Project 523

The Project 523 (or task number five hundred and twenty-three; Chinese: 523项目)[1] is a code name for the secret military project of the People's Republic of China during and after the Cultural Revolution, for antimalarial medications, which were urged in the Vietnam War.[2] The name stood for 23 May, the day the project was launched in 1967. It was aimed at finding new drugs for malaria, the disease which claimed more lives than the actual battles.[3] At the behest of Hồ Chí Minh, Prime Minister of the Democratic Republic of Vietnam (then North Vietnam), Zhou Enlai, the Premier of the People's Republic of China, convinced Mao Zedong, Chairman of the Communist Party of China, to start a mass project for development of new antimalarial drug "to keep [the] allies' troops combat-ready", as they put down in the meeting minute. More than 500 Chinese scientists were recruited. The project was divided into two streams, one for developing synthetic compounds, and the other for investigating traditional Chinese medicine. The latter proved to be the more fruitful, directly resulting in the discovery and development of a class of new antimalarial drugs called artemisinins.[4] It was officially terminated in 1981.

For their high efficacy, safety and stability, artemisinins such as artemether and artesunate became the drugs of choice in falciparum malaria. Their combination drugs are advocated by the World Health Organization, and are included in the World Health Organization's List of Essential Medicines. Among the scientists of the project, Zhou Yiqing and his team at the Institute of Microbiology and Epidemiology of the Chinese Academy of Military Medical Sciences, were awarded the European Inventor Award of 2009 in the category "Non-European countries" for the development of Coartem (artemether-lumefantrine combination drug).[5] Tu Youyou of the Qinghaosu Research Center, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, received both the 2011 Lasker-DeBakey Clinical Medical Research Award and 2015 Nobel Prize in Physiology or Medicine for her role in the discovery of artemisinin.[6]

Background

The Vietnam War was fought between the North Vietnam (supported by the Communist countries such as Soviet Union and China) and the South Vietnam (supported by the United States and its allies). The conflicts started in 1954 and became large-scale battles by 1961.[7] Although in a better warfare position, the People's Army of Vietnam (North Vietnamese Army) and its allies in the South, Viet Cong, suffered increasing mortality because of malaria epidemics. In some battle fields military strengths were reduced to half of the original, and in severe cases 90% of the troops were disabled.[8] Hồ Chí Minh, Prime Minister of the Democratic Republic of Vietnam (then North Vietnam), asked his compatriot Zhou Enlai, the Premier of the People's Republic of China, for medical help. By that time Mao Zedong, the Chairman of the Communist Party of China, had just introduced Cultural Revolution (1966-1971) which had resulted in closing of universities and banishment of many scientists and intellectuals. Mao, however, took Hồ Chí Minh's plea seriously and approved a military project. On 23 May 1967 a mass gathering of about 600 scientists was convened that included military personnel, scientists of different trades, including traditional practitioners. The meeting was the beginning of the military-research programme, code-named Project 523, simply named after the date (23 May) it was launched.[2] The project was divided into two streams, one for developing synthetic compounds, and the other for investigating traditional Chinese medicine. It was classified a top secret state mission. The project itself saved many scientists from the atrocities of Cultural Revolution.[8]

Execution and achievements

As the first line strategy, the troops were given synthetic drugs. Drug combinations using pyrimethamine and dapsone, pyrimethamine and sulfadoxine, and sulfadoxine and piperaquine phosphate were tested in the battlefield.[9] But these drug had serious adverse effects.[8] Therefore, the primary focus was to examine traditional Chinese medicines and look for new compounds. The first drug of interest was changshan, which was depicted in the earliest materia medica, the Canon of the Divine Husbandman’s Materia Medica. It is an extract from the roots of the plant Dichroa febrifuga. Among one of the earliest examined plants was huanghuahao (sweet wormwood, or scientifically, Artemisia annua). These two plants became a huge success in modern pharmacology.

