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Artemisia annua as a Traditional HerbalAntimalarialMerlin Willcox, Gerard Bodeker, Geneviève Bourdy,Vikas Dhingra, Jacques Falquet, Jorge F.S. Ferreira,Bertrand Graz, Hans-Martin Hirt, Elisabeth Hsu,Pedro Melillo de Magalhães, Damien Provendier,and Colin W. Wright The species Artemisia annua L (Asteraceae) is native to China. Its ancient Chinese name,Qing Hao, literally means “green herb.” The genus Artemisia comprises over 400 species,many of which have an aromatic, bitter taste.
A. annua is so named because it is almost the only member of the genus with an annual cycle.
It is a shrub, often growing over 2 m high (Ferreira et al., 1997; see Figure 3.1 and Figure3.2). Its leaves and flowers contain artemisinin, first isolated in China in 1971; this is theconstituent with the greatest antimalarial activity (see Table 3.3). Artemisinin has been foundin only two other species, Artemisia apiacea and Artemisia lancea (Tan et al., 1998).
Artemisinin is poorly soluble in oil or water, so is usually administered orally, although it canbe given rectally (Ashton et al., 1998) and, when suspended in oil, intramuscularly (Titulaer etal., 1990). Synthetic derivatives that are water soluble (artesunate) and oil soluble(artemether) have been developed to enable intravenous and intramuscular administration,respectively (Van Agtmael et al., 1999a). It is now universally accepted that this family ofcompounds is among the most powerful antimalarial drugs ever discovered. Thepharmacological and clinical evidence is well documented (Wright and Warhurst, 2002;Wilairatana and Looareesuwan, 2002). Artemisinin cannot be synthesized cost effectively, soit is still extracted from A. annua aerial parts. Therefore, the science of commercial cultivationof A. annua , to maximize artemisinin yields, is already well developed (Laughlin et al.,2002). However, the end product is often unaffordable for the poor.
Other Artemisia species have antimalarial activity without containing artemisinin(Valecha et al., 1994). A. absinthium and Artemisia abrotanum were used to treat malariain Europe, but their activity is attributable to other constitutents (Cubukcu et al., 1990;Deans and Kennedy, 2002). Artemisia afra extracts are effective against P. falciparum invitro, and this activity is attributable to a complex mixture of flavonoids and sesquiterpenelactones, rather than to a single compound (Kraft et al., 2003). Some of these phytochemicalsmay also contribute to the activity of A. annua. A. annua contains many different classes of compounds: at least 28 monoterpenes, 30sesquiterpenes, 12 triterpenoids and steroids, 36 flavonoids, 7 coumarins, and 4aromatic and 9 aliphatic compounds (Bhakuni et al., 2002). Artemisinin is not the onlyantimalarial compound in A. annua. The callus of the plant has some antimalarial activityeven though it contains no artemisinin (François et al., 1993). Furthermore, the water-solublefraction of A. annua, after extraction of artemisinin, has an antipyretic effect (Chang and But,1986).
Synergistic activity of other constituents of A. annua
Artemisinin is only 1 of 29 sesquiterpenes in A. annua. Some of these are in much greaterconcentrations than artemisinin in wild strains of the plant: arteannuin B (two to fourtimes) and artemisinic acid (seven to eight times). Both of these have antibacterial andantifungal properties (Dhingra et al., 2000). Arteannuin B used alone was found to beineffective and toxic in rat malaria, but it potentiated the effect of artemisinin (Changand But, 1986). However, in hybrid plants with a high artemisinin content, the concentrationof artemisinic acid is much lower (Magalhães, personal communication). In addition, A.
annua produces at least 36 flavonoids. Many of these have antimalarial activityin vitro, although the inhibitory concentration 50% (IC 50) is much higher thanthat of artemisinin (Table 3.4). Five of these, artemetin, casticin, chrysoplenetin,chrysosplenol-D, and cirsilineol, have been shown selectively to potentiate thein vitro activity of artemisinin against P. falciparum (Liu et al., 1992). Casticin, at aconcentration of 5µ mol/l, induced a three- to fivefold reduction in the IC 50for artemisinin (Elford et al., 1987). Chrysosplenol-D has the strongest potentiating effect,and this is also the most abundant flavone in plant material (Liu et al., 1992). Interestingly,the flavones do not potentiate the antimalarial activity of chloroquine (Elford et al., 1987).
Although they have no effect on hemin themselves, they do catalyze the reaction ofartemisinin with hemin (Bilia et al., 2002) and may also help to solubilize artemisinin (seeabove).
In Vitro antimalarial Activity of Constituents of A. annua (IC50, µM)
Source: Liu, K.C.-S. et al., (1992), Plant Cell Rep, 11, 637–640
The effect of all the flavones in combination with artemisinin has not been investigated. Otherflavones, and indeed other components of A. annua, may have a similar effect; they have notall been tested because it is difficult to purify them. The antimalarial properties of thetraditional preparation of A. annua most probably reside in the combination of manyconstituents, not just artemisinin.
