Artemisinin - Wiki

Artemisinin - Wikipedia, the free encyclopedia
http://en.wikipedia.org/wiki/Artemisinin
Artemisinin
From Wikipedia, the free encyclopedia
Artemisinin /rtmsnn/, also known as Qinghaosu (Chinese: ), and its derivatives are a group of
drugs that possess the most rapid action of all current drugs against Plasmodium falciparum malaria.[1]
Treatments containing an artemisinin derivative (artemisinin-combination therapies, ACTs) are now standard
treatment worldwide for P. falciparum malaria. Artemisinin is isolated from the plant Artemisia annua, sweet
wormwood, a herb employed in Chinese traditional medicine. It can now also be produced using genetically
engineered yeast.
Artemisinin
Chemically, artemisinin is a sesquiterpene lactone containing an unusual peroxide bridge. This peroxide is
believed to be responsible for the drug's mechanism of action. Few other natural compounds with such a
peroxide bridge are known.[2]
Use of the drug by itself as a monotherapy is explicitly discouraged by the World Health Organization, as
there have been signs that malarial parasites are developing resistance to the drug. Therapies that combine
artemisinin with some other antimalarial drug are the preferred treatment for malaria and are both effective
and well tolerated in patients. The drug is also increasingly being used in Plasmodium vivax malaria,[3] as well
as being a topic of research in cancer treatment.
Systematic (IUPAC) name

(3R,5aS,6R,8aS,9R,12S,12aR)-Octahydro-3,6,9-trimethyl3,12-epoxy-12H-pyrano[4,3-j]-1,2-benzodioxepin-10(3H)-one
Clinical data
Contents
Legal status
Routes
Oral
Identifiers
1 History
1.1 Etymology
1.2 Discovery
2 Artemisinin derivatives
3 Indications
3.1 Uncomplicated malaria
3.2 Severe malaria
3.3 Cancer treatment
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CAS number
63968-64-9
ATC code
P01BE01
PubChem
CID 68827
ChemSpider
62060
UNII
9RMU91N5K2
KEGG
D02481
ChEBI
CHEBI:223316
2014/11/05 09:26 PM
3.4 Helminth parasites

4 Resistance
ChEMBL
CHEMBL77
Synonyms
Artemisinine, Qinghaosu
5 Adverse effects
Chemical data
6 Mechanism of action
Formula
C15H22O5
7 Dosing
Mol. mass
282.332 g/mol
8 Production and price
SMILES
9 Synthesis
InChI
9.1 Biosynthesis in A. annua
Physical data
9.2 Chemical synthesis
Density
1.24 0.1 g/cm
9.3 Synthesis in engineered organisms
Melt. point
152157 C (306315 F)
10 References
(what is this?) (verify)
11 External links
History
Etymology
Artemisinin is an antimalarial lactone derived from qing hao (Artemisia annua or sweet wormwood). The medicinal value of this plant has been known to
the Chinese for at least 2,000 years. In 1596, Li Shizhen recommended tea made from qing hao specifically to treat malaria symptoms in his "Compendium of
Materia Medica". The genus name is derived from the Greek goddess Artemis and, more specifically, may have been named after Queen Artemisia II of Caria, a
botanist and medical researcher in the fourth century bce.[4]
Discovery
Artemisia annua (A. annua) is a common herb found in many parts of the world, and has been used by Chinese herbalists for more than two thousand years in
the treatment of malaria. The earliest record dates back to 200 BC, in the "Fifty-two Prescriptions" unearthed from the Mawangdui Han Dynasty tombs.[5] Its
antimalarial application was first described, in Zhouhou Beiji Fang ("The Handbook of Prescriptions for Emergencies", Chinese: ), edited in the
middle of the fourth century by Ge Hong; in that book, 43 malaria treatment methods were recorded.[6] Images of the original scientific papers that record the
history of the discovery, have been available online since 2006.[7]
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In 1967, a plant screening research program, under the name Project 523, was set up by the Chinese army to find an adequate
treatment for malaria; the program and early clinical work were ordered of Chairman Mao Zedong at the request of North
Vietnamese leaders to provide assistance for their malaria-ridden army.[8] In the course of this research, Tu Youyou
discovered artemisinin in the leaves of Artemisia annua (annual wormwood; 1972).[9] The drug is named Qinghaosu (Chinese:
) in Chinese. It was one of many candidates tested as possible treatments for malaria by Chinese scientists, from a list of nearly
5000 traditional Chinese medicines. Tu Youyou also discovered that a low-temperature extraction process could be used to isolate
an effective antimalarial substance from the plant; Tu says she was influenced by a traditional Chinese herbal medicine source
saying that this herb should be steeped in cold water.[10] The extracted substance, once subject to purification, proved to be a usable
antimalarial drug.[11] A 2012 review reported that artemisinin-based therapies were the most effective drugs for treatment of malaria
at that time;[12] it was also reported to clear malaria parasites from patients' bodies faster than other drugs. In addition to artemisinin,
Project 523 developed a number of products that can be used in combination with artemisinin, including lumefantrine, piperaquine,
and pyronaridine.[9]
Artemisia annua
For many years after the discovery, access to the purified drug and the plant from which it was extracted were restricted by the
Chinese government. It was not until the Chinese economic reform in the late 1970s and early 1980s that news of the discovery reached scientists outside China
via results published in the Chinese Medical Journal (in 1979).[13] Ying Lee, one of the scientists involved in the research into artemisinin, said the Chinese had
distrusted the West at the time. The research was met with skepticism at first, partly because the chemical structure of artemisinin, particularly the peroxide
portion, appeared to be too unstable to be a viable drug.[2]
In the late 1990s, Novartis bought a new Chinese patent for a combination treatment with artemether and lumefantrine, providing the first artemisinin-based
combination therapies (ACTs) (Coartem) at reduced prices to the World Health Organisation.[14] In 2006, after artemisinin had become the treatment of choice
for malaria, the WHO called for an immediate halt to single-drug artemisinin preparations in favor of combinations of artemisinin with another malaria drug, to
reduce the risk of parasites developing resistance.[15]
In 2011, Tu Youyou was awarded the prestigious Lasker-DeBakey Clinical Medical Research Award for her role in the discovery and development of
artemisinin.[9][16] The New York Times notes that the discovery of artemisinin is under consideration for a future Nobel Prize in Physiology or Medicine.[17]
Artemisinin derivatives
Because artemisinin itself has physical properties such as poor bioavailability that limit its effectiveness, semisynthetic derivatives of artemisinin have been
developed. These include:
Artesunate (water-soluble: for oral, rectal, intramuscular, or intravenous use)
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Artemether (lipid-soluble: for oral, rectal or intramuscular use)

