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Artemisinin () and its semisynthesis derivatives are a group of medication used in the treatment of malaria due to Plasmodium falciparum. It was discovered in 1972 by Tu Youyou, who shared the 2015 Nobel Prize in Physiology or Medicine for her discovery. Artemisinin-based combination therapies (ACTs) have become standard treatment worldwide for P. falciparum malaria as well as malaria due to other species of Plasmodium. Artemisinin can be extracted from the herb Artemisia annua (sweet wormwood), which is used in traditional Chinese medicine. Alternatively, it can be prepared by a Semisynthesis method from a precursor compound that can be produced using a genetically engineered yeast, which is much more efficient than extraction from the plant.
Artemisinin and its derivatives are all sesquiterpene lactones containing an unusual Organic peroxide bridge. This endoperoxide 1,2,4-trioxane ring is responsible for their antimalarial properties. Few other natural compounds with such a peroxide bridge are known.
Artemisinin and its derivatives have been used for the treatment of malarial and Helminthiasis infections. Advantages of such treatments over other anti-parasitics include faster parasite elimination and broader efficacy across the parasite life-cycle; disadvantages include their low bioavailability, poor pharmacokinetic properties, and high cost. Moreover, 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 Drug resistance to the drug. Combination therapies, featuring artemisinin or its derivatives alongside some other antimalarial drug, constitute the contemporary standard-of-care treatment regimen for malaria.
For severe malaria, the WHO recommends intravenous or intramuscular treatment with the artemisinin derivative artesunate for at least 24 hours. 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. Where artesunate is not available, the WHO recommends intramuscular injection of the less potent artemisinin derivative artemether. For children less than six years old, if injected artesunate is not available the WHO recommends rectal administration of artesunate, followed by referral to a facility with the resources for further care.
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.
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. A synthetic compound with a similar trioxolane structure (a ring containing three oxygen atoms) named arterolane 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.
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.
Artemisinins can be used alone, but this leads to a high rate of recrudescence 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.
Two main mechanisms of resistance drive Plasmodium 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 (like pfcrt in chloroquine resistance) or an increased number of the gene copies (like pfmdr1 copy number in mefloquine resistance). The second is a change in the parasite target due to mutations in corresponding genes (like, at the cytosol level, dhfr and dhps in sulfadoxine-pyrimethamine resistance or, at the mitochondrion level, cytochrome b in atovaquone resistance). Resistance of P. falciparum to the new artemisinin compounds involves a novel mechanism corresponding to a quiescence phenomenon.
A wide variety of further routes continue to be explored, from early days until today, including total synthesis routes from ( R)-(+)-pulegone, isomenthene, and even cyclohexenone, as well as routes better described as partial or semisynthesis from a more plentiful biosynthetic precursor, artemisinic acid—in the latter case, including some very short and very high yielding biomimetic synthesis examples (of Roth and Acton, and Haynes et al., 3 steps, 30% yield), which again feature the singlet oxygen ene chemistry.
In 2006, a team from UC Berkeley reported they had engineered Saccharomyces 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 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 Artemisia annua. A three-step oxidation of amorpha-4,11-diene gives the resulting artemisinic acid.
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.
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. 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.
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.
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. "Effectiveness of Non-Pharmaceutical Forms of Artemisia annua L. against malaria". World Health Organization. Global Malaria Programme. Position Statement (June 2012). Retrieved April 2020.
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 Photochemistry 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.
Named qinghaosu (l=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 a 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 Onchocerciasis and lymphatic filariasis, as well as showing efficacy against an expanding number of other parasitic diseases".
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