Artemisia Species in Traditional Chinese Medicine and the Discovery of Artemisinin

2015

Qing hao-an antimalarial herb

A herb, named Qing Hao (usually pronounced ching how) in Chinese, sweet Annie or sweet wormwood in English, and properly known as Artemisia annua L. has become well known in western countries during the last 20 years. Herbal companies, which deal with traditional Chinese medicine (TCM), receive several inquiries concerning this herb every day. A. question commonly asked by those about to travel to Africa or S.E. Asia is “Can I take the herb called Qing Hao to prevent malaria during my trip?” Unfortunately, the answer has disappointed many people because although this herb is used for the treatment of malaria in TCM, usually combined with other herbs, it is not recommended for the prevention of the disease or as a deterrent to mosquitoes. However, the leaves of Qing Hao were burned as a fumigant insecticide to kill mosquitoes in ancient China but this practice no longer continues today since the development and marketing of more efficient mosquito-repellant devices.

The discovery of artemisinin

Qing Hao is a herb commonly used in China with a long history of use as an antipyretic to treat the alternate chill and fever symptoms of malaria and other “heat syndromes” in the traditional Chinese medical system. The name Qing Hao first appeared in a silk book excavated from the tomb at Mawangdui belonging to the Han dynasty; it was entitled “Wu Shi Er Bin Fang” (Prescriptions for Fifty-two ailments) and dated from as early as 168 BC, and described the use of Qing Hao for the treatment of haemorrhoids. In 340 AD, Qing Hao was recorded for the first time as a treatment for fevers in a medical book, “Zhou Hou Bei Ji Fang” (Handbook of Prescriptions for Emergency Treatment). In this work, the author, Ge Hong, recommended that, to reduce fevers one should soak a handful of Qing Hao in one sheng () of water, strain the liquor and drink it all. Li Shi-Zhen, the author of the famous materia medica “Ben Cao Gang Mu” (1596 AD), based on the former medical text records and his own experience, stated that malaria with chills and fever could be treated with Qing Hao (). Qing Hao has been recommended for use alone or with other herbs for malaria as well as for other conditions ().

Qing Hao is the aerial part of Artemisia annua L. of the family Asteraceae (formerly Compositae), and it is now officially listed in the Chinese pharmacopoeia (). In the early literature, Qing Hao referred to two species, Artemisia annua and A. apiacea but nowadays Qing Hao is usually taken to be Artemisia annua.

In 1967, the Chinese government began a systematic examination of plant species used in traditional chinese medicine in order to discover new drugs, especially for malaria. The many plants tested included Qing Hao, but no activity was seen when hot-water extracts of this herb were tested in mice infected with the rodent malaria parasite Plasmodium berghei. However, when cold ether extracts of Qing Hao were tested, encouraging activity was observed ().

Since then, Chinese researchers in many institutions have devoted considerable resources to investigate the active components responsible for the anti-malarial activities of the crude drug Qing Hao and this has resulted in the discovery of the active compound, Qinghaosu, which means “a principle from Qing Hao” and which was also referred to as arteannuin and artemisinine; today, the accepted western name is artemisinin (since the compound is a terpene, not an alkaloid as the suffix-ine implies). Artemisinin was first isolated and identified in 1972 as a novel compound with its chemical structure representing a new type of sesquiterpene lactone with an unusual endoperoxide moiety ().

Following intensive investigations into the pharmacology, pharmacokinetics and toxicology of artemisinin and its natural and synthetic derivatives, artemisinin was found to have a rapid schizonticidal action (i.e. it kills the forms of malaria parasites infecting red blood cells), with low toxicity (). Of particular significance was its remarkably potent therapeutic effect against malaria caused by drug-resistant Plasmodium falciparum. In clinical studies with 2099 patients infected with Plasmodium vivax or P. falciparum, artemisinin showed very good therapeutic efficacy in almost all patients without obvious side effects (). Moreover, artemisinin was also found to be effective in the treatment of chloroquine resistant falciparum malaria and its often fatal complication, cerebral malaria ().

The discovery of a new potent antimalarial from a traditional chinese medicine herb was so significant that it attracted great attention from the World Health Organsation and a number of research establishments around the world. Although artemisinin has been synthesised by a few research groups in several countries, the high cost made synthetic artemisinin an uneconomic choice for large-scale production of the drug so that it is extracted from its natural source (). Consequently, many taxonomy-orientated scientists started screening dozens of other Artemisia species in an attempt to find new source plant for artemisinin but Artemisia annua remains the only species that is known to produce artemisinin.

Several hundred years ahead of modern medicine, practitioners of traditional chinese medicine recorded the presence of a biological clock in human body, the diagnosis of diabetes, the function of hormones, described the circulation of the blood and the application of inoculation (). The discovery of artemisinin from a traditional chinese medicine herb is an excellent example of the contribution that traditional chinese medicine may make to modern medical science.

