Artemether

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Artemether
Artemether.svg
Artemether 3D balls.png
Clinical data
Trade names Many [1]
AHFS/Drugs.com International Drug Names
Routes of
administration 		Intramuscular [2] Oral
ATC code
Legal status
Legal status
  • UK: POM (Prescription only)
  • In general: ℞ (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
ChemSpider
UNII
KEGG
ChEBI
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard 100.189.847 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C16H26O5
Molar mass 298.379 g·mol−1
3D model (JSmol)
Melting point 86 to 88 °C (187 to 190 °F)
  • 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 Yes check.svgY
  • Key:SXYIRMFQILZOAM-HVNFFKDJSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Artemether is a medication used for the treatment of malaria. [2] The injectable form is specifically used for severe malaria rather than quinine. [2] In adults, it may not be as effective as artesunate. [2] It is given by injection in a muscle. [2] It is also available by mouth in combination with lumefantrine, known as artemether/lumefantrine. [3] [4]

Contents

Artemether causes relatively few side effects. [5] An irregular heartbeat may rarely occur. [5] While there is evidence that use during pregnancy may be harmful in animals, there is no evidence of concern in humans. [5] The World Health Organization (WHO) therefore recommends its use during pregnancy. [5] It is in the artemisinin class of medication. [5]

Artemether has been studied since at least 1981, and has been in medical use since 1987. [6] It is on the World Health Organization's List of Essential Medicines. [7]

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. [8] Artemether can also be used to treat severe malaria. [2]

The World Health Organization (WHO) recommends the treatment of uncomplicated P. falciparum with artemisinin-based combination therapy. [9] 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. [10]

Artemether can also be used in treating and preventing trematode infections of schistosomiasis when used in combination with praziquantel. [11]

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. [12] [13]

Side effects

Possible side effects include cardiac effects such as bradycardia and QT interval prolongation. [14] Also, possible central nervous system toxicity has been shown in animal studies. [15] [16]

Drug interactions

Plasma artemether level was found to be lower when the combination product was used with lopinavir/ritonavir. [16] There is also decreased drug exposure associated with concurrent use with efavirenz or nevirapine. [17] [18]

Artemether/lumefantrine should not be used with drugs that inhibit CYP3A4. [19]

Hormonal contraceptives may not be as efficacious when used with artemether/lumefantrine. [19]

Pharmacology

Mechanism of action

Artemether is an artemisinin derivative and the mechanism of action for artemisinins is.[ medical citation needed ]

Artemether interact with ferriprotoporphyrin IX (heme) or ferrous ions in the acidic parasite food vacuole, and generates cytotoxic radical species [ medical citation needed ]

The accepted mode of action of the peroxide containing drug involve its interaction with heme (byproduct of hemoglobin degradation), derived from the proteolysis of haemoglobin. This interaction results in the formation of toxic oxygen and carbon centered radicals.[ medical citation needed ]

One of the proposed mechanisms is that through inhibiting anti-oxidant and metabolic enzymes, artemisinin 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. [20]

Another possible mechanism of action suggests 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. [21]

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. [4]

Artemether is metabolized in the human body to the active metabolite, dihydroartemisinin, primarily by hepatic enzymes CYP3A4/5. [4] Both the parent drug and active metabolite are eliminated with a half-life of about 2 hours. [4]

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, [22] which acts by creating reactive free radicals in addition to affecting the membrane transport system of the plasmodium organism. [14]

Related Research Articles

<span class="mw-page-title-main">Malaria</span> Medical condition

Malaria is a mosquito-borne infectious disease that affects humans and other vertebrates. Human malaria causes symptoms that typically include fever, fatigue, vomiting, and headaches. In severe cases, it can cause jaundice, seizures, coma, or death. Symptoms usually begin 10 to 15 days after being bitten by an infected Anopheles mosquito. If not properly treated, people may have recurrences of the disease months later. In those who have recently survived an infection, reinfection usually causes milder symptoms. This partial resistance disappears over months to years if the person has no continuing exposure to malaria.

