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| Pronunciation | /ɑːrtɪˈmɪsɪnɪn/ |
| Other names | Artemisinine, qinghaosu |
| Routes of administration | Oral |
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| ECHA InfoCard | 100.110.458 |
| Chemical and physical data | |
| Formula | C15H22O5 |
| Molar mass | 282.336 g·mol−1 |
| 3D model (JSmol) | |
| Density | 1.24 ± 0.1 g/cm3 |
| Melting point | 152 to 157 °C (306 to 315 °F) |
| Boiling point | decomposes |
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Artemisinin (/ˌɑːrtɪˈmiːsɪnɪn/) and itssemisyntheticderivatives are a group ofdrugs used in the treatment ofmalaria due toPlasmodium falciparum.[1] It was discovered in 1972 byTu Youyou, who shared the 2015Nobel Prize in Physiology or Medicine for her discovery.[2]Artemisinin-based combination therapies (ACTs) have become standard treatment worldwide forP. falciparum malaria as well as malaria due to other species ofPlasmodium.[3] Artemisinin can beextracted from the herbArtemisia annua (sweet wormwood), which is used intraditional Chinese medicine. Alternatively, it can be prepared by asemi-synthetic method from a precursor compound that can be produced using agenetically engineeredyeast, which is much more efficient than extraction from the plant.[4]
Artemisinin and its derivatives are allsesquiterpene lactones containing an unusualperoxide bridge. This endoperoxide1,2,4-trioxane ring is responsible for their antimalarial properties. Few other natural compounds with such a peroxide bridge are known.[5]
Artemisinin and its derivatives have been used for the treatment of malarial andparasitic worm (helminth) infections. Advantages of such treatments over other anti-parasitics include faster parasite elimination and broader efficacy across the parasite life-cycle; disadvantages include their lowbioavailability, poorpharmacokinetic properties, and high cost.[6][7] Moreover, use of the drug by itself as amonotherapy is explicitly discouraged by theWorld Health Organization,[8] as there have been signs that malarial parasites are developingresistance to the drug.[9]Combination therapies, featuring artemisinin or its derivatives alongside some other antimalarial drug, constitute the contemporary standard-of-care treatment regimen for malaria.[10]
TheWorld Health Organization (WHO) recommends artemisinin or one of its derivatives ― typically in combination with a longer-lastingpartner drug ― as frontline therapy for all cases of malaria.[3] Foruncomplicated malaria, the WHO recommends three days of oral treatment with any of five artemisinin-based combination therapies (ACTs):artemether/lumefantrine,artesunate/amodiaquine (ASAQ),artesunate/mefloquine,dihydroartemisinin/piperaquine, orartesunate/sulfadoxine/pyrimethamine.[3] In each of these combinations, the artemisinin derivative rapidly kills the parasites, but is itself rapidly cleared from the body.[11] The longer-lived partner drug kills the remaining parasites and provides some lingering protection from reinfection.[12]
Forsevere malaria, the WHO recommendsintravenous orintramuscular treatment with the artemisinin derivativeartesunate for at least 24 hours.[13] Artesunate treatment is continued until the treated person is well enough to take oral medication. They are then given a three-day course of an ACT, for uncomplicated malaria.[13] Where artesunate is not available, the WHO recommends intramuscular injection of the less potent artemisinin derivativeartemether.[14] For children less than six years old, if injected artesunate is not available the WHO recommendsrectal administration of artesunate, followed by referral to a facility with the resources for further care.[13]
Artemisinins are not used for malaria 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.[citation needed]
The WHO recommends avoiding ACT for women in their first trimester of pregnancy due to a lack of research on artemisinin's safety in early pregnancy. Instead the WHO recommends a seven-day course ofclindamycin andquinine.[15] For pregnant women in their second or third trimesters, the WHO recommends a normal treatment course with an ACT.[16] For some other groups, certain ACTs are avoided due to side effects of the partner drug: sulfadoxine-pyrimethamine is avoided during the first few weeks of life as it interferes with the action ofbilirubin and can worsenneonatal jaundice.[17] InHIV-positive people, the combination oftrimethoprim/sulfamethoxazole,zidovudine-containingantiretroviral treatments, andASAQ is associated withneutropenia. The combination of the HIV drugefavirenz and ASAQ is associated with liver toxicity.[18]
Artemisinins are generally well tolerated at the doses used to treat malaria.[19] The side effects from the artemisinin class of medications are similar to the symptoms of malaria:nausea,vomiting,loss of appetite, anddizziness. Mild blood abnormalities have also been noted. A rare but serious adverse effect isallergic reaction.[19][20] One case of significantliver 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).[21] The drugs used in combination therapies can contribute to the adverse effects experienced by those undergoing treatment. Adverse effects in patients with acuteP. falciparum malaria treated with artemisinin derivatives tend to be higher.[22]
