Project 523
Project 523 (
For their high efficacy, safety and stability, artemisinins such as
Background
The Vietnam War was fought between North Vietnam (with support from Communist countries such as Soviet Union and China) and South Vietnam (with support from the United States and its allies). The conflicts began in 1954 and became large-scale battles by 1961.
Execution and achievements
As the first line strategy, the troops were given synthetic drugs. Drug combinations using
Febrifugine from chángshān
The first interest was on chángshān, the root extract of Dichroa febrifuga. In the 1940s, Chinese scientists had shown that it was effective against different species of Plasmodium.[16] American scientists isolated febrifugine as its major active antimalarial compound.[17] The project scientists confirmed the antimalarial activity but found it unsuitable for human use due to its overwhelming potency and toxicity, outrivaling that of quinine.[18] After the project, the compound remained under investigation, with attempts to discover suitable derivatives,[19][20][21] among which halofuginone is an effective drug against malaria, cancer, fibrosis and inflammatory disease.[22]
Discovery of artemisinin and its derivatives
The fourth-century Chinese physician Ge Hong's book Zhouhou Beiji Fang (Chinese: 《肘後備急方》; lit. 'The Handbook of Prescriptions for Emergencies'') described Artemisia annua extract, called qinghao, as a treatment of malarial fever.[23] Tu Youyou and her team were the first to investigate. In 1971 they found that their extract from the dried leaves (collected from Beijing) did not indicate any antimalarial activity.[4] On careful reading of Ge's description they changed their extraction method of using fresh leaves under low temperature. Ge explicitly describes the recipe as: "qinghao, one bunch, take two sheng [2 × 0.2 L] of water for soaking it, wring it out, take the juice, ingest it in its entirety".[1] Following the findings of scientists at the Yunnan Institute of Pharmacology, they found that only the fresh plant specimen collected from Sichuan province would yield the active compound.[3] They made the purified extract into tablets, which showed very low activity. They soon realized that the compound was very insoluble and made it in capsules instead. On 4 October 1971 they successfully treated malaria in experimental mice (infected with Plasmodium berghei) and monkeys (infected with Plasmodium cynomolgi) using the new extract.[4]
In August 1972 they reported a clinical trial in which 21 malarial patients were cured. In 1973 the Yunnan scientists and those at the Shandong Institute of Pharmacology independently obtained the antimalarial compound in a crystalline form gave the name huanghaosu or huanghuahaosu,[3] eventually renamed qinghaosu (yet later to be popularised as "artemisinin", after the botanical name).[12] The same year Tu synthesized the compound dihydroartemisinin from the extract. This compound was more soluble and potent than the native compound. Other scientists subsequently synthesized other artemisinin derivatives, of which the most important are artemether and artesunate.[24] All clinical trials by this time confirmed that artemisinins are more effective than the conventional antimalarial drugs, such as chloroquine and quinine.[12] A group of scientists in Shanghai, including chemist Wu Yulin, determined artemisinin's chemical structure in 1975 and published it in 1977 when the secrecy rules lifted.[3] The artemisinins became the most potent as well as the safest and most rapidly acting antimalarial drugs,[25] recommended by the World Health Organization for the treatment of different types of malaria.[26]
Discovery of synthetic drugs
Project 523 also resulted in the discovery of synthetic drugs such as pyronaridine in 1973, lumefantrine in 1976 and naphthoquine in 1986. These are all antimalarial drugs and are still used in artemisinin-combination therapy.[12]
Termination and legacy
After Saigon fell on 30 April 1975, ending the Vietnam War, the military purpose of Project 523 subsided. Researchers could not publish their findings but could share their works within the working groups. The first publication in English (and thus circulated outside China) was in the December 1979 issue of the Chinese Medical Journal, authored simply by the Qinghaosu Antimalaria Coordinating Research Group.[27] This attracted collaboration with the Special Programme for Research and Training in Tropical Diseases (TDR), sponsored by the United Nations Children's Fund, the United Nations Development Programme, the World Bank, and WHO, but the research remained closed to non-Chinese scientists. By the early 1980s, research had practically stopped, and the project was officially terminated in 1981.[8] The TDR took this opportunity to organise the first international conference in Beijing on artemisinin and its variants in 1981. Supported by WHO, the Chinese Ministry of Health established the National Chinese Steering Committee for Development of Qinghaosu and its Derivatives to continue the important achievements of Project 523.[8]
