by Joe Barnett
The annual herb Artemisia annua L. belongs to the Asteraceae (i.e. the daisy family) and is the natural source of the lifesaving antimalarial drug artemisinin. Common names for A. annua include annual wormwood, sweet wormwood, sweet annie and sweet sagewort. A. annua is a slow-growing wind-pollinated plant, native to temperate Asia and Eastern Europe, and is now also naturalized in North America (Woerdenbag & Pras 2002).
The genus Artemisia consists of over 400 species, ranging from tall bushes to low-growing shrubs, with habitats reaching from the Alps to the steppes. The highest concentration of Artemisia species is found in Asia (Mucciarelli & Maffei 2002). Familiar members of the genus include wormwood (A. absinthum L., notorious for its use in the spirit absinthe), the culinary herb tarragon (A. dracunculus L.), and mugwort (which may refer to A. vulgaris or many other Artemisia species, used either as a food or medicine in many parts of Eurasia). The desirable properties of these herbs are largely the result of their aromatic essential oils. The same can be said of A. annua L., whose oil, described as “grassy, fresh, and bitter with a camphoraceous nuance”, has uses in the cosmetics and perfumery industries, and has been reported to have antifungal and antibacterial properties (Woerdenbag & Pras 2002). However, for A. annua, the economic importance of the oil is secondary to the plant’s antimalarial properties.
Traditional use of Artemisia annua
In Traditional Chinese Medicine (TCM), A. annua is known as Qing Hao (literally “blue-green herb”) (Laughlin, Heazlewood & Beattie 2002) and is included in the official Pharmacopoeia of the People’s Republic of China. Records of the herb’s medicinal use stretch back over 2000 years (Laughlin, Heazlewood & Beattie 2002; Mucciarelli & Maffei 2002). The official drug consists of the dried aerial parts of A. annua, which are collected in autumn when in full bloom, before removing the older stems and drying in the shade (Tang & Eisenbrand 1992).
Practitioners of TCM classify herbs in terms of four properties: hot, warm, cool and cold, and five tastes: sour, bitter, sweet, pungent and salty. These categories are related to the concepts of Yin and Yang. Essentially, warm and hot herbs are considered Yang (masculine) whereas cool and cold herbs are considered Yin (feminine). A. annua is classified as bitter, pungent and cold or cool in nature, so it is deemed appropriate for treatment of a deficiency of Yin, summer heat stroke or an “excess of heat” which could be due to a fever. With a view to tailoring or personalising the prescription to the specific needs of the patient, TCM practitioners frequently employ complex mixtures of many different herbs or even animal products such as in the preparation Qing Hao Bie Jia Tang, which consists of a decoction* of the shell of the Chinese softshell turtle with Qing Hao (Yu & Zhong 2002). However, its use in the treatment of symptoms linked to malaria has become the main focus of recent research.
*In a decoction, the ingredients are pulverised and boiled in water. Unlike an infusion, the herbal ingredients are boiled in the water for some length of time. In an infusion, the ingredients are simply added to hot water (like a tea).
The discovery of artemisinin
Artemisinin, the active antimalarial compound present in A. annua, was discovered in China against the backdrop of the Cultural Revolution and the proxy war against the USA in Vietnam. In the Vietnam War, malaria was an enormous problem for both sides since it incapacitated a significant proportion of troops (Beadle & Hoffman 1993). While the USA launched a hugely expensive research program that eventually lead to the development of the drug mefloquine (Croft 2007), the Chinese turned instead to their well-documented heritage of traditional medicines. A project was launched (sometimes referred to as project 523) as a cooperation between scientists and historians, who together methodically screened different herbs that were known to be traditionally used for their antimalarial properties (Hsu 2006).
Qing Hao was among the first herbs to be screened as part of project 523 but in the initial tests, where the herb was used to make an infusion , the antimalarial results were minimal. By 1971, the researchers had carried out a series of experiments on A. annua but had not obtained any particularly encouraging results (Hsu 2006). The turning point came when researchers at the Institute of Traditional Medicine in Beijing came across an interesting sentence from the work “Emergency Prescriptions Kept up one’s Sleeve” by polymath Ge Hong (284-363). The crucial passage translates as: “Another recipe: Qing Hao, one bunch, take two sheng (∼400 mL) of water for soaking it, wring it out, take the juice, ingest it in its entirety” (Youyou 2011). In other words, the best form extraction is one in cold water.