Dihydroartemisinin
Artelinic acid
Artemotil
There are also simplified analogs in preclinical research.[18]
A synthetic compound with a similar trioxolane structure (ring containing three oxygen atoms) named arterolane[19] showed promise in in vitro testing. Phase II
testing in patients with malaria was not as successful as hoped, but the manufacturer decided to start Phase III testing anyway.[20] A combination with
piperaquine is also in development.
Indications
Uncomplicated malaria
Artemisinins can be used alone, but this leads to a high rate of recrudescence (return of parasites) and other drugs are required to clear the body of all parasites
and prevent recurrence. The World Health Organization (WHO) is pressuring manufacturers to stop making the uncompounded drug available to the medical
community at large, aware of the catastrophe that would result if the malaria parasite developed resistance to artemisinins.[21]
The WHO has recommended artemisinin combination therapies (ACT) be the first-line therapy for P. falciparum malaria worldwide.[22] Combinations are
effective because the artemisinin component kills the majority of parasites at the start of the treatment, while the more slowly eliminated partner drug clears the
remaining parasites.[23]
Several fixed-dose ACTs are now available containing an artemisinin component and a partner drug which has a long half-life, such as mefloquine (ASMQ[24]),
lumefantrine (Coartem), amodiaquine (ASAQ), piperaquine (Duo-Cotecxin), and pyronaridine (Pyramax). Increasingly, these combinations are being made to
GMP standard. A separate issue concerns the quality of some artemisinin-containing products being sold in Africa and Southeast Asia.[25][26]
Artemisinins are not used for malaria prophylaxis (prevention) because of the extremely short activity (half-life) of the drug. To be effective, it would have to be
administered multiple times each day.
Severe malaria
Artesunate administered by intravenous or intramuscular injection has proven superior to quinine in large, randomised controlled trials in both adults [27] and
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children.[28] Combining all trials comparing these two drugs, artesunate is associated with a mortality rate that is approximately 30% lower than that of
quinine.[28] Reasons for this difference include reduced incidence of hypoglycaemia, easier administration and more rapid action against circulating and
sequestered parasites. Artesunate is now recommended by the WHO for treatment of all cases of severe malaria.
Cancer treatment
Artemisinin is undergoing early research and testing for the treatment of cancer.[29] Artemisinin has anticancer effects in experimental models of hepatocellular
carcinoma.[30] Artemisinin has a peroxide lactone group in its structure, and it is thought that when the peroxide comes into contact with high iron concentrations
(common in cancerous cells), the molecule becomes unstable and releases reactive oxygen species. It has been shown to reduce angiogenesis and the expression
of vascular endothelial growth factor in some tissue cultures. Recent pharmacological evidence demonstrates the artemisinin derivative dihydroartemisinin
targets human metastatic melanoma cells in vitro with induction of phorbol-12-myristate-13-acetate-induced protein 1 dependent mitochondrial apoptosis that
occurs downstream of iron-dependent generation of cytotoxic oxidative stress.[31]
Helminth parasites
Serendipitous discovery was made in China while searching for novel anthelmintics for schistosomiasis. Artemisinin was effective against schistosomes, the
human blood flukes, which are the second-most prevalent parasitic infections, after malaria. Artemisinin and its derivatives are all potent anthelmintics.[32]
Artemisinins were later found to possess a broad spectrum of activity against a wide range of trematodes, including Schistosoma japonicum, S. mansoni, S.
haematobium, Clonorchis sinensis, Fasciola hepatica, and Opisthorchis viverrini. Clinical trials were also successfully conducted in Africa among patients with
schistosomiasis.[33] A randomized, double-blind, placebo-controlled trial also revealed the efficacy against schistosome infection in Cte d'Ivoire[34] and
China.[35]
Resistance
Clinical evidence for artemisinin resistance in southeast Asia was first reported in 2008,[36] and was subsequently confirmed by a detailed study from western
Cambodia.[37] Resistance in neighbouring Thailand was reported in 2012,[38] and in Northern Cambodia, Vietnam and Eastern Myanmar in 2014.[39][40]
Emerging resistance was reported in Southern Laos, central Myanmar and North-Eastern Cambodia in 2014.[39][40] The parasite's kelch gene on chromosome 13
appears to be a reliable molecular marker for clinical resistance in southeast Asia.[41]
In April 2011, the WHO stated that resistance to the most effective antimalarial drug, artemisinin, could unravel national (India) malaria control programs, which
have achieved significant progress in the last decade. WHO advocates the rational use of antimalarial drugs and acknowledges the crucial role of community
health workers in reducing malaria in the region.[42]
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Adverse effects
Artemisinins are generally well tolerated at the doses used to treat malaria.[43] The side effects from the artemisinin class of medications are similar to the
symptoms of malaria: nausea, vomiting, anorexia, and dizziness. Mild blood abnormalities have also been noted. A rare but serious adverse effect is allergic
reaction.[43][44] One case of significant liver inflammation has been reported in association with prolonged use of a relatively high-dose of artemisinin for an
unclear reason (the patient did not have malaria).[45] The drugs used in combination therapies can contribute to the adverse effects experienced by those
undergoing treatment. Adverse effects in patients with acute P. falciparum malaria treated with artemisinin derivatives tend to be higher.[46]
Mechanism of action
Most artemisinins used today are prodrugs of the biologically active metabolite dihydroartemisinin, which is active during the stage when the parasite is located
inside red blood cells. Although there is no consensus regarding the mechanism through which artemisinin derivatives kill the parasites,[47] several lines of
evidence indicate that artemisinins exert their antimalarial action by radical formation that depends on their endoperoxide bridge. When the parasite that causes
malaria infects a red blood cell, it consumes hemoglobin within its digestive vacuole, a process that generates oxidative stress.[48] In one theory of the mechanism
of action the iron of the heme directly reduces the peroxide bond in artemisinin, generating high-valent iron-oxo species and resulting in a cascade of reactions
that produce reactive oxygen radicals which damages the parasite and lead to its death.[49] However, the likelihood of this mechanism has been debated.[50] A
more recently described alternative is that artemisinins disrupt cellular redox cycling.[51] Artesunate has been shown to potently inhibit the essential Plasmodium
falciparum exported protein 1 (EXP1), a membrane glutathione S-transferase.[52]
Numerous studies have investigated the type of damage oxygen radicals may induce. For example, Pandey et al. have observed inhibition of digestive vacuole
cysteine protease activity of malarial parasites by artemisinin.[53] These observations were supported by ex vivo experiments showing accumulation of
hemoglobin in the parasites treated with artemisinin and inhibition of hemozoin formation by malaria parasites, although this inhibition was not seen in an in vitro
B-hematin inhibition assay.[54] Electron microscopic evidence linking artemisinin action to the parasite's digestive vacuole has been obtained showing that the
digestive vacuole membrane suffers damage soon after parasites are exposed to artemisinin.[55] This would also be consistent with data showing that the digestive
vacuole is already established by the mid-ring stage of the parasite's blood cycle,[56] a stage that is sensitive to artemisinins but not other antimalarials. However,
fluorescently tagged artemisinin was seen in the Golgi, ER and mitochondria, rather than the digestive vacuole, suggesting that the vacuolar damage may be a
downstream effect, and also that tiny ring stages (containing minimal digested material) are highly susceptible to artemisinins.[57][58][59]
Other suggested targets include the mitochondrial electron transport chain [60] and the parasite's SERCA pump (PfATP6/PfSERCA);[61] neither theory has
gained widespread acceptance.
Dosing
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Artemisinin derivatives have half-lives of the order of an hour, and therefore require at least daily dosing over several days. For example, the WHO-approved
adult dose of co-artemether (artemether-lumefantrine) is 4 tablets at 0, 8, 24, 36, 48 and 60 hours (six doses).[62][63]
Artemisinin is not soluble in water, therefore Artemisia annua tea was postulated not to contain pharmacologically significant amounts of artemesinin.[64]
However, this conclusion was rebuked by several experts who stated that hot water (85 C), and not boiling water, should be used to prepare the tea. Although
Artemisia tea is not recommended as a substitute for the ACT (artemisinin combination therapies), more clinical studies on its tea preparation have been
suggested.[65]
Production and price

