NationMaster - Encyclopedia: Artemisinin

Artemisinin (pronounced /ɑrtɨˈmɪsɨnɨn/) is a drug used to treat multi-drug resistant strains of falciparum malaria. The compound (a sesquiterpene lactone) is isolated from the shrub Artemisia annua long used in traditional Chinese medicine. Not all shrubs of this species contain artemisinin. Apparently it is only produced when the plant is subjected to certain conditions, most likely biotic or abiotic stress. It can be synthesized from artemisinic acid.^[1] The regulation of therapeutic goods, that is drugs and therapeutic devices, varies by jurisdiction. ... In pharmacology and toxicology, a route of administration is the path by which a drug, fluid, poison or other substance is brought into contact with the body. ... This article does not cite any references or sources. ... Binomial name Welch, 1897 Plasmodium falciparum is a protozoan parasite, one of the species of Plasmodium that cause malaria in humans. ... Malaria is a vector-borne infectious disease caused by protozoan parasites. ... Sesquiterpene lactones are a class of chemical found in my plants that can cause allergic reactions. ... Binomial name Artemisia annua Artemisia annua is the official Latin name for a plant better known by names such as sweet sagewood, sweet wormwood, annual sagebrush, or Chinese wormwood. ... Traditional Chinese medicine shop in Tsim Sha Tsui, Hong Kong. ... Look up biotic in Wiktionary, the free dictionary. ... This article or section does not adequately cite its references or sources. ...

History

Artemisia has been used by Chinese herbalists for more than a thousand years in the treatment of many illnesses, such as skin diseases and malaria. The earliest record dates back to 200 BC , in the "Fifty two Prescriptions" unearthed from the Mawangdui Han Dynasty Tombs. Its antimalarial application was first described in Zhouhou Beji Fang ("The Handbook of Prescriptions for Emergencies"), edited in the middle of fourth century by Ge Hong. In the 1960s a research program was set up by the Chinese army to find an adequate treatment for malaria. In 1972, in the course of this research, Tu Youyou (Chinese: 屠呦呦)^[2] discovered artemisinin in the leaves of Artemisia annua. The drug is named Qinghaosu (Chinese: 青蒿素) in Chinese. It was one of many candidates then tested by Chinese scientists from a list of nearly 200 traditional Chinese medicines for treating malaria. It was the only one that was effective. See also Herbalism A Herbalist is: 1. ... Peoples Liberation Army redirects here. ... Binomial name Artemisia annua Artemisia annua is the official Latin name for a plant better known by names such as sweet sagewood, sweet wormwood, annual sagebrush, or Chinese wormwood. ... Traditional Chinese medicine shop in Tsim Sha Tsui, Hong Kong. ... Malaria is a vector-borne infectious disease caused by protozoan parasites. ...

It remained largely unknown to the rest of the world for about ten years, until results were published in a Chinese medical journal. The report was met with skepticism at first, because the Chinese had made unsubstantiated claims about having found treatments for malaria before. In addition, the chemical structure of artemisinin, particularly the peroxide, appeared to be too unstable to be a viable drug. A peroxide is a compound containing an oxygen-oxygen single bond. ...

For many years, access to the purified drug and the plant it was extracted from were restricted by the Chinese government. However, Artemisia annua is a common shrub and has been found in many parts of the world, including along the Potomac River, in Washington, D.C. The Potomac River flows into the Chesapeake Bay, located along the mid-Atlantic coast of the United States (USA). ... For other uses, see Washington, D.C. (disambiguation). ...

Currently, artemisinin is widely used in China and Southeast Asia for treatment of malaria. It is often used without taking precautions against conditions that might lead to resistance of the malaria parasite to this drug, leading to concern that the effectiveness of artemisinin may be reduced in the near future, as is the case with other classes of antimalarial drugs. Antimalarial drugs are designed to prevent or treat malaria. ...