Traditional Chinese medicine

A large population in South East Asia has used traditional chinese medicine for thousands of years, and it is still practised in parallel with western medicine in the healthcare system in China owing to its unique theoretical basis and proven therapeutic efficacy. The theory and practise of traditional chinese medicine is complex and space does not permit a detailed consideration here; however, a brief account is given below in order to help the reader appreciate the use of Artemisia species in TCM.

The underlying principle of traditional chinese medicine lies in the comprehensive and dynamic application of the theories of Yin-Yang and the Five Elements. Everything in the universe is considered to have the opposite but inter-related aspects, Yin and Yang. When the Yin and Yang are balanced in a human body, the person is in a healthy condition, not only less susceptible to diseases, but also likely to have a better quality of life; conversely, illness is the result of an imbalance of Yin and Yang in the body. The aim of treatment in traditional chinese medicine is always to restore the balance of the Yin and Yang. The theory of Five Elements (metal, wood, water, fire and earth), relates the properties of the five elements to universally interdependent and mutually restraining relationships of matters. This theory is used in traditional chinese medicine to explain the correlation and pathological influences among five viscera, (heart, liver, spleen, lung and kidney), and to guide the diagnosis and the treatment.

Traditional Chinese medicine consists of acupuncture, massage, Qi-Gong (Chinese deep-breathing excercises), medicated diet and herbal treatment with herbal treatment holding a dominant position. The theory of the herb property is one of the most important parts of the TCM. According to this theory, herbs have four properties – hot, warm, cool and cold, and five tastes – sour, bitter, sweet, pungent and salty. Basically, herbs with a hot or warm property have the nature of Yang and herbs with a cool or cold property have the nature of Yin. This forms the very basis of the theory of traditional chinese medicine materia medica. In line with the Yin-Yang concept in traditional chinese medicine diagnosis, the use of a Yin herb or a Yang herb to re-balance the Yin and Yang in the different organs in the body and to treat the illnesses accordingly can be appreciated. Herbs in traditional chinese medicine are also uniquely considered to have selective therapeutic effects on certain parts of the body and this is called channel tropism. This resembles the concept of drug targeting in modern pharmaceutical research although the origin of the “magic bullet” concept is unlikely to have been derived from channel tropism! Both the herbal property and the channel tropism represent the different pharmacological functions of each herb.

Herbs with the property of cold or cool are able to clear heat, to purge the pathogenic fire and to detoxify, and can be used to treat heat syndromes. For example, Artemisia herb (Artemisia annua) and Coptis root (Coptis chinensis) are cool in nature and are used to treat internal heat caused by bacterial infections or by non-infectious disease. However, these two herbs are not necessarily inter-changeable in their usage because they are different in other respects. Herbs with the property of warm and hot are able to warm internally, to expel cold and to tonify Yang, and are thus used to treat cold syndromes. For example, ginger (Zingiber offtcinale), and cinnamon bark, (Cinnamomum cassia) are hot in nature and are commonly used to warm the interior and expel cold. Herbs with a sour taste possess astringent actions and can be used to treat sweating and diarrhoea, such as Schisandra fruit (Scbisandra chinensis), for excessive sweating and Cherokee rosehip (Rosa laevigata), for chronic diarrhoea. Herbs with sweet taste usually possess a tonifying (or strenghening) function, such as wolfberry fruit, (Lycium barbarum) used for tonifying the liver and kidney and the Chinese date, (Ziziphus jujuba) used for tonifying the blood.

TCM is characterised by its unique understanding of the human body’s physiology and pathology, and by its intricate methods of diagnosis and treatment of diseases. traditional chinese medicine regards the human body as an organic whole, whose component parts are physiologically interconnected, so a local lesion may affect the entire body and indeed it may well be a result of the imbalance of some other parts of the body. Disorders of internal organs may be reflected on the surface of the body. When a Chinese practitioner sees a patient, he/she will usually gather all the relevant information through four methods of diagnosis (inspection, listening and smelling, inquiring and pulse-feeling), then differentiate symptoms and signs into “Zheng” of a certain nature (syndrome). He/she will make a diagnosis based on “Eight Principal Syndromes”, i.e. Yin and Yang, interior and exterior, cold and heat, deficiency and excessiveness, but it is important to appreciate that each syndrome will be further differentiated according to the particular symptoms present.