An unusual component of the artemisinin molecules is an endoperoxide 1,2,4-trioxane ring. This is the main antimalarial centre of the molecule.[23] Modifications at carbon 10 (C10) position give rise to a variety of derivatives which are more powerful than the original compound.[24] Because the physical properties of artemisinin itself, such as poor bioavailability, limit its effectiveness, semisyntheticderivatives of artemisinin have been developed. Derivatives ofdihydroartemisinin were made since 1976.Artesunate,arteether, andartemether were first synthesized in 1986. Many derivatives have been produced of whichartelinic acid,artemotil, artemisone, SM735, SM905, SM933, SM934, and SM1044 are among the most powerful compounds.[25][26] There are also simplified analogs inpreclinical development.[27] Over 120 other derivatives have been prepared, but clinical testing has not been possible due to lack of financial support.[23]
Artemisinin is poorly soluble in oils and water. Therefore, it is typically administered via the digestive tract, either by oral or rectal administration. Artesunate however can be administered via the intravenous and intramuscular, as well as the oral and rectal routes.[28] A synthetic compound with a similar trioxolane structure (a ring containing three oxygen atoms) namedRBx-11160[29] showed promise inin 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.[30]
As of 2018, the exact mechanism of action of artemisinins has not been fully elucidated.[31] Artemisinin itself is aprodrug of the biologically activedihydroartemisinin. Thismetabolite undergoes cleavage of itsendoperoxide ring inside theerythrocytes. As the drug molecules come in contact with thehaem (associated with thehemoglobin of the red blood cells), theiron(II) oxide breaks the endoperoxide ring.[32] This process producesfree radicals that in turn damage susceptible proteins, resulting in the death of the parasite.[33][34] In 2016 artemisinin was shown to bind to a large number of targets suggesting that it acts in a promiscuous manner. Artemisinin's endoperoxide moiety is however less sensitive to free iron(II) oxide, and therefore more active in the intraerythrocytic stages ofP. falciparum.[35] In contrast, clinical practice shows that unlike other antimalarials, artemisinin is active during all life cycle stages of the parasite.[36]
Clinical evidence for artemisinindrug resistance in southeast Asia was first reported in 2008,[37] and was subsequently confirmed by a detailed study from westernCambodia.[38][39] Resistance in neighbouringThailand was reported in 2012,[40] and in northern Cambodia,Vietnam and easternMyanmar in 2014.[41][42] Emerging resistance was reported in southernLaos, central Myanmar and northeastern Cambodia in 2014.[41][42] The parasite'skelch gene on chromosome 13 appears to be a reliable molecular marker for clinical resistance in Southeast Asia.[43]
In 2011, the WHO stated that resistance to the most effective antimalarial drug, artemisinin, could unravel national Indian 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.[44]
Artemisinins can be used alone, but this leads to a high rate ofreturn of parasites and other drugs are required to clear the body of all parasites and prevent a recurrence. The 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.[45]
Two main mechanisms of resistance drivePlasmodium resistance to antimalarial drugs. The first one is an efflux of the drug away from its action site due to mutations in different transporter genes (likepfcrt inchloroquine resistance) or an increased number of the gene copies (like pfmdr1 copy number inmefloquine resistance). The second is a change in the parasite target due to mutations in corresponding genes (like, at the cytosol level,dhfr anddhps insulfadoxine-pyrimethamine resistance or, at the mitochondrion level,cytochrome b inatovaquone resistance). Resistance ofP. falciparum to the new artemisinin compounds involves a novel mechanism corresponding to a quiescence phenomenon.[46]
The biosynthesis of artemisinin in the plantArtemisia annua is believed to involve themevalonate pathway (MVA) and the cyclization offarnesyl diphosphate (FDP). It is not clear whether thenon-mevalonate pathway can also contribute 5-carbon precursors (IPP orDMAPP), 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.[47] Ring expansion by the cleavage of hydroperoxide and a second oxygen-mediated hydroperoxidation finish the biosynthesis of artemisinin.[48][49]
The total synthesis of artemisinin has been performed from available organic starting materials, using basic organic reagents, many times. The first two total syntheses were astereoselective synthesis by Schmid and Hofheinz atHoffmann-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).[50] 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 diastereoselective; and further reduction, oxidation, and desilylation steps performed on this mono-carbocyclic intermediate, including a finalsinglet oxygen-utilizingphotooxygenation andene reaction, which, after acidic workup closed the three remaining oxacyclic rings of the desired product, artemisinin, in a single step.[50][51][52] (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,[50] and even2-cyclohexen-1-one,[53] as well as routes better described as partial orsemisyntheses from a more plentiful biosynthetic precursor, artemisinic acid—in the latter case, including some very short and very high yieldingbiomimetic synthesis examples (of Roth and Acton, and Haynes et al., 3 steps, 30% yield), which again feature the singlet oxygen ene chemistry.[54][50][55][56]