Because artemisinin itself has physical properties such as poor bioavailability that limit its effectiveness, semi-synthetic derivatives of artemisinin, including artemether and artesunate, have been developed. However, their activity is not long lasting, with significant decreases in effectiveness after one to two hours. To counter this drawback, artemisinin is given alongside lumefantrine to treat uncomplicated falciparum malaria. Lumefantrine has a half-life of about 3 to 6 days. Such a treatment is called ACT (artemisinin-based combination therapy); other examples are artemether-lumefantrine, artesunate-mefloquine, artesunate-amodiaquine, and artesunate-sulfadoxine/pyrimethamine. Recent trials have shown that ACT is more than 90% effective, with a recovery of malaria after three days, especially for the chloroquine-resistant Plasmodium falciparum. In pharmacology, bioavailability is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. ... This article is about derivatives and differentiation in mathematical calculus. ... Artemisinin is a drug used to treat multi-drug resistant strains of falciparum malaria. ... Artemisinin is a drug used to treat multi-drug resistant strains of falciparum malaria. ... Lumefantrine (or benflumetol) is an antimalarial drug. ... In contemporary usage, the expression combination therapy most often refers to the simultaneous administration of two or more medications to treat a single disease, but the expression is also used when other types of therapy are used at the same time. ... Mefloquine is an orally administered antimalarial drug used as a prophylaxis against and treatment for malaria. ... amidoquine ... Pyrimethamine (DaraprimÂ®) is a medication used for protozoal infections. ... Chloroquine is a 4-aminoquinoline drug long used in the treatment or prevention of malaria. ... Binomial name Welch, 1897 Plasmodium falciparum is a protozoan parasite, one of the species of Plasmodium that cause malaria in humans. ...

The World Health Organisation has recommended that a switch to ACT should be made in all countries where the malaria parasite has developed resistance to chloroquine. Artemisinin and its derivatives are now standard components of malaria treatment in China, Vietnam, and some other countries in Asia and Africa, where they have proved to be safe and effective anti-malarial drugs. They have minimal adverse side effects. Currently, artemisinin is not widely available in the United States or Canada, but is easy to find in Africa and Asia. There have been some concerns about the quality of some products on offer in Africa.^[3] For other meanings of the acronym WHO, see WHO (disambiguation) WHO flag Headquartered in Geneva, Switzerland, the World Health Organization (WHO) is an agency of the United Nations, acting as a coordinating authority on international public health. ... Chloroquine is a 4-aminoquinoline drug long used in the treatment or prevention of malaria. ...

To counter the present shortage in leaves of Artemisia annua, researchers have been searching for a way to develop artemisinin artificially in the laboratory. A recent paper in Nature^[4] presented a genetically engineered yeast that can synthesize a precursor called artemisinic acid which can be chemically converted to Artemisinin. The compound called OZ-277 (also known as RBx11160), developed by Jonathan Vennerstrom at the University of Nebraska, has proved to be even more effective than the natural product in test-tube trials. A six month trial of the drug on human subjects in Thailand was started in January 2005. There are also plans to have the plant grow in other areas of the world (outside Vietnam and China). Seal of the University of Nebraska The University of Nebraska is one of two public university systems in the state of Nebraska, USA. The system has four universities and a technical college: University of Nebraska-Lincoln University of Nebraska at Omaha University of Nebraska at Kearney University of Nebraska Medical...

Analogues

There are a number of derivatives and analogues within the artemisinin family: In chemistry, analogs or analogues are compounds in which one or more individual atoms have been replaced, either with a different atom, or with a different functional group. ...

Artemisinin is a drug used to treat multi-drug resistant strains of falciparum malaria. ... Artemisinin is a drug used to treat multi-drug resistant strains of falciparum malaria. ... Arteether, also known as Rapither AB, Î±/Î² arteether, is a fast acting blood schizontocide specifically indicated for the treatment of chloroquine-resistant Plasmodium falciparum malaria and cerebral malaria cases. ... Dihydroartemisinin is a drug used to treat malaria. ... Artelinic acid (or its salt, artelinate) is an experimental drug that is being investigated as a treatment for malaria. ...

