Accepted Manuscript Publication process involving the discovery of artemisinin (qinghaosu) before 1985 Man-Yuan Wang PII:
S2221-1691(16)30335-5
DOI:
10.1016/j.apjtb.2016.04.009
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APJTB 304
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Asian Pacific Journal of Tropical Biomedicine
Received Date: 29 March 2016 Accepted Date: 7 April 2016
Please cite this article as: Wang M-Y, Publication process involving the discovery of artemisinin (qinghaosu) before 1985, Asian Pacific Journal of Tropical Biomedicine (2016), doi: 10.1016/ j.apjtb.2016.04.009. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Title: Publication process involving the discovery of artemisinin (qinghaosu) before 1985
Affiliations: School of Traditional Chinese Medicine, Capital Medical University, Beijing 100069, China
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Authors: Man-Yuan Wang*
*Corresponding author: Man-Yuan Wang, School of Traditional Chinese Medicine, Capital Medical University, Beijing 100069, China. Tel: +86-010-83911635 E-mail:
[email protected]
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This manuscript included 0 table and 7 figures.
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The journal implements double-blind peer review practiced by specially invited international editorial board members.
Article history: Received 29 Mar 2016 Accepted 7 Apr 2016
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Available online 8 Apr 2016
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EDITOR’S NOTE All the original references were provided by the Nobel Laureate Youyou Tu. The publication process involving the discovery of artemisinin was collected and sorted by her first PhD student, Associate Professor Man-Yuan Wang. Through the publication of this article, the journal expects to provide a reference to the scientists who dedicated to the research of artemisinin, especially those who are interested in the discovery process of artemisinin.
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1. Introduction
Diseases caused by parasites have been puzzling humans for thousands of years, remaining one of the major problems in the field of global health. Mosquito-borne tropical parasitic diseases are kinds of diseases with serious harmfulness which especially affect populations in the world’s poorest areas and also turn to be a huge barrier hindering mankind’s health and happiness from improvement. In 2015, William C. Campbell, Satoshi Ōmura and Youyou Tu won the Nobel Prize in Physiology or Medicine owing to their revolutionary contributions to prevent and
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treat the most destructive parasitic diseases. The Nobel Prize in Physiology or Medicine is a global important award with great influence in the biological sciences. The 2015 Nobel Prize in Physiology or Medicine has further led to wide discussions among tropical biomedical research workers around the world. The awards of the Nobel Prizes often involve a time delay. They can be awarded to the scientific achievements
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which were made several years, more than a decade or even decades ago. The scientific achievement of Youyou Tu was made decades ago. Her scientific research was conducted in the 1970s. Since Youyou Tu is the first Chinese
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Scientist winning this global prestigious award, when the news was announced, an extensive discussion arose at hometown and abroad. From another point of view, after Youyou Tu won the Lasker-DeBakery Clinical Medical Research Award in 2011, researchers have paid more and more attention to artemisinin (qinghaosu) and the treatment of malaria. Therefore, domestic and overseas scientists have published a lot of related reviews which promote the
understanding of the discovery and development of artemisinin[1-5]. Because of the special background, there were incomprehension and controversies in assessment of the discovery process of artemisinin. The incomprehension and controversies even exist after Youyou Tu won the Nobel Prize,
which reflects that people give a lot of attention to important scientific and technological inventions and their socialcultural impacts and also demonstrates that many scientific researchers are still not clear of the concrete ownership of the main achievement of artemisinin project. Youyou Tu is the only rewarded person of the scientific achievement of
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artemisinin project who was chosen to won the 2015 Nobel Prize in Physiology or Medicine, which triggers the cognitive desire of people both here and abroad towards how the mainstream academic community evaluates the individual contribution of the achievement of artemisinin project. Only one key documental information (“Tu et al., Yao Xue Xue Bao (1981) 16, 366-370 (Chinese)”) was listed in the Award Bulletin. The Nobel committee did not
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give any other information about the achievement evaluation. “The main scientific research was carried out in 1970s”, “Many artemisinin-related articles has been published before 1981” and “Related articles were published
anonymously or in the name of a team” reminded many people of why the article in 1981 of Youyou Tu was chosen as the key reference for her Nobel Prize. Up to now, there is no article studying the public publishing process of the
scientific achievement of artemisinin. In this study, based on the related original references, the author strived to
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restore the process and expected to answer those related questions. In 1985, D. L. Klayman published an article named “Qinghaosu (artemisinin): an antimalarial drug from China” in Science[6]. After that, the handling method of
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most articles related to the discovery of artemisinin agreed with that article. That was a general statement: the specific inventor of the new anti-malaria therapy was not clear. Hence, the study aimed to stress the publication process involving the discovery of artemisinin before 1985 so as to provide more reference information to those related personnel.
