pmid = 8891104 | doi = 10.1016/S1054-3589(08)60952-7 | isbn = 9780120329380 | author-link3 = Gary H. Posner }}</ref> Malaria is caused by ]s, primarily '']'', which largely reside in ] and itself contains iron-rich ]-groups (in the form of ]).<ref>{{cite journal | vauthors = Posner GH, O'Neill PM | title = Knowledge of the proposed chemical mechanism of action and cytochrome p450 metabolism of antimalarial trioxanes like artemisinin allows rational design of new antimalarial peroxides | journal = Accounts of Chemical Research | volume = 37 | issue = 6 | pages = 397–404 | date = June 2004 | pmid = 15196049 | doi = 10.1021/ar020227u }}</ref> In 2015 artemisinin was shown to bind to a large number targets suggesting that it acts in a promiscuous manner.<ref name = "Zhou_2016">{{cite journal | vauthors = Zhou Y, Li W, Xiao Y | title = Profiling of Multiple Targets of Artemisinin Activated by Hemin in Cancer Cell Proteome | journal = ACS Chemical Biology | volume = 11 | issue = 4 | pages = 882–888 | date = April 2016 | pmid = 26854499 | doi = 10.1021/acschembio.5b01043 }}</ref> Recent mechanism research discovered that artemisinin targets a broad spectrum of proteins in the human cancer cell proteome through heme-activated radical alkylation.<ref name = "Zhou_2016" /> |
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==Chemistry== |
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==Chemistry== |
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Dihydroartemisinin has a low solubility in water of less than 0.1 g/L. Consequently, its use may result in side effects caused by minor, yet much more soluble, additives (]s) such as Cremophor EL.<ref>{{cite journal | vauthors = Liu K, Dai L, Li C, Liu J, Wang L, Lei J | title = Self-assembled targeted nanoparticles based on transferrin-modified eight-arm-polyethylene glycol-dihydroartemisinin conjugate | journal = Scientific Reports | volume = 6 | pages = 29461 | date = July 2016 | pmid = 27377918 | pmc = 4932499 | doi = 10.1038/srep29461 | bibcode = 2016NatSR...629461L }}</ref> |
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The lactone of artemisinin could selectively be reduced with mild hydride-reducing agents, such as ], ], and ] to dihydroartemisinin (a lactol) in over 90% yield. It is a novel reduction, because normally lactone cannot be reduced with sodium borohydride under the same reaction conditions (0-5 ˚C in methanol). Reduction with LiAlH4 leads to some rearranged products. It was surprising to find that the lactone was reduced, but that the peroxy group survived. However, the lactone of deoxyartemisinin resisted reduction with ] and could only be reduced with ] to the ] deoxydihydroartimisinin. These results show that the peroxy group assists the reduction of lactone with sodium borohydride to a lactol, but not to the alcohol which is the over-reduction product. No clear evidence for this reduction process exists.{{Citation needed|date=March 2011}} |
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The lactone of artemisinin could selectively be reduced with mild hydride-reducing agents, such as ], ], and ] to dihydroartemisinin (a lactol) in over 90% yield. It is a novel reduction, because normally lactones cannot be reduced with sodium borohydride under the same reaction conditions (0–5 ˚C in methanol). Reduction with LiAlH<sub>4</sub> leads to some rearranged products. It was surprising to find that the lactone was reduced, but that the peroxy group survived. However, the lactone of deoxyartemisinin resisted reduction with ] and could only be reduced with ] to the ] deoxydihydroartimisinin. These results show that the peroxy group assists the reduction of lactone with sodium borohydride to a lactol, but not to the alcohol which is the over-reduction product. No clear evidence for this reduction process exists.{{Citation needed|date=March 2011}} |
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==Dosing== |
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Dihydroartemisinin is available as a fixed drug combination with ] (each tablet contains 40 mg of dihydroartemisinin and 320 mg of piperaquine; trade name '''Artekin''', manufactured by ]). |
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==Society and culture== |
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The adult dose is 1.6/12.8 mg/kg per dose (rounded up or down to the nearest half tablet) given at 0 h, 8 h, 24 h, and 48 h. Alternatively, the same total dose may be given once daily for three days.<ref>{{cite journal | author=Ashley EA, McGready R, Hutagalung R, ''et al.'' | title=A randomized, controlled study of a simple, once-daily regimen of dihydroartemisinin-piperaquine for the treatment of uncomplicated, multidrug-resistant falciparum malaria | journal=Clin Infect Dis | year=2005 | volume=41 | pages=425–32 | url=http://www.journals.uchicago.edu/CID/journal/issues/v41n4/36148/36148.html | doi=10.1086/432011 | format= – <sup></sup> | pmid=16028147 | issue=4 }} {{Dead link|date=June 2008}}</ref> |
