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Artemisia annua

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"Sweet annie" redirects here. For the song, see Sweet Annie.

Artemisia annua
Scientific classification Edit this classification
Kingdom: Plantae
Clade: Tracheophytes
Clade: Angiosperms
Clade: Eudicots
Clade: Asterids
Order: Asterales
Family: Asteraceae
Genus: Artemisia
Species:
A. annua
Binomial name
Artemisia annua
Synonyms[1]

Artemisia chamomilla C.Winkl.

Artemisia annua, also known as sweet wormwood,[2] sweet annie, sweet sagewort, annual mugwort[3] or annual wormwood, is a common type of wormwood native to temperate Asia, but naturalized in many countries including scattered parts of North America.[4][5][6][7]

An extract of A. annua, called artemisinin (or artesunate), is a medication used to treat malaria.[8] Discovery of artemisinin and its antimalarial properties by the Chinese scientist Tu Youyou led to the award of the 2011 Lasker Prize and 2015 Nobel Prize in Physiology or Medicine.[9]

Description

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Artemisia annua belongs to the plant family of Asteraceae and is an annual short-day plant. Its stem is erect and brownish or violet-brown. The plant itself is hairless and naturally grows from 30 to 100 cm tall, although in cultivation plants can 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.[10] The artemisinin content in dried leaves is in between 0% and 1.5%.[11] New hybrids of Artemisia annua developed in Switzerland can reach a leaf artemisinin content of up to 2%.[12] Also, four new genotypes developed by a collaboration between the USDA and Purdue University with 2% leaf artemisinin were recently released for researchers involved in the production of artemisinin.[13] The small flowers have a diameter of 2–2.5 mm and are arranged in loose panicles. Their color is greenish-yellow. 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).[10][14]

Agricultural practice

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Artemisia annua
Seeds

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 highest.[11] Dry leaf yields of Artemisia annua plantations vary between 0.5 and 3 tonnes per hectare.[12]

Growth Phases[11] Days after sowing
Seed germination 4–10
Appearance of 1st pair of leaves 15–30
Appearance of 2nd pair of leaves 21–50
Branching 60–90
Cessation of growth in height 170–200
Flowering 190–240
Full fruition 230–280
Withering 260–310

In terms of the climate A. annua prefers sunny and warm conditions. Its optimal growth temperature lies between 20 and 25 °C. Annual temperature sums of 3500–5000 °C (sum of temperatures higher than 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 than 1150 mm). Especially the seedlings of A. annua. are susceptible to drought or water logging. 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.[11] 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.[15]

A. annua is best sown in rows to facilitate the removal of weeds, which has to be done mechanically or manually because herbicides are typically not used. It is recommended to sow 1.4 – 2 seeds per square meter.[12] The fertilizer requirements are at a low level. Potassium should be used as base fertilizer. It is taken up by the plant during the whole growing season.[11] Nitrogen is required during early branching stages, an amount of approximately 70 kg N/ha is sufficient for the plant.[16] Phosphate on the other hand is required during the blooming stages. Phosphate fertilization can lead to a higher artemisinin content in the leaves.[17] The application of salicylic acid to the leaves shortly before harvesting the plant also can raise its artemisinin content.[18] Besides few viral diseases, Artemisia a. has no major diseases that need to be controlled.

The harvest of the plant is best done when plants reach peak artemisinin, which may be in the state of flower budding, for early-flowering cultivars. However, for late flowering cultivars that were reported to reach peak artemisinin in early September in the United States, the harvest will happen about a month before the flowering stage when plants produce more artemisinin in leaves. This peak artemisinin in early September was observed for Brazilian, Chinese, and Swiss clones in West Virginia.[19] Drying the plants before extraction will significantly increase artemisinin as dihydroartemisinic acid and artemisinic acid seem to be converted into artemisinin.[20] The whole plant is harvested and cut into branches which are dried in the sun or an oven. Some report that drying artemisia plants at 45 °C for 24h increased artemisinin and maintained leaf antioxidant capacity.[21] The dry branches are shaken or beaten to separate the leaves from the stem. The leaves are then packed into fabric bags and shipped for further processing.[11] The optimum storage conditions are either 20 °C with 85% relative humidity (RH) or 30 °C with 30–40% RH.[11]

Artemisinin and other phytochemicals

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In 1971, scientists demonstrated that 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.[8][22] Artemisinin may be extracted using a low-boiling-point solvent, such as diethylether, is found in the glandular trichomes of the leaves, stems, and inflorescences, and is concentrated in the upper portions of plants within new growth.[8][23]