China and Vietnam provide 70% and East Africa 20% of the raw plant material. Seedlings are grown in nurseries and then transplanted into fields. It takes about
8 months for them to reach full size. The plants are harvested, the leaves are dried and sent to facilities where the artemisinin is extracted using solvent, typically
hexane. Alternative extraction methods have been proposed.[66] The market price for artemisinin has fluctuated widely, between $120 and $1200 per kilogram
from 2005 to 2008.[67]
After negotiation with the WHO, Novartis and Sanofi-Aventis provide ACT drugs at cost on a nonprofit basis; however, these drugs are still more expensive than
other malaria treatments.[68] Artesunate injection for severe malaria treatment is made by the Guilin Factory in China where production has received WHO
prequalification,[69] an indicator of drug quality.
High-yield varieties of Artemisia are being produced by the Centre for Novel Agricultural Products at the University of York using molecular breeding
techniques.[67]
Using seed supplied by Action for Natural Medicine (ANAMED), the World Agroforestry Centre (ICRAF) has developed a hybrid, dubbed A3, which can grow
to a height of 3 m and produce 20 times more artemisinin than wild varieties. In northwestern Mozambique, ICRAF is working together with a medical
organisation, Mdecins sans frontires, ANAMED and the Ministry of Agriculture and Rural Development to train farmers on how to grow the shrub from
cuttings, and to harvest and dry the leaves to make artemisia tea.
In April 2013, Sanofi announced the launch[70] of a production facility in Garessio, Italy, to manufacture the anti-plasmodial drug on a large scale. The
partnership to create a new pharmaceutical manufacturing process was led by PATHs Drug Development program (through an affiliation with OneWorld
Health), with funding from the Bill & Melinda Gates Foundation and based on a modified biosynthetic process for artemisinic acid, initially designed by Jay
Keasling at the University of California, Berkeley and optimized by Amyris. The reaction is followed by a photochemical process creating singlet oxygen to
obtain the end product. Sanofi expects to produce 25 tons of artemisinin in 2013, ramping up the production to 55-60 tons in 2014. The price per kg will be
$350400, roughly the same as the botanical source.[71] Despite concerns that this equivalent source would lead to the demise of companies, which produce this
substance conventionally through extraction of A. annua biomass, an increased supply of this drug will likely produce lower prices and therefore increase the
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availability for ACTs treatment. In August 2014, Sanofi announced the release of the first batch of semisynthetic artemisinin. 1.7 million doses of Sanofi's
ArteSunate AmodiaQuine Winthrop (ASAQ Winthrop), a fixed-dose artemisinin-based combination therapy will be shipped to half a dozen African countries
over the next few months.[72]
Synthesis
Biosynthesis in A. annua
The biosynthesis of artemisinin is believed to involve the mevalonate pathway (MVA) and the cyclization of farnesyl diphosphate (FDP). It is not clear whether
the non-mevalonate pathway pathway can also contribute 5-carbon precursors (IPP or/and DMAPP), as occurs in other sesquiterpene biosynthetic systems. The
routes from artemisinic alcohol to artemisinin remain controversial, and they differ mainly in when the reduction step takes place. Both routes suggested
dihydroartemisinic acid as the final precursor to artemisinin. Dihydroartemisinic acid then undergoes photo-oxidation to produce dihydroartemisinic acid
hydroperoxide. Ring expansion by the cleavage of hydroperoxide and a second oxygen-mediated hydroperoxidation finish the biosynthesis of artemisinin.
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Chemical synthesis
The total synthesis of the sesquiterpene lactone, artemisinin (quinghaosu) has been performed from available organic starting materials, using basic organic
reagents, many times. The first two total syntheses were a "remarkable... stereoselective synthesis" by Schmid and Hofheinz at Hoffmann-La Roche in Basel
starting from ()-isopulegol (13 steps, 5% overall yield) and a concurrent synthesis by Zhou and coworkers at the Shanghai Institute of Organic Chemistry from
R-(+)-citronellal (20 steps, 0.3% overall yield).[73] Key steps of the Schmid-Hofheinz approach included an initial Ohrloff stereoselective
hydroboration/oxidation to establish the "off-ring" methyl stereocenter on the propene side chain; two sequential lithium-reagent mediated alkylations that
introduced all needed carbon atoms and that were, together highly diasteroselective; and further reduction, oxidation, and desilylation steps performed on this
mono-carbocyclic intermediate, including a final singlet oxygen-utilizing photooxygenation and ene reaction, which, after acidic workup closed the three
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remaining oxacyclic rings of the desired product, artemisinin, in a single step.[73][74] (In essence, the final oxidative ring closing operation in these syntheses
accomplishes the closing three biosynthetic steps shown above.)
A wide variety of further routes continue to be explored, from early days until today, including total synthesis routes from R-(+)-pulegone, isomenthene,[73] and
even 2-cyclohexen-1-one,[75] as well as routes better described as partial or semisyntheses from a more plentiful biosynthetic precursor, artemisinic acidin the
latter case, including some very short and very high yielding biomimetic synthesis examples (of Roth and Acton, and Haynes et al., e.g., 3 steps, 30% yield),
which again feature the singlet oxygen ene chemsitry.[73][76][77]
Synthesis in engineered organisms