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In combination with ], brands include:{{citation needed|date=October 2016}} |
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Dihydroartemisinin is also sold in Africa as Cotecxin in 60 mg tablets, which is manufactured by Zhejiang Holley Nanhu Pharmaceutical Co., Ltd., in China. |
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* D-Artepp (GPSC) |
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* Artekin (Holleykin) |
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* Diphos (Genix Pharma) |
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* TimeQuin (Sami Pharma) |
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* Eurartesim (Sigma Tau; by Good Manufacturing Practices) |
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* Duocotecxin (Holley Pharm) |
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Alone:{{citation needed|date=October 2016}} |
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==Activity as experimental cancer chemotherapeutic== |
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*Cotecxin (Zhejiang Holley Nanhu Pharmaceutical Co.) |
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Accumulative research suggests that dihydroartemisinin and other artemisinin-based endoperoxide compounds may display activity as experimental cancer chemotherapeutics.<ref>{{cite journal |author=Efferth T |title=Molecular pharmacology and pharmacogenomics of artemisinin and its derivatives in cancer cells |journal=Curr. Drug Targets |volume=7 |issue=4 |pages=407–21 |year=2006 |pmid=16611029 |url=http://www.ncbi.nlm.nih.gov/pubmed/16611029 |doi=10.2174/138945006776359412}}</ref> Recent pharmacological evidence demonstrates that dihydroartemisinin targets human metastatic melanoma cells with induction of NOXA-dependent mitochondrial apoptosis that occurs downstream of iron-dependent generation of cytotoxic oxidative stress.<ref>{{cite journal |author=Cabello CM, Lamore SD, Bair WB 3rd, Qiao S, Azimian S, Lesson JL, Wondrak GT |title=The redox antimalarial dihydroartemisinin targets human metastatic melanoma cells but not primary melanocytes with induction of NOXA-dependent apoptosis |journal=Invest. New Drugs |year=2011 |pmid=21547369 |url=http://www.ncbi.nlm.nih.gov/pubmed/21547369 |doi=10.1007/s10637-011-9676-7}}</ref> |
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==Research== |
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==Commercial preparations== |
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Accumulative research suggests that dihydroartemisinin and other artemisinin-based endoperoxide compounds may display activity as experimental cancer chemotherapeutics.<ref>{{cite journal | vauthors = Efferth T | title = Molecular pharmacology and pharmacogenomics of artemisinin and its derivatives in cancer cells | journal = Current Drug Targets | volume = 7 | issue = 4 | pages = 407–421 | date = April 2006 | pmid = 16611029 | doi = 10.2174/138945006776359412 }}</ref> Recent pharmacological evidence demonstrates that dihydroartemisinin targets human metastatic melanoma cells with induction of NOXA-dependent mitochondrial apoptosis that occurs downstream of iron-dependent generation of cytotoxic oxidative stress.<ref>{{cite journal | vauthors = Cabello CM, Lamore SD, Bair WB, Qiao S, Azimian S, Lesson JL, Wondrak GT | title = The redox antimalarial dihydroartemisinin targets human metastatic melanoma cells but not primary melanocytes with induction of NOXA-dependent apoptosis | journal = Investigational New Drugs | volume = 30 | issue = 4 | pages = 1289–1301 | date = August 2012 | pmid = 21547369 | pmc = 3203350 | doi = 10.1007/s10637-011-9676-7 }}</ref> |
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In combination with ]: |
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*Duocotecxin (Holley Pharm) |
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*Artekin (Holleykin) |
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==References== |
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== References == |
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{{reflist}} |
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{{Reflist}} |
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== Further reading == |
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{{refbegin}} |
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* {{cite journal | vauthors = Jansen FH | title = The pharmaceutical death-ride of dihydroartemisinin | journal = Malaria Journal | volume = 9 | pages = 212 | date = July 2010 | pmid = 20649950 | pmc = 2916014 | doi = 10.1186/1475-2875-9-212 | doi-access = free }} |
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{{refend}} |
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{{Antimalarials}} |
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{{Antimalarials}} |
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{{Portal bar | Medicine}} |
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