Artemether
Encyclopedia
Artemether is an antimalarial for the treatment of multi-drug resistant strains of falciparum
malaria
. It is combined with Lumefantrine
and sold by Novartis
under the brand names Riamet and Co-Artem.
, 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.
P. falciparum
and P. vivax
. It is 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.
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
.
growth and angiogenesis
in rat
s. 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.
Plasmodium falciparum
Plasmodium falciparum is a protozoan parasite, one of the species of Plasmodium that cause malaria in humans. It is transmitted by the female Anopheles mosquito. Malaria caused by this species is the most dangerous form of malaria, with the highest rates of complications and mortality...
malaria
Malaria
Malaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium. The disease results from the multiplication of Plasmodium parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases...
. It is combined with Lumefantrine
Lumefantrine
Lumefantrine is an antimalarial drug. It is only used in combination with artemether. The term "co-artemether" is sometimes used to describe this combination....
and sold by Novartis
Novartis
Novartis International AG is a multinational pharmaceutical company based in Basel, Switzerland, ranking number three in sales among the world-wide industry...
under the brand names Riamet and Co-Artem.
Chemical nature
It is a methyl ether derivative of artemisininArtemisinin
Artemisinin , also known as Qinghaosu , and its derivatives are a group of drugs that possess the most rapid action of all current drugs against falciparum malaria. Treatments containing an artemisinin derivative are now standard treatment worldwide for falciparum malaria...
, which is a peroxide lactone
Lactone
In chemistry, a lactone is a cyclic ester which can be seen as the condensation product of an alcohol group -OH and a carboxylic acid group -COOH in the same molecule...
isolated from the Chinese
China
Chinese civilization may refer to:* China for more general discussion of the country.* Chinese culture* Greater China, the transnational community of ethnic Chinese.* History of China* Sinosphere, the area historically affected by Chinese culture...
antimalarial plant, Artemisia annua
Artemisia annua
Artemisia annua, also known as Sweet Wormwood, Sweet Annie, Sweet Sagewort or Annual Wormwood , is a common type of wormwood that is native to temperate Asia, but naturalized throughout the world.-Characteristics:...
. It is also known as dihydroartemisinin methyl ether, but its correct chemical nomenclature
International Union of Pure and Applied Chemistry
The International Union of Pure and Applied Chemistry is an international federation of National Adhering Organizations that represents chemists in individual countries. It is a member of the International Council for Science . The international headquarters of IUPAC is located in Zürich,...
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.
Antimalarial
Artemether is highly effective against the blood schizonts of both malarial parasitesPlasmodium
Plasmodium is a genus of parasitic protists. Infection by these organisms is known as malaria. The genus Plasmodium was described in 1885 by Ettore Marchiafava and Angelo Celli. Currently over 200 species of this genus are recognized and new species continue to be described.Of the over 200 known...
P. falciparum
Plasmodium falciparum
Plasmodium falciparum is a protozoan parasite, one of the species of Plasmodium that cause malaria in humans. It is transmitted by the female Anopheles mosquito. Malaria caused by this species is the most dangerous form of malaria, with the highest rates of complications and mortality...
and P. vivax
Plasmodium vivax
Plasmodium vivax is a protozoal parasite and a human pathogen. The most frequent and widely distributed cause of recurring malaria, P. vivax is one of the four species of malarial parasite that commonly infect humans. It is less virulent than Plasmodium falciparum, which is the deadliest of the...
. It is applied in combination with lumefantrine
Lumefantrine
Lumefantrine is an antimalarial drug. It is only used in combination with artemether. The term "co-artemether" is sometimes used to describe this combination....
in clinical treatments of malaria
Malaria
Malaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium. The disease results from the multiplication of Plasmodium parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases...