Antimalarial medications or simply antimalarials are a type of antiparasitic chemical agent, often naturally derived, that can be used to treat or to prevent malaria, in the latter case, most often aiming at two susceptible target groups, young children and pregnant women. As of 2018, modern treatments, including for severe malaria, continued to depend on therapies deriving historically from quinine and artesunate, both parenteral (injectable) drugs, expanding from there into the many classes of available modern drugs. Incidence and distribution of the disease is expected to remain high, globally, for many years to come; moreover, known antimalarial drugs have repeatedly been observed to elicit resistance in the malaria parasite—including for combination therapies featuring artemisinin, a drug of last resort, where resistance has now been observed in Southeast Asia. As such, the needs for new antimalarial agents and new strategies of treatment remain important priorities in tropical medicine. As well, despite very positive outcomes from many modern treatments, serious side effects can impact some individuals taking standard doses.

<i>Plasmodium falciparum</i> Protozoan species of malaria parasite

Plasmodium falciparum is a unicellular protozoan parasite of humans, and the deadliest species of Plasmodium that causes malaria in humans. The parasite is transmitted through the bite of a female Anopheles mosquito and causes the disease's most dangerous form, falciparum malaria. It is responsible for around 50% of all malaria cases. P. falciparum is therefore regarded as the deadliest parasite in humans. It is also associated with the development of blood cancer and is classified as a Group 2A (probable) carcinogen.

<i>Artemisia annua</i> Herb known as sweet wormwood used to treat malaria

Artemisia annua, also known as sweet wormwood, sweet annie, sweet sagewort, annual mugwort or annual wormwood, is a common type of wormwood native to temperate Asia, but naturalized in many countries including scattered parts of North America.

<span class="mw-page-title-main">Artemisinin</span> Group of drugs used against malaria

Artemisinin and its semisynthetic derivatives are a group of drugs used in the treatment of malaria due to Plasmodium falciparum. It was discovered in 1972 by Tu Youyou, who shared the 2015 Nobel Prize in Physiology or Medicine for her discovery. Artemisinin-based combination therapies (ACTs) are now standard treatment worldwide for P. falciparum malaria as well as malaria due to other species of Plasmodium. Artemisinin is extracted from the plant Artemisia annua a herb employed in Chinese traditional medicine. A precursor compound can be produced using a genetically engineered yeast, which is much more efficient than using the plant.

<span class="mw-page-title-main">Artesunate</span> Chemical compound

Artesunate (AS) is a medication used to treat malaria. The intravenous form is preferred to quinine for severe malaria. Often it is used as part of combination therapy, such as artesunate plus mefloquine. It is not used for the prevention of malaria. Artesunate can be given by injection into a vein, injection into a muscle, by mouth, and by rectum.

<i>Plasmodium knowlesi</i> Species of single-celled organism

Plasmodium knowlesi is a parasite that causes malaria in humans and other primates. It is found throughout Southeast Asia, and is the most common cause of human malaria in Malaysia. Like other Plasmodium species, P. knowlesi has a life cycle that requires infection of both a mosquito and a warm-blooded host. While the natural warm-blooded hosts of P. knowlesi are likely various Old World monkeys, humans can be infected by P. knowlesi if they are fed upon by infected mosquitoes. P. knowlesi is a eukaryote in the phylum Apicomplexa, genus Plasmodium, and subgenus Plasmodium. It is most closely related to the human parasite Plasmodium vivax as well as other Plasmodium species that infect non-human primates.

Artemether/lumefantrine, sold under the trade name Coartem among others, is a combination of the two medications artemether and lumefantrine. It is used to treat malaria caused by Plasmodium falciparum that is not treatable with chloroquine. It is not typically used to prevent malaria. It is taken by mouth.

<span class="mw-page-title-main">Dihydroartemisinin</span> Drug used to treat malaria

Dihydroartemisinin is a drug used to treat malaria. Dihydroartemisinin is the active metabolite of all artemisinin compounds and is also available as a drug in itself. It is a semi-synthetic derivative of artemisinin and is widely used as an intermediate in the preparation of other artemisinin-derived antimalarial drugs. It is sold commercially in combination with piperaquine and has been shown to be equivalent to artemether/lumefantrine.

<span class="mw-page-title-main">Lumefantrine</span> Group of enantiomers

Lumefantrine is an antimalarial drug. It is only used in combination with artemether. The term "co-artemether" is sometimes used to describe this combination. Lumefantrine has a much longer half-life compared to artemether, and is therefore thought to clear any residual parasites that remain after combination treatment.

Artesunate/amodiaquine, sold under the trade name Camoquin among others, is a medication used for the treatment of malaria. It is a fixed-dose combination of artesunate and amodiaquine. Specifically it recommended for acute uncomplicated Plasmodium falciparum malaria. It is taken by mouth.