SAFETY AND TOLERABILITY
The presence of multiple chemical constituents in herbal preparations of A. annua raises thequestion as to their safety. However, artemisinin has now been used in several millionpatients, with only one report of neurological side effects following artesunate treatment(WHO, 1998b; White et al., 1999; Wilairatana and Looareesuwan, 2002). A literature searchhas not revealed any animal toxicity studies, but the herb extract has been evaluated in Chinaand was deemed to be of low toxicity. Five hundred ninety patients were treated with the herbextract, and of these, 3.4% developed gastrointestinal symptoms such as nausea, vomiting,abdominal pain, and diarrhea. No adverse effects were observed in patients with cardiac,renal, or hepatic dysfunction, or in pregnant women (Chang and But, 1986). Interestingly, the pharmacokinetics of artemisinin are not affected in patients with cirrhosis of the liver (DeVries et al., 1997), but artemisinin does induce certain liver enzymes, and thus interacts withsome other drugs such as omeprazole (Svensson et al., 1998). Observational studies in Africafound that 25% of malaria patients being treated with A. annua infusion had nausea, althoughnone vomited. Other mild adverse events during treatment included dizziness, tinnitus,pruritus, and abdominal pain (Hirt, 2001).
A. annua can be regarded as an established traditional medicine, as it has been widely usedand is included in the pharmacopoeia of the People’s Republic of China (Mueller et al., 2000).
Nevertheless, any future clinical trials of A. annua preparations should carefully monitorsubjective side effects as well as end-organ function.
CULTIVATION
A. annua is native not only to China but also to Japan, Korea, Vietnam, Myanmar, northernIndia, and southern Siberia through to eastern Europe (WHO, 1998a). It has been introducedto many other countries, in Europe, North America, and the Tropics (Laughlin et al., 2002).
Seed varieties have been adapted by breeding for lower latitudes, and cultivation has beensuccessfully achieved in many tropical countries, for example, in the Congo (Mueller et al.,2000), India (Mukherjee, 1991), and Brazil (Milliken, 1997; Carvalho et al., 1997; DeMagalhães et al., 1997).
The tiny seeds succeed best when sown on top of well-aerated soil, as they germinate in thelight (Hirt and Lindsey, 2000); in areas with a heavy soil, the plants can first be developed ina greenhouse. In order to maximize the yield of artemisinin, the critical factor is day length,because the plant usually grows in the long summer days at high latitudes and flowers whenthe day length shortens. The concentration of artemisinin peaks around the time of flowering,although in some cases this may be just before flowering, and in other cases during fullflowering (Ferreira et al., 1995a; Laughlin et al., 2002).
In wild-type plants, the greatest concentration of artemisinin is found in the inflorescence,although it occurs in all other aerial parts of the plant, except the seed (Ferreira et al., 1997).
In artemisinin-rich plants, the greatest concentration of artemisinin occurs at the beginning ofthe flowering season (De Magalhães, personal communication).
It used to be thought that sun and oven drying reduced the artemisinin content and that it wasbest to air-dry leaves in the shade (Laughlin et al., 2002). However, Simonnet et al. (2001)found that sun-drying plants in the field increased the artemisinin content (perhaps bypromoting conversion of some precursors to artemisinin), but that if drying continued formore than a week, leaves were lost, decreasing the overall yield. The optimum wouldtherefore seem to be drying in the field for 1 week, followed by air-drying in the shade.
Although artemisinin content is affected by climate and time of harvesting, the main influence
is genetic variation. Ferreira et al. (1995b) evaluated the same 23 clones of A. annua, which
varied from 0.001 to 0.35% artemisinin, under tissue culture, greenhouse, and field
conditions. Broadsense heritability analyses indicated that artemisinin was mainly under
genetic, not environmental, control. Delabays et al. (2002) confirmed that genes outplay the
environment by studying different varieties, which yielded from 0.02 to about 1.4%
artemisinin. Efforts have been made to increase the artemisinin content as far as possible,
by exploring the natural variability. This has been achieved in a hybrid (A. annua var.
Artemis, seeds available from www.anamed.org) and in a nonhybrid strain collected from
Vietnam (Sutakavatin, 2002, personal communication). However artemisinin yield dependsnot only on its concentration, but also on the total number of leaves and branches. TheInstitute of Materia Medica in Vietnam has been breeding plants for all three of thesecharacteristics, to optimize artemisinin yield (Dong and Thuan, 2003).
ANAMED RECOMMENDATIONS FOR TREATMENT
Anamed (Action for Nature and Medicine) is an NGO promoting the use of traditionalmedicines (). It distributes seeds of a recently developed artemisinin-richgenotype of A. annua. Hirt (2001) recommends an infusion of 5 g of dried leaves on which 1 l of boiling water ispoured and left to cool for 15 minutes (for a 60-kg adult; 2.5 g of leaves for a 30-kg child and1.25 g for a 15-kg child). This method extracts 55% of the artemisinin into the water, and 35to 40% remains in the leaves. Only 5% is lost, in contrast to a decoction (when the plant isboiled in water for several minutes), where 50% of the artemisinin is lost, because it is notheat stable. An infusion in full fat milk can increase the proportion of artemisinin extracted to80%.
De Magalhães et al. (2003) advises that as artemisinin reacts with iron, the tea should beprepared in pots made of other materials.
Anamed recommends the dose of 250 ml of the infusion, taken every 6 hours for 7 days; thisdose is based on that in the Chinese pharmacopoeia, which recommends a dose of 4.5 to 9 gdaily.
Preparations containing whole Artemisia leaves are likely to have a higher artemisinin contentthan filtered decoctions or infusions, if equivalent doses are used, because much of theartemisinin will remain in the leaves rather than be dissolved in the water.
An alternative is [therefore] to swallow 1 g of dried leaves three times a day, but hereAnamed has only made a few positive observations.
Anamed is also observing patients treated with an enema using double the dose of leaves andhalf the amount of water; there have been some positive results, but further research isawaited (Hirt, personal communication).

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