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.[24] A. annua contains diverse phytochemicals, including polyphenols such as coumarins, flavones, flavonols, and phenolic acids which have unknown biological properties in vivo.[25][26] Other phytochemicals include 38 sesquiterpenes.[8] Dihydroartemisinin is the active metabolite of artemisinin, and artesunate is a water-soluble derivative of artemisinin.[8]

Malaria treatment

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Research to develop antimalarial drugs led to the discovery of artemisinin in the 1970s by the Chinese scientist Tu Youyou, who shared the 2015 Nobel Prize in Physiology or Medicine.[9][22][27] 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.[8][22]

Artemisinin is a sesquiterpene lactone with an endoperoxide bridge and has been produced as an antimalarial drug.[8] 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).[11][28] Research has found that artemisinin is not soluble in water and the concentrations in these infusions are considered insufficient to treat malaria.[29][30][31] A 2012 review stated that artemisinin-based remedies are the most effective drugs for the treatment of malaria.[32] A 2013 review suggested that although Artemisia annua may not cause hepatotoxicity, haematotoxicity, or hyperlipidemia, it should be used cautiously during pregnancy owing to a potential risk of embryotoxicity at a high dose.[33]

The WHO has approved riamet (Coartem), a combination of lumefantrine (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.[8]

Mechanism

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The proposed mechanism of action of artemisinin involves cleavage of endoperoxide bridges by iron, producing free radicals (hypervalent iron-oxo species, epoxides, aldehydes, and dicarbonyl compounds) which damage biological macromolecules causing oxidative stress in the cells of the malaria parasite.[8][34] Malaria is caused by apicomplexans, primarily Plasmodium falciparum, which largely reside in red blood cells and contain iron-rich heme-groups (in the form of hemozoin).[8][35] In 2015, artemisinin was shown to bind to a large number of cell targets, indicating its potential for diverse effects.[36]

Artemisinin resistance

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Despite global efforts in combating malaria, it remains a large burden for the population, particularly in tropical and subtropical regions.[8][37] As of 2013, it seems that the pathogenic agent of malaria is becoming resistant to artemisinin-based drugs.[38][39] Emergence of artemisinin resistance has been identified in Cambodia and the border of Thailand.[40] Although the WHO recommends artemisinin-based remedies for treating uncomplicated malaria, artemisinin resistance has become a concern.[37] The causes that affected the emergence of artemisinin resistance include the use of artemisinin-based remedies.[37] 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.[37] Resistance will likely spread to other endemic areas across the world.[40]

Traditional medicine

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In traditional Chinese medicine (TCM), A. annua is prepared with hot water to treat fever.[8][27] Owing to duplication in ancient TCM sources, A. annua is more commonly referred to as qinghao (Chinese: 青蒿; pinyin: qīnghāo), the modern Chinese name for Artemisia carvifolia, as opposed to its current Chinese name huanghuahao.[41]

