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The Viet-Công, Artemisia annua, arteannuin B and artemisinin

December 30, 2016 - 22:05 -- Pierre Lutgen

Artemisia annua came under the spotlight during the Vietnam War. Viêt-Cong who operated in swamps and rain forests lost more soldiers by mosquito bites than by American bullets. Ho Chi Min turned to China for help. Researchers at the Chinese Institute of Material Medicine had found a region of China that reported no malaria cases, and when they investigated, they discovered that its people drank a decoction of Artemisia annua at the first symptoms of malaria. And actually, wild Artemisia has been used for millenniums in several regions of China and is still used to treat fevers and malaria. It was easy to acquire tons of this dried herb for Viêt-Cong. Taken as an infusion it worked wonders. The Americans, faithful to their less efficient pills, never knew what was going on.

         CJ Puotinen, Artemisinin, malaria and cancer, NEHA Internat, Winter 2003

Already in 1967, confronted with a strong recrudescence of malaria in the Southern provinces the Chinese authorities launched a nationwide program involving several hundred Chinese scientists. A part of this project, called “Program 523” endeavored to explore the traditional Chinese herbal medicine. More than 1000 samples of different herbs have been studied by the modern methods and isolation of the active principles is monitored with antimalarial screening in animal models. Many active principles had been isolated, for example yingzhaosu, from the traditional antimalarial medicine Dichroa febrifuga and Arbotrys uncinatus. It appears thus that these activities had started several years before the Vietnam war and the request for help by the Vietcong. And that the scientific activities took place in a nationwide program and not hidden somewhere in basements.

         Xiao-Tian Liang, We-Shuo Fang, Medical Chemistry of Bioactive Natural Products. Edited by Chinese Academy of Medicinal Sciences Beijing. Translation Wiley Interscience 2006

Studies with extracts from Artemisia annua started only in 1972 and this may be under the influence of some informations which came from Europe. Let’s not forget that Artemisia annua is growing wild on most European coastal river banks: Elbe, Rhine, Po, Rhone, Danube. Serbians presented their research results on Artemisia annua in February 1972 at an international conference in India. The reference to this work is quoted in the book Chinese Materia Medica, CRC Press, New York 1993 by You-Ping Zhu.

          D. Jeremić, A. Jokić, A. Behbud and M. Stefanović, New Type of Sesquiterpene Lactones Isolated From Artemisia Annua L. – Ozonide of Dihydro Arteannuin”, 8th International Symposium on The Chemistry of Natural Products, New Delhi, 1972, C-54, 221

One year later it was published in a well known peer reviewed journal Tetrahedron Letters

          D.Jeremić, A. Jokić, A. Behbud, M. Stefanović, A new type of sesquiterpene lactone isolated from Artemisia annua L., Tedrahedron Letters 1973 Vol 14- Iss 32, 3039-3042

The molecule was further described in 1974

          Uskoković MR, Williams TH, Blount JF. The structure and absolute configuration of arteannuin B. Helvetica chimica acta 57:3 1974 Apr 27 pg 600-2 and  Helv Chim Acta, 1974, 27;57, 602-15.

In the early 1970 the Swiss at the ETH Zürich were working on arteannuin B and published their results.. They hardly could have contacts with the Chinese and the administration of Artemisia annua infusions to Vietcong soldiers.

          DG Leppard, M Rey, AS Dreiding, R Grieb. The structure of arteannuin B and its hydrolysis product. Helv Chim Acta, 1974, 27;57, 602-15.

All this may explain why the Chinese started their Artemisia annua work with arteannuin B. Principal administrator of the project was Zhang Jianfang and it involved research teams in Hainan, Yunnan, Shandong, Beijing.

          Mao-Tian Liang, Wei-Shuo Fang, editors, Medical Chemistry of Bioactive Natural Products, Wiley-Interscience, 2006 New Jersey

The first trials with arteannuin B (qinghaosu II) were started in Hainan in October 1973 by doctor Li Chuangjie. A total of eight cases were studied, three with vivax and five with falciparum malaria. In both infections, the temperature normalization took 30 hours and parasitemia was cleared in 65 hours. But during follow-up parasites reappeared after a few days or weeks. Two patients did not respond and were considered treatment failures. To a large extent it is logical that the work in Yugoslavia and in China started with arteannuin B because the Artemisia species available were both of the type rich in artannuin B and poor in are artemisinin. Especially the Artemisia annua from the Beijing province.

         Youyou Tu . The discovery of artemisinin (qinghaosu) and gifts from Chinese medicine. Nature Medicine. 2011, 17, 1217–1220 doi:10.1038/nm.2471

By the end of 1972, the Beijing Institute of Chinese Materia Medica had identified and separated out several active constituents, one of which had an antimalarial effect and was named qinghaosu II. In 1973 preclinical animal toxicology testing was done at. Arteannuin B (qinghaosu II) showed cardiac toxicity in some animals. This explains why progress slowed in the years 1973. Finally arteannuin B was tested on three researchers and showed no apparent toxicity. Leaders therefore agreed to start clinical trials with arteannuin B. A clinical trial with thirty vivax malaria patients was run in the Shandong province and compared favourably with chloroquine. At the same time Zhan Eryi and Luo Zeyuan at the Yunnan Institute of Materia Medica improved the extraction methods and isolated white crystals with good antimalarial properties. This was called qinghaosu or artemisinin.. In January 1974, the head office organized a meeting of all district office leaders of Project 523. In May 1974, a clinical trial with artemisinin was completed with 26 vivax malaria cases. In most cases, no parasites were detectable in the blood 48 hours after drug administration. But the recurrence rates were high, in 4 out of 5 patients. Similar results were obtained in November 1974 by Li Guaqiao’s team for 18 falciparum malaria cases. At the end of February 1975, the national head office called for another meeting of all province leaders at Beiwei Road Hotel in Beijing ant it was decided that all research units should concentrate their efforts on artemisinin.

