artemether
{{Short description|Chemical compound}}
{{Drugbox
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 457818137
| drug_name =
| IUPAC_name = (3R,5aS,6R,8aS,9R,10S,12R,12aR)-10-methoxy-3,6,9-trimethyldecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]-2-benzopyran
| image = artemether.svg
| image_class = skin-invert-image
| width = 150
| image2 = Artemether ball-and-stick model from xtal 2007.png
| width2 = 200
| Drugs.com = {{drugs.com|international|artemether}}
| pregnancy_AU =
| pregnancy_US = C
| pregnancy_category =
| legal_AU =
| legal_CA =
| legal_UK = POM
| legal_US =
| legal_status = Rx only
| routes_of_administration = Intramuscular Oral
| bioavailability =
| protein_bound =
| metabolism =
| elimination_half-life =
| excretion =
| CAS_number_Ref = {{cascite|correct|CAS}}
| CAS_number = 71963-77-4
| ATC_prefix = P01
| ATC_suffix = BE02
| ATC_supplemental=
| PubChem = 68911
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB06697
| ChemSpiderID_Ref= {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 62138
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = C7D6T3H22J
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D02483
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 195280
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL =
| PDB_ligand = D8Z
| chemical_formula =
| C=16 | H=26 | O=5
| smiles = C[C@@H]1CC[C@@H]3C42OO[C@](C)(CC[C@@H]12)O[C@H]4O[C@H](OC)[C@@H]3C
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C16H26O5/c1-9-5-6-12-10(2)13(17-4)18-14-16(12)11(9)7-8-15(3,19-14)20-21-16/h9-14H,5-8H2,1-4H3/t9-,10-,11+,12+,13+,14-,15-,16-/m1/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = SXYIRMFQILZOAM-HVNFFKDJSA-N
| melting_point = 86
| melting_high = 88
}}
Artemether is a medication used for the treatment of malaria.{{cite journal | vauthors = Esu EB, Effa EE, Opie ON, Meremikwu MM | title = Artemether for severe malaria | journal = The Cochrane Database of Systematic Reviews | volume = 6 | issue = 6 | pages = CD010678 | date = June 2019 | pmid = 31210357 | pmc = 6580442 | doi = 10.1002/14651858.CD010678.pub3 }} The injectable form is specifically used for severe malaria rather than quinine. In adults, it may not be as effective as artesunate. It is given by injection in a muscle. It is also available by mouth in combination with lumefantrine, known as artemether/lumefantrine.
Artemether causes relatively few side effects. An irregular heartbeat may rarely occur. While there is evidence that use during pregnancy may be harmful in animals, there is no evidence of concern in humans. The World Health Organization (WHO) therefore recommends its use during pregnancy. It is in the artemisinin class of medication.{{cite journal | vauthors = Kovacs SD, Rijken MJ, Stergachis A | title = Treating severe malaria in pregnancy: a review of the evidence | journal = Drug Safety | volume = 38 | issue = 2 | pages = 165–181 | date = February 2015 | pmid = 25556421 | pmc = 4328128 | doi = 10.1007/s40264-014-0261-9 }}
Artemether has been studied since at least 1981, and has been in medical use since 1987.{{cite book| vauthors = Rao Y, Zhang D, Li R |title=Tu Youyou and the Discovery of Artemisinin: 2015 Nobel Laureate in Physiology or Medicine|date=2016|publisher=World Scientific|isbn=9789813109919|page=162|url=https://books.google.com/books?id=nmZtDQAAQBAJ&pg=PA162|url-status=live|archive-url=https://web.archive.org/web/20170910151644/https://books.google.com/books?id=nmZtDQAAQBAJ&pg=PA162|archive-date=2017-09-10}} It is on the World Health Organization's List of Essential Medicines.{{cite book | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}
Medical uses
Artemether is an antimalarial drug for uncomplicated malaria caused by P. falciparum (and chloroquine-resistant P. falciparum) or chloroquine-resistant P. vivax parasites.{{cite journal | vauthors = Makanga M, Krudsood S | title = The clinical efficacy of artemether/lumefantrine (Coartem) | journal = Malaria Journal | volume = 8 | issue = Suppl 1 | pages = S5 | date = October 2009 | pmid = 19818172 | pmc = 2760240 | doi = 10.1186/1475-2875-8-S1-S5 | doi-access = free }} Artemether can also be used to treat severe malaria.
