Artemether

Artemether (INN)

File:Artemether.svg
Systematic (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
Clinical data
AHFS/Drugs.com	International Drug Names
Pregnancy category	US: C (Risk not ruled out)
Legal status	UK: POM (Prescription only)
Routes of administration	Oral
Identifiers
CAS Number	71963-77-4 N
ATC code	P01BE02 (WHO)
PubChem	CID: 68911
DrugBank	DB06697 Y
ChemSpider	62138 Y
UNII	C7D6T3H22J Y
KEGG	D02483 Y
ChEBI	CHEBI:195280 Y
ChEMBL	CHEMBL1237051 N
Chemical data
Formula	C16H26O5
Molecular mass	298.374 g/mol
SMILES C[C@@H]1CC[C@@H]3C42OO[C@](C)(CC[C@@H]12)O[C@H]4O[C@H](OC)[C@@H]3C
InChI 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 Y Key:SXYIRMFQILZOAM-HVNFFKDJSA-N Y
NY (what is this?)  (verify)

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. Its is available in combination with lumefantrine. This combination is available as generic medication.

Medical uses

Antimalarial

Artemether is effective against the blood schizonts of both malarial parasites P. falciparum and P. vivax. It, however, may not be as good as artesunate for severe malaria.

It is available by itself, but usually given in combination with lumefantrine in treatments of malaria. World Health Organization guidelines for the treatment of uncomplicated falciparum malaria recommend the use of this artemisinin-based combination therapy. Zambia was the first African country to adopt artemether/lumefantrine (commonly called Coartem) as first-line therapy in national malaria treatment guidelines in 2002. Clinical records show that by 2008, the rates of in-patient malaria cases and deaths decreased by 61% and 66%, respectively, compared with the 2001-2002 reference period. In South Africa, also, the number of malaria-related outpatient cases and hospital admissions of each fell by 99% from 2001 to 2003, and malaria-related deaths decreased by 97% over the same period.

The efficacy of the six-dose regimen of Coartem has been confirmed in many different populations around the world, consistently achieving 28-day polymerase chain reaction-corrected cure rates of >95% in the evaluable population, rapidly clearing parasitaemia and fever, and demonstrating a significant gametocidal effect, even in areas of widespread parasite resistance to other antimalarials. Coartem is more effective than quinine, the classical antimalarial. For P. vivax infection, combination with piperaquine is more effective than Coartem.

Artemether has been assigned to category C by the FDA on the basis of animal data which show an association with fetal loss and deformity. However, clinical data appear to show that artemether is safe in pregnancy. A meta-analysis that looked at artemether in 945 pregnant women did not find evidence of harm, and a clinical trial of artemether-lumefantrine designed to look at this question found fewer adverse events in the 138 pregnant women treated with artemther-lumefantrine than women treated with quinine.

Anthelmintic

During the early 1980s, Chinese scientists, by serendipity, discovered that artemether was not only an antimalarial agent, but also effective against the blood flukes. Eventually, laboratory experiments have confirmed the broad spectrum of activity against different trematodes, including all human schistosomes, Clonorchis sinensis, Fasciola hepatica, and Opisthorchis viverrini. These studies revealed that artemether exhibits the highest activity against juvenile stages of the trematodes, while adult worms are significantly less susceptible. In addition, no indication of neurotoxicity was seen following repeated high doses. Randomized controlled clinical trials confirmed that artemether, orally administered at a dose of 6 mg/kg once every 2–3 weeks, results in no drug-related adverse effects, and significantly reduces the incidence and intensity of schistosome infections, including those of Schistosoma mansoni, S. japonicum, and S. haematobium.

Chemical nature

It is a methyl ether derivative of artemisinin, which is a peroxide 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.

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.

See also

• Artemether/lumefantrine
  • Lumefantrine