Febrifugine from changshan

The first interest was on changshan, the root extract of Dichroa febrifuga. In the 1940s Chinese scientists had shown that changshan was effective against different species of Plasmodium.[10] American scientists isolated febrifugine as its major active antimalarial compound.[11] The project scientists confirmed the antimalarial activity, but found that it was so potent and toxic—much more potent than quinine—that it was unsuitable for human use.[12] (After the project, the compound is still under investigation with attempts to discover suitable derivatives,[13][14][15] among which halofuginone is shown to be an effective drug in malaria, cancer, fibrosis and inflammatory disease.[16])

Discovery of artemisinin and its derivatives

Artemisia annua, the source of the best antimalarial drugs

Artemisia annua extract, called qinghao, was described vividly in the fourth-century Chinese physician Ge Hong's book Zhouhou Beiji Fang (The Handbook of Prescriptions for Emergencies) as a treatment of malarial fever.[17] 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. On careful reading of Ge Hong's description they changed their extraction method of using fresh leaves under low temperature. Ge Hong 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". They found that the fresh plant specimen collected from Sichuan province only could yield the active compound. They made the purified extract into tablets, which but showed very low activity. They soon realized that the compound was very insoluble, and hence, made it in capsules. On 8 March 1972 they reported successful treatment of malaria in experimentally infected mice using the new extract. In August 1972 they reported clinical trial in which 21 malarial patients were cured. In 1973 scientists at the Yunnan Institute of Materia Medica and Shandong Institute of Traditional Medicine and Materia Medica obtained the antimalarial compound in a crystalline form gave the name huanghaosu or huanghuahaosu, which was eventually renamed qinghaosu (yet later to be popularised as artemisinin, after the botanical name).[9] (The chemical structure of artemisinin was worked out only in 1975, and published in 1977.) The same year Tu synthesized the compound dihydroartemisinin from the extract. This compound was more soluble and potent than native compound. Other derivatives artemisinin derivatives were also subsequently synthesized by other workers, of which the most important are artemether and artesunate.[18] All clinical trials by this time confirmed that artemisinins are more effective than the conventional antimalarial drugs, such as chloroquine and quinine.[9] They are now recognised not only as the most potent, but also as the safest and rapidly acting antimalarial drugs.[19]

Artesunate and its combination drugs

Artesunate is synthesized from dihydroartemisinin (DHA) using succinic acid. It is exceptionally chemically stable, and hence, is the only drug among artemisins produced in oral tablets, rectal capsule and intravenous injection.[20] Clinical trials have shown that it is the most potent drug for severe malaria due to Plasmodium falciparum.[21] The World Health Organization has specifically adopted it in 2006 as the only drug for first line treatment of complicated malaria (but in combination with other antimalarials to prevent drug resistance),[22] and is included in the World Health Organization's List of Essential Medicines.[23] Artesunate combination drugs (such as artesunate/amodiaquine[24] and artesunate/mefloquine[25]) are more effective than artemether-based drugs.[26]

Discovery of synthetic drugs

The 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 used in artemisinin-combination therapy.[9]

Termination and aftermath

After the fall of Saigon on 30 April 1975, ending the Vietnam War, the military purpose of Project 523 was subsiding. Researchers were not allowed to publish their finding, but were allowed to 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 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, to collaborate, but the research was not yet open to non-Chinese scientists. By the early 1980s research had practically stopped, and the project was officially terminated in 1981.[8] Then the TDR took the opportunity and organised 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. They made their first international publication in 1982 in The Lancet, whereby they reported the comparative efficacy of artemisinin and mefloquine on chloroquine-resistant Plasmodium falciparum.[28] (Keith 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.[29]) 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.[30]

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. Zhou showed that artemether combined with another antimalarial lumefantrine was the most potent of all antimalarial drugs. He worked alone for four years, and was joined by Ning Dianxi and his team in 1985. They found that in clinical trials the combined tablet had very high cure rate of severe malaria, more than 95%, including in areas where multi-drug resistance is experienced.[31] They applied for patent in 1991, but was granted only in 2002. In 1992 they got it registered as a new drug in China. Noticing this, Novartis signed a pack for mass production. In 1999 Novartis obtained the international licensing rights and gave the brand name Coartem. The drug was approved by the US Food and Drug Administration in 2009.[32]