References

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  1. ^ The Plant List Artemisia annua L.
  2. ^ English Names for Korean Native Plants (PDF). Pocheon: Korea National Arboretum. 2015. p. 359. ISBN 978-89-97450-98-5. Archived from the original (PDF) on 25 May 2017. Retrieved 25 January 2016 – via Korea Forest Service.
  3. ^ BSBI List 2007 (xls). Botanical Society of Britain and Ireland. Archived from the original (xls) on 2015-06-26. Retrieved 2014-10-17.
  4. ^ Flora of China Vol. 19, 20 and 21 Page 523 Sweet Annie, sweet sagewort, armoise annuelle Artemisia annua Linnaeus, Sp. Pl. 2: 847. 1753.
  5. ^ Flora of China Vol. 20–21 Page 691 黄花蒿 huang hua hao Artemisia annua Linnaeus, Sp. Pl. 2: 847. 1753
  6. ^ Flora of Pakistan
  7. ^ Altervista Flora Italiana, Assenzio annuale Artemisia annua L.[permanent dead link‍]
  8. ^ a b c d e f g h i j k l "Sweet wormwood (Artemisia annua L.)". Drugs.com. 23 March 2020. Retrieved 20 December 2020.
  9. ^ a b "Youyou Tu – Facts and biography: The Nobel Prize in Physiology or Medicine 2015". The Nobel Foundation. 2015. Retrieved 20 December 2020.
  10. ^ a b "Artemisia annua (sweet wormwood)". Royal Botanic Gardens. Archived from the original on October 6, 2015. Retrieved November 25, 2015.
  11. ^ a b c d e f g h WHO monograph on good agricultural and collection practices (GACP) for Artemisia annua L. (PDF). World Health Organization. 2006.
  12. ^ a b c Simonnet, X.; Quennoz, M.; Carlen, C. (2006). "New Artemisia annua hybrids with high artemisinin content". XXVII International Horticultural Congress-IHC2006: International Symposium on Asian Plants with Unique Horticultural 769: 371–373.
  13. ^ Wetzstein, Hazel Y.; Janick, Jules; Ferreira, Jorge F. S. (2019-11-01). "Germplasm Release of Four High-artemisinin Clones of Artemisia annua L." HortScience. 54 (11): 2081–2082. doi:10.21273/HORTSCI14385-19. ISSN 0018-5345.
  14. ^ Forestry, Government of Alberta, Alberta Agriculture and (1993-09-01). "Using 1,000 Kernel Weight for Calculating Seeding Rates and Harvest Losses". www1.agric.gov.ab.ca. Retrieved 2015-11-15.{{cite web}}: CS1 maint: multiple names: authors list (link)
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  18. ^ Pu, Gao-Bin; et al. (2009). "Salicylic acid activates artemisinin biosynthesis in Artemisia annua L". Plant Cell Reports. 28 (7): 1127–1135. doi:10.1007/s00299-009-0713-3. PMID 19521701. S2CID 29237295.
  19. ^ Ferreira, Jorge F. S.; Benedito, Vagner A.; Sandhu, Devinder; Marchese, José A.; Liu, Shuoqian (2018-08-13). "Seasonal and Differential Sesquiterpene Accumulation in Artemisia annua Suggest Selection Based on Both Artemisinin and Dihydroartemisinic Acid may Increase Artemisinin in planta". Frontiers in Plant Science. 9. doi:10.3389/fpls.2018.01096. ISSN 1664-462X. PMC 6102481. PMID 30154807.
  20. ^ Ferreira, Jorge F. S.; Luthria, Devanand L. (2010-02-10). "Drying Affects Artemisinin, Dihydroartemisinic Acid, Artemisinic Acid, and the Antioxidant Capacity of Artemisia annua L. Leaves". Journal of Agricultural and Food Chemistry. 58 (3): 1691–1698. doi:10.1021/jf903222j. ISSN 0021-8561. PMID 20050663.
  21. ^ Ferreira, Jorge F. S.; Luthria, Devanand L. (2010-02-10). "Drying Affects Artemisinin, Dihydroartemisinic Acid, Artemisinic Acid, and the Antioxidant Capacity of Artemisia annua L. Leaves". Journal of Agricultural and Food Chemistry. 58 (3): 1691–1698. doi:10.1021/jf903222j. ISSN 0021-8561. PMID 20050663.
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  23. ^ Duke SO, Paul RN (1993). "Development and Fine Structure of the Glandular Trichomes of Artemisia annua L.". Int. J. Plant Sci. 154 (1): 107–18. doi:10.1086/297096. JSTOR 2995610. S2CID 86584892.
    Ferreira JF, Janick J (1995). "Floral Morphology of Artemisia annua with Special Reference to Trichomes". Int. J. Plant Sci. 156 (6): 807. doi:10.1086/297304. S2CID 84594350.
  24. ^ Tom Phillips (October 6, 2015). "Tu Youyou: how Mao's challenge to malaria pioneer led to the Nobel prize". The Guardian.
