Artemether

Last updated
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. [1] [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. [1] [3]

Contents

Artemether causes relatively few side effects. [4] An irregular heartbeat may rarely occur. [4] While there is evidence that use during pregnancy may be harmful in animals, there is no evidence of concern in humans. [4] The World Health Organization (WHO) therefore recommends its use during pregnancy. [4] It is in the artemisinin class of medication. [4]

Artemether has been studied since at least 1981, and has been in medical use since 1987. [5] It is on the World Health Organization's List of Essential Medicines. [6]

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. [1] [7] 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. [8] 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. [9]

Artemether can also be used in treating and preventing trematode infections of schistosomiasis when used in combination with praziquantel. [10]

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. [11] [12]

Side effects

Possible side effects include cardiac effects such as bradycardia and QT interval prolongation. [1] [13] Also, possible central nervous system toxicity has been shown in animal studies. [14] [15]

Drug interactions

Plasma artemether level was found to be lower when the combination product was used with lopinavir/ritonavir. [15] There is also decreased drug exposure associated with concurrent use with efavirenz or nevirapine. [16] [17]

Artemether/lumefantrine should not be used with drugs that inhibit CYP3A4. [1] [18]

Hormonal contraceptives may not be as efficacious when used with artemether/lumefantrine. [18]

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. [19]

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. [3]

Artemether is metabolized in the human body to the active metabolite, dihydroartemisinin, primarily by hepatic enzymes CYP3A4/5. [3] Both the parent drug and active metabolite are eliminated with a half-life of about 2 hours. [3]

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

Related Research Articles

<span class="mw-page-title-main">Malaria</span> Mosquito-borne infectious disease

Malaria is a mosquito-borne infectious disease that affects vertebrates and Anopheles mosquitoes. 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. The mosquito vector is itself harmed by Plasmodium infections, causing reduced lifespan.

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. 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 an 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.

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.

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 malaria in pregnancy which is life-threatening to both pregnant women and unborn fetuses. PAM occurs when a pregnant woman contracts malaria, generally as a result of Plasmodium falciparum infection, and because she is pregnant, is at greater risk of associated complications such as placental malaria. Placental malaria interferes with the transmission of vital substances through the fetal placenta, which can result in stillbirths, miscarriages, and dangerously low birth weights.

The mainstay of malaria diagnosis has been the microscopic examination of blood, utilizing blood films. Although blood is the sample most frequently used to make a diagnosis, both saliva and urine have been investigated as alternative, less invasive specimens. More recently, modern techniques utilizing antigen tests or polymerase chain reaction have been discovered, though these are not widely implemented in malaria endemic regions. Areas that cannot afford laboratory diagnostic tests often use only a history of subjective fever as the indication to treat for malaria.

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/mefloquine is a medication used to treat malaria. It is a fixed dose combination of artesunate and mefloquine. Specifically it is recommended to treat uncomplicated falciparum malaria. It is taken by mouth.

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

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