The partnership to develop semisynthetic artemisinin was led by PATHs Drug Development program (through an affiliation with OneWorld Health), with
funding from the Bill & Melinda Gates Foundation. The project began in 2004, and initial project partners included the University of California, Berkeley (which
provided the technology on which the project was based a process that genetically altered yeast to produce artemisinic acid); and Amyris, Inc. (a
biotechnology firm in California, which refined the process to enable large-scale production and developed scalable processes for transfer to an industrial
partner).
In 2006, a team from UC Berkeley reported they had engineered Saccharomyces cerevisiae yeast to produce small amount of the precursor artemisinic acid. The
synthesized artemisinic acid can then be transported out, purified and chemically converted into artemisinin that they claim will cost roughly $0.25 per dose. In
this effort of synthetic biology, a modified mevalonate pathway was used, and the yeast cells were engineered to express the enzyme amorphadiene synthase and
a cytochrome P450 monooxygenase (CYP71AV1), both from A. annua. A three-step oxidation of amorpha-4,11-diene gives the resulting artemisinic acid.[78]
The Berkeley method was augmented using technology from various other organizations. The final successful technology is based on inventions licensed from
UC Berkeley and the National Research Council (NRC) Plant Biotechnology Institute of Canada.
Commercial production of semisynthetic artemisinin is now underway at Sanofi's site in Garessio, Italy. This second source of artemisinin is poised to enable a
more stable flow of key antimalarial treatments to those who need them most.[70] The production goal is set at 35 tons for 2013. It is expected to increase to
50-60 tons per year in 2014, supplying approximately 1/3 of the global annual need for artemisinin.
On May 8, 2013, WHOs Prequalification of Medicines Programme announced the acceptability of semisynthetic artemisinin for use in the manufacture of
active pharmaceutical ingredients submitted to WHO for prequalification, or that have already been qualified by WHO.[79] Sanofis API produced from
semisynthetic artemisinin (artesunate) was also prequalified by WHO on May 8, 2013, making it the first semisynthetic artemisinin derivative prequalified.
In 2010, a team from Wageningen University reported they had engineered a close relative of tobacco, Nicotiana benthamiana, that can also produce the
precursor artemisinic acid.[80]
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References
This article contains public domain text from the CDC as cited
1. ^ White NJ (July 1997). "Assessment of the pharmacodynamic properties of
8. ^ Jianfang, Zhang (2006). A Detailed Chronological Record of Project 523 and
antimalarial drugs in vivo" (https://www.ncbi.nlm.nih.gov/pmc/articles
the Discovery and Development of Qinghaosu (Artemisinin)
/PMC163932). Antimicrob. Agents Chemother. 41 (7): 141322. PMC 163932
(http://books.google.co.uk/books?id=fFaxhXYg8uAC&
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC163932). PMID 9210658
dq=A+Detailed+Chronological+Record+of+Project+523+and+the+Discovery+a
(https://www.ncbi.nlm.nih.gov/pubmed/9210658).
nd+Development+of+Qinghaosu+(Artemisinin)&source=gbs_navlinks_s).
2. ^ a b Royal Society of Chemistry (July 2006). "Artemisinin and a new
9. ^ a b c Miller L.H. and Su X. (September 16, 2011). "Artemisinin: discovery
generation of antimalarial drugs" (http://www.rsc.org/Education/EiC/issues
from the Chinese herbal garden" (http://www.sciencedirect.com/science/article
/2006July/Artemisinin.asp). Education in Chemistry.
/pii/S0092867411009500). Cell (CAMBRIDGE, MA 02139, USA: Cell Press)
3. ^ Douglas NM, Anstey NM, Angus BJ, Nosten F, Price RN (June 2010).
146 (6): 855858. doi:10.1016/j.cell.2011.08.024 (http://dx.doi.org
"Artemisinin combination therapy for vivax malaria"
/10.1016%2Fj.cell.2011.08.024). ISSN 0092-8674 (https://www.worldcat.org
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3350863). Lancet Infect Dis
/issn/0092-8674). PMC 3414217 (https://www.ncbi.nlm.nih.gov/pmc/articles
10 (6): 40516. doi:10.1016/S1473-3099(10)70079-7 (http://dx.doi.org
/PMC3414217). PMID 21907397 (https://www.ncbi.nlm.nih.gov/pubmed
/10.1016%2FS1473-3099%2810%2970079-7). PMC 3350863
/21907397).

4. ^ Various (Jul 2014). "Etymologia: Artemisinin" (http://wwwnc.cdc.gov
/eid/article/20/7/et-2007_article). Emerg Infect Dis [Internet] (CDC) 20 (7).
doi:10.3201/eid2007.ET2007 (http://dx.doi.org/10.3201%2Feid2007.ET2007).
Retrieved July 4, 2014.
5. ^ "Medical manuscripts from Ma Wang Dui" (http://qinghaosu.blogspot.com.ar
/2008/05/medical-manuscripts-from-ma-wang-dui.html). Qingaosu Project.
6. ^ "Zhou Hou Bei Ji Fang" (http://qinghaosu.blogspot.com.ar/2008/05/zhouhou-bei-ji-fang.html). Qingaosu Project.
10. ^ "Lasker Award Rekindles Debate Over Artemisinin's Discovery |

Science/AAAS | News" (http://news.sciencemag.org/asia/2011/09/lasker-awardrekindles-debate-over-artemisinins-discovery). News.sciencemag.org. Retrieved
2014-01-07.
11. ^ Miller, Louis H.; Su, Xinzhuan (2011). "Artemisinin: Discovery from the
Chinese Herbal Garden" (https://www.ncbi.nlm.nih.gov/pmc/articles
/PMC3414217). Cell 146 (6): 8558. doi:10.1016/j.cell.2011.08.024
(http://dx.doi.org/10.1016%2Fj.cell.2011.08.024). PMC 3414217
7. ^ Burns, William. Qingaosu Project http://qinghaosu.blogspot.com/ |url=

missing title (help). Retrieved 8 August 2014.
11 of 19
2014/11/05 09:26 PM
12. ^ Fairhurst, RM; Nayyar, GM; Breman, JG; Hallett, R; Vennerstrom, JL; Duong,
18. ^ Gary H. Posner; Michael H. Parker; Northrop, John; Elias, Jeffrey S.;
S; Ringwald, P; Wellems, TE; Plowe, CV; Dondorp, AM (2012). "Artemisinin-
Ploypradith, Poonsakdi; Xie, Suji; Shapiro, Theresa A. (1999). "Orally Active,
resistant malaria: Research challenges, opportunities, and public health
Hydrolytically Stable, Semisynthetic, Antimalarial Trioxanes in the Artemisinin
implications" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3414557). The
Family". J. Med. Chem. 42 (2): 300304. doi:10.1021/jm980529v
American journal of tropical medicine and hygiene 87 (2): 23141.
(http://dx.doi.org/10.1021%2Fjm980529v). PMID 9925735
doi:10.4269/ajtmh.2012.12-0025 (http://dx.doi.org
/10.4269%2Fajtmh.2012.12-0025). PMC 3414557
19. ^ Vennerstrom JL, Arbe-Barnes S, Brun R, et al. (August 2004). "Identification
of an antimalarial synthetic trioxolane drug development candidate". Nature
430 (7002): 9004. doi:10.1038/nature02779 (http://dx.doi.org
13. ^ "Antimalaria studies on Qinghaosu". Chin. Med. J. 92 (12): 8116.