  25. ^ Ferreira, Jorge F. S.; Luthria, Devanand L.; Sasaki, Tomikazu; Heyerick, Arne (2010-04-29). "Flavonoids from Artemisia annua L. as antioxidants and their potential synergism with artemisinin against malaria and cancer". Molecules. 15 (5): 3135–3170. doi:10.3390/molecules15053135. PMC 6263261. PMID 20657468.
  26. ^ Nahar, Lutfun; Guo, Mingquan; Sarker, Satyajit D. (2019). "A review on the latest advances in extraction and analysis of artemisinin (Review)" (PDF). Phytochemical Analysis. 31 (1): 5–14. doi:10.1002/pca.2873. ISSN 0958-0344. PMID 31370102. S2CID 199382005.
  27. ^ a b "Hard to swallow". Nature. 448 (7150): 105–6. 2007. Bibcode:2007Natur.448S.105.. doi:10.1038/448106a. PMID 17625521.
  28. ^ van der Kooy F, Sullivan SE (2013). "The complexity of medicinal plants: the traditional Artemisia annua formulation, current status and future perspectives". J Ethnopharmacol (Review). 150 (1): 1–13. doi:10.1016/j.jep.2013.08.021. PMID 23973523.
  29. ^ Mueller, Markus S; Runyambo, Nyabuhanga; Wagner, Irmela; Borrmann, Steffen; Dietz, Klaus; Heide, Lutz (2004). "Randomized controlled trial of a traditional preparation of Artemisia annua L. (Annual Wormwood) in the treatment of malaria". Trans R Soc Trop Med Hyg. 98 (5): 318–21. doi:10.1016/j.trstmh.2003.09.001. PMID 15109558.
  30. ^ Räth, K; Taxis, K; Walz, G; Gleiter, CH; Li, SM; Heide, L (1 February 2004). "Pharmacokinetic study of artemisinin after oral intake of a traditional preparation of Artemisia annua L. (annual wormwood)". Am J Trop Med Hyg. 70 (2): 128–32. doi:10.4269/ajtmh.2004.70.128. PMID 14993622.
  31. ^ Jansen FH (2006). "The herbal tea approach for artemesinin as a therapy for malaria?". Trans R Soc Trop Med Hyg. 100 (3): 285–6. doi:10.1016/j.trstmh.2005.08.004. PMID 16274712.
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  33. ^ Abolaji, AO; Eteng, MU; Ebong, PE; Brisibe, EA; Dar, A; Kabir, N; Choudhary, MI (2013). "A safety assessment of the antimalarial herb Artemisia annua during pregnancy in Wistar rats". Phytotherapy Research. 27 (5): 647–54. doi:10.1002/ptr.4760. PMID 22736625. S2CID 22650085.
  34. ^ Cumming JN; Ploypradith P; Posner GH (1996). Antimalarial Activity of Artemisinin (Qinghaosu) and Related Trioxanes: Mechanism (S) of Action. Advances in Pharmacology. Vol. 37. pp. 253–97. doi:10.1016/S1054-3589(08)60952-7. ISBN 9780120329380. PMID 8891104.
  35. ^ Gary H. Posner & Paul M. O’Neil (2004). "Knowledge of the Proposed Chemical Mechanism of Action and Cytochrome P450 Metabolism of Antimalarial Trioxanes Like Artemisinin Allows Rational Design of New Antimalarial Peroxides". Acc. Chem. Res. 37 (6): 397–404. doi:10.1021/ar020227u. PMID 15196049.
  36. ^ Wang J, Zhang CJ, Chia WN, Loh CC, Li Z, Lee YM, He Y, Yuan LX, Lim TK, Liu M, Liew CX, Lee YQ, Zhang J, Lu N, Lim CT, Hua ZC, Liu B, Shen HM, Tan KS, Lin Q (2015). "Haem-activated promiscuous targeting of artemisinin in Plasmodium falciparum". Nature Communications. 6: 10111. Bibcode:2015NatCo...610111W. doi:10.1038/ncomms10111. PMC 4703832. PMID 26694030.
  37. ^ a b c d Chrubasik, C; Jacobson, RL (2010). "The development of artemisinin resistance in malaria: Reasons and solutions". Phytotherapy Research. 24 (7): 1104–6. doi:10.1002/ptr.3133. PMID 20578122. S2CID 37901416.
  38. ^ News published on the Center for Strategic and International Studies website (Nov. 7, 2013)
  39. ^ Tulloch, Jim; David, Benedict; Newman, Robert D; Meek, Sylvia (2013). "Artemisinin-resistant malaria in the Asia-Pacific region". The Lancet. 381 (9881): e16–7. doi:10.1016/S0140-6736(12)61820-0. PMID 23122219. S2CID 1814045.
  40. ^ a b Na-Bangchang, K; Karbwang, J (2013). "Emerging artemisinin resistance in the border areas of Thailand". Expert Review of Clinical Pharmacology. 6 (3): 307–22. doi:10.1586/ecp.13.17. PMID 23656342. S2CID 207210000.
  41. ^ Liu, Artemisia (2015-10-09). "【2015诺贝尔奖】青蒿素、青蒿、黄花蒿，究竟什么关系？" [2015 Nobel: Artemisinin, qinghao, and huanghuahao, how are they related?] (in Chinese). guokr. Retrieved 19 January 2017.
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