Artemether

Artemether
Clinical data
AHFS/Drugs.com International Drug Names
Pregnancy
category
  • US: C (Risk not ruled out)
Routes of
administration		 Oral
ATC code P01BE02 (WHO)
Legal status
Legal status
  • UK: POM (Prescription only)
Identifiers
CAS Number 71963-77-4 N
PubChem (CID) 68911
DrugBank DB06697 YesY
ChemSpider 62138 YesY
UNII C7D6T3H22J YesY
KEGG D02483 YesY
ChEBI CHEBI:195280 YesY
ChEMBL CHEMBL1237051 N
Chemical and physical data
Formula C16H26O5
Molar mass 298.374 g/mol
3D model (Jmol) Interactive image
 NYesY (what is this?)  (verify)

Artemether is an antimalarial medication for the treatment of multiple drug-resistant strains of Plasmodium falciparum malaria. It is given by injection in a muscle.[1]

Chemically, it is a semi-synthetic derivative of artemisinin.

It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.[2] It is available in combination with lumefantrine, known as artemether/lumefantrine, which is available as a generic medication.

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.[3] Artemether can also be used to treat severe malaria.[4]

The World Health Organization recommends the treatment of uncomplicated P. falciparum with artemisinin-based combination therapy.[5] 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.[6]

Artemether can also be used in treating and preventing trematode infections of schistosomiasis when used in combination with praziquantel.[7]

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.[8][9]

Side effects

Possible side effects include cardiac effects such as bradycardia and QT interval prolongation.[10] Also, possible central nervous system toxicity has been shown in animal studies.[11][12]

Drug interactions

Plasma artemether level was found to be lower when the combination product was used with lopinavir/ritonavir.[12] There is also decreased drug exposure associated with concurrent use with efavirenz or nevirapine.[13][14]

Artemether/lumefantrine should not be used with drugs that inhibit CYP3A4.[15]

Hormonal contraceptives may not be as efficacious when used with artemether/lumefantrine.[15]

Pharmacology

Mechanism of action

Artemether is an artemisinin derivative and the mechanism of action for artemisinins is unknown.[16][17]

One of the proposed mechanisms is that through inhibiting anti-oxidant and metabolic enzymes, artemistinin derivatives inflict oxidative and metabolic stress on the cell. Some pathways affected may concern glutathione and glucose metabolism. As a consequence, lesions and reduced growth of the parasite may result.[16]

Another possible mechanism of action suggests that arteristinin drugs exert their cidal action through 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.[17]

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.[18]

Artemether is metabolized in the human body to the active metabolite, dihydroartemisinin, primarily by hepatic enzymes CYP3A4/5.[18] Both the parent drug and active metabolite are eliminated with a half-life of about 2 hours.[18]

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,[19] which acts by creating reactive free radicals in addition to affecting the membrane transport system of the plasmodium organism.[10]