Cancer treatment

Artemisinin is under early research and testing for treatment of cancer, primarily by researchers at the University of Washington.^[5]^[6] Artemisinin has a peroxide lactone group in its structure. It is thought that when the peroxide comes into contact with high iron concentrations (common in cancerous cells), the molecule becomes unstable and releases reactive oxygen species. It has been shown to reduce angiogenesis and the expression of vascular endothelial growth factor in some tissue cultures. Experimental cancer treatments are medical therapies intended or claimed to treat cancer (see also tumor) by improving on, supplementing or replacing conventional methods (surgery, chemotherapy, radiation, and immunotherapy). ... Cancer is a class of diseases or disorders characterized by uncontrolled division of cells and the ability of these to spread, either by direct growth into adjacent tissue through invasion, or by implantation into distant sites by metastasis (where cancer cells are transported through the bloodstream or lymphatic system). ... The general structure of an organic peroxide. ... A lactone is a cyclic ester in organic chemistry. ... Reactive oxygen species (ROS) include oxygen ions, free radicals and peroxides both inorganic and organic. ... Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. ... Vascular endothelial growth factor (VEGF) is an important signaling protein involved in both vasculogenesis (the de novo formation of the embryonic circulatory system) and angiogenesis (the growth of blood vessels from pre-existing vasculature). ...

Mechanism of action

The specific mechanism of action of artemisinin is not well understood, and there is ongoing research directed at elucidating it. When the parasite that causes malaria infects a red blood cell, it consumes hemoglobin and liberates free heme, an iron-porphyrin complex. The iron reduces the peroxide bond in artemisinin generating high-valent iron-oxo species, resulting in a cascade of reactions that produce reactive oxygen radicals which damage the parasite leading to its death.^[7] Wikipedia does not yet have an article with this exact name. ... Structure of Heme b A heme or haem is a prosthetic group that consists of an iron atom contained in the center of a large heterocyclic organic ring called a porphyrin. ... In chemistry, radicals (often referred to as free radicals) are atomic or molecular species with unpaired electrons on an otherwise open shell configuration. ...

Numerous studies have investigated the type of damage that these oxygen radicals may induce. For example, Pandey et al. have observed inhibition of digestive vacuole cysteine protease activity of malarial parasite by artemisinin.^[8] These observations were further confirmed by ex vivo experiments showing accumulation of hemoglobin in the parasites treated with artemisinin, suggesting inhibition of hemoglobin degradation. They found artemisinin to be a potent inhibitor of hemozoin formation activity of malaria parasite.

A 2005 study investigating the mode of action of artemisinin using a yeast model demonstrated that the drug acts on the electron transport chain, generates local reactive oxygen species, and causes the depolarization of the mitochondrial membrane.^[9]

Artemisinins have also been shown to inhibit PfATP6, a SERCA-type enzyme (calcium transporter) and artemisinin has been shown to compete with thapsigargin for SERCA binding, though artemesinin is much less toxic to mammalian cells. These experiments however, have only been conducted in a recombinant system (Xenopus oocytes), and it remains to be verified within P. falciparum parasites. Resistance to artemisinin is conferred by a single mutation in the calcium transporter (PfATP6). This mutation has been studied in the laboratory but recently a study from French Guiana in field isolates of malaria parasites has identified a different mutation in the calcium transporter (PfATP6) that is associated with resistance to artemether, lending support to the idea that PfATP6 is the target for artemisinins.^[10] HIV protease in a complex with the protease inhibitor ritonavir. ... SERCA stands for Sarco/Endoplasmic Reticulum Ca2+-ATPase SERCA resides in the sarcoplasmic reticulum (SR) within muscle cells. ... Ribbon diagram of the enzyme TIM, surrounded by the space-filling model of the protein. ... Thapsigargin is a tightly-binding inhibitor of a class of enzymes known by the acronym SERCA, which stands for sarco / endoplasmic reticulum Ca 2+ ATPase. ...

Dosing

The WHO approved adult dose of co-artemether (artemether-lumofantrine) for malaria is 4 tablets at 0, 8, 24, 36, 48 and 60 hours (six doses).^[11]^[12] This has been proven to be superior to regimens based on amodiaquine.^[13] Artemesinin is not soluble in water and therefore Artemesia annua tea was postulated not to contain pharmacologically significant amounts of artemesinin.^[14]. However, this conclusion was rebuked by several experts who stated that hot water (85 ^oC), and not boiling water, should be used to prepare the tea. Although Artemisia tea is not recommended as a substitute for the ACT (artemisinin combination therapies) more clinical studies on artemisia tea preparation are needed.^[15] The artemesinins are not used for malaria prophylaxis (prevention) because to be efficacious, they must be taken twice or three times a day throughout the risk period. amidoquine ...

