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. 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. 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. in 2010, a team from wageningen university and research reported they had engineered a close relative of tobacco, nicotiana benthamiana, that can also produce the precursor, artemisinic acid. 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 a solvent, typically hexane. alternative extraction methods have been proposed. the market price for artemisinin has fluctuated widely, between us$120 and $1,200 per kilogram from 2005 to 2008. the chinese company artepharm created a combination artemisinin and piperaquine drug marketed as artequick. in addition to clinical research performed in china and southeast asia, artequick was used in large-scale malaria eradication efforts in the comoros. those efforts, conducted in 2007, 2012, and 2013–14, produced a 95–97% reduction in the number of malaria cases in the comoros. 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. artesunate injection for severe malaria treatment is made by the guilin pharmaceutical factory in china where production has received who prequalification. high-yield varieties of artemisia are being produced by the centre for novel agricultural products at the university of york using molecular breeding techniques. 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 meters and produce 20 times more artemisinin than wild varieties. in northwestern mozambique, 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 of a. annua plant materials, including tea, for the prevention and treatment of malaria. in 2013, sanofi announced the launch 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 by path'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 by jay keasling at uc 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 tonnes in 2014. the price per kilogram will be us$350–400, roughly the same as the botanical source. 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 availability for act treatment. in 2014, sanofi announced the release of the first batch of semisynthetic artemisinin. 1.7 million doses of sanofi's asaq, a fixed-dose artemisinin-based combination therapy will be shipped to half a dozen african countries over the next few months. 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. metabolism after ingestion or injection, artemisinin and its derivatives (arteether, artemether, and artesunate) are all rapidly converted in the bloodstream to dihydroartemisinin (dha), which has 5–10 times greater antimalarial potency than artemisinin. dha is eventually converted in the liver into metabolites such as deoxyartemisinin, deoxydihydroartemisinin, and 9,10-dihydrodeoxyartemisinin. these reactions are catalyzed by the enzymes cyp2a6, cyp3a4, and cyp3a5, which belong to the cytochrome p450 group present in the smooth endoplasmic reticulum. these metabolites lack antimalarial properties due to the loss of the endoperoxide group (deoxyartemisinin however has anti-inflammatory and antiulcer properties.) all these metabolites undergo glucuronidation, after which they are excreted through the urine or feces. glucuronosyltransferases, in particular ugt1a9 and ugt2b7, are responsible for this process. dha is also removed through bile as minor glucuronides. due to their rapid metabolism, artemisinin and its derivatives are relatively safe drugs with a relatively high therapeutic index. history etymology artemisinin is an antimalarial lactone derived from qinghao (青蒿, artemisia annua or sweet wormwood). in 1596, li shizhen recommended tea made from qinghao 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 bc. discovery main article: project 523 artemisia annua artemisia annua – a common herb 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 the people's liberation army to find an adequate treatment for malaria; the program and early clinical work were ordered by mao zedong at the request of north vietnamese leaders to provide assistance for their malaria-ridden army. in the course of this research in 1972, tu youyou discovered artemisinin in the leaves of artemisia annua. named qinghaosu (chinese: 青蒿素; lit. 'compound of green-blue wormwood'), it was one of many candidates tested as possible treatments for malaria by chinese scientists, from a list of nearly 2,000 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 the handbook of prescriptions for emergency treatments written in 340 ce by ge hong saying that this herb should be steeped in cold water. this book contained the useful reference to the herb: "a handful of qinghao immersed with two litres of water, wring out the juice and drink it all." tu's team subsequently isolated an extract. results were published in the chinese medical journal in 1979. the extracted substance, once subject to purification, proved to be useful starting point to obtain purified artemisinin. a 2012 review reported that artemisinin-based therapies were the most effective drugs for treatment of malaria at that time; 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. 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. 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. in 2011, tu youyou was awarded the lasker-debakey clinical medical research award for her role in the discovery and development of artemisinin. on october 5, 2015, she was awarded half of the 2015 nobel prize in physiology or medicine for discovering artemisinin, "a drug that has significantly reduced the mortality rates for patients suffering from malaria". the other half of the prize was awarded jointly to william c. campbell and satoshi ōmura for discovering avermectin, "the derivatives of which have radically lowered the incidence of river blindness and lymphatic filariasis, as well as showing efficacy against an expanding number of other parasitic diseases". research new artemisinin-based combination therapies the who notes four additional acts that are in preliminary clinical trials or regionally used for which there is no evidence to recommend widespread use: artesunate/pyronaridine, arterolane-piperaquine, artemisinin-piperaquine base, and artemisinin/naphthoquine. helminthiasis a serendipitous discovery was made in china in the early 1980s while searching for novel anthelmintics for schistosomiasis that 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 antihelmintics. 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. cancer artemisinin and its derivatives are under laboratory research for their potential anti-cancer effects. as of 2018, only preliminary clinical research had been conducted using artemisininin derivatives in various cancers, with no approved clinical applications. autoimmune disease artemisinin derivatives may suppress immune reactions, such as inflammation. one derivative, sm934, was approved in 2015 by the chinese national medical products administration for a clinical trial as a drug for systemic lupus erythematosus.