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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 [[International Union of Pure and Applied Chemistry|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.
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 [[International Union of Pure and Applied Chemistry|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<ref>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.</ref>, which acts by creating reactive free radicals in addition to affecting the membrane transport system of the plasmodium organism<ref>{{Cite web|url=http://www.antimicrobe.org/drugpopup/artemether.htm|title=Artemether|website=www.antimicrobe.org|access-date=2016-11-09}}</ref>.
It is a relatively lipophilic and unstable drug<ref>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.</ref>, which acts by creating reactive free radicals in addition to affecting the membrane transport system of the plasmodium organism<ref>{{Cite web|url=http://www.antimicrobe.org/drugpopup/artemether.htm|title=Artemether|website=www.antimicrobe.org|access-date=2016-11-09}}</ref>.

== Mechanism of action ==
As mentioned in previous sections, Artemether is an artemistinin derivative. There are different proposals regarding the mechanism of action for this group of medications.

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<ref>{{Cite journal|last=Saeed|first=Mohamed E. M.|last2=Krishna|first2=Sanjeev|last3=Greten|first3=Henry Johannes|last4=Kremsner|first4=Peter G.|last5=Efferth|first5=Thomas|date=2016-08-01|title=Antischistosomal activity of artemisinin derivatives in vivo and in patients|url=http://www.sciencedirect.com/science/article/pii/S1043661815301584|journal=Pharmacological Research|volume=110|pages=216–226|doi=10.1016/j.phrs.2016.02.017}}</ref>.    

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<ref>{{Cite journal|last=Guo|first=Zongru|date=2016-03-01|title=Artemisinin anti-malarial drugs in China|url=http://www.sciencedirect.com/science/article/pii/S2211383516300089|journal=Acta Pharmaceutica Sinica B|volume=6|issue=2|pages=115–124|doi=10.1016/j.apsb.2016.01.008|pmc=4788711|pmid=27006895}}</ref>.


==Pharmacokinetics and pharmacodynamics==
==Pharmacokinetics and pharmacodynamics==
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A commonly cited theory that the parasite's SERCA pump (PfATP6 / PfSERCA) is a target of artemether has been increasingly questioned by some, although this hypothesis has been discussed in detail by others . It is now clear that the original studies claiming specific interactions between SERCAs and artemether were undertaken in a ''Xenopus'' oocyte system with a poor signal:noise ratio.
A commonly cited theory that the parasite's SERCA pump (PfATP6 / PfSERCA) is a target of artemether has been increasingly questioned by some, although this hypothesis has been discussed in detail by others . It is now clear that the original studies claiming specific interactions between SERCAs and artemether were undertaken in a ''Xenopus'' oocyte system with a poor signal:noise ratio.
Other mechanisms of action for artemether include their ability to reduce fever by production of signals to hypothalamus thermoregulatory center. Now, recent research has shown the presence of a new, previously unknown cyclooxygenase enzyme COX-3, found in the brain and spinal cord, which is selectively inhibited by artemether, and is distinct from the two already known cyclooxygenase enzymes COX-1 and COX-2. It is now believed that this selective inhibition of the enzyme COX-3 in the brain and spinal cord explains the ability of artemether in relieving pain and reducing fever which is produced by malaria. {{citation needed|date=October 2012}}
Other mechanisms of action for artemether include their ability to reduce fever by production of signals to hypothalamus thermoregulatory center. Now, recent research has shown the presence of a new, previously unknown cyclooxygenase enzyme COX-3, found in the brain and spinal cord, which is selectively inhibited by artemether, and is distinct from the two already known cyclooxygenase enzymes COX-1 and COX-2. It is now believed that this selective inhibition of the enzyme COX-3 in the brain and spinal cord explains the ability of artemether in relieving pain and reducing fever which is produced by malaria. {{citation needed|date=October 2012}}

== Interactions ==
There are more studies done based on the combination product artemether/lumefantrine compared to artemether. Askling et al. pointed out that the combination product can cause QTc prolongation. With concurrent use of other medications that prolong QTc, this influence can be more pronounced<ref name=":0">{{Cite journal|last=Askling|first=Helena H.|last2=Bruneel|first2=Fabrice|last3=Burchard|first3=Gerd|last4=Castelli|first4=Francesco|last5=Chiodini|first5=Peter L.|last6=Grobusch|first6=Martin P.|last7=Lopez-Vélez|first7=Rogelio|last8=Paul|first8=Margaret|last9=Petersen|first9=Eskild|date=2012-01-01|title=Management of imported malaria in Europe|url=http://dx.doi.org/10.1186/1475-2875-11-328|journal=Malaria Journal|volume=11|pages=328|doi=10.1186/1475-2875-11-328|issn=1475-2875|pmc=3489857|pmid=22985344}}</ref>.