References

  1. ↑ Baker, J. R.; Baker, John Robin; Muller, R.; Rollinson, D. (2001). Advances in Parasitology. Greenwood Publishing Group. p. 205. ISBN 9780120317509.
  2. ↑ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
  3. ↑ Makanga, Michael; Krudsood, Srivicha (2009-10-12). "The clinical efficacy of artemether/lumefantrine (Coartem)". Malaria Journal. 8 (Suppl 1): S5. doi:10.1186/1475-2875-8-S1-S5. ISSN 1475-2875. PMC 2760240Freely accessible. PMID 19818172.
  4. ↑ Esu, E; Effa, EE; Opie, ON; Uwaoma, A; Meremikwu, MM (Sep 11, 2014). "Artemether for severe malaria.". The Cochrane database of systematic reviews. 9: CD010678. doi:10.1002/14651858.CD010678.pub2. PMID 25209020.
  5. ↑ Information, National Center for Biotechnology; Pike, U. S. National Library of Medicine 8600 Rockville; MD, Bethesda; Usa, 20894 (2015-01-01). TREATMENT OF UNCOMPLICATED PLASMODIUM FALCIPARUM MALARIA. World Health Organization.
  6. ↑ Information, National Center for Biotechnology; Pike, U. S. National Library of Medicine 8600 Rockville; MD, Bethesda; Usa, 20894 (2015-01-01). TREATMENT OF UNCOMPLICATED MALARIA CAUSED BY P. VIVAX, P. OVALE, P. MALARIAE OR P. KNOWLESI. World Health Organization.
  7. ↑ Pérez del Villar, Luis; Burguillo, Francisco J.; López-Abán, Julio; Muro, Antonio (2012-01-01). "Systematic review and meta-analysis of artemisinin based therapies for the treatment and prevention of schistosomiasis". PloS One. 7 (9): e45867. doi:10.1371/journal.pone.0045867. ISSN 1932-6203. PMC 3448694Freely accessible. PMID 23029285.
  8. ↑ Dellicour S, Hall S, Chandramohan D, Greenwood B (2007). "The safety of artemisinins during pregnancy: a pressing question". Malaria J. 6: 15. doi:10.1186/1475-2875-6-15.
  9. ↑ Piola P, Nabasumba C, Turyakira E, et al. (2010). "Efficacy and safety of artemether—lumefantrine compared with quinine in pregnant women with uncomplicated Plasmodium falciparum malaria: an open-label, randomised, non-inferiority trial". Lancet Infect Dis. 10 (11): 762–769. doi:10.1016/S1473-3099(10)70202-4.
  10. 1 2 "Artemether". www.antimicrobe.org. Retrieved 2016-11-09.
  11. ↑ "WHO Model Prescribing Information: Drugs Used in Parasitic Diseases - Second Edition: Protozoa: Malaria: Artemether". apps.who.int. Retrieved 2016-11-09.
  12. 1 2 Askling, Helena H.; Bruneel, Fabrice; Burchard, Gerd; Castelli, Francesco; Chiodini, Peter L.; Grobusch, Martin P.; Lopez-Vélez, Rogelio; Paul, Margaret; Petersen, Eskild (2012-01-01). "Management of imported malaria in Europe". Malaria Journal. 11: 328. doi:10.1186/1475-2875-11-328. ISSN 1475-2875. PMC 3489857Freely accessible. PMID 22985344.
  13. ↑ Van geertruyden, J.-P. "Interactions between malaria and human immunodeficiency virus anno 2014". Clinical Microbiology and Infection. 20 (4): 278–285. doi:10.1111/1469-0691.12597. PMC 4368411Freely accessible. PMID 24528518.
  14. ↑ Kiang, Tony K. L.; Wilby, Kyle J.; Ensom, Mary H. H. (2013-10-26). "Clinical Pharmacokinetic Drug Interactions Associated with Artemisinin Derivatives and HIV-Antivirals". Clinical Pharmacokinetics. 53 (2): 141–153. doi:10.1007/s40262-013-0110-5. ISSN 0312-5963.
  15. 1 2 Stover, Kayla R.; King, S. Travis; Robinson, Jessica (2012-04-01). "Artemether-Lumefantrine: An Option for Malaria". Annals of Pharmacotherapy. 46 (4): 567–577. doi:10.1345/aph.1Q539. ISSN 1060-0280. PMID 22496476.
  16. 1 2 Saeed, ME; Krishna, S; Greten, HJ; Kremsner, PG; Efferth, T (August 2016). "Antischistosomal activity of artemisinin derivatives in vivo and in patients.". Pharmacological research. 110: 216–26. PMID 26902577.
  17. 1 2 Guo, Zongru (2016-03-01). "Artemisinin anti-malarial drugs in China". Acta Pharmaceutica Sinica B. 6 (2): 115–124. doi:10.1016/j.apsb.2016.01.008. PMC 4788711Freely accessible. PMID 27006895.
  18. 1 2 3 "Coartem Label" (PDF). FDA. March 2015.
  19. ↑ B.M.J. De Spiegeleer, M. D’Hondt, E. Vangheluwe, K. Vandercruyssen, B.G.I. De Spiegeleer, H. Jansen, I. Koijen, J. Van Gompel. Relative response factor determination of artemether degradants with a dry heat stress approach. Journal of Pharmaceutical and Biomedical Analysis 70 (2012) 111– 116.

See also

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