<span class="mw-page-title-main">History of malaria</span> History of malaria infections

The history of malaria extends from its prehistoric origin as a zoonotic disease in the primates of Africa through to the 21st century. A widespread and potentially lethal human infectious disease, at its peak malaria infested every continent except Antarctica. Its prevention and treatment have been targeted in science and medicine for hundreds of years. Since the discovery of the Plasmodium parasites which cause it, research attention has focused on their biology as well as that of the mosquitoes which transmit the parasites.

PfATP6, also known as PfSERCA or PfATPase6, is a calcium ATPase gene encoded by the malaria parasite Plasmodium falciparum. The protein is thought to be a P-type ATPase involved in calcium ion transport.

<span class="mw-page-title-main">Piperaquine</span> Chemical compound

Piperaquine is an antiparasitic drug used in combination with dihydroartemisinin to treat malaria. Piperaquine was developed under the Chinese National Malaria Elimination Programme in the 1960s and was adopted throughout China as a replacement for the structurally similar antimalarial drug chloroquine. Due to widespread parasite resistance to piperaquine, the drug fell out of use as a monotherapy, and is instead used as a partner drug for artemisinin combination therapy. Piperaquine kills parasites by disrupting the detoxification of host heme.

Project 523 is a code name for a 1967 secret military project of the People's Republic of China to find antimalarial medications. Named after the date the project launched, 23 May, it addressed malaria, an important threat in the Vietnam War. At the behest of Ho Chi Minh, Prime Minister of North Vietnam, Zhou Enlai, the Premier of the People's Republic of China, convinced Mao Zedong, Chairman of the Chinese Communist Party, to start the mass project "to keep [the] allies' troops combat-ready", as the meeting minutes put it. More than 500 Chinese scientists were recruited. The project was divided into three streams. The one for investigating traditional Chinese medicine discovered and led to the development of a class of new antimalarial drugs called artemisinins. Launched during and lasting throughout the Cultural Revolution, Project 523 was officially terminated in 1981.

Pregnancy-associated malaria (PAM) or placental malaria is a presentation of the common illness that is particularly life-threatening to both mother and developing fetus. PAM is caused primarily by infection with Plasmodium falciparum, the most dangerous of the four species of malaria-causing parasites that infect humans. During pregnancy, a woman faces a much higher risk of contracting malaria and of associated complications. Prevention and treatment of malaria are essential components of prenatal care in areas where the parasite is endemic – tropical and subtropical geographic areas. Placental malaria has also been demonstrated to occur in animal models, including in rodent and non-human primate models.

Piperaquine/dihydroartemisinin (DHA/PPQ), sold under the brand name Eurartesim among others, is a fixed dose combination medication used in the treatment of malaria. It is a combination of piperaquine and dihydroartemisinin. Specifically it is used for malaria of the P. falciparum and P. vivax types. It is taken by mouth.

Zhou Yiqing is a professor of medicine at the Institute of Microbiology and Epidemiology of the People's Liberation Army Academy of Military Medical Sciences. He was one of the scientists who participated in the Project 523 of the Chinese Government under Chairman Mao Zedong. The project resulted in the discovery of artemisinins, a class of antimalarial drugs, from the medicinal plant Artemisia annua.

Artesunate/pyronaridine, sold under the brand name Pyramax, is a fixed-dose combination medication for the treatment of malaria. It can be used for malaria of both the P. falciparum and P. vivax types. It combines artesunate and pyronaridine. It is taken by mouth.

Moses R Kamya, is a Ugandan physician, academic, researcher and academic administrator, who serves as Professor and Chair of the Department Medicine, Makerere University School of Medicine, a component of Makerere University College of Health Sciences.