Synthesis

In 2006 a team from Berkeley published an article claiming that they had engineered Saccharomyces cerevisiae microbes that can produce the precursor artemisinic acid. The synthesized artemisinic acid can then be transported out, purified and turned into a drug that they claim will cost roughly 0.25 cents per dose. Details of the formation of artemisinic acid involves a mevalonate pathway, expression of amorphadiene synthase, a novel cytochrome P450 monooxygenase (CYP71AV1) and its redox partner from A. annua. A three-step oxidation of amorpha-4,11-diene gives the resulting artemisinic acid.^[16] Amyris Biotechnologies is collaborating with UC Berkeley and the Institute for One World Health to further develop this technology.^[17] Binomial name Meyen ex E.C. Hansen Saccharomyces cerevisiae is a species of budding yeast. ... The University of California, Berkeley (also known as Cal, UC Berkeley, UCB, or simply Berkeley) is a prestigious, public, coeducational university situated in the foothills of Berkeley, California to the east of San Francisco Bay, overlooking the Golden Gate and its bridge. ...

Using seed supplied by Action for Natural Medicine (ANAMED), the World Agroforestry Centre (ICRAF) has developed a hybrid, dubbed A3, which can grow to a height of 3 m and which produces 20 times more artemisinin than wild varieties. In northwestern Mozambique, ICRAF is working together with a medical organisation, Médecins sans frontières (MSF), ANAMED and the Ministry of Agriculture and Rural Development to train farmers on how to grow the shrub from cuttings, and to harvest and dry the leaves to make artemisia tea. Cultivation of this crop may well prove a valuable niche market for Africa, given the strong demand for the plant from pharmaceutical laboratories.

The biosynthesis of artemisinin is shown at the bottom in three parts: The formation of IPP and DMAPP, the formation of E,Z-FPP and finally the formation of Artemisinin.

The total synthesis of Artemisinin can also be performed using basic organic reagents. In 1982, G. Schmid and W. Hofheinz published a paper showing the complete synthesis of artemisinin. Their starting material was (-)-Isopulegol (2) which as converted to methoxymethyl ether (3). The ether was hydroborated and then underwent oxidative workup to give (4). The primary hydroxyl group was then benzylated and the methoxymethyl ether was cleaved resulting in (5) which would be oxidized to (6). Next, the compound was protonated and treated with (E)-(3-iodo-1-methyl-1-propenyl)-trimethylsilane to give (7). This resulting ketone was reacted with lithium methoxy(trimethylsily)methylide to obtain two diastereomeric alcohols, (8a) and (8b). 8a was then debenzylated using (Li, NH3) to give lactone (9). The vinylsilane was then oxidized to ketone (10). The ketone was then reacted with fluoride ion that caused it to undergo desilylation, enol ether formation and carboxylic acid formation to give (11). An introduction of a hydroperoxide function at C(3) of 11 gives rise to (12). Finally, this underwent photooxygenation and then treated with acid to produce artemisinin.^[18]

