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''Artemisia annua'', also known as sweet wormwood, sweet annie, sweet sagewort, annual mugwort or annual wormwood (), is a common type of
wormwood Wormwood may refer to: Biology * Several plants of the genus ''Artemisia'': ** ''Artemisia abrotanum'', southern wormwood ** '' Artemisia absinthium'', common wormwood, grande wormwood or absinthe wormwood ** ''Artemisia annua'', sweet wormwood o ...
native to temperate Asia, but naturalized in many countries including scattered parts of
North America North America is a continent in the Northern Hemisphere and almost entirely within the Western Hemisphere. It is bordered to the north by the Arctic Ocean, to the east by the Atlantic Ocean, to the southeast by South America and the Car ...
. An
extract An extract is a substance made by extracting a part of a raw material, often by using a solvent such as ethanol, oil or water. Extracts may be sold as tinctures, absolutes or in powder form. The aromatic principles of many spices, nuts, h ...
of ''A. annua'', called artemisinin (or
artesunate Artesunate (AS) is a medication used to treat malaria. The intravenous form is preferred to quinine for severe malaria. Often it is used as part of Artemisinin-based combination therapy, combination therapy, such as artesunate plus mefloquine. I ...
), is a medication used to treat malaria. Discovery of artemisinin and its antimalarial properties by the Chinese scientist, Tu Youyou, led to award of the 2011
Lasker Prize The Lasker Awards have been awarded annually since 1945 to living persons who have made major contributions to medical science or who have performed public service on behalf of medicine. They are administered by the Lasker Foundation, which was f ...
and 2015 Nobel Prize in Physiology or Medicine.


Description

''Artemisia annua'' belongs to the plant family of '' Asteraceae'' and is an annual short-day plant. Its stem is erect brownish or violet brown. The plant itself is hairless and naturally grows from 30 to 100 cm tall, although in cultivation it is possible for plants to reach a height of 200 cm. The leaves of ''A. annua'' have a length of 3–5 cm and are divided by deep cuts into two or three small leaflets. The intensive aromatic scent of the leaves is characteristic. The artemisinin content in dried leaves is in between 0% and 1.5%. New hybrids of ''Artemisia annua'' developed in Switzerland can reach a leaf artemisinin content of up to 2%. The small flowers have a diameter of 2–2.5 mm and are arranged in loose panicles. Their color is green-yellowish. The seeds are brown achenes with a diameter of only 0.6–0.8 mm. Their thousand-kernel weight (TKW) averages around 0.03 g (in comparison, wheat has a TKW of approximately 45 g).


Agricultural practice

The growing period of ''Artemisia annua'' from seeding through to harvest is 190–240 days, depending on the climate and altitude of the production area. The plant is harvested at the beginning of flowering when the artemisinin content is the highest. Dry leaf yields of ''Artemisia annua'' plantations vary between 0.5 and 3 tonnes per hectare. In terms of the climate ''A. annua'' prefers sunny and warm conditions. Its optimal growth temperature lies within 20 and 25 °C. Annual temperature sums of 3500–5000 °C (sum of temperatures higher 10 °C over one year) are required to guarantee a proper maturing. The rainfall during the growing season should not be less than 600 mm (annual rainfall higher 1150 mm). Especially the seedlings of ''A. annua''. are susceptible to drought or water lodging. The mature plants on the other hand are quite resistant to those climate conditions. Nevertheless, the preferred soil conditions for ''A. annua'' are light soils with deep topsoils and good drainage properties. But it is reported, that the plant is adaptable to different soil types. Paired with the relatively low demand on the environment ''Artemisia annua'' can have characteristics of a neophytic plant. ''A. annua'' is best sown in rows to facilitate removal of weeds, which has to be done mechanically or manually because
herbicide Herbicides (, ), also commonly known as weedkillers, are substances used to control undesired plants, also known as weeds.EPA. February 201Pesticides Industry. Sales and Usage 2006 and 2007: Market Estimates. Summary in press releasMain page fo ...
s are typically not used. It is recommended to sow 1.4 – 2 seeds per square meter. The fertilizer requirements are on a low level. Potassium should be used as base fertilizer. It is taken up by the plant during the whole growing season. Nitrogen is required during early branching stages, an amount of approximately 70 kg N/ha is sufficient for the plant. Phosphate on the other hand is required during the blooming stages. Phosphate fertilization can lead to a higher artemsinin content in the leaves. The application of salicylic acid on the leaves shortly before harvesting the plant also can raise its artemisinin content. Besides few viral diseases ''Artemisia a.'' has no major diseases that need to be controlled. The harvest of the plant is best done in the state of flower budding. The whole plant is harvested and cut into branches which are dried in the sun or in an oven. The drying temperature should not exceed 40 °C. The dry branches are shaken or beaten to separate the leaves from the stem. The leaves are then packed into fabric bags and shipped to further processing. It is important that the temperatures during transportation and storage never get higher than 40 °C, otherwise artemisinin gets volatile and is lost into the air. The leaves should not be crushed before long time storage (one year). The optimal storage conditions are either 20 °C with 85% relative humidity (RH) or 30 °C with 30–40% RH.