. World Health Organization
World Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...
guidelines for the treatment of uncomplicated falciparum malaria
Plasmodium falciparum
Plasmodium falciparum is a protozoan parasite, one of the species of Plasmodium that cause malaria in humans. It is transmitted by the female Anopheles mosquito. Malaria caused by this species is the most dangerous form of malaria, with the highest rates of complications and mortality...
recommend the use of this artemisinin
Artemisinin
Artemisinin , also known as Qinghaosu , and its derivatives are a group of drugs that possess the most rapid action of all current drugs against falciparum malaria. Treatments containing an artemisinin derivative are now standard treatment worldwide for falciparum malaria...
-based combination therapy, and approved by Swissmedic
Swissmedic
Swissmedic, the Swiss Agency for Therapeutic Products, is the Swiss surveillance authority for medicines and medical devices, registered in Berne. It started operations on 1 January 2002 as successor of Interkantonale Kontrollstelle für Heilmittel , which was itself the successor of Schweizerische...
in December 2008 and recently approved by the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
. Zambia
Zambia
Zambia , officially the Republic of Zambia, is a landlocked country in Southern Africa. The neighbouring countries are the Democratic Republic of the Congo to the north, Tanzania to the north-east, Malawi to the east, Mozambique, Zimbabwe, Botswana and Namibia to the south, and Angola to the west....
was the first African country to adopt artemether/lumefantrine
Lumefantrine
Lumefantrine is an antimalarial drug. It is only used in combination with artemether. The term "co-artemether" is sometimes used to describe this combination....
(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
Malaria
Malaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium. The disease results from the multiplication of Plasmodium parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases...
cases and deaths decreased by 61% and 66%, respectively, compared with the 2001-2002 reference period. In South Africa
South Africa
The Republic of South Africa is a country in southern Africa. Located at the southern tip of Africa, it is divided into nine provinces, with of coastline on the Atlantic and Indian oceans...
also the number of malaria
Malaria
Malaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium. The disease results from the multiplication of Plasmodium parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases...
-related outpatient cases and hospital admissions to each fall by 99% from 2001 to 2003, and malaria
Malaria
Malaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium. The disease results from the multiplication of Plasmodium parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases...
-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
Polymerase chain reaction
The polymerase chain reaction is a scientific technique in molecular biology to amplify a single or a few copies of a piece of DNA across several orders of magnitude, generating thousands to millions of copies of a particular DNA sequence....
-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
Antimalarial drug
Antimalarial medications, also known as antimalarials, are designed to prevent or cure malaria. Such drugs may be used for some or all of the following:* Treatment of malaria in individuals with suspected or confirmed infection...
. Coartem is much more effective than quinine
Quinine
Quinine is a natural white crystalline alkaloid having antipyretic , antimalarial, analgesic , anti-inflammatory properties and a bitter taste. It is a stereoisomer of quinidine which, unlike quinine, is an anti-arrhythmic...
, the classical antimalarial. Randomised clinical trial in Uganda
Uganda
Uganda , officially the Republic of Uganda, is a landlocked country in East Africa. Uganda is also known as the "Pearl of Africa". It is bordered on the east by Kenya, on the north by South Sudan, on the west by the Democratic Republic of the Congo, on the southwest by Rwanda, and on the south by...
shows cure rate of malaria
Malaria
Malaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium. The disease results from the multiplication of Plasmodium parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases...
as high as 96% in the Coartem-treated group compared with 64% for the quinine
Quinine
Quinine is a natural white crystalline alkaloid having antipyretic , antimalarial, analgesic , anti-inflammatory properties and a bitter taste. It is a stereoisomer of quinidine which, unlike quinine, is an anti-arrhythmic...
group. For Plasmodium vivax
Plasmodium vivax
Plasmodium vivax is a protozoal parasite and a human pathogen. The most frequent and widely distributed cause of recurring malaria, P. vivax is one of the four species of malarial parasite that commonly infect humans. It is less virulent than Plasmodium falciparum, which is the deadliest of the...
infection, combination with piperaquine
Piperaquine
Piperaquine is an antimalarial drug, a bisquinoline first synthesised in the 1960s, and used extensively in China and Indochina as prophylaxis and treatment during the next 20 years. Usage declined in the 1980s as piperaquine-resistant strains of P. falciparum arose and artemisinin-based...