December 1979. PMID 117984 (https://www.ncbi.nlm.nih.gov/pubmed
/117984).
14. ^ D. MNeil (2012). "For Intrigue, Malaria Drug Gets the Prize".
(http://www.nytimes.com/2012/01/17/health/for-intrigue-malariadrug-artemisinin-gets-the-prize.html?pagewanted=all) NYTimes, Health.
Retrieved 20. April 2013.
15. ^ "WHO calls for an immediate halt to provision of single-drug artemisinin
/10.1038%2Fnature02779). PMID 15318224 (https://www.ncbi.nlm.nih.gov

/pubmed/15318224).
20. ^ C.H. Unnikrishnan (September 21, 2007). "Blow to Ranbaxy drug research
plans" (http://www.livemint.com/2007/09/21011423/Blow-to-Ranbaxydrugresearch.html). livemint.com.
21. ^ Rehwagen C (May 2006). "WHO ultimatum on artemisinin monotherapy is
showing results" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1463909).
BMJ 332 (7551): 1176. doi:10.1136/bmj.332.7551.1176-b (http://dx.doi.org
malaria pills" (http://www.who.int/mediacentre/news/releases/2006/pr02/en/).
/10.1136%2Fbmj.332.7551.1176-b). PMC 1463909
WHO. 19 January 2006.
16. ^ Elizabeth Weise, "'America's Nobel' awarded to Chinese scientist"

(http://www.usatoday.com/tech/science/story/2011-09-12/lasker-awards
/50371124/1), USA Today, 12 September 2011, accessed September 12, 2011.
17. ^ "For Intrigue, Malaria Drug Gets the Prize" (http://www.nytimes.com/2012/01
22. ^ Guidelines for the Treatment of Malaria. Geneva: World Health
Organization. 2006. ISBN 92-4-154694-8.
23. ^ White NJ (April 2004). "Antimalarial drug resistance"
/17/health/for-intrigue-malaria-drug-artemisinin-gets-the-prize.html?_r=1). New
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC385418). J. Clin. Invest. 113
York Times. 16 January 2012.
(8): 108492. doi:10.1172/JCI21682 (http://dx.doi.org/10.1172%2FJCI21682).

PMC 385418 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC385418).
PMID 15085184 (https://www.ncbi.nlm.nih.gov/pubmed/15085184).
12 of 19
2014/11/05 09:26 PM
24. ^ Krudsood S, Looareesuwan S, Tangpukdee N, et al. (June 2010). "New
29. ^ University of Washington: Artemisinin (http://depts.washington.edu
Fixed-Dose Artesunate-Mefloquine Formulation against Multidrug-Resistant
/bioe/about/news/artemisinin.html) Lai H, Singh NP, Sasaki T. (2013)
Plasmodium falciparum in Adults: a Comparative Phase IIb Safety and
Development of artemisinin compounds for cancer treatment. Invest New Drugs
Pharmacokinetic Study with Standard-Dose Nonfixed Artesunate plus
31:230-246.
Mefloquine" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2935027).
30. ^ Hou J, Wang D, Zhang R, Wang H (2008). "Experimental therapy of
Antimicrob Agents Chemother 54 (9): 37307. doi:10.1128/AAC.01187-09
hepatoma with artemisinin and its derivatives: in vitro and in vivo activity,
(http://dx.doi.org/10.1128%2FAAC.01187-09). PMC 2935027
chemosensitization, and mechanisms of action"
(http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&
pmid=18765544). Clin Cancer Res 14 (7): 55195530.
25. ^ "Malaria drugs recalled in Kenya" (http://news.bbc.co.uk/2/hi/africa

/6951586.stm). BBC News. 17 August 2007.
26. ^ Newton P, Proux S, Green M, et al. (June 2001). "Fake artesunate in
southeast Asia". Lancet 357 (9272): 194850.
doi:10.1158/1078-0432.CCR-08-0197 (http://dx.doi.org
/10.1158%2F1078-0432.CCR-08-0197). PMID 18765544
31. ^ Cabello CM, Lamore SD, Bair WB 3rd, Qiao S, Azimian S, Lesson JL,
doi:10.1016/S0140-6736(00)05085-6 (http://dx.doi.org
Wondrak GT (2011). "The redox antimalarial dihydroartemisinin targets human
/10.1016%2FS0140-6736%2800%2905085-6). PMID 11425421
metastatic melanoma cells but not primary melanocytes with induction of
NOXA-dependent apoptosis" (https://www.ncbi.nlm.nih.gov/pmc/articles
27. ^ Dondorp A, Nosten F, Stepniewska K, Day N, White N (2005). "Artesunate
/PMC3203350). Invest. New Drugs 30 (4): 1289301.
versus quinine for treatment of severe falciparum malaria: a randomised trial".
doi:10.1007/s10637-011-9676-7 (http://dx.doi.org
Lancet 366 (9487): 71725. doi:10.1016/S0140-6736(05)67176-0
/10.1007%2Fs10637-011-9676-7). PMC 3203350
(http://dx.doi.org/10.1016%2FS0140-6736%2805%2967176-0).
28. ^
ab
Dondorp AM, Fanello CI, Hendriksen IC, et al. (November 2010).
32. ^ Xiao SH. (2005). "Development of antischistosomal drugs in China, with
"Artesunate versus quinine in the treatment of severe falciparum malaria in
particular consideration to praziquantel and the artemisinins". Acta Trop. 96
African children (AQUAMAT): an open-label, randomised trial"
(23): 153167. doi:10.1016/j.actatropica.2005.07.010 (http://dx.doi.org
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3033534). Lancet 376 (9753):
/10.1016%2Fj.actatropica.2005.07.010). PMID 16112072
164757. doi:10.1016/S0140-6736(10)61924-1 (http://dx.doi.org
/10.1016%2FS0140-6736%2810%2961924-1). PMC 3033534

