Natural Artemisinin to synthetic – a scientific devpt to improve access to Artesunate therapy

The recent press report on the delivery of first large scale batches of anti-malarial treatments manufactured with semi-synthetic Artemisinin to malaria endemic countries in Africa brings hope for improved access to the effective malaria treatment to millions of patients worldwide. Artemisinin is currently the gold standard for malaria treatment worldwide and the access to treatment is largely dependent on its supply (availability) and price.

Artemisinin based combination therapies (ACT) are the first line treatment recommended worldwide for the treatment of malaria caused by Plasmodium falciparum, the most dangerous of the Plasmodium parasites that infect humans. The ACT is also effective in Plasmodium vivax. Though much progress has been achieved in controlling malaria, it continues to be one of the killer diseases. In 2000, there were 207 million cases of malaria with 6,27,000 deaths worldwide. In India malaria is one of the major public health problems with around 1.5 million confirmed cases annually.  Half of the reported cases are due to Plasmodium falciparum.

The discovery of Artemisinin has a wonderful history. In ancient times the cinchona bark was used to treat mysterious fever, similar to present day malaria. Later with isolation of quinine and synthesis of chloroquine, the malaria was treated successfully. But, with development of resistance, the chloroquine started losing its efficiency as anti-malarial. The need of an alternative effective remedy was felt during the war between Unites States and Vietnam in 1960s. American research led to the development of mefloquine and halofantrine. The other side Vietnam looked for to China for an alternative to chloroquine. On the request of Vietnam, the Chinese Government launched a massive research programme in 1967 which led to the isolation of an effective anti-malarial Artemisinin from the plant Artemisia annua. Though the drug was discovered in 1972 and subsequently used as an effective malarial medicine in China, it was not known to the rest of the world till the discovery results were published in Chinese Medical Journal in 1979. This was due to Chinese closed cultural and economic policy.

Artemisinin is isolated from the plant Artemisia annua, a traditionally used Chinese herb. Artemisia annua has been used throughout the ages to treat various ailments. In ancient Chinas, symptoms relating to Plasmodium falciparum infections were effectively treated with Artemisia plant. Artemisia annua, commonly known as Qinghaosu, is cultivated mainly in China and Vietnam. This combined cultivation meets approximately 80 per cent of the global requirement. East Africa cultivates and supplies the remaining 20 per cent of the global requirement. It takes about eight months for Artemisia to reach full growth. After harvesting, the dried leaves are used for extraction. The bulk drug or pharmaceutical companies converts Artemisinin into derivatives artemether, Artesunate, or dihydroartemisinin and manufacture finished ACT products.

Following the World Health Organization’s recommendation for ACT products as first line treatment for uncomplicated malaria, the demand for Artemisinin has increased sharply. The number of ACT treatment courses has increased significantly from 11 million in 2005 to 181 million in 2010. There have been some gaps between demand and supply. This gap has caused wide spread fluctuation in raw material price and global shortages of ACTs. This led to the increased production in China and Africa to ease out the shortage and even caused an oversupply in 2007. As usual the price has fallen to significant extent. The cultivators have stopped this Artemisia and switched to better economic crop which led further erratic availability of Artemisinin.

Realising the issues of natural Artemisinin, research continued throughout the world to initiate large scale production of this important anti-malarial. PATH, an international not for profit organization, and international pharmaceutical giant, Sanofi, joined hands  with the University of California, UC Berkley and Amyris. PATH’s drug development programme was supported by Bill and Melinda Gates Foundation. UC Berkley and Amyris Laboratories provided the much needed biotechnological process to produce partially synthetic Artemisinin. The process uses the genetically modified yeast to produce the precursor molecule of Artemisinin. Sanofi exploited its chemistry expertise and long industrial experience converting the laboratory scale research into a commercial production. There is no difference in quality of natural Artemisinin and semi-synthetic Artemisinin which ensures equal efficacy and safety.

The usefulness of ACTs is threatened by the emergence and spread of drug resistant malaria. There have been signs of declined efficacy of Artemisinin in South Asia region. Though more serious threat is noted in Cambodia and Thailand, the resistance could spread and/or emerge spontaneously elsewhere. Artemisinin resistance is just delayed parasitic clearance observed after treatment with Artemisinin. Delayed parasite clearance does not mean that it would lead to treatment failure. The World Health Organization has been discouraging the mono therapy with Artemisinin but use only combination therapy with other anti-malarials to prevent the development of resistance. Research has identified a molecular marker that is associated with delayed parasite clearance. The molecular marker could allow for more precise mapping and monitoring of geographical distribution and spread of resistance. However, one concern remains. When the Artemisia leaves have been in use for more than 2000 years, there is no resistance; but with Artemisinin the resistance becomes an issue within a short span of its use.

While a multiple strategies are necessary to ensure timely availability of the Artemisinin based combination therapies in saving lives, this advancement of technology in developing semi-synthetic Artesunate based malarial medicines is an important step towards improving global accessibility of this life saving therapy. The technology offers an additional consistent, reliable and inexpensive source of Artemisinin.