The World Health Organization (WHO) recommends the treatment of uncomplicated P. falciparum with artemisinin-based combination therapy.{{Cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK294441/|title=Treatment of Uncomplicated Plasmodium falciparum Malaria|date=2015-01-01|publisher=World Health Organization|url-status=live|archive-url=https://web.archive.org/web/20170910151644/https://www.ncbi.nlm.nih.gov/books/NBK294441/|archive-date=2017-09-10}} Given in combination with lumefantrine, it may be followed by a 14-day regimen of primaquine to prevent relapse of P. vivax or P. ovale malarial parasites and provide a complete cure.{{Cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK294428/|title=Treatment Of Uncomplicated Malaria Caused By P. vivax, P. ovale, P. malariae or P. knowlesi|date=2015-01-01|publisher=World Health Organization|url-status=live|archive-url=https://web.archive.org/web/20170910151644/https://www.ncbi.nlm.nih.gov/books/NBK294428/|archive-date=2017-09-10}}
Artemether can also be used in treating and preventing trematode infections of schistosomiasis when used in combination with praziquantel.{{cite journal | vauthors = Pérez del Villar L, Burguillo FJ, López-Abán J, Muro A | title = Systematic review and meta-analysis of artemisinin based therapies for the treatment and prevention of schistosomiasis | journal = PLOS ONE | volume = 7 | issue = 9 | pages = e45867 | date = 2012-01-01 | pmid = 23029285 | pmc = 3448694 | doi = 10.1371/journal.pone.0045867 | doi-access = free | bibcode = 2012PLoSO...745867P }}
Artemether is rated category C by the FDA based on animal studies where artemisinin derivatives have shown an association with fetal loss and deformity. Some studies, however, do not show evidence of harm.{{cite journal | vauthors = Dellicour S, Hall S, Chandramohan D, Greenwood B | title = The safety of artemisinins during pregnancy: a pressing question | journal = Malaria Journal | volume = 6 | pages = 15 | date = February 2007 | pmid = 17300719 | pmc = 1802871 | doi = 10.1186/1475-2875-6-15 | doi-access = free }}{{cite journal | vauthors = Piola P, Nabasumba C, Turyakira E, Dhorda M, Lindegardh N, Nyehangane D, Snounou G, Ashley EA, McGready R, Nosten F, Guerin PJ | display-authors = 6 | title = Efficacy and safety of artemether-lumefantrine compared with quinine in pregnant women with uncomplicated Plasmodium falciparum malaria: an open-label, randomised, non-inferiority trial | journal = The Lancet. Infectious Diseases | volume = 10 | issue = 11 | pages = 762–769 | date = November 2010 | pmid = 20932805 | doi = 10.1016/S1473-3099(10)70202-4 | hdl-access = free | hdl = 10144/116337 }}
Side effects
Possible side effects include cardiac effects such as bradycardia and QT interval prolongation.{{Cite web|url=http://www.antimicrobe.org/drugpopup/artemether.htm|title=Artemether|website=www.antimicrobe.org|access-date=2016-11-09|url-status=live|archive-url=https://web.archive.org/web/20170223123545/http://www.antimicrobe.org/drugpopup/artemether.htm|archive-date=2017-02-23}} Also, possible central nervous system toxicity has been shown in animal studies.{{Cite web|url=http://apps.who.int/medicinedocs/en/d/Jh2922e/2.5.10.html#Jh2922e.2.5.10|title=WHO Model Prescribing Information: Drugs Used in Parasitic Diseases - Second Edition: Protozoa: Malaria: Artemether|website=apps.who.int|access-date=2016-11-09|url-status=dead|archive-url=https://web.archive.org/web/20161110043655/http://apps.who.int/medicinedocs/en/d/Jh2922e/2.5.10.html#Jh2922e.2.5.10|archive-date=2016-11-10}}{{cite journal | vauthors = Askling HH, Bruneel F, Burchard G, Castelli F, Chiodini PL, Grobusch MP, Lopez-Vélez R, Paul M, Petersen E, Popescu C, Ramharter M, Schlagenhauf P | display-authors = 6 | title = Management of imported malaria in Europe | journal = Malaria Journal | volume = 11 | pages = 328 | date = September 2012 | pmid = 22985344 | pmc = 3489857 | doi = 10.1186/1475-2875-11-328 | doi-access = free }}