Artemisinin and other phytochemicals

In 1971, scientists demonstrated the plant extracts had antimalarial activity in primate models, and in 1972, the active ingredient, artemisinin (formerly referred to as arteannuin), was isolated and its chemical structure described. Artemisinin may be extracted using a low boiling point solvent, such as
diethylether Diethyl ether, or simply ether, is an organic compound in the ether class with the formula , sometimes abbreviated as (see Pseudoelement symbols). It is a colourless, highly volatile, sweet-smelling ("ethereal odour"), extremely flammable liq ...
, and is found in the glandular trichomes of the leaves, stems, and inflorescences, and is concentrated in the upper portions of plant within new growth. The first isolation of artemisinin from the herb occurred from a military project known as Project 523, following the study of traditional medicine pharmacopoeias performed by Tu Youyou and other researchers within the project. ''A. annua'' contains diverse
phytochemical Phytochemicals are chemical compounds produced by plants, generally to help them resist fungi, bacteria and plant virus infections, and also consumption by insects and other animals. The name comes . Some phytochemicals have been used as poisons ...
s, including polyphenols such as coumarins,
flavone Flavone is an organic compound with the formula . A white solid, flavone is a derivative of chromone with a phenyl (Ph) substituent adjacent to the ether group. The compound is of little direct practical importance, but susbstituted derivatives, t ...
s, flavonols, and phenolic acids which have unknown biological properties in vivo. Other phytochemicals include 38 sesquiterpenes.
Dihydroartemisinin Dihydroartemisinin (also known as dihydroqinghaosu, artenimol or DHA) is a drug used to treat malaria. Dihydroartemisinin is the active metabolite of all artemisinin compounds (artemisinin, artesunate, artemether, etc.) and is also available as ...
is the active
metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...
of artemisinin, and artesunate is a water-soluble derivative of artemisinin.


Malaria treatment

Research to develop antimalarial drugs led to the discovery of artemisinin in the 1970s by Chinese scientist, Tu Youyou, who shared the 2015 Nobel Prize in Physiology or Medicine. An improved extract was obtained by using a low-temperature, ether-based extraction method, further showing the artemisinin derivative, artemether, to be an effective antimalarial drug. Artemisinin is a sesquiterpene lactone with an
endoperoxide In organic chemistry, organic peroxides are organic compounds containing the peroxide functional group (). If the R′ is hydrogen, the compounds are called hydroperoxides, which are discussed in that article. The O−O bond of peroxides easily b ...
bridge and has been produced as an antimalarial drug. The efficacy of tea, made with either water or urine and ''A. annua'', for the treatment of malaria is dubious, and is discouraged by the World Health Organization (WHO). Research has found that artemisinin is not soluble in water and the concentrations in these infusions are considered insufficient to treat malaria. A 2012 review stated that artemisinin-based remedies are the most effective drugs for the treatment of malaria. A 2013 review suggested that although ''Artemisia annua'' may not cause hepatotoxicity, haematotoxicity, or hyperlipidemia, it should be used cautiously during pregnancy due to a potential risk of embryotoxicity at a high dose. The WHO has approved
riamet Artemether/lumefantrine, sold under the trade name Coartem among others, is a combination of the two medications artemether and lumefantrine. It is used to treat malaria caused by ''Plasmodium falciparum'' that is not treatable with chloroquine ...
(Coartem), a combination of
lumefantrine Lumefantrine (or benflumetol) is an antimalarial drug. It is only used in combination with artemether. The term "co-artemether" is sometimes used to describe this combination. Lumefantrine has a much longer half-life compared to artemether, and i ...
(120 mg) and artemether (an artemisinin derivative extracted with ether, 20 mg) in repeat treatments over two days, producing efficacy of up to 98% against malaria.