The group of scientists included Tu Youyou who would later be widely credited with the discovery of artemisinin and in 2015 was awarded a Nobel Prize for her work. Tu Youyou recognised the significance of Ge Hong’s specification of fresh (as opposed to dry) herb, and the use of low temperatures. These details suggested that the active compound might be easily decomposed by heat. On this basis, the scientists tried extracting the herb with organic solvents and minimal heating. The extracts prepared in this manner displayed exceptional antimalarial activity, with almost 100% efficacy in killing malaria parasites in mice and monkeys (Youyou 2004; Cui & Su 2009; Awofeso 2011).
One puzzling aspect of the traditional extraction as reported by Ge Hong is still yet to be conclusively explained; the active compound artemisinin is now known to have very low solubility in water, so how can an efficacious medicine be made using only cold water for extraction? It has been suggested that the important part here is the “wringing” step, which might cause the release of various oily compounds from the plant which form an emulsion and help to extract the artemisinin. Other compounds may also have a synergistic antimalarial effect when combined with artemisinin (Hsu 2006).
In a collaborative effort of Chinese researchers, the active compound was eventually isolated and in 1975 its structure was elucidated. The compound was given the Chinese name Qing Hao Su, meaning “a principle from Qing Hao” (Youyou 2011). The name more commonly used in the international scientific literature is artemisinin. Artemisinin has a unique type of structure including a particularly unusual feature called an endoperoxide group, which has been found to be essential to its antimalarial activity.
Semi-synthetic artemisinin-based drugs
Soon after its discovery, it was clear that artemisinin was a powerful antimalarial drug. However, its effectiveness was limited by poor bioavailability (i.e. the efficiency with which it enters the circulatory system) when given orally. To improve on this, chemists developed other drugs by making small alterations to the structure of artemisinin. This resulted in the drugs artemether, arteether and artesunate. These drugs are more potent than artemisinin itself, and are now among the most effective antimalarials on the market.
Artemisinin Combination Therapy
The search to find new antimalarials is a race against the malaria parasites, which will inevitably develop resistance to any new drug. If artemisinin-type drugs are used alone, often a small number of parasites will survive in the patient. Thus the few parasites that are resistant to the drug are selected out and are able to proliferate. In order to prevent or at least slow down the development of resistance, artemisinin-type drugs are usually used in combination with other types of antimalarials, which ensures that the malaria parasites are completely eliminated. This works because any given malaria parasite is unlikely to possess resistance to both types of drugs. These combination therapies are about 90% effective, provided there are no medical complications (Howitt et al. 2016). In fact, in 2006, the WHO called for pharmaceutical companies to stop producing drugs that contain only artemisinin-type drugs, in favour of combination drugs (WHO 2006). Despite these measures, resistance to artemisinin is already emerging, especially in Southeast Asia (Ashley et al. 2014).
A. annua: a locally produced remedy for malaria?
Malaria is often described as a disease of poverty. There seems to be a vicious cycle whereby malaria causes poverty and poverty causes malaria (Worrall et al. 2005). Hence it is important that antimalarial drugs can be provided at low cost. It has been suggested that A. annua could be used as a self-reliant treatment in Africa (de Ridder et al. 2008; Mueller et al. 2000). The idea is that instead of extracting the active compound artemisinin and formulating it into a pharmaceutical drug with all the expenses that would entail, a crude preparation (such as a tea or juice) could be used.
Preliminary trials of A. annua tea have had quite positive results, showing that A. annua can be cultivated successfully in Africa and that the tea is capable of reducing parasite levels in patients’ blood below detectable limits, eliminating symptoms of malaria. However, there are some problems with this approach. As mentioned above, the use of artemisinin-type drugs alone is not recommended since it selects out malaria parasites that are resistant to artemisinin and in the long-run will cause an increase in artemisinin-resistant malaria. There is no reason to believe that this rule should not apply to these teas as much as it applies to pure pharmaceutical drugs. Another problem is the difficulty of controlling the dose. The levels of artemisinin in the teas will vary according to the methods used for extraction, collection and harvesting, as well as environmental factors. Various techniques have been suggested to improve the activity of the teas. For example, adding fatty substances like coffee creamer to the tea might aid in the extraction of artemisinin (de Ridder et al. 2008).