References

  1. ↑ "Artemether - Drugs.com". www.drugs.com. Archived from the original on 20 December 2016. Retrieved 7 December 2016.
  2. 1 2 3 4 5 6 Esu EB, Effa EE, Opie ON, Meremikwu MM (June 2019). "Artemether for severe malaria". The Cochrane Database of Systematic Reviews. 6 (6): CD010678. doi:10.1002/14651858.CD010678.pub3. PMC   6580442 . PMID   31210357.
  3. ↑ "Artemether and Lumefantrine". The American Society of Health-System Pharmacists. Archived from the original on 20 December 2016. Retrieved 28 November 2016.
  4. 1 2 3 4 "Coartem- artemether and lumefantrine tablet". DailyMed. 5 August 2019. Retrieved 26 April 2020.
  5. 1 2 3 4 5 Kovacs SD, Rijken MJ, Stergachis A (February 2015). "Treating severe malaria in pregnancy: a review of the evidence". Drug Safety. 38 (2): 165–181. doi:10.1007/s40264-014-0261-9. PMC   4328128 . PMID   25556421.
  6. ↑ Rao Y, Zhang D, Li R (2016). Tu Youyou and the Discovery of Artemisinin: 2015 Nobel Laureate in Physiology or Medicine. World Scientific. p. 162. ISBN   9789813109919. Archived from the original on 2017-09-10.
  7. ↑ World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. 2019. hdl: 10665/325771 . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  8. ↑ Makanga M, Krudsood S (October 2009). "The clinical efficacy of artemether/lumefantrine (Coartem)". Malaria Journal. 8 (Suppl 1): S5. doi: 10.1186/1475-2875-8-S1-S5 . PMC   2760240 . PMID   19818172.
  9. ↑ Treatment of Uncomplicated Plasmodium falciparum Malaria. World Health Organization. 2015-01-01. Archived from the original on 2017-09-10.
  10. ↑ Treatment Of Uncomplicated Malaria Caused By P. vivax, P. ovale, P. malariae or P. knowlesi. World Health Organization. 2015-01-01. Archived from the original on 2017-09-10.
  11. ↑ Pérez del Villar L, Burguillo FJ, López-Abán J, Muro A (2012-01-01). "Systematic review and meta-analysis of artemisinin based therapies for the treatment and prevention of schistosomiasis". PLOS ONE. 7 (9): e45867. Bibcode:2012PLoSO...745867P. doi: 10.1371/journal.pone.0045867 . PMC   3448694 . PMID   23029285.
  12. ↑ Dellicour S, Hall S, Chandramohan D, Greenwood B (February 2007). "The safety of artemisinins during pregnancy: a pressing question". Malaria Journal. 6: 15. doi: 10.1186/1475-2875-6-15 . PMC   1802871 . PMID   17300719.
  13. ↑ Piola P, Nabasumba C, Turyakira E, Dhorda M, Lindegardh N, Nyehangane D, et al. (November 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". The Lancet. Infectious Diseases. 10 (11): 762–769. doi:10.1016/S1473-3099(10)70202-4. hdl: 10144/116337 . PMID   20932805.
  14. 1 2 "Artemether". www.antimicrobe.org. Archived from the original on 2017-02-23. Retrieved 2016-11-09.
  15. ↑ "WHO Model Prescribing Information: Drugs Used in Parasitic Diseases - Second Edition: Protozoa: Malaria: Artemether". apps.who.int. Archived from the original on 2016-11-10. Retrieved 2016-11-09.
  16. 1 2 Askling HH, Bruneel F, Burchard G, Castelli F, Chiodini PL, Grobusch MP, et al. (September 2012). "Management of imported malaria in Europe". Malaria Journal. 11: 328. doi: 10.1186/1475-2875-11-328 . PMC   3489857 . PMID   22985344.
  17. ↑ Van Geertruyden JP (April 2014). "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 TK, Wilby KJ, Ensom MH (February 2014). "Clinical pharmacokinetic drug interactions associated with artemisinin derivatives and HIV-antivirals". Clinical Pharmacokinetics. 53 (2): 141–153. doi:10.1007/s40262-013-0110-5. PMID   24158666. S2CID   1281113.
  19. 1 2 Stover KR, King ST, Robinson J (April 2012). "Artemether-lumefantrine: an option for malaria". The Annals of Pharmacotherapy. 46 (4): 567–577. doi:10.1345/aph.1Q539. PMID   22496476. S2CID   7678606.
  20. ↑ 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: 216–226. doi:10.1016/j.phrs.2016.02.017. PMID   26902577.
  21. ↑ Guo Z (March 2016). "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.
  22. ↑ De Spiegeleer BM, D'Hondt M, Vangheluwe E, Vandercruyssen K, De Spiegeleer BV, Jansen H, et al. (November 2012). "Relative response factor determination of β-artemether degradants by a dry heat stress approach". Journal of Pharmaceutical and Biomedical Analysis. 70: 111–116. doi:10.1016/j.jpba.2012.06.002. hdl: 1854/LU-2938963 . PMID   22770733.
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