13 of 19
2014/11/05 09:26 PM
33. ^ Keiser J, Utzinger J. (2007). "Artemisinins and synthetic trioxolanes in the
37. ^ Dondorp, A. M.; Nosten, F. O.; Yi, P.; Das, D.; Phyo, A. P.; Tarning, J.;
treatment of helminth infections". Current Opinion in Infectious Diseases 20
Lwin, K. M.; Ariey, F.; Hanpithakpong, W.; Lee, S. J.; Ringwald, P.; Silamut,
(6): 605612. doi:10.1097/QCO.0b013e3282f19ec4 (http://dx.doi.org
K.; Imwong, M.; Chotivanich, K.; Lim, P.; Herdman, T.; An, S. S.; Yeung, S.;
/10.1097%2FQCO.0b013e3282f19ec4). PMID 17975411
Singhasivanon, P.; Day, N. P. J.; Lindegardh, N.; Socheat, D.; White, N. J.
(2009). "Artemisinin Resistance inPlasmodium falciparumMalaria"
34. ^ Utzinger J, N'Goran EK, N'Dri A, Lengeler C, Xiao S, Tanner M. (2000).
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3495232). New England
"Oral artemether for prevention of Schistosoma mansoni infection: randomised
Journal of Medicine 361 (5): 455467. doi:10.1056/NEJMoa0808859
controlled trial" (http://linkinghub.elsevier.com/retrieve
(http://dx.doi.org/10.1056%2FNEJMoa0808859). PMC 3495232
/pii/S0140673600021140). Lancet 355 (9212): 13205.
doi:10.1016/S0140-6736(00)02114-0 (http://dx.doi.org
/10.1016%2FS0140-6736%2800%2902114-0). PMID 10776745

35. ^ Li YS, Chen HG, He HB, Hou XY, Ellis M, McManus DP. (2005). "A
38. ^ Phyo AP, Nkhoma S, Stepniewska K, et al. (2012). "Emergence of

artemisinin-resistant malaria on the Western border of Thailand: a longitudinal
study." (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525980). Lancet 379
double-blind field trial on the effects of artemether on Schistosoma japonicum
(9830): 19606. doi:10.1016/S0140-6736(12)60484-X (http://dx.doi.org
infection in a highly endemic focus in southern China". Acta Trop. 96 (23):
/10.1016%2FS0140-6736%2812%2960484-X). PMC 3525980
184190. doi:10.1016/j.actatropica.2005.07.013 (http://dx.doi.org
/10.1016%2Fj.actatropica.2005.07.013). PMID 16112071
36. ^ Noedl, H; Se, Y; Schaecher, K; Smith, B. L.; Socheat, D; Fukuda, M. M.;
Artemisinin Resistance in Cambodia 1 (ARC1) Study Consortium (2008).
"Evidence of artemisinin-resistant malaria in western Cambodia". New England
39. ^ a b Briggs, Helen (30 July 2014) Call for 'radical action' on drug-resistant
malaria (http://www.bbc.co.uk/news/health-28569966) BBC News, health,
Retrieved 30 July 2013
40. ^ a b Ashley, Elizabeth A.; Dhorda, Mehul; et al (July 31, 2014). "Spread of
Journal of Medicine 359 (24): 261920. doi:10.1056/NEJMc0805011
Artemisinin Resistance in Plasmodium falciparum Malaria"
(http://dx.doi.org/10.1056%2FNEJMc0805011). PMID 19064625
(http://www.nejm.org/doi/full/10.1056
/NEJMoa1314981?query=featured_home). The New England Journal of

Medicine 371 (5): 411423. doi:10.1056/NEJMoa1314981 (http://dx.doi.org
/10.1056%2FNEJMoa1314981). PMID 25075834
14 of 19
2014/11/05 09:26 PM
41. ^ Ariey, F. D. R.; Witkowski, B.; Amaratunga, C.; Beghain, J.; Langlois, A. C.;
47. ^ Kappe SH, Vaughan AM, Boddey JA, Cowman AF (May 2010). "That was
Khim, N.; Kim, S.; Duru, V.; Bouchier, C.; Ma, L.; Lim, P.; Leang, R.; Duong,
then but this is now: malaria research in the time of an eradication agenda".
S.; Sreng, S.; Suon, S.; Chuor, C. M.; Bout, D. M.; Mnard, S.; Rogers, W. O.;
Science 328 (5980): 8626. doi:10.1126/science.1184785 (http://dx.doi.org
Genton, B.; Fandeur, T.; Miotto, O.; Ringwald, P.; Le Bras, J.; Berry, A.; Barale,
/10.1126%2Fscience.1184785). PMID 20466924 (https://www.ncbi.nlm.nih.gov
J. C.; Fairhurst, R. M.; Benoit-Vical, F. O.; Mercereau-Puijalon, O.; Mnard, D.
/pubmed/20466924).
(2013). "A molecular marker of artemisinin-resistant Plasmodium falciparum
48. ^ Ginsburg, H.; Atamna, H. (1994). "The redox status of malaria-infected
malaria". Nature 505 (7481): 5055. doi:10.1038/nature12876
erythrocytes: An overview with an emphasis on unresolved problems". Parasite
(http://dx.doi.org/10.1038%2Fnature12876). PMID 24352242
(Paris, France) 1 (1): 513. PMID 9140469 (https://www.ncbi.nlm.nih.gov
/pubmed/9140469).
42. ^ Drugs immunity may fail malaria fight (http://www.thejakartapost.com
49. ^ Cumming JN; Ploypradith P; Posner GH (1997). "Antimalarial activity of
/news/2011/04/23/drugs-immunity-may-fail-malaria-fight.html). The Jakarta
artemisinin (qinghaosu) and related trioxanes: mechanism(s) of action". Adv.
Post, April 23, 2011.
Pharmacol. 37: 25397. doi:10.1016/S1054-3589(08)60952-7 (http://dx.doi.org
43. ^
ab
Taylor WR, White NJ (2004). "Antimalarial drug toxicity: a review".
Drug Saf 27 (1): 2561. doi:10.2165/00002018-200427010-00003

(http://dx.doi.org/10.2165%2F00002018-200427010-00003). PMID 14720085
44. ^ Leonardi E, Gilvary G, White NJ, Nosten F (2001). "Severe allergic reactions
/10.1016%2FS1054-3589%2808%2960952-7). PMID 8891104

50. ^ Haynes, RK; Cheu, KW; N'Da, D; Coghi, P; Monti, D (Aug 2013).
"Considerations on the mechanism of action of artemisinin antimalarials: part
1--the 'carbon radical' and 'heme' hypotheses.". Infectious disorders drug
to oral artesunate: a report of two cases". Trans. R. Soc. Trop. Med. Hyg. 95
targets 13 (4): 21777. doi:10.2174/1871526513666131129155708
(2): 1823. doi:10.1016/S0035-9203(01)90157-9 (http://dx.doi.org
(http://dx.doi.org/10.2174%2F1871526513666131129155708).
/10.1016%2FS0035-9203%2801%2990157-9). PMID 11355556
45. ^ "Hepatitis Temporally Associated with an Herbal Supplement Containing
51. ^ Haynes, R. K.; Cheu, K. W.; Li, K. Y.; Tang, M. M. K.; Wong, H. N.; Chen,
M. J.; Guo, Z. F.; Guo, Z. H.; Coghi, P.; Monti, D. (2011). "A Partial
Artemisinin Washington, 2008" (http://www.cdc.gov/mmwr/preview
Convergence in Action of Methylene Blue and Artemisinins: Antagonism with
/mmwrhtml/mm5831a3.htm). CDC.
Chloroquine, a Reversal with Verapamil, and an Insight into the Antimalarial
46. ^ R. Price et al. (1999). "Adverse effects in patients with acute falciparum
Activity of Chloroquine". ChemMedChem 6 (9): 16031615.
malaria treated with artemisinin derivatives" (http://www.ajtmh.org/cgi/content
doi:10.1002/cmdc.201100184 (http://dx.doi.org/10.1002%2Fcmdc.201100184).
/abstract/60/4/547). American Journal of Tropical Medicine and Hygiene 60
(4): 547555. PMID 10348227 (https://www.ncbi.nlm.nih.gov/pubmed