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 ChineseChina
Chinese civilization may refer to:* China for more general discussion of the country.* Chinese culture* Greater China, the transnational community of ethnic Chinese.* History of China* Sinosphere, the area historically affected by Chinese culture...
scientists, by serendipity, discovered that artemether was not only an antimalarial agent, but also effective against the blood flukes
Schistosoma
A genus of trematodes, Schistosoma, commonly known as blood-flukes and bilharzia, includes flatworms which are responsible for a highly significant parasitic infection of humans by causing the disease schistosomiasis, and are considered by the World Health Organization as the second most...
. Eventually, laboratory experiments have confirmed the broad spectrum of activity against different trematodes, including all human schistosomes
Schistosoma
A genus of trematodes, Schistosoma, commonly known as blood-flukes and bilharzia, includes flatworms which are responsible for a highly significant parasitic infection of humans by causing the disease schistosomiasis, and are considered by the World Health Organization as the second most...
, Clonorchis sinensis
Clonorchis sinensis
Clonorchis sinensis, the Chinese liver fluke, is a human liver fluke in the class Trematoda, Phylum Platyhelminthes. This parasite lives in the liver of humans, and is found mainly in the common bile duct and gall bladder, feeding on bile...
, Fasciola hepatica
Fasciola hepatica
Fasciola hepatica, also known as the common liver fluke or sheep liver fluke, is a parasitic flatworm of the class Trematoda, phylum Platyhelminthes that infects the livers of various mammals, including humans. The disease caused by the fluke is called fascioliasis . F...
and Opisthorchis viverrini
Opisthorchis viverrini
Opisthorchis viverrini, common name Southeast Asian liver fluke, is a trematode parasite from the family Opisthorchiidae that attacks the area of the bile duct. Infection is acquired when people ingest raw or undercooked fish. It causes the disease opisthorchiasis...
. 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
Neurotoxicity
Neurotoxicity occurs when the exposure to natural or artificial toxic substances, which are called neurotoxins, alters the normal activity of the nervous system in such a way as to cause damage to nervous tissue. This can eventually disrupt or even kill neurons, key cells that transmit and process...
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
Schistosoma mansoni
Schistosoma mansoni is a significant parasite of humans, a trematode that is one of the major agents of the disease schistosomiasis. The schistosomiasis caused by Schistosoma mansoni is intestinal schistosomiasis....
, S. japonicum
Schistosoma japonicum
Schistosoma japonicum is an important parasite and one of the major infectious agents of schistosomiasis.This parasite has a very wide host range, infecting at least 31 species of wild mammals, including 9 carnivores, 16 rodents, one primate , two insectivores and three artiodactyls and therefore...
and S. haematobium
Schistosoma haematobium
Schistosoma haematobium is an important digenetic trematode, and is found in the Middle East, India, Portugal and Africa. It is a major agent of schistosomiasis; more specifically, it is associated with urinary schistosomiasis....
.
Anticancer
Artemether has been shown to have significant anticancer and antitumor activities. It is demonstrated that artemether caused strong inhibitory effects on brain gliomaGlioma
A glioma is a type of tumor that starts in the brain or spine. It is called a glioma because it arises from glial cells. The most common site of gliomas is the brain.-By type of cell:...
growth and angiogenesis
Angiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
in rat
Rat
Rats are various medium-sized, long-tailed rodents of the superfamily Muroidea. "True rats" are members of the genus Rattus, the most important of which to humans are the black rat, Rattus rattus, and the brown rat, Rattus norvegicus...
s. It exhibits a dose- and time-dependent cytotoxicity
Cytotoxicity
Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are a chemical substance, an immune cell or some types of venom .-Cell physiology:...
, and induced apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
and G2 cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
arrest in ovarian cancer cell lines, human leukemia HL60 cells, and human pancreatic cancer BxPC-3 and AsPC-1 cells.