artemether

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/10/14 10:33:38」(JST)

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Artemether

Clinical data
AHFS/Drugs.com	International Drug Names
Pregnancy cat.	C (US)
Legal status	POM (UK)
Routes	Oral
Identifiers
CAS number	71963-77-4 N
ATC code	P01BE02
PubChem	CID 68911
DrugBank	DB06697
ChemSpider	62138 Y
UNII	C7D6T3H22J Y
KEGG	D02483 Y
ChEBI	CHEBI:195280 Y
ChEMBL	CHEMBL1237051 N
Chemical data
Formula	C16H26O5
Mol. 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
N (what is this?)  (verify)

Artemether (INN) is an antimalarial for the treatment of multi-drug resistant strains of falciparum malaria. It's combination (co-formulation) with Lumefantrine has first been marketed by Novartis under the brand names Riamet and Coartem. Today, this combination therapy is available as generic from several manufacturers.

Chemical nature

It is a methyl ether derivative of artemisinin, which is a peroxide lactone isolated from the Chinese 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.

Uses

Antimalarial

Artemether is highly effective against the blood schizonts of both malarial parasites P. falciparum and P. vivax. It is available as mono-therapy but usually applied in combination with lumefantrine in clinical treatments of malaria. World Health Organization guidelines for the treatment of uncomplicated falciparum malaria recommend the use of this artemisinin-based combination therapy, and approved by Swissmedic in December 2008 and recently approved by the United States Food and Drug Administration. 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 to each fall 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 patient 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 much more effective than quinine, the classical antimalarial. Randomised clinical trial in Uganda shows cure rate of malaria as high as 96% in the Coartem-treated group compared with 64% for the quinine group. For Plasmodium 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 shows an association with fetal-loss and deformity. However, clinical data appears to show that artemether is safe in pregnancy. A meta-analysis of 14 clinical trials that looked at artemether use in a total of 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 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, there are no indication of neurotoxicity 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 Scistosoma mansoni, S. japonicum and S. haematobium.

Anticancer

Artemether has been shown to have significant anticancer and antitumor activities. It is demonstrated that artemether caused strong inhibitory effects on brain glioma growth and angiogenesis in rats. It exhibits a dose- and time-dependent cytotoxicity, and induced apoptosis and G2 cell cycle arrest in ovarian cancer cell lines, human leukemia HL60 cells, and human pancreatic cancer BxPC-3 and AsPC-1 cells.

Other uses

Some medications have more than one effect on the body. In addition to anti malarial action Artemether has analgesic–antipyretic effects on the body by relieving pain and reducing fever.

Pharmacokinetics and pharmacodynamics of artemether

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 in 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 mechanism of action for artemether including 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 produced by malaria.^{[citation needed]}

References

UpToDate Contents

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• 1. 抗マラリア剤：概要 antimalarial drugs an overview
• 2. 合併症のない熱帯熱マラリアの治療 treatment of uncomplicated falciparum malaria
• 3. 重症熱帯熱マラリアの治療 treatment of severe falciparum malaria
• 4. 薬物および毒素による外因性非自己免疫性溶血性貧血 extrinsic nonautoimmune hemolytic anemia due to drugs and toxins
• 5. Prevention and treatment of malaria in pregnant women

English Journal

• Interspecies allometric scaling of antimalarial drugs and potential application to pediatric dosing.

• Senarathna SM1, Batty KT2.
• Antimicrobial agents and chemotherapy.Antimicrob Agents Chemother.2014 Oct;58(10):6068-78. doi: 10.1128/AAC.02538-14. Epub 2014 Aug 4.
• Pharmacopeial recommendations for administration of antimalarial drugs are the same weight-based (mg/kg of body weight) doses for children and adults. However, linear calculations are known to underestimate pediatric doses; therefore, interspecies allometric scaling data may have a role in predictin
• PMID 25092696

• Enhanced antimalarial activity by a novel artemether-lumefantrine lipid emulsion for parenteral administration.

• Ma Y1, Lu T2, Zhao W2, Wang Y2, Chen T2, Mei Q2, Chen T3.
• Antimicrobial agents and chemotherapy.Antimicrob Agents Chemother.2014 Oct;58(10):5658-65. doi: 10.1128/AAC.01428-13. Epub 2014 Jun 30.
• Artemether and lumefantrine (also known as benflumetol) are difficult to formulate for parenteral administration because of their low aqueous solubility. Cremophor EL as an emulsion excipient has been shown to cause serious side effects. This study reports a method of preparation and the therapeutic
• PMID 24982079

• Medication exposure during pregnancy: a pilot pharmacovigilance system using health and demographic surveillance platform.

• Mosha D, Mazuguni F, Mrema S, Abdulla S, Genton B.
• BMC pregnancy and childbirth.BMC Pregnancy Childbirth.2014 Sep 15;14(1):322. [Epub ahead of print]
• BACKGROUND: There is limited safety information on most drugs used during pregnancy. This is especially true for medication against tropical diseases because pharmacovigilance systems are not much developed in these settings. The aim of the present study was to demonstrate feasibility of using Healt
• PMID 25223541

Japanese Journal

• アーテメター・ルメファントリン合剤の日本人における使用経験

• 感染症学雑誌 = The journal of the Japanese Association for Infectious Diseases 88(6), 833-839, 2014-11
• NAID 40020299653

• Community-based scheduled screening and treatment of malaria in pregnancy for improved maternal and infant health in The Gambia, Burkina Faso and Benin: study protocol for a randomized controlled trial

• Trials 15, 340, 2014-08-28
• NAID 120005477056

• Congenital Malaria in China

• PLoS Neglected Tropical Diseases 8(3), e2622, 2014-03-13
• NAID 120005438937

Related Links

• Artemetherとは - goo Wikipedia (ウィキペディア)

Artemether (INN) is an antimalarial for the treatment of multi-drug resistant strains of falciparum malaria. Its combination (co-formulation) with Lumefantrine has first been marketed by Novartis under the brand names Riamet and ...

• Artemether and Lumefantrine: MedlinePlus Drug Information

Artemether and lumefantrine may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away: headache dizziness weakness muscle or joint pain tiredness difficulty falling asleep or staying ...

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