/10348227).
15 of 19
2014/11/05 09:26 PM
52. ^ Lisewski, A. M.; Quiros, J. P.; Ng, C. L.; Adikesavan, A. K.; Miura, K;
56. ^ Abu Bakar N, Klonis N, Hanssen E, Chan C, Tilley L (February 2010).
Putluri, N; Eastman, R. T.; Scanfeld, D; Regenbogen, S. J.; Altenhofen, L;
"Digestive-vacuole genesis and endocytic processes in the early
Llins, M; Sreekumar, A; Long, C; Fidock, D. A.; Lichtarge, O (2014).
intraerythrocytic stages of Plasmodium falciparum". J. Cell. Sci. 123 (Pt 3):
"Supergenomic Network Compression and the Discovery of EXP1 as a
44150. doi:10.1242/jcs.061499 (http://dx.doi.org/10.1242%2Fjcs.061499).
Glutathione Transferase Inhibited by Artesunate". Cell 158 (4): 91628.
doi:10.1016/j.cell.2014.07.011 (http://dx.doi.org
57. ^ Liu, Y; Lok, CN; Ko, BC; Shum, TY; Wong, MK; Che, CM (April 2, 2010).
/10.1016%2Fj.cell.2014.07.011). PMID 25126794
"Subcellular localization of a fluorescent artemisinin derivative to endoplasmic
reticulum.". Org Lett. 12 (7): 14201423. doi:10.1021/ol902890j
53. ^ Pandey AV, Tekwani BL, Singh RL, Chauhan VS (July 1999). "Artemisinin,
an endoperoxide antimalarial, disrupts the hemoglobin catabolism and heme
detoxification systems in malarial parasite". J. Biol. Chem. 274 (27): 193838.
(http://dx.doi.org/10.1021%2Fol902890j). PMID 20192248

58. ^ Golenser, J; Waknine, JH; Krugliak, M; Hunt, NH; Grau, GE (Dec 2006).
doi:10.1074/jbc.274.27.19383 (http://dx.doi.org
"Current perspectives on the mechanism of action of artemisinins.". Int J
/10.1074%2Fjbc.274.27.19383). PMID 10383451
Parasitol 36 (14): 14271441. doi:10.1016/j.ijpara.2006.07.011
(http://dx.doi.org/10.1016%2Fj.ijpara.2006.07.011). PMID 17005183
54. ^ Haynes, RK; Monti, D; Taramelli, D; Basilico, N; Parapini, S; Olliaro, P

(March 2003). "Artemisinin antimalarials do not inhibit hemozoin formation"
59. ^ Eckstein-Ludwig, U; Webb, RJ; Van Goethem, ID; East, JM; Lee, AG;
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC149339). Antimicrob Agents
Kimura, M; O'Neill, PM; Bray, PG; Ward, SA; Krishna, S (Aug 21, 2003).
Chemother. 47 (3): 1175. doi:10.1128/aac.47.3.1175.2003 (http://dx.doi.org
"Artemisinins target the SERCA of Plasmodium falciparum.". Nature 424
/10.1128%2Faac.47.3.1175.2003). PMC 149339 (https://www.ncbi.nlm.nih.gov
(6951): 957961. doi:10.1038/nature01813 (http://dx.doi.org
/pmc/articles/PMC149339). PMID 12604568 (https://www.ncbi.nlm.nih.gov
/pubmed/12604568).
/pubmed/12931192).
55. ^ del Pilar Crespo M, Avery TD, Hanssen E, et al. (January 2008).
16 of 19
60. ^ Li W, Mo W, Shen D, et al. (September 2005). "Yeast Model Uncovers Dual
"Artemisinin and a Series of Novel Endoperoxide Antimalarials Exert Early
Roles of Mitochondria in the Action of Artemisinin"
Effects on Digestive Vacuole Morphology" (https://www.ncbi.nlm.nih.gov
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1201371). PLoS Genet. 1 (3):
/pmc/articles/PMC2223901). Antimicrob. Agents Chemother. 52 (1): 98109.
e36. doi:10.1371/journal.pgen.0010036 (http://dx.doi.org
doi:10.1128/AAC.00609-07 (http://dx.doi.org/10.1128%2FAAC.00609-07).
/10.1371%2Fjournal.pgen.0010036). PMC 1201371
PMC 2223901 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2223901).
2014/11/05 09:26 PM
61. ^ Eckstein-Ludwig, U.; Webb, R. J.; Van Goethem, I. D. A.; East, J. M.; Lee,
66. ^ Lapkin, Alexei A.; Peters, Martina; Greiner, Lasse; Chemat, Smain; Leonhard,
A. G.; Kimura, M.; O'Neill, P. M.; Bray, P. G.; Ward, S. A.; Krishna, S. (2003).
Kai; Liauw, Marcel A.; Leitner, Walter (1 January 2010). "Screening of new
"Artemisinins target the SERCA of Plasmodium falciparum". Nature 424
solvents for artemisinin extraction process using ab initio methodology". Green
Chemistry 12 (2): 241. doi:10.1039/b922001a (http://dx.doi.org
/10.1039%2Fb922001a). and literature cited therein
/pubmed/12931192).
62. ^ Vugt MV, Wilairatana P, Gemperli B, et al. (1999). "Efficacy of six doses of
artemether-lumefantrine (benflumetol) in multidrug-resistant Plasmodium
falciparum malaria". Am J Trop Med Hyg 60 (6): 93642. PMID 10403324
63. ^ Lefevre G, Looareesuwan S, Treeprasertsuk S, et al. (2001). "A clinical and
pharmacokinetic trial of six doses of artemether-lumefantrine for multidrugresistant Plasmodium falciparum malaria in Thailand". Am J Trop Med Hyg 64
67. ^ a b "Report of the Artemisinin Enterprise Conference 2008"

(http://www.york.ac.uk/org/cnap/artemisiaproject/pdfs/AEconference-reportweb.pdf).
68. ^ Artemisinin combination therapies (http://www.york.ac.uk/org/cnap
/artemisiaproject/fact_sheets_acts.htm), CNAP Artemisia Project
69. ^ http://www.mmv.org/partnering/guilin-pharmaceutical--achievingprequalification-price-affordable-in-africa
70. ^ a b Pantjushenko, Elena. "Sanofi and PATH announce the launch of
(56): 24756. PMID 11463111 (https://www.ncbi.nlm.nih.gov/pubmed
large-scale production of semisynthetic artemisinin against malaria"
/11463111).
(http://www.path.org/news/press-room/422/). PATH.
64. ^ Jansen FH (2006). "The herbal tea approach for artemesinin as a therapy for
71. ^ Mark Peplow (April 2013). "Sanofi launches malaria drug production to
malaria?". Trans R Soc Trop Med Hyg 100 (3): 2856.
maintain stability in Artemisinin availability" (http://www.rsc.org
doi:10.1016/j.trstmh.2005.08.004 (http://dx.doi.org
/chemistryworld/2013/04/sanofi-launches-malaria-drug-production).
/10.1016%2Fj.trstmh.2005.08.004). PMID 16274712
chemistryworld online (RSC). Retrieved April 19, 2013.
65. ^ RITAM Artemisia annua Task Force (2007). "Artemisia Annua as a Herbal
72. ^ Palmer, Eric (19 August 2014). "Sanofi shipping new malaria treatment
manufactured from 'semisynthetic artemisinin' "
Tea for Malaria" (http://www.bioline.org.br/request?tc07001). Afr J Tradit
(http://www.fiercepharmamanufacturing.com/story/sanofi-shipping-new-malaria-
Complement Altern Med 4 (1): 1213. ISSN 0189-6016
treatment-manufactured-semisynthetic-artemisini/2014-08-19).
(https://www.worldcat.org/issn/0189-6016). PMC 2816434
fiercepharmamanufacturing.com. Retrieved 14 September 2014.

73. ^ a b c d Michael C. Pirrung & Andrew T. Morehead, Jr. (1997) A

Sesquidecade of Sesquiterpenes, 1980-1994: Part A. Acyclic and Monocyclic
Sesquiterpenes, Part 1, in The Total Synthesis of Natural Products, Vol 10 (D
Goldsmith, Ed.) New York:John Wiley & Sons, pp. 90-96. see
[books.google.com/books?isbn=047012962X], accessed 19 June 2014.
17 of 19
2014/11/05 09:26 PM
74. ^ Schmid G., Hofheinz W. (1983). "Total Synthesis of qinghaosu". J. Am.
78. ^ Ro DK, Paradise EM, Ouellet M, et al. (April 2006). "Production of the
Chem. Soc. 105 (3): 6245. doi:10.1021/ja00341a054 (http://dx.doi.org
antimalarial drug precursor artemisinic acid in engineered yeast". Nature 440
/10.1021%2Fja00341a054).
75. ^ Zhu Chunyin, Cook Silas P (2012). "A Concise Synthesis of

(+)-Artemisinin". J. Amer. Chem. Soc. 134 (33): 1357713579.
doi:10.1021/ja3061479 (http://dx.doi.org/10.1021%2Fja3061479).
76. ^ Lvesque F, Seeberger PH (2012). "Continuous-Flow Synthesis of the
Anti-Malaria Drug Artemisinin". Angewandte Chemie International Edition 51
(7): 17061709. doi:10.1002/anie.201107446 (http://dx.doi.org
/10.1002%2Fanie.201107446).
77. ^ Turconi Jol, Griolet Frdric, Guevel Ronan, Oddon Gilles, Villa Roberto,

/pubmed/16612385).
79. ^ Pantjushenko, Elena. "Semisynthetic artemisinin achieves WHO
prequalification" (http://www.path.org/news/press-room/430/). PATH.
Retrieved 8 February 2014.
80. ^ van Herpen, TW.; Cankar, K.; Nogueira, M.; Bosch, D.; Bouwmeester, HJ.;
Beekwilder, J. (3 December 2010). Yang, Haibing, ed. "Nicotiana benthamiana
as a Production Platform for Artemisinin Precursors"
Geatti Andrea, Hvala Massimo, Rossen Kai, Gller Rudolf et al. (2014).
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2997059). PLoS ONE 5 (12):
"Semisynthetic artemisinin, the chemical path to industrial production". Org.
e14222. doi:10.1371/journal.pone.0014222 (http://dx.doi.org
Proc. Research Devel 18 (3): 417422. doi:10.1021/op4003196
/10.1371%2Fjournal.pone.0014222). PMC 2997059
(http://dx.doi.org/10.1021%2Fop4003196).

External links
History, Aetiology, Pathophysiology, Clinical Features, Diagnosis, Treatment, Complications And Control Of
Malaria: Artemisinin Derivatives (http://www.malariasite.com/malaria/artemisinin.htm)
Design and synthesis of antimalarial endoperoxides (http://www.organic-chemistry.org/Highlights
Look up artemisinin in
Wiktionary, the free
dictionary.
/2004/25OctoberA.shtm)
van Vugt M, Looareesuwan S, Wilairatana P, et al. (2000). "Artemether-lumefantrine for the treatment of multidrug-resistant falciparum malaria". Trans.
R. Soc. Trop. Med. Hyg. 94 (5): 5458. doi:10.1016/S0035-9203(00)90082-8 (http://dx.doi.org/10.1016%2FS0035-9203%2800%2990082-8).
Daviss B (2005). "Malaria, Science, and Social Responsibility: Nonprofit drug-development partnership seeks to cure the ills of developing nations"
18 of 19
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(http://www.the-scientist.com/2005/3/28/42/1). The Scientist 19 (6): 42.

Research on the use of artemisinin for cancer treatment (http://depts.washington.edu/bioe/about/news/artemisinin.html)
Artemisinin Researchers blend folk treatment, high tech for promising anti-cancer compound (http://www.uwnews.org/article.asp?articleID=8139)
BBC Horizon documentary about artemisinin (http://www.bbc.co.uk/sn/tvradio/programmes/horizon/malaria_prog_summary.shtml)
Artemisia Annua, by Memorial-Sloan Kettering Cancer Center (http://www.mskcc.org/mskcc/html/11571.cfm?RecordID=650&tab=HC)
Use of Artemisinin for Cancer Treatment and Bacterial Infection, Henry Lai, Ph.D., University of Washington (streaming video, Spring 2005)
(http://www.bioeng.washington.edu/video/#spring05/bioe599jL5.wmv)
Assured Artemisinin Supply System, support the global production of sufficient Artemisia/artemisinin to meet the expanded needs (http://www.a2s2.org)
Artemisinin latest patents (http://tgs.freshpatents.com/Artemisinin-bx1.php), covering use in fighting infections, including viral infections; fighting cancer;
various novel derivatives and ACTs; high-yielding Artemisia plants; and extraction methods.
Retrieved from "http://en.wikipedia.org/w/index.php?title=Artemisinin&oldid=632131797"
Categories: Antimalarial agents Chinese inventions Experimental cancer drugs Organic peroxides Sesquiterpene lactones Trioxanes
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