Drug interactions
Plasma artemether level was found to be lower when the combination product was used with lopinavir/ritonavir. There is also decreased drug exposure associated with concurrent use with efavirenz or nevirapine.{{cite journal | vauthors = Van Geertruyden JP | title = Interactions between malaria and human immunodeficiency virus anno 2014 | journal = Clinical Microbiology and Infection | volume = 20 | issue = 4 | pages = 278–285 | date = April 2014 | pmid = 24528518 | pmc = 4368411 | doi = 10.1111/1469-0691.12597 }}{{cite journal | vauthors = Kiang TK, Wilby KJ, Ensom MH | title = Clinical pharmacokinetic drug interactions associated with artemisinin derivatives and HIV-antivirals | journal = Clinical Pharmacokinetics | volume = 53 | issue = 2 | pages = 141–153 | date = February 2014 | pmid = 24158666 | doi = 10.1007/s40262-013-0110-5 | s2cid = 1281113 }}
Artemether/lumefantrine should not be used with drugs that inhibit CYP3A4.{{cite journal | vauthors = Stover KR, King ST, Robinson J | title = Artemether-lumefantrine: an option for malaria | journal = The Annals of Pharmacotherapy | volume = 46 | issue = 4 | pages = 567–577 | date = April 2012 | pmid = 22496476 | doi = 10.1345/aph.1Q539 | s2cid = 7678606 }}
Hormonal contraceptives may not be as efficacious when used with artemether/lumefantrine.
Pharmacology
= Mechanism of action =
A possible mechanism of action is that artemisinin drugs exert their cidal action by inhibiting PfATP6. Since PfATP6 is an enzyme regulating cellular calcium concentration, its malfunctioning will lead to intracellular calcium accumulation, which in turns causes cell death.{{cite journal | vauthors = Guo Z | title = Artemisinin anti-malarial drugs in China | journal = Acta Pharmaceutica Sinica. B | volume = 6 | issue = 2 | pages = 115–124 | date = March 2016 | pmid = 27006895 | pmc = 4788711 | doi = 10.1016/j.apsb.2016.01.008 }}
=Pharmacokinetics=
Absorption of artemether is improved 2- to 3-fold with food. It is highly bound to protein (95.4%). Peak concentrations of artemether are seen 2 hours after administration.{{cite web | title=Coartem- artemether and lumefantrine tablet | website=DailyMed | date=5 August 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7866ec19-dfac-47d4-a53f-511a12643cbf | access-date=26 April 2020}}
Artemether is metabolized in the human body to the active metabolite, dihydroartemisinin, primarily by hepatic enzymes CYP3A4/5. Both the parent drug and active metabolite are eliminated with a half-life of about 2 hours.
Chemistry
Artemether is a methyl ether derivative of artemisinin, which is a peroxide-containing lactone isolated from the antimalarial plant Artemisia annua. It is also known as dihydroartemisinin methyl ether, but its correct chemical nomenclature is (+)-(3-alpha,5a-beta,6-beta,8a-beta, 9-alpha,12-beta,12aR)-decahydro-10-methoxy-3,6,9-trimethyl-3,12-epoxy-12H-pyrano(4,3-j)-1,2-benzodioxepin.
It is a relatively lipophilic and unstable drug,{{cite journal | vauthors = De Spiegeleer BM, D'Hondt M, Vangheluwe E, Vandercruyssen K, De Spiegeleer BV, Jansen H, Koijen I, Van Gompel J | display-authors = 6 | title = Relative response factor determination of β-artemether degradants by a dry heat stress approach | journal = Journal of Pharmaceutical and Biomedical Analysis | volume = 70 | pages = 111–116 | date = November 2012 | pmid = 22770733 | doi = 10.1016/j.jpba.2012.06.002 | hdl-access = free | hdl = 1854/LU-2938963 | url = https://biblio.ugent.be/publication/2938963 }} which acts by creating reactive free radicals in addition to affecting the membrane transport system of the plasmodium organism.
References
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{{Antimalarials}}
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Category:World Health Organization essential medicines
Category:Wikipedia medicine articles ready to translate