        Zhang Jianfang editor. A detailed Chronological Record of Project 523 and the Discovery and Development of QingHaosu (Artemisinin), Translation Keith and Muoi Arnold 2006, ISBN: 978-1-62212-164-9

        FH Jansen; Z Yin. 2002. Who Discovered Artemisinin? ISBN 90-807479-1-2. 25

One of the first peer reviewed papers of the Chinese team with the name of Tu Youyou and relating the discovery of artemisinin was published in 1979 by a team of Chinese scientists. Tu Youyou was not the main author but co-author.

        Liu JM, Ni MY, Fan JF, Tu YY, Wu ZH, Wu YL, Chou WS (1979) Structure and reaction of Arteannuin. Acta Chim Sin 37:129–143

Another paper was published at the same date without names.

        Qinghaosu Antimalaria Coordinating Research Group: Antimalaria Studies on Qinghaosu, Chinese Medical Journal. 1979, 92.12

At the same date the Ministry of Health nominated 6 institutions for the Discovery of Qinghaosu Award:

-          Academy of Chinese Traditional Medicine

-          Shandong Institute of Traditional Medicine

-          Yunnan Institute of Materia Medica

-          Institute of Biophysics of the Chinese Academy of Sciences

-          Shanghai Institute of Organic Chemsistry

-          Guangzhou College of Traditional Medicine

Apparently, Tu Youyou is not the person who first discovered the antimalarial action of the extract, and not the first person who isolated the antimalarial Qinghaosu either, and these parts of work were not done under her instruction. Isolation of the active ingredient, inhibition of parasites in mice and primary clinical trials were carried out by three institutions respectively. Artemisinin was in fact discovered in 1972 from the leaves of Artemisia annua by Zhenxsin Wei There were critical voices in China after Tu Youyou won the Nobel prize. “I feel happiness and sorrow” said Liu Changhua, a professor of history.” I am happy that the drug has saved lives, but if this is the path Chinese medicine has to take in the future I am sad. Western drug companies examine traditional pharmacopeia around the world looking for new drugs. If this is the path we must go down, I think it is a disrespect of our cultural heritage. Artemisia has been in continuous use for centuries to fight malaria and other fevers”. Dr. Nicholas J. White, a prominent Oxford malaria researcher, said it was “not fair to credit this discovery to one individual”. During all these years the research on Artemisia annua extracts continued and other molecules were studied. Deoxoqinghaosu was synthesized from arteannuic acid and it was found more effective against K173 strain of Plasmodium berghei than the natural compound qinghaosu.

         B Ye; Y-L Wu; G-F Li; X-Q Jiao, Antimalarial activity of deoxoqinghasosu, Acta Pharm. Sin., 1991

There was also some hope that other Artemisia plants might contain molecules more efficient than arteannuin B or artemisinin. This is not a surprise because Chinese scientist Shengua (1095) and Li Shisten (1593) had found that Artemisia apiacea which does not contain any artemisinin had better antimalaria properties than Artemisia annua. A large variety of Artemisia plants was studied in these years by the Chinese: Artemisia eriopoda. Artemisia argyi, Artemisia anomala, Artemisia japonica, Artemisia apiacea, Artemisia gmelini,

         Yin Jianping, Tu Youyou, Chemical constituents of woolystalk wormwood (Artemisia eriopoda).  Zhongcaoyao 1989, 149-50 ISSN 0253-2670

         Gu Yuncheng, Tu Youyou, Chemical constituents of Japanese wormwood (Artemisa japonica), Zhongcaoyao, 1993, 24(3) CODEN : CTYAD8

         Wu Chongming, Tu Youyou, Isolation and identification of the lipophilic constituents from Artemisia argyi,  Zhongcaoyao, Tongbao 1985 10(1) 31-2, ISSN 0254-0029

         Xiao YQ, Tu Youyou, Identification of the lipohilic constituents of Artemisia anomala. Yao Xue XUE Bao, 1984, 19, 909-913

         Wu C, Tu Youyou, Studies on the constituents of Artemisia apiacea Hance, Chin Trad Herbal Drugs 1985, 6. 2-3.

         Wu C, Tu Youyou, Studies on the constituents of Artemisia gmelini. Chin Bull Bot 1985 3, 34-7

This is not a surprise because Chinese scientist Shengua (1095) and Li Shisten (1593) had found that Artemisia apiacea which does not contain any artemisinin had better antimalarial properties than Artemisia annua. All these studies of the team around Tu Youyou reflect some lack of confidence in artemisinin and Artemisia annua. It looks like searching for a needle in a haystack.

The continuing failure rates with monotherapy of arteannuin B and artemisinin prompted some trials with Artemisia annua extracts administered in capsules. The result was encouraging. The cure rate for Plasmodium berghei and Plasmodium vivax infections was 100%. This formulation was found to be better than chloroquine in fever subsidence and disappearance of malarial symptoms, while the recrudescence rate was still high, the latter could be inhibited by increasing therapeutic course or daily dosing time.

          Wan YD, Zang QZ , Wang JS Studies on the antimalarial action of gelatin capsule of Artemisia annua. Chinese Journal of Parasitology & Parasitic Diseases 1992, 10(4):290-294