It is normal practice in traditional chinese medicine for some different diseases to be treated with similar herbs while diseases which appear to be similar (from a western point of view), may be treated with different herbs depending on the differentiation of syndromes. For example, a patient suffering from a cold who has symptoms of severe chilliness, slight fever and a tongue with thin, white fur, which indicates the exterior wind-cold syndrome, should be treated with herbs which are pungent in taste and warm in property. If a patient with a cold has symptoms of high fever, mild chilliness and a tongue with thin yellow fur, which indicates the exterior wind-heat syndrome, he should be treated with those herbs which are mild, diaphoretic, pungent in taste and cool in property.

Artemisia Annua in Chinese Traditional Medicine

Other species of Artemisia used in traditional chinese medicine

There are 184 artemisia species and 44 varieties found in China. Most of them are distributed in the north, northeast and north west of China, with some in eastern, central and southern areas. Most species of Artemisia contain polyacetylenes, flavonoids and terpenoids but some species also contain other types of constituents such as cyanogenic glycosides and coumarins.

According to a national survey of the medicinal plants of China, more than sixty Artemisia species are used in different areas for certain ailments such as inflammation, liver and stomach disorders and gynaecological problems (). The leaves of more than ten species are used for the preparation of moxas (). A. number of Artemisia species are used as choleretic, anti-inflammatory and diuretic agents in the treatment of hepatitis. Two of these are A. scoparia and A. capillaris and are known by the same Chinese name as Yin Chen. Both species contain essential oils, flavones and coumarins. A. flavone, capillarisin, the major constituent of A. capillaris, together with two new stereoisomeric constituents, capillartemisin A. and B, showed choleretic effects in experiment studies. The coumarin derivative sco-parone isolated from both species had a preventative effect on carbon tetrachloride or galactosamine-induced hepatotoxicity in hepatocyte cell cultures, (), and also had anti-inflammatory and analgesic effects (). Decoctions of Yin Chen have been used in many clinical studies for icteric hepatitis with good success. In one study, 32 patients with icteric hepatitis were treated with 30-45 g of Yin Chen to be made into a decoction taken daily. In all cases, fever subsided quickly, jaundice disappeared, and the liver returned to normal size. The mean length of treatment was seven days (). Other species used locally for the same purpose include A. anethifolia, A. anethoides and A. demissa.

More than ten Artemisia species are used in traditional chinese medicine for certain gynaecological problems. According to the theory of TCM, a number of conditions, such as amenorrhea, menstrual pain and prolonged menstrual bleeding, are usually related to Qi (vital energy) and blood deficiency, Qi stagnation or blood stasis due to cold. Thus those herbs with the acrid and warm property can be used to treat such ailments with a good clinical response and various species of Artemisia which have the same property are often the principal ingredients of traditional chinese medicine formulae for the illnesses mentioned above ().

Along with acupuncture, the application of moxibution is used in TCM. It is carried out by applying an ignited moxa cone or moxa stick on the acu-points to elicit heat stimulation. It exerts an effect by warming and regulating the channels, promoting the circulation of Qi and blood. Moxibustion is often combined with acupuncture for the treatment and prevention of many diseases including pain relief and injury management.

There are number of herbal materials used to make moxa cones or sticks but the dried leaves of mugwort, (Artemisia vulgaris leaf) is the most common one. The dried leaves are pounded into fine pieces (moxa wool), which can then be easily shaped into moxa cones or prepared as moxa sticks for use. A. good example of the therapeutic application of the mugwort moxa stick is its use to stimulate acupuncture point BL 67, (Zhi Yin), to promote the turning of a foetus in breech presentation. This technique is taught in every traditional chinese medicine university in China and a recent randomised, controlled clinical study demonstrated its effectiveness ().

Pure moxa sticks contain only mugwort as the main ingredient, while medicated moxa sticks may contain some or all of the following materials: Cortex Cinnamon (cinnamon bark), Rhizoma Zingiberis (ginger rhizome), Flos Caryophylli (flowers of Dianthus sp.), Radix Angelicae Pubescentis (Angelica pubescens root), Herba Asari (Asarum sieboldii herb), Radix Angelicae Dahuricae (Angelica daburica root), Rhizoma Atractylodis (Atractylodes macrocephala rhizome), Myrrha (myrrh), Olibanum (frankincense) and Pericarpium Xanthoxyli (Xanthoxylum bungeanum fruit peel). Although there is no report of any chemical effects, apart from heat, of moxibustion in classical TCM, it is likely that essential oil containing herbs in moxa sticks play a part in the therapeutic results of moxibustion.

While over sixty Artemisia species are used for medicinal purposes, the active chemicals of most of the species are still unknown. The demand for further research on this genus can be justified with special emphasis upon their chemistry, taxonomy, and clinical verification of claimed therapeutic efficacy.

 

Selections from the book: “Artemisia”. Edited by Colin W. Wright. Series: “Medicinal and Aromatic Plants — Industrial Profiles”. 2002.