Plasma artemether level was found to be lower when the combination product was used with lopinavir/ritonavir<ref name=":0" />. There was also decreased drug exposure associated with concurrent use with efavirenz or nevirapine<ref>{{Cite journal|last=Van geertruyden|first=J.-P.|title=Interactions between malaria and human immunodeficiency virus anno 2014|url=http://linkinghub.elsevier.com/retrieve/pii/S1198743X14602731|journal=Clinical Microbiology and Infection|volume=20|issue=4|pages=278–285|doi=10.1111/1469-0691.12597|pmc=4368411|pmid=24528518}}</ref>.

An autoinduction phenomenon is observed with the metabolism of artemether<ref>{{Cite journal|last=Kiang|first=Tony K. L.|last2=Wilby|first2=Kyle J.|last3=Ensom|first3=Mary H. H.|date=2013-10-26|title=Clinical Pharmacokinetic Drug Interactions Associated with Artemisinin Derivatives and HIV-Antivirals|url=http://link.springer.com/article/10.1007/s40262-013-0110-5|journal=Clinical Pharmacokinetics|language=en|volume=53|issue=2|pages=141–153|doi=10.1007/s40262-013-0110-5|issn=0312-5963}}</ref>. Despite of this, Stover et al. cautioned toward concurrent treatment of artemether/lumefantrine and CYP 3A4 inhibitors<ref name=":1">{{Cite journal|last=Stover|first=Kayla R.|last2=King|first2=S. Travis|last3=Robinson|first3=Jessica|date=2012-04-01|title=Artemether-Lumefantrine: An Option for Malaria|url=http://aop.sagepub.com/content/46/4/567|journal=Annals of Pharmacotherapy|language=en|volume=46|issue=4|pages=567–577|doi=10.1345/aph.1Q539|issn=1060-0280|pmid=22496476}}</ref>.

It is also worth noting that hormonal contraceptives may not be as efficacious when used with artemether/lumefantrine<ref name=":1" />.


== References ==
== References ==

Revision as of 22:09, 9 November 2016

Artemether
Clinical data
AHFS/Drugs.comInternational Drug Names
Routes of
administration		Oral
ATC code
Legal status
Legal status
  • UK: POM (Prescription only)
Identifiers
  • (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
CAS Number
PubChem CID
DrugBank
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KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.189.847 Edit this at Wikidata
Chemical and physical data
FormulaC16H26O5
Molar mass298.374 g/mol g·mol−1
3D model (JSmol)
  • C[C@@H]1CC[C@@H]3C42OO[C@](C)(CC[C@@H]12)O[C@H]4O[C@H](OC)[C@@H]3C
  • InChI=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 checkY
  • Key:SXYIRMFQILZOAM-HVNFFKDJSA-N checkY
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Artemether is an antimalarial for the treatment of multiple drug-resistant strains of Plasmodium falciparum malaria.

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.[1] Its 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.[2] For severe malaria, studies had shown artesunate to be more effective.[3]

The World Health Organization recommends the treatment of uncomplicated P. falciparum with artemisinin-based combination therapy. [4] Given in combination with lumefantrine, it must be followed by a 14 day regimen of primaquine to prevent relapse of the malarial parasites and provide a complete cure. [5]

Artemether is 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.[6][7]

Artemether has also shown efficacy against treating and preventing trematode infections of schistosomiasis when used in combination with praziquantel. [8]

Currently, artemether is being studied for its anticancer properties in animals based on its molecular structure. [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]

Chemical nature

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[12], which acts by creating reactive free radicals in addition to affecting the membrane transport system of the plasmodium organism[13].

Mechanism of action

As mentioned in previous sections, Artemether is an artemistinin derivative. There are different proposals regarding the mechanism of action for this group of medications.

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[14].    

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[15].