These studies have also revealed a problem with recrudescence i.e. recurrence of disease symptoms, often months after the apparently successful treatment. This is due to a few different factors, namely the short half-life of artemisinin within the patient, the small amounts of artemisinin in the tea, and the fact that artemisinin cannot kill all the malaria parasites within the patient, only the ones at certain stages of their life-cycle (Mueller et al. 2004).
Production of artemisinin
One problem shared by many plant-derived drugs is variability in the content of the active compound. It is possible to breed varieties of A. annua that produce larger amounts of artemisinin, but changes in environmental factors such as temperature, nutrient availability, time of harvest etc. can still cause variations in artemisinin levels (Delabays, Darbellay & Galland 2002). To avoid gambling the supply of artemisinin on the vagaries of Nature, several other approaches for the production of artemisinin-type drugs have been devised.
One approach is “total synthesis” i.e. production of the drug from scratch using the methods of organic chemistry. Several different groups of organic chemists have managed to make artemisinin. However, since artemisinin is quite a complex molecule it is difficult to design a process which is efficient enough to compete with simply growing the plant. Total synthesis is unlikely to become a major source of the drug in the near future (Wang et al. 2014).
In the plant itself, artemisinin is made from a closely related chemical called artemisinic acid. In some cases, the levels of artemisinic acid can be ten times as high as artemisinin. Therefore, one possible strategy is to extract the artemisinic acid from the plant and chemically convert it to artemisinin (Laughlin, Heazlewood & Beattie 2002).
Another high-tech approach obviates the need to grow the plant at all. Instead, the genes responsible for production of artemisinic acid are introduced into the genome of baker’s yeast. The yeast is then easily grown on a large scale. Genetically engineered yeast is now capable of producing 25 grams of artemisinic acid per litre of fermentation broth, making this a feasible way of manufacturing the drug (Paddon et al. 2013). The pharmaceutical company Sanofi has now started producing artemisinin in this manner, operating under a “no profit, no loss” scheme (Amyris 2013). While this breakthrough promises to lower the price and stabilize the supply of artemisinin, it has been argued (Thomas 2013) that the new technology represents an assault on the livelihoods of A. annua farmers, and that sufficient artemisinin can be produced from botanical sources alone. This whole controversy serves as a reminder that malaria should not be considered solely as a technological problem; the eventual eradication of malaria will require not only scientific innovation, but also concerted advances in the fields of public health and socio-economics, as well as committed political engagement (Hemingway & Bates 2003; Hausmann-Muela & Eckl 2015).
There are other drugs in various stages of development that are based on traditionally used Chinese herbs (Graziose et al. 2010), but artemisinin has undoubtedly been the most successful so far. The success story of artemisinin could be interpreted as a vindication of the study of traditional medicines, but also provides an illustration of the complexity that is inherent when researching Nature as source of medicines.
© Joe Barnett, MSc student (2015 – 2016),
Research Cluster ‘Biodiversity and Medicines’ / Centre for Pharmacognosy and Phytotherapy, UCL School of Pharmacy, Univ. London, 29 – 39 Brunswick Sq., London WC1N 1AX
In this essay, we do not intend to advise or recommend herbs for medicinal or health use. This information is for educational purposes only and should not be considered as a recommendation or an endorsement of any particular medical or health treatment. The use of any such product should be based on the appropriate advice of a health care professional or based on the information available in the patient information leaflets (i.e. for THR products). The information provided should not be used during any medical emergency or for the diagnosis or treatment of any medical condition.
– A.-annua in bloom: “Artemisia annua L.” Dipartimento di Scienze della Vita, Università di Trieste, Progetto Dryades, Picture by Andrea Moro, Creative Commons Share-Alike 3.0 License
– Ge Hong: Wellcome Images collection, image number L0039323. Creative Commons Attribution only licence CC BY 4.0
– Molecular structure of artemisinin: own work
– Artesunate: public domain – Author: Eggi -https://de.wikipedia.org/wiki/Benutzer:Eggi
– A. annua botanical illustration: “Artemisia annua”, USDA-NRCS PLANTS Database / Britton, N.L., and A. Brown. 1913. Illustrated flora of the northern states and Canada. Vol. 3: 526., public domain
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