ARTEMISININA

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ARTEMISININA
(3R,5aS,6R,8aS,9R,12S,12aR)-octa-hidro-3,6,9-trimetil-3,12-epoxi-12H-pirano[4,3-j]-1,2-benzodioxepin-10(3H)-ona 
Artemisinina tem um anel 1,2,4-trioxano que é único e essencial para a actividade
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É UMA PERÓXIDOLACTONA (éster cíclico) SESQUITERPÉNICA
 ISOLADA DO ARBUSTO Artemisia annua
E HÁ MUITO USASA NA MEDICINA TRADICIONAL CHINESA 
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Ponte endoperóxido
Lactona
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Artemisinina
Derivados da Artemisinia
Lactona Sesquiterpénica Trioxano
Qinghaosu – em chinês 
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Artemisinin blocks a calcium channel.
Pandey et al observed inhibition of digestive vacuole cysteine protease activity of malarial parasite by artemisinin. 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 hemeozoin 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 (Li et al., 2005). This work was published in PLOS Genetics, September 2005, Volume 1, Issue 3.
Resistance is confered by a single mutation in the calcium channel. This has been observed only under laboratory conditions. (A.-C. Uhleman et al. Nature Struct. Mol. Bio. 12, 628-629;2005)
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A Artemisinina BLOQUEIA UM CANAL DE CÁLCIO
TEM PROPRIEDADES
ANTIMALÁRICAS E
ANTICANCERÍGENAS, entre outras
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LOCAL DE ACÇÃO
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Mechanism of Action
Killing of malaria parasite is mediated by production free radicals
Artemisinin derivatives lacking endoperoxide bridge are devoid of antimalarial activity
Addition of free radical generating compounds enhances antimalarial activity
Antioxidants block antimalarial activity
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Mechanism of Action
Heme/iron mediates breakage of endoperoxide bridge
Chloroquine antagonizes the antimalarial activity
Iron chelators antagonize antiparasitic effect of artemisinin
Artemisinin-derived free radicals bind to protein through alkylation
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Mecanismo de Acção
They are believed to kill intraerythrocytic Plasmodium by interacting with the heme discarded by proteolysis of ingested hemoglobin. Complexation of heme with the peroxide bond followed by electron transfer generates an oxy radical that evolves to the ultimate parasiticidal agent. 
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Mechanism of Action
Inhibit homozoin biosynthesis or cause hemozoin degradation
Inhibit hemoglobin digestion by malaria parasites
Forms covalent adducts with malarial proteins
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The Mechanism of Accumulation of Chloroquine in the Parasite Food Vacuole. Chloroquine travels down a pH gradient and inside the parasite becomes diprotonated. This form of the drug (shown in blue) is impermeable to biological membranes. On the right of the figure is a generic structure of a parasite targeted artemisinin derivative 
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Adverse Reactions
Very few adverse reactions
Common side effects include
Nausea
Vomiting
Anorexia
dizziness
Safe for pregnant women
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More potent derivatives have also been developed from artemisinin, such as artemether and artesunate. However, their activity decreases 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.
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, but sticking to one of the European (often Belgian) manufacturers could overcome this problem.
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 presented a geneticly engineered yeast that created a closely related compound which can be efficently convered into 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).
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Quinolines and artemisinin: chemistry, biology and history. Bray PG, Ward SA, O'Neill PM. Division of Molecular and Biochemical Parasitology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK. p.g.bray@liv.ac.uk Plasmodium falciparum is the most important parasitic pathogen in humans, causing hundreds of millions of malaria infections and millions of deaths each year. At present there is no effective malaria vaccine and malaria therapy is totally reliant on the use of drugs. New drugs are urgently needed because of the rapid evolution and spread of parasite resistance to the current therapies. Drug resistance is one of the major factors contributing to the resurgence of malaria, especially resistance to the most affordable drugs such as chloroquine. We need to fully understand the antimalarial mode of action of the existing drugs and the way that the parasite becomes resistant to them in order to design and develop the new therapies that are so urgently needed. In respect of the quinolines and artemisinins, great progress has been made recently in studying the mechanisms of drug action and drug resistance in malaria parasites. Here we summarize from a historical, biological and chemical, perspective the exciting new advances that have been made in the study of these important antimalarial drugs. Review PMID: 16265885 [PubMed - in process] 
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