Pharmacokinetics and pharmacodynamics

Artemether interacts with ferriprotoporphyrin IX (“heme”), or ferrous ions, in the acidic parasite food vacuole, which results in the generation of cytotoxic radical species. The generally accepted mechanism of action of peroxide antimalarials involves interaction of the peroxide-containing drug with heme, a hemoglobin degradation byproduct, derived from proteolysis of hemoglobin. This interaction is believed to result in the formation of a range of potentially toxic oxygen and carbon-centered radicals. Numerous studies have investigated the type of damage oxygen radicals may induce. For example, Pandey et al. have observed inhibition of digestive vacuole cysteine protease activity of malarial parasites by artemether. These observations were supported by ex vivo experiments showing accumulation of hemoglobin in the parasites treated with artemether and inhibition of hemozoin formation by malaria parasites. Electron microscopic evidence linking artemisinin action to the parasite's digestive vacuole has been obtained showing that the digestive vacuole membrane suffers damage soon after parasites are exposed to artemether. This would also be consistent with data showing that the digestive vacuole is already established by the mid-ring stage of the parasite's blood cycle, a stage that is sensitive to artemether, but not other antimalarials. A commonly cited theory that the parasite's SERCA pump (PfATP6 / PfSERCA) is a target of artemether has been increasingly questioned by some, although this hypothesis has been discussed in detail by others . It is now clear that the original studies claiming specific interactions between SERCAs and artemether were undertaken in a Xenopus oocyte system with a poor signal:noise ratio. Other mechanisms of action for artemether include their ability to reduce fever by production of signals to hypothalamus thermoregulatory center. Now, recent research has shown the presence of a new, previously unknown cyclooxygenase enzyme COX-3, found in the brain and spinal cord, which is selectively inhibited by artemether, and is distinct from the two already known cyclooxygenase enzymes COX-1 and COX-2. It is now believed that this selective inhibition of the enzyme COX-3 in the brain and spinal cord explains the ability of artemether in relieving pain and reducing fever which is produced by malaria. [citation needed]

Interactions

There are more studies done based on the combination product artemether/lumefantrine compared to artemether. Askling et al. pointed out that the combination product can cause QTc prolongation. With concurrent use of other medications that prolong QTc, this influence can be more pronounced[16].

Plasma artemether level was found to be lower when the combination product was used with lopinavir/ritonavir[16]. There was also decreased drug exposure associated with concurrent use with efavirenz or nevirapine[17].

An autoinduction phenomenon is observed with the metabolism of artemether[18]. Despite of this, Stover et al. cautioned toward concurrent treatment of artemether/lumefantrine and CYP 3A4 inhibitors[19].

It is also worth noting that hormonal contraceptives may not be as efficacious when used with artemether/lumefantrine[19].

References

  1. ^ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
  2. ^ 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 2760240. PMID 19818172.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  3. ^ 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.
  4. ^ Barnes KI, Chanda P, Ab Barnabas G (2009). "Impact of the large-scale deployment of artemether/lumefantrine on the malaria disease burden in Africa: case studies of South Africa, Zambia and Ethiopia". Malar J. 8 (1): S8. doi:10.1186/1475-2875-8-S1-S8. PMC 2760243. PMID 19818175.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  5. ^ Cabrera, Mynthia; Cui, Liwang (2015-12-01). "In Vitro Activities of Primaquine-Schizonticide Combinations on Asexual Blood Stages and Gametocytes of Plasmodium falciparum". Antimicrobial Agents and Chemotherapy. 59 (12): 7650–7656. doi:10.1128/AAC.01948-15. ISSN 1098-6596. PMC 4649191. PMID 26416869.
  6. ^ 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.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  7. ^ 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.
  8. ^ 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 3448694. PMID 23029285.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  9. ^ Ferreira, Jorge F. S.; Luthria, Devanand L.; Sasaki, Tomikazu; Heyerick, Arne (2010-04-29). "Flavonoids from Artemisia annua L. as antioxidants and their potential synergism with artemisinin against malaria and cancer". Molecules (Basel, Switzerland). 15 (5): 3135–3170. doi:10.3390/molecules15053135. ISSN 1420-3049. PMID 20657468.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  10. ^ "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. ^ 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.
  13. ^ "Artemether". www.antimicrobe.org. Retrieved 2016-11-09.
  14. ^ Saeed, Mohamed E. M.; Krishna, Sanjeev; Greten, Henry Johannes; Kremsner, Peter G.; Efferth, Thomas (2016-08-01). "Antischistosomal activity of artemisinin derivatives in vivo and in patients". Pharmacological Research. 110: 216–226. doi:10.1016/j.phrs.2016.02.017.
  15. ^ 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 4788711. PMID 27006895.
  16. ^ a b 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 3489857. PMID 22985344.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  17. ^ 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 4368411. PMID 24528518.
  18. ^ 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.
  19. ^ a b 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.

See also

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