Artemisinin, extracted from artemisia annua extract, has been used for more than two thousand years by Chinese herbalists to treat illnesses. Artemisinin and its derivatives such as Artesunate, Artemether, Dihydroartemisinin, etc are a group of drugs that possess the most rapid action of all current drugs against falciparum malaria. China and Vietnam provide 70% and East Africa 20% of the raw plant material of artemisinin. Seedlings are grown in nurseries and then transplanted into fields. It takes about 8 months for them to reach full size. Artemisinin is extracted using solvent, typically hexane. And now Semi-synthetic artemisinin hits the international market and World Health Organization (WHO) accepts its legal status in anti-malarial treatment.

 

Artemisia Annua (Sweet Wormwood) is a shrubby perennial native to China. The leaf of the plant contains up to 0.04 percent Artemisinin. This herb has been used over the centuries by Chinese medical practitioners. Artemisinin came to the attention of the World Health Organization in the 1970s when Quinine lost efficacy against malaria.

The story of artemisinin began in China in the late 1960s. After a brief respite, lasting only a few decades, malaria was once again on the increase. Malariai is a mosquito-borne infectious d sease of humans and other animals caused by protists (a type of microorganism) of the genus Plasmodium. Human malaria could only be transmitted by Anopheles mosquitoes. DDT, at first heralded as the insecticide that would eradicate the mosquito, was being withdrawn because the vector had developed resistance to it. Chloroquine, developed by the US military towards the end of World War II to kill the Plasmodium parasite, was also losing its effectiveness in much of South East Asia, South America and - increasingly - in Africa. (Chloroquine inhibits the polymerisation of the toxic haem group, an accumulation of which kills the parasite.) In the absence of an effective insecticide or an effective vaccine, a new antimalarial drug seemed to be the only hope. 

 

Against this scene of increasing resistance, and of the on-going wars in neighboring Cambodia and Vietnam, the Chinese Government began a systematic examination of plants used in traditional Chinese medicine with the aim of finding a new antimalarial. The herb Artemisia annua, or 'qinghao', was one of several hundred species listed in the Chinese pharmacopeia to be considered. According to its listing, A. annua is cool in nature (yin) and can therefore be used to treat internal heat conditions (yang). In fact, the first report of the use of qinghao in this context had appeared in 1596 AD - in the Chinese materia medica, Bencao Gangmu - for treating 'hot and cold due to intermittent fever illness'. According to the old pharmacopeias, one bunch of the leaves, collected in spring or summer, was taken with two 'sheng' of water and pounded with a pestle and mortar to express the 'juice'. (This procedure was, perhaps, intended to improve the recovery of essential oils from the leaves, in which the active principal, artemisinin, as it is called outside China, is now known to be most concentrated.) 

 

However, when the Chinese scientists made hot water extracts of A. annua according to the ancient texts, they observed no activity against mice infected with the rodent malarial parasite, Plasmodium berghei. Fortunately though, they also tested cold ethereal extracts of qinghao. These did show encouraging activity, and it was not long before 'qinghaosu' (meaning 'principle from qinghao' in Chinese) - a stable and easily crystallisable compound - had been isolated and characterised.

How may artemisinins work? Artemisinins act via mechanisms that are distinct from other antimalarial classes, including those that inhibit well defined targets such as enzymes of folate biosynthesis, the DOXP reductase pathway or the cytochrome electron transport system. The peroxide within the 1,2,4-trioxane system of artemisinins is essential for antimalarial activity.

Though its precise modes of action are still being elucidated, artemisinin is thought to act by a two-step mechansim. First, intracellular free iron induces a chemical reaction in the endoperoxide moiety that generates carbon-based free radicals. Second, these free radicals act as alkylating agents inducing apoptotic cell death through caspase pathway activation. This reaction is selectively toxic to cells in pathologic conditions in which intracellular free iron levels are uncontrollably elevated, such as cancer cells. By comparison, rapidly dividing "normal cells" are better at regulating and storing iron, and are not as affected by artemisinin's chemical reaction, which has been confirmed in numerous studies. 

Artemisinin is the only drug effective against malaria and hundreds of millions of doses are prescribed for that purpose every year. The artemisinin molecule has an affinity for iron, which the malarial parasite sequesters internally. Artemisinin enters the malarial parasite and combines with sequestered iron to create Reactive Oxygen Species, rupturing the parasite.

 

Like malarial parasites, cancer cells concentrate and sequester high levels of iron. Moreover cancer cells over express cell surface receptors for iron-containing compounds like ferritin and holotransferrin. Therefore, Artemisinin has a high affinity for cancer cells, and upon entering the cell combines with intercellular iron creating ROS-mediated apoptosis. Artemisinin is the only chemotherapeutic agent that lacks the tertiary amine necessary to usher the drug back out of the cell.

Artemisinin has been well known as the number 1 antimalarial medicine for treating malaria worldwide, and three key benefits are summarized as below:

Extracted from the plant Artemesia annua L. (sweet wormwood, also known as the Chinese herbal Qinghao), Artemisinin has been used for centuries to kill parasites, particularly worms and flukes, which are present in us all, and which by their nature sap energy resources from the body and create by-products that need to be excreted, thus becoming a body burden.

Malaria is a preventable and treatable mosquito-borne disease, whose main victims are children under five years of age in Africa. According to the malaria report of World Health Organization (WHO), The World Malaria Report 2012 summarizes data received from 104 malaria-endemic countries and territories for 2011. Ninety-nine of these countries had on-going malaria transmission. According to the latest WHO estimates, there were about 219 million cases of malaria in 2010 and an estimated 660 000 deaths. Africa is the most affected continent: about 90% of all malaria deaths occur there.

 

Antimalarial drug resistance is a major concern for the global effort to control malaria. P. falciparum resistance to artemisinins has been detected in four countries in South East Asia: in Cambodia, Myanmar, Thailand and Viet Nam. There is an urgent need to expand containment efforts in affected countries. For now, ACTs remain highly effective in almost all settings, so long as the partner drug in the combination is locally effective.

 

Mosquito resistance to at least one insecticide used for malaria control has been identified in 64 countries around the world. In May 2012, WHO and the Roll Back Malaria Partnership released the Global Plan for Insecticide Resistance Management in malaria vectors, a five-pillar strategy for managing the threat of insecticide resistance.

Artemisinin contains two oxygen atoms linked together in what is known as an 'endoperoxide bridge', which could react with an iron atom to form free radicals. Artemisinin becomes toxic to malaria parasites when it reacts with the high iron content of the parasites, generating free radicals, and leading to damage to the parasite.

By this same mechanism, Artemisinin becomes toxic to cancer cells which sequester relatively large amounts of iron compared to normal, healthy human cells. According to the Gordon Research Institute, tests have been conducted which show that Artemisinin causes rapid and extensive damage and death in cancer cells and yet has relatively low toxicity to normal cells.

According to over 3000 clinical case studies, when used for the treatment of tertian fever, it is better than chloroquine in terms of time to suppress the pathogen. No adverse effects in clinical cases have been reported. However, the short term recurrence rate is higher than chloroquine. So.WHO approval in 2004 novartis sold to Africa. Our company supply artemisinin to Novartis from 2005, being the largest artemisinin raw material manufacturer and supplier in China. And hope we can help some somewhere.

According to large amount of clinical study, for the treatment of malaria, use intramuscular injections of 0.3g each time each day for three days, for a total amount of 0.9 -1.2g; Double first dose for severe case. 

Key words

Artemisinin - Artemisia annua - Asteraceae - tissue culture - biotransformation - antimalarial drug