The first international collaboration was between Keith Arnold at the Roche Far East Research Foundation, Hong Kong, and Chinese researchers Jing-Bo Jiang, Xing-Bo Guo, Guo-Qiao Li, and Yun Cheung Kong.[28] They made their first international publication in 1982 in The Lancet, in which they reported the comparative efficacy of artemisinin and mefloquine on chloroquine-resistant Plasmodium falciparum.[29] Arnold was among those who developed mefloquine in 1979 and was planning to test the new drug in China. He and his wife Moui became the most important people in translating the historical account of the Project 523 and bringing it to international recognition.[30] The Division of Experimental Therapeutics at the Walter Reed Army Institute of Research, under the United States Army, was the first to produce artemisinin and its derivatives outside China. Their production paved the way for commercial success.[31]
Invention of Coartem
Artemether was more promising for clinical drug than its parent molecule artemisinin. In 1981, the National Steering Committee for Development of Qinghaosu (artemisinin) and its Derivatives authorised Zhou Yiqing, who was working at the Institute of Microbiology and Epidemiology of the Chinese Academy of Military Medical Sciences, to work on artemether.[32] Zhou showed that artemether combined with another antimalarial lumefantrine was the most potent of all antimalarial drugs. He worked alone for four years, and Ning Dianxi and his team joined Zhou in 1985. They found that in clinical trials the combined tablet had cure rate of severe malaria of more than 95%, including in areas where multi-drug resistance is experienced.[33] They applied for patent in 1991 but received it only in 2002. In 1992, they registered it as a new drug in China. Noticing this, Novartis signed a pact for mass production. In 1999, Novartis obtained the international licensing rights and gave the brand name Coartem. The US Food and Drug Administration approved the drug in 2009.[34]
See also
- Yunnan Baiyao
- Drug discovery
- Antimalarial medication
- Artemisinin (major contributors: Yu Yagang (余亚纲), Gu Guoming (顾国明), Tu Youyou (屠呦呦), Luo Zeyuan (罗泽渊), Li Guoqiao (李国桥) et al., 1972)
- Dihydroartemisinin (Tu Youyou et al., 1973)
- Pyronaridine (1973)
- Artemether (Li Ying (李英), 1975)
- Lumefantrine (1976)
- Artesunate (Li Guoqiao (李国桥), 1977)
- Artemether/lumefantrine (Zhou Yiqing (周义清), 1985)
- Naphthoquine (1986)
- History of science and technology in the People's Republic of China
- List of Chinese discoveries and List of Chinese inventions
- Chinese herbology and Traditional Chinese medicine
References
- ^ PMID 16722826.
- ^ a b Senthilingam, Meera. "Chemistry in its element: compounds: Artemisinin". Chemistry World. Royal Society of Chemistry. Retrieved 27 April 2015.
- ^ a b c d e f Hao, Cindy (2011-09-29). "Lasker Award Rekindles Debate Over Artemisinin's Discovery". Science. Retrieved 2020-07-23.
- ^ S2CID 10021463.
- ^ "European Inventor Award: An Ancient Cure for Malaria". European Patent Office. Retrieved 23 April 2015.
- ^ Shapiro, Lucy. "Lasker~DeBakey Clinical Medical Research Award 2011 Winners". Lasker Foundation. Archived from the original on 23 June 2015. Retrieved 29 April 2015.
- ^ Spector, Ronald H. "Vietnam War". Encyclopædia Britannica. Retrieved 27 April 2015.
- ^ PMID 19876540.
- JSTOR 4377015.
- ^ Phillips, Tom (11 May 2016). "The Cultural Revolution: all you need to know about China's political convulsion". The Guardian. Retrieved 27 September 2019.
- ISBN 978-1976739583.
The personnel working for Project 523 was divided into several groups: The clinical group (going to malaria endemic areas and observe the efficacy of the existing anti-malarial drugs), Chinese medicine group (searching literature, and going to folks to find recipes, and collecting herbs' sample), and the chemical synthesis group (doing the synthesis work of new drugs in cooperation with pharmaceutical companies).
- ^ PMID 19803708.
- PMID 15728920.
- .
- PMID 27957318.
- S2CID 4115563.
- PMID 15422372.
- PMID 20695174.
- PMID 15728920.
- PMID 22247880.
- PMID 24650700.
- PMID 22327401.
- PMID 16566952.
- PMID 3887571.
- PMID 17434195.
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- PMID 117984.
- PMID 22059236.
- S2CID 28166535.
- ^ McNeil, D.G.Jr. (16 January 2012). "For Intrigue, Malaria Drug Gets the Prize". The New York Times. Retrieved 4 May 2015.
- PMID 18693553.
- PMID 19876540.
- PMID 19818172.
- PMID 19818170.
Further reading
- Jianfang, Zhang (2013). Detailed Chronological Record of Project 523 and the Discovery and Development of Qinghaosu (Artemisinin). Translated by Arnold, Keith; Arnold, Muoi. Houston, Texas: Strategic Book Publishing. ISBN 978-1-62212-164-9.