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2. Communication of the research work progress of the prevention and treatment of malaria (in 1972)
From August 1972 to October 1972, artemisinin extracts were firstly used in clinical trials by the research team of Youyou Tu. Local people with strong immunity and external people without immunity were selected. The types of malaria were from Plasmodium vivax (P. vivax) to Plasmodium falciparum (P. falciparum). A total of 21 clinical antimalaria cases were observed. There were 11 cases infected by P. vivax, 9 cases by P. falciparum and 1 case by mixed
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species of Plasmodium. The clinical results were pretty satisfactory. The average defervescence time of P. vivax cases was 19 h, while the average defervescence time of P. falciparum patients was 36 h. The species of Plasmodium all
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turned negative. The related results were collected and managed by malaria prevention and controlling organizations of Guangdong. The content in the red box in Figure 1 is the first publication of the curative effect of artemisinin extracts on clinical anti-malaria. It was confirmed that anti-malaria research of artemisinin in Beijing (Scientific team of Youyou Tu, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences) had made a great
progress.
3. Kexue Tongbao (in 1977)
The chemical structure of artemisinin was issued by Kexue Tongbao in 1977[7], which was accomplished by
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researchers of the scientific team of Youyou Tu and colleagues of Institute of Biophysics of Chinese Academy of Sciences and Shanghai Institute of Organic Chemistry of Chinese Academy of Sciences. The publication application was reported to the Ministry of Health. And after approved, the paper was submitted to Kexue Tongbao on 20th February 1976. Then the paper (A new sesquiterpene lactone-Qinghaosu) was published in issue No.
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3 in 1977. Considering the confidentiality requirement of Chinese military force missions, in order to prevent further development of medical use by other countries, the paper was published in the name of “the Collaborating Group of
Qinhaosu Structure”. The paper only reported the chemical structure and partial physical and chemical properties of
artemisinin, but its excellent anti-malaria activity was not reported. The concrete content was shown in Figure 2. After
the publication, the related contents have been indexed by Chemical Abstracts (C.A. 1977, 87, 98788g), which
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promoted the process that artemisinin was concerned by international peers. The related reference demonstrated that
the Institute of Chinese Materia Medica of China Academy of Chinese Medical Sciences was the main institution
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which was in charge of the relative research achievements.
4. Yao Xue Tong Bao (in 1979), Acta Chimica Sinica (in 1979), Chinese Medical Journal (in 1979)
In November 1978, based on the early preliminary meeting (Xiangshan, Beijing), the National Leading Group Office of Malaria Prevention and Controlling Research hold a conference about artemisinin assessment in Yangzhou,
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Jiangsu Province. Among early-stage artemisinin-related conferences, this conference firstly invited media representatives, promoting the publicity of the related achievement. According to the outward information of the conference, over 40 units from ten provinces, cities and municipalities participated in the clinical trials. A total of 6 555 cases were tested (529 cases were completed by China Academy of Chinese Medical Sciences), and 2 099 cases of them were artemisinin preparations. In practical clinical work, many kinds of dosage forms were used such as
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solid dispersions, tablets, capsules, injections, suppositories and so on. Clinical cases included malaria infected by P. vivax or P. falciparum and cerebral malaria. After the conference, all relevant units and researchers published the
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related research achievement to make the research progress of artemisinin against malaria known to the public. A series of researches, such as “Studies on new antimalarial drug qinghaosu”, “Chemical structure and reaction of
arteannuin”, “Antimalarial studies on qinghaosu” and so forth, have reported the research achievement of the
chemical structure, physical and chemical properties, structure study, antimalarial activity, pharmacology and toxicology of artemisinin in Chinese or English. These papers were signed collectively and the first affiliation was the Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences. The concrete contents were shown in Figure 3[8-10]. The publication of this batch of papers has promoted the international recognition degree of the anti-malaria drug artemisinin studied by Chinese scientists, which have laid the foundation of the further internationalization of the drug.
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5. Zhong Yao Tong Bao (in 1981), Acta Pharmaceutica Sinica (in 1981)
In 1981, with the change of social environment, the research results of Artemisia annua L. (A. annua) and artemisinin were further arranged and issued by the scientific research group of Youyou Tu with a personal signature.
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Zhong Yao Tong Bao published an article entitled “Studies on the constituents of Artemisia annua L. and derivatives of qinghaosu (brief report)”, providing a summary of the specific development of the chemical components of A.
annua, the research results on the artemisinin derivatives and preliminary structure-activity relationship[11]. Acta
Pharmaceutica Sinica also published an article entitled “Studies on the constituents of Artemisia annua L. I” briefly introducing the extraction, separation and structural identification of artemisinin and presenