Artemisinin

From Free net encyclopedia

Artemisinin
Image:Artemisinin.png
Chemical name	(3R,5aS,6R,8aS,9R,12S,12aR)- octahydro-3,6,9-trimethyl-3,12-epoxy-12H- pyrano[4,3-j]-1,2-benzodioxepin-10(3H)-one
Chemical formula	C₁₅H₂₂O₅
Molecular mass	282.332 g/mol
Synonyms	Artemisinine, Qinghaosu
CAS number	63968-64-9
ATC code	P01BE01
Density	x.xxx g/cm³
Melting point	152 - 157 °C
Boiling point	xx.x °C
SMILES	CC1CCC2C(C(=O)OC3C24C1CCC(O3)(OO4)C)C
Disclaimer and references

Artemisinin 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.

1 Cancer Treatment
2 History
3 How it works
4 Schistosomiasis treatment
5 External links

[edit]

Cancer Treatment

Artemisinin is also under early research and testing for treatment of cancer. 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.

[edit]

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. In the 1960s a research program was set up by the Chinese army to find an adequate treatment of malaria. In 1972, in the course of this research, Tu Youyou discovered artemsinin in the leaves of Artemisia annua. The drug is named qinghaosu (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.

It remained largely unknown to the rest of the world for about 10 years, due to the Chinese government at the time. The rest of the world finally found out about the drug from an article in a Chinese medical journal. People were sceptical at first, because the Chinese had made unsubstantiated statements about having found treatments of malaria before. Another reason was the peroxide part of the molecule. It was thought unlikely this would be a stable molecule, and so would not last long enough to be effective. This turned out not to be the case.

The Chinese government at the time, however, was very wary of western scientists, and would not give anyone either the plant or the refined drug. People around the world now started looking for the shrub themselves, to see if they could find it. They finally found it along the Potomac river, in Washington, D.C. Apparently it was a very common shrub, found in many parts of the world--In fact, it was often treated as a garden weed. It took another 10 years of research before the drug finally became commercially available. By this time relations between China and the rest of the world had improved, and scientific information could be exchanged.

The drug is used these days in China and Vietnam without much regard to taking precautions against creating resistance of the malaria parasite to this drug as well, but nevertheless no resistance has been encountered in these parts of the world. Because ot the method of action, it is unlikely that resistance to artemisinine and derivatives will become a problem in the near future.

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. 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).

[edit]

How it works

The compound has a peroxide group in its structure. When the peroxide comes into contact with high iron concentrations, the molecule becomes unstable and "explodes" into free radicals. This is because the oxygen atoms are highly electronegative, and the iron in the body is in the form of positively charged ions. This results in a high mechanical strain on the chemical bonds of the peroxide group. High concentrations of iron are found in red blood cells, which is also where the malaria parasites are found. When the compound enters the red blood cell, it will release the free radicals, which are highly destructive to the parasites. An alternative theory suggests that artemisinins inhibit a calcium transporter in the parasite and by specifically inhibiting this target, they kill parasites. The peroxide group in artemisinins is still crucial to activity, but the target is highly selected rather than a result of "explosion" into activity by free radicals.

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.

Since no resistance has yet emerged to artemisinins, it is possible that artemisinins have many targets on the parasites.

[edit]

Schistosomiasis treatment

Artesunate, a potent derivative of artemisinin, is an important treatment for schistosomiasis. It is usually used in conjunction with or as an alternative to praziquantel.

[edit]