See also

References

  1. ↑ Hsu, Elisabeth (2006). "Reflections on the 'discovery' of the antimalarial qinghao". British Journal of Clinical Pharmacology 61 (6): 666–670. doi:10.1111/j.1365-2125.2006.02673.x. PMC 1885105. PMID 16722826.
  2. 1 2 Senthilingam, Meera. "Chemistry in its element: compounds: Artemisinin". Chemistry World. Royal Society of Chemistry. Retrieved 27 April 2015.
  3. ↑ Awofeso, Niyi (2011). "Project 523: transformation of Artemisinin from traditional Chinese medicine to mainstream anti-malaria chemotherapy". Spatula DD 1 (2): 113–118. doi:10.5455/spatula.20110514053140.
  4. ↑ Tu, Youyou (2011). "The discovery of artemisinin (qinghaosu) and gifts from Chinese medicine". Nature Medicine 17 (10): 1217–1220. doi:10.1038/nm.2471. PMID 21989013.
  5. ↑ "European Inventor Award: An Ancient Cure for Malaria". European Patent Office. Retrieved 23 April 2015.
  6. ↑ Shapiro, Lucy. "Lasker~DeBakey Clinical Medical Research Award 2011 Winners". Lasker Foundation. Retrieved 29 April 2015.
  7. ↑ Spector, Ronald H. "Vietnam War". Encyclopædia Britannica. Retrieved 27 April 2015.
  8. 1 2 3 4 5 Weiyuan, C (2009). "Ancient Chinese anti-fever cure becomes panacea for malaria". Bulletin of the World Health Organization 87 (10): 743–744. doi:10.2471/BLT.09.051009. PMC 2755319. PMID 19876540.
  9. 1 2 3 4 Cui, Liwang; Su, Xin-zhuan (2009). "Discovery, mechanisms of action and combination therapy of artemisinin". Expert Review of Anti-infective Therapy 7 (8): 999–1013. doi:10.1586/eri.09.68. PMC 2778258. PMID 19803708.
  10. ↑ Jang, C. S.; Fu, F. Y.; Huang, K. C.; WangG, C. Y. (1948). "Pharmacology of Ch'ang Shan (Dichroa febrifuga), a Chinese Antimalarial Herb". Nature 161 (4089): 400–401. doi:10.1038/161400b0.
  11. ↑ Coatney, GR; Cooper, WC; Culwell, WB; White, WC; Imboden, CA Jr (1950). "Studies in human malaria. XXV. Trial of febrifugine, an alkaloid obtained from Dichroa febrifuga lour., against the Chesson strain of Plasmodium vivax". Journal. National Malaria Society (U.S.) 9 (2): 183–186. PMID 15422372.
  12. ↑ Butler, AR; Khan, S; Ferguson, E (2010). "A brief history of malaria chemotherapy". The Journal of the Royal College of Physicians of Edinburgh 40 (2): 172–177. doi:10.4997/JRCPE.2010.216. PMID 20695174.
  13. ↑ Jiang, S.; Zeng, Q.; Gettayacamin, M.; Tungtaeng, A.; Wannaying, S.; Lim, A.; Hansukjariya, P.; Okunji, C. O.; Zhu, S.; Fang, D. (2005). "Antimalarial Activities and Therapeutic Properties of Febrifugine Analogs". Antimicrobial Agents and Chemotherapy 49 (3): 1169–1176. doi:10.1128/AAC.49.3.1169-1176.2005. PMC 549280. PMID 15728920.
  14. ↑ Sen, Debanjan; Banerjee, Anirban; Ghosh, AshokeKumar; Chatterjee, TapanKumar (2010). "Synthesis and antimalarial evaluation of some 4-quinazolinone derivatives based on febrifugine". Journal of Advanced Pharmaceutical Technology & Research 1 (4): 401. doi:10.4103/0110-5558.76439. PMC 3255402. PMID 22247880.
  15. ↑ McLaughlin, Noel P.; Evans, Paul; Pines, Mark (2014). "The chemistry and biology of febrifugine and halofuginone". Bioorganic & Medicinal Chemistry 22 (7): 1993–2004. doi:10.1016/j.bmc.2014.02.040. PMID 24650700.
  16. ↑ Keller, Tracy L; Zocco, Davide; Sundrud, Mark S; Hendrick, Margaret; Edenius, Maja; Yum, Jinah; Kim, Yeon-Jin; Lee, Hak-Kyo; et al. (2012). "Halofuginone and other febrifugine derivatives inhibit prolyl-tRNA synthetase". Nature Chemical Biology 8 (3): 311–317. doi:10.1038/nchembio.790. PMC 3281520. PMID 22327401.