References

^ Acton, N. & Roth, R.J. On the conversion of dihydroartemisinic acid into artemisinin. J. Org. Chem. 57, 3610-3614 (1992)
^ ChinaVitae: Tu Youyou
^ http://news.bbc.co.uk/2/hi/africa/6951586.stm
^ Ro DK and Paradise EM et al. Production of the antimalarial drug precursor artemisinic acid in engineered yeast. Nature. (2006) 440: 940-943.
^ University of Washington: News]
^ [http://depts.washington.edu/bioe/about/news/artemisinin.html University of Washington: Artemisinin
^ Cumming, Jared N.; Ploypradith, Poonsakdi; Posner, Gary H.. Antimalarial activity of artemisinin (qinghaosu) and related trioxanes: mechanism(s) of action. Advances in Pharmacology (San Diego) (1997), 37 253-297.
^ Pandey et al
^ Li et al., PLOS Genetics, September 2005, Volume 1, Issue 3
^ A.-C. Uhlemann et al. Nature Struct. Mol. Biol. 12, 628-629;2005
^ Vugt MV, Wilairatana P, Gemperli B, et al. (1999). "Efficacy of six doses of artemether-lumefantrine (benflumetol) in multidrug-resistant Plasmodium falciparum malaria". Am J Trop Med Hyg 60 (6): 936–42. PMID 10403324.
^ Lefevre G, Looareesuwan S, Treeprasertsuk S, et al. (2001). "A clinical and pharmacokinetic trial of six doses of artemether-lumefantrine for multidrug-resistant Plasmodium falciparum malaria in Thailand.". Am J Trop Med Hyg 64 (5–6): 247–56. PMID 11463111.
^ Mutabingwa TK, Anthony D, Heller A, et al. (2005). "Amodiaquine alone, amodiaquine+sulfadoxine-pyrimethamine, amodiaquine+artesunate, and artemether-lumefantrine for outpatient treatment of malaria in Tanzanian children: a four-arm randomised effectiveness trial". Lancet 365 (9469): 1474–80. PMID 15850631.
^ Jansen FH (2006). "The herbal tea approach for artemesinin as a therapy for malaria?". Trans R Soc Trop Med Hyg 100 (3): 285–6. doi:10.1016/j.trstmh.2005.08.004.
^ Bioline
^ Richmond Sarpong, Jay D. Keasling. "Production of the antimalarial drug precursor artemisinic acid in engineered yeast" Nature 440, 940-943 (13 April 2006)
^ Amyris Biotechnologies
^ G. Schmid, W. Hofheinz. "Total Synthesis of qinghaosu" J. Am. Chem. Soc.; 1983; 105 (3); 624-625

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Wiktionary (a portmanteau of wiki and dictionary) is a multilingual, Web-based project to create a free content dictionary, available in over 151 languages. ... Antiprotozoal agents (ATC code: ATC P01) is a class of pharmaceuticals used in treatment of protozoal infections. ... Antimalarial drugs are designed to prevent or treat malaria. ... A section of the Anatomical Therapeutic Chemical Classification System. ... amidoquine ... Chloroquine is a 4-aminoquinoline drug long used in the treatment or prevention of malaria. ... Hydroxychloroquine is an antimalarial drug, sold under the trade name PlaquenilÂ®, also used to reduce inflammation in the treatment of Rheumatoid arthritis (see Disease-modifying antirheumatic drugs) and lupus. ... The 8-aminoquinoline family of drugs contains three members, primaquine, tafenoquine and pamaquine and are used in the treatment of malaria. ... Pamaquine is an 8-aminoquinoline drug used for the treatment of malaria. ... Primaquine or Primaquine Phosphate. ... Mefloquine is an orally administered antimalarial drug used as a prophylaxis against and treatment for malaria. ... Quinine (IPA: ) is a natural white crystalline alkaloid having antipyretic (fever-reducing), anti-smallpox, analgesic (painkilling), and anti-inflammatory properties and a bitter taste. ... Biguanides (ATC A10 BA) form a class of oral hypoglycemic drugs used for diabetes mellitus treatment. ... Proguanil (proguanil hydrochloride) is a prophylactic antimalarial drug, which works by stopping the malaria parasite, Plasmodium falciparum and Plasmodium vivax, from reproducing once it is in the red blood cells. ... Cycloguanil is an antimalarial drug. ... Pyrimethamine (DaraprimÂ®) is a medication used for protozoal infections. ... Artemisinin is a drug used to treat multi-drug resistant strains of falciparum malaria. ... Artemisinin is a drug used to treat multi-drug resistant strains of falciparum malaria. ... Artenimol is an antimalarial drug. ... Artemotil (INN; also known as arteether or Î±/Î² arteether, trade name Rapither AB), is a fast acting blood schizontocide specifically indicated for the treatment of chloroquine-resistant Plasmodium falciparum malaria and cerebral malaria cases. ... Halofantrine is a drug used to treat malaria. ... Lumefantrine (or benflumetol) is an antimalarial drug. ...

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