Mechanism

The proposed mechanism of action of artemisinin involves cleavage of endoperoxide bridges by iron, producing
free radicals In chemistry, a radical, also known as a free radical, is an atom, molecule, or ion that has at least one unpaired valence electron. With some exceptions, these unpaired electrons make radicals highly chemically reactive. Many radicals spont ...
( hypervalent iron-oxo species,
epoxides In organic chemistry, an epoxide is a cyclic ether () with a three-atom ring. This ring approximates an equilateral triangle, which makes it strained, and hence highly reactive, more so than other ethers. They are produced on a large scale for ...
, aldehydes, and dicarbonyl compounds) which damage biological macromolecules causing oxidative stress in the cells of the malaria parasite. Malaria is caused by
apicomplexan The Apicomplexa (also called Apicomplexia) are a large phylum of parasitic alveolates. Most of them possess a unique form of organelle that comprises a type of non-photosynthetic plastid called an apicoplast, and an apical complex structure. The ...
s, primarily ''
Plasmodium falciparum ''Plasmodium falciparum'' is a Unicellular organism, unicellular protozoan parasite of humans, and the deadliest species of ''Plasmodium'' that causes malaria in humans. The parasite is transmitted through the bite of a female ''Anopheles'' mosqu ...
'', which largely reside in
red blood cells Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek language, Greek ''erythros'' for "red" and ''k ...
and contain iron-rich heme-groups (in the form of
hemozoin Haemozoin is a disposal product formed from the digestion of blood by some blood-feeding parasites. These hematophagous organisms such as malaria parasites (''Plasmodium spp.''), ''Rhodnius'' and ''Schistosoma'' digest haemoglobin and release high ...
). In 2015, artemisinin was shown to bind to a large number cell targets, indicating its potential for diverse effects.


Artemisinin resistance

Despite global efforts in combating malaria, it remains a large burden for the population, particularly in tropical and subtropical regions. As of 2013, it seems that the pathogenic agent of malaria is becoming resistant to artemisinin-based drugs. Emergence of artemisinin resistance has been identified in Cambodia and the border of Thailand. Although the WHO recommends artemisinin-based remedies for treating uncomplicated malaria, artemisinin resistance has become a concern. The causes that affected the emergence of artemisinin resistance include the use of artemisinin-based remedies. Encouraging herbal alternatives are in the pipeline, but a more dependable solution for the eradication of malaria would be the creation of an effective vaccination. Resistance will likely spread to other endemic areas across the world.


Traditional medicine

In traditional Chinese medicine (TCM), ''A. annua'' is prepared with hot water to treat fever. Due to duplication in ancient TCM sources, ''A. annua'' is more commonly referred to as ''qinghao'' (), the modern Chinese name for ''
Artemisia carvifolia Artemisia may refer to: People * Artemisia I of Caria (fl. 480 BC), queen of Halicarnassus under the First Persian Empire, naval commander during the second Persian invasion of Greece * Artemisia II of Caria (died 350 BC), queen of Caria under th ...
'', as opposed to its current Chinese name ''huanghuahao''.


References


External links


Distribution of artemisinin in ''Artemisia annua''Project to improve artemesinin yield at the University of York (UK)Data sheet about ''Artemisia annua''
from Purdue University {{Taxonbar, from=Q1308044 annua Medicinal plants of Asia Flora of Asia Plants described in 1753 Taxa named by Carl Linnaeus