  17. ↑ Hsu, Elisabeth (2006). "The history of qing hao in the Chinese materia medica". Transactions of the Royal Society of Tropical Medicine and Hygiene 100 (6): 505–508. doi:10.1016/j.trstmh.2005.09.020. PMID 16566952.
  18. ↑ Klayman, D. (1985). "Qinghaosu (artemisinin): an antimalarial drug from China". Science 228 (4703): 1049–1055. doi:10.1126/science.3887571. PMID 3887571.
  19. ↑ Dondorp, Arjen M.; Day, Nick P.J. (2007). "The treatment of severe malaria". Transactions of the Royal Society of Tropical Medicine and Hygiene 101 (7): 633–634. doi:10.1016/j.trstmh.2007.03.011. PMID 17434195.
  20. ↑ Morris, Carrie A; Duparc, Stephan; Borghini-Fuhrer, Isabelle; Jung, Donald; Shin, Chang-Sik; Fleckenstein, Lawrence (2011). "Review of the clinical pharmacokinetics of artesunate and its active metabolite dihydroartemisinin following intravenous, intramuscular, oral or rectal administration". Malaria Journal 10 (1): 263. doi:10.1186/1475-2875-10-263. PMC 3180444. PMID 21914160.
  21. ↑ Phu, Nguyen H; Tuan, Phung Q; Day, Nicholas; Mai, Nguyen TH; Chau, Tran TH; Chuong, Ly V; Sinh, Dinh X; White, Nicholas J; Farrar, Jeremy; Tran, Hien T (2010). "Randomized controlled trial of artesunate or artemether in Vietnamese adults with severe falciparum malaria". Malaria Journal 9 (1): 97. doi:10.1186/1475-2875-9-97. PMC 2873528. PMID 20398339.
  22. ↑ WHO (2006). "Guidelines for the Treatment of Malaria" (PDF). Retrieved 28 April 2015.
  23. ↑ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
  24. ↑ Lacaze, Catherine; Kauss, Tina; Kiechel, Jean-René; Caminiti, Antonella; Fawaz, Fawaz; Terrassin, Laurent; Cuart, Sylvie; Grislain, Luc; Navaratnam, Visweswaran; Ghezzoul, Bellabes; Gaudin, Karen; White, Nick J; Olliaro, Piero L; Millet, Pascal (2011). "The initial pharmaceutical development of an artesunate/amodiaquine oral formulation for the treatment of malaria: a public-private partnership". Malaria Journal 10 (1): 142. doi:10.1186/1475-2875-10-142. PMC 3128010. PMID 21605361.
  25. ↑ Wells, Susan; Diap, Graciela; Kiechel, Jean-René (2013). "The story of artesunate–mefloquine (ASMQ), innovative partnerships in drug development: case study". Malaria Journal 12 (1): 68. doi:10.1186/1475-2875-12-68. PMC 3640935. PMID 23433060.
  26. ↑ Li, Qigui; Weina, Peter (2010). "Artesunate: The Best Drug in the Treatment of Severe and Complicated Malaria". Pharmaceuticals 3 (7): 2322–2332. doi:10.3390/ph3072322.
  27. ↑ Qinghaosu Antimalaria Coordinating Research Group (1979). "Antimalaria studies on Qinghaosu". Chinese Medical Journal 92 (12): 811–816. PMID 117984.
  28. ↑ Jiang, Jing-Bo; Guo, Xing-Bo; Li, Guo-Qiao; Cheung Kong, Yun; Arnold, Keith (1982). "Antimalarial activity of mefloquine and qinghaosu". The Lancet 320 (8293): 285–288. doi:10.1016/S0140-6736(82)90268-9. PMID 6124713.
  29. ↑ McNeil, D.G.Jr. (16 January 2012). "For Intrigue, Malaria Drug Gets the Prize". The New York Times. Retrieved 4 May 2015.
  30. ↑ Weina, PJ (2008). "Artemisinins from folklore to modern medicine--transforming an herbal extract to life-saving drugs". Parassitologia 50 (1-2): 25–9. PMID 18693553.
  31. ↑ Makanga, Michael; Krudsood, Srivicha (2009). "The clinical efficacy of artemether/lumefantrine (Coartem®)". Malaria Journal 8 (Suppl 1): S5. doi:10.1186/1475-2875-8-S1-S5. PMC 2760240. PMID 19818172.
  32. ↑ Premji, Zulfiqarali G (2009). "Coartem®: the journey to the clinic". Malaria Journal 8 (Suppl 1): S3. doi:10.1186/1475-2875-8-S1-S3. PMC 2760238. PMID 19818170.

Further reading

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