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Artemisinin and Traditional Chinese Medicine (TCM)

December 2, 2019

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Artemisia annua found in China
Photo credit: by Jorge Ferreira - Original work by Jorge Ferreira, Public Domain; Wikipedia Commons

Artemisia annua is a common 1) ___ found in many parts of the world, and has been used by Chinese herbalists for more than 2000 years in the treatment of malaria. The earliest record dates back to 200 BCE, in the Fifty-two Prescriptions unearthed from the Mawangdui. Its antimalarial application was first described in Zhouhou Beiji Fang (The Handbook of Prescriptions for Emergencies, edited in the middle of the 4th century CE by Ge Hong. In that book, 43 malaria treatment methods were recorded. Images of the original scientific papers that record the history of the discovery, have been available online since 2006.

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 2) ___. The program and early clinical work were ordered of 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. The drug is named qinghaosu in Chinese. It was one of many candidates tested as possible treatments for malaria by Chinese scientists from a list of nearly 5,000 traditional 3) ___ 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."

Artemisinin and its semisynthetic derivatives are a group of drugs used against malaria due to Plasmodium falciparum. It was discovered in 1972 by Tu Youyou, a Chinese scientist, who was co-recipient of the 2015 Nobel Prize in Medicine for her discovery. 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 Traditional Chinese 4) ___ (TCM). A precursor compound can be produced using a genetically-engineered yeast, which is much more efficient than using the plant.

Chemically, artemisinin is a sesquiterpene lactone containing an unusual peroxide bridge. This endoperoxide 1,2,4-trioxane ring is responsible for the drug's mechanism of action. Few other natural compounds with such a peroxide bridge are known.

Artemisinin and its derivatives have been used for the treatment of malarial and parastic worm (helminth) infections. They have the advantage over other drugs in having an ability to kill faster and kill all the life cycle stages of the parasites. But low bioavailability, poor pharmacokinetic properties and high 5) ___ of the drugs are major drawbacks of their use. 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 or its derivatives with some other antimalarial drug are the preferred treatment for malaria.

Artemisinin and its derivatives are also under laboratory research for their potential anti-cancer effects. As of 2018, only preliminary clinical research had been conducted using 6) ___ derivatives in various cancers, with no approved clinical applications. Artemisinin derivatives are known for their ability to suppress immune reactions such as inflammation. One derivative, SM934, was approved in 2015 by the China Food and Drug Administration for clinical trial as a drug for systemic lupus erythematosus. Experiments in animal models have given good results. It can regulate T cell subsets, inhibit the activation of B cells, block the production of inflammatory cytokines and NF-?B signal transduction pathway.

Artemisinins are generally well tolerated at the doses used to treat malaria. The side effects from the artemisinin class of medications are similar to the symptoms of malaria: nausea, vomiting, loss of appetite, and dizziness. Mild blood abnormalities have also been noted. A rare but serious adverse effect is allergic reaction. 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). The drugs used in combination therapies can contribute to the adverse effects experienced by those undergoing treatment. Adverse 7) ___ in patients with acute P. falciparum malaria treated with artemisinin derivatives tend to be higher.

The partnership to develop semisynthetic artemisinin was led by PATH's 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 (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 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 A. annua. A three-step oxidation of amorpha-4,11-diene gives the resulting artemisinic acid. 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. The production goal was originally set at 35 tons for 2013 50-60 tons per year thereafter, supplying approximately one third of the global annual 8) ___ for artemisinin. On May 8, 2013, WHO's Prequalification of Medicines Program 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 reported they had engineered a close relative of tobacco, Nicotiana benthamiana, that can also produce the precursor artemisinic acid. 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 Chinese company Artepharm created a combination artemisinin and piperaquine drug marketed as Artequick. In addition to clinical studies 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-Aventis 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, M?decins sans frontieres, 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 9) ___. In April 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 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. The price per kilogram is 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 10) ___ and therefore increase the availability for ACTs treatment.

ANSWERS: 1) herb; 2) malaria; 3) Chinese; 4) medicine; 5) cost; 6) artemisinin; 7) effects; 8) need; 9) tea; 10) prices

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