The partnership to develop semisynthetic artemisinin was led byPATH's Drug Development program (through an affiliation with OneWorld Health), with funding from theBill & Melinda Gates Foundation. The project began in 2004, and initial project partners included theUniversity of California, Berkeley (which provided the technology on which the project was based – a process that genetically altered yeast to produce artemisinic acid)[57] and Amyris (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 engineeredSaccharomyces cerevisiae yeast to produce a 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 US$0.25 per dose. In this effort ofsynthetic biology, a modified mevalonate pathway was used, and the yeast cells were engineered to express the enzymeamorphadiene synthase and acytochrome P450monooxygenase (CYP71AV1), both fromArtemisia annua. A three-step oxidation ofamorpha-4,11-diene gives the resulting artemisinic acid.[58]
The UC 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.[citation needed]
Commercial production of semisynthetic artemisinin is now underway atSanofi'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.[59] The production goal is set at 35 tonnes for 2013. It is expected to increase to 50–60 tons per year in 2014, supplying approximately one-third of the global annual need for artemisinin.[citation needed]
In 2013, WHO's 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.[60] Sanofi's active pharmaceutical ingredient (API) produced from semisynthetic artemisinin (artesunate) was also prequalified by WHO on May 8, 2013, making it the first semisynthetic artemisinin derivative prequalified.[citation needed]
In 2010, a team fromWageningen University and Research reported they had engineered a close relative of tobacco,Nicotiana benthamiana, that can also produce the precursor, artemisinic acid.[61]
China and Vietnam provide 70% and East Africa 20% of the raw plant material.[62] 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 a solvent, typicallyhexane. Alternative extraction methods have been proposed.[63] The market price for artemisinin has fluctuated widely, betweenUS$120 and $1,200 per kilogram from 2005 to 2008.[64]
The Chinese companyArtepharm created a combination artemisinin andpiperaquine drug marketed as Artequick. In addition toclinical research performed in China and southeast Asia, Artequick was used in large-scale malaria eradication efforts in theComoros. Those efforts, conducted in 2007, 2012, and 2013–14, produced a 95–97% reduction in the number of malaria cases in the Comoros.[65]
After negotiation with the WHO,Novartis and Sanofi provide ACT drugs at cost on a nonprofit basis; however, these drugs are still more expensive than other malaria treatments.[66] Artesunate injection for severe malaria treatment is made by theGuilin Pharmaceutical factory in China where production has received WHO prequalification.[67] High-yield varieties ofArtemisia are being produced by the Centre for Novel Agricultural Products at theUniversity of York using molecular breeding techniques.[64]
Using seed supplied by Action for Natural Medicine (ANAMED), theWorld Agroforestry Centre (ICRAF) has developed a hybrid, dubbed A3, which can grow to a height of 3 meters and produce 20 times more artemisinin than wild varieties. In northwesternMozambique, ICRAF is working together with a medical organization,Médecins Sans Frontières, 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. However, the WHO does not recommend the use ofA. annua plant materials, including tea, for the prevention and treatment of malaria.[68]
In 2013, Sanofi announced the launch[59] of a production facility in Garessio, Italy, to manufacture the antiplasmodial drug on a large scale. The partnership to create a new pharmaceutical manufacturing process was led byPATH's 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 byJay Keasling at UC Berkeley and optimized byAmyris. The reaction is followed by aphotochemical 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 tonnes in 2014. The price per kilogram will be US$350–400, roughly the same as the botanical source.[69] Despite concerns that this equivalent source would lead to the demise of companies, which produce this substance conventionally through extraction ofA. annua biomass, an increased supply of this drug will likely produce lower prices and therefore increase the availability for ACT treatment. In 2014, Sanofi announced the release of the first batch of semisynthetic artemisinin. 1.7 million doses of Sanofi'sASAQ, a fixed-dose artemisinin-based combination therapy will be shipped to half a dozen African countries over the next few months.[70]
A 2016 systematic review of four studies from East Africa concluded that subsidizing ACT in the private retail sector in combination with training and marketing has led to the increased availability of ACT in stores, increased use of ACT for febrile children under five years of age, and decrease in the use of older, less effective antimalarials among children under five years of age. The underlying studies did not determine if the children had malaria nor determine if there were health benefits.[71]
After ingestion or injection, artemisinin and its derivatives (arteether, artemether, and artesunate) are all rapidly converted in the bloodstream todihydroartemisinin (DHA), which has 5–10 times greater antimalarial potency than artemisinin.[72] DHA is eventually converted in the liver into metabolites such as deoxyartemisinin, deoxydihydroartemisinin, and 9,10-dihydrodeoxyartemisinin. These reactions are catalyzed by the enzymesCYP2A6,CYP3A4, andCYP3A5, which belong to thecytochrome P450 group present in thesmooth endoplasmic reticulum. These metabolites lack antimalarial properties due to the loss of the endoperoxide group (deoxyartemisinin however has anti-inflammatory and antiulcer properties.[73]) All these metabolites undergoglucuronidation, after which they are excreted through the urine or feces.Glucuronosyltransferases, in particularUGT1A9 andUGT2B7, are responsible for this process. DHA is also removed throughbile as minorglucuronides. Due to their rapid metabolism, artemisinin and its derivatives are relatively safe drugs with a relatively hightherapeutic index.[6]
Artemisinin is an antimalarial lactone derived fromqinghao (青蒿,Artemisia annua or sweet wormwood). In 1596,Li Shizhen recommended tea made fromqinghao specifically to treat malaria symptoms in hisCompendium of Materia Medica. The genus name is derived from the Greek goddessArtemis and, more specifically, may have been named after QueenArtemisia II of Caria, a botanist and medical researcher in the fourth century BC.[74]
Artemisia annua – a commonherb found in many parts of the world. In 1967, a plant screening research program, under a secret military program code-named "Project 523", was set up by thePeople's Liberation Army to find an adequate treatment for malaria; the program and early clinical work were ordered byMao Zedong at the request ofNorth Vietnamese leaders to provide assistance for their malaria-ridden army.[75] In the course of this research in 1972,Tu Youyou discovered artemisinin in the leaves ofArtemisia annua.[76]
Namedqinghaosu (Chinese:青蒿素;lit. 'compound of green-blue wormwood'),[76][77] it was one of many candidates tested as possible treatments for malaria by Chinese scientists, from a list of nearly 2,000traditional Chinese medicines.[78] 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 sourceThe Handbook of Prescriptions for Emergency Treatments written in 340 CE byGe Hong saying that this herb should be steeped in cold water.[79] This book contained the useful reference to the herb: "A handful ofqinghao immersed with two litres of water, wring out the juice and drink it all."
Tu's team subsequently isolated anextract.[76] Results were published in theChinese Medical Journal in 1979.[76][80][5] The extracted substance, once subject to purification, proved to be a useful starting point to obtain purified artemisinin.[76] A 2012 review reported that artemisinin-based therapies were the most effective drugs for treatment of malaria at that time;[81] 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, includinglumefantrine,piperaquine, andpyronaridine.[76]
In the late 1990s, Novartis filed a new Chinese patent for a combination treatment with artemether/lumefantrine, providing the first artemisinin-based combination therapies (Coartem) at reduced prices to the WHO.[82] 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.[83]
In 2011, Tu Youyou was awarded theLasker-DeBakey Clinical Medical Research Award for her role in the discovery and development of artemisinin.[76][84] On October 5, 2015, she was awarded half of the 2015Nobel Prize in Physiology or Medicine for discovering artemisinin, "a drug that has significantly reduced the mortality rates for patients suffering from malaria".[2] The other half of the prize was awarded jointly toWilliam C. Campbell andSatoshi Ōmura for discoveringavermectin, "the derivatives of which have radically lowered the incidence ofriver blindness andlymphatic filariasis, as well as showing efficacy against an expanding number of other parasitic diseases".[2]
The WHO notes four additional ACTs that are in preliminaryclinical trials or regionally used for which there is no evidence to recommend widespread use:artesunate/pyronaridine,arterolane-piperaquine, artemisinin-piperaquine base, and artemisinin/naphthoquine.[85]
A serendipitous discovery was made in China in the early 1980s while searching for novelanthelmintics forschistosomiasis that artemisinin was effective againstschistosomes,[86][87] the human bloodflukes, which are the second-most prevalent parasitic infections, after malaria. Artemisinin and its derivatives are all potent antihelmintics.[88] Artemisinins were later found to possess a broad spectrum of activity against a wide range oftrematodes, includingSchistosoma japonicum,S. mansoni,S. haematobium,Clonorchis sinensis,Fasciola hepatica, andOpisthorchis viverrini.[89][90]
Artemisinin and its derivatives are under laboratory research for their potential anti-cancer effects.[1][91] As of 2018, only preliminary clinical research had been conducted using artemisininin derivatives in various cancers, with no approved clinical applications.[92]
Artemisinin derivatives may suppress immune reactions, such as inflammation. One derivative, SM934, was approved in 2015 by the ChineseNational Medical Products Administration for a clinical trial as a drug forsystemic lupus erythematosus.[93]
Artemisinin may be potentially useful for treating symptoms of polycystic ovary syndrome (PCOS).[94]
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Media related toArtemisinin at Wikimedia CommonsArtemisinin has proven to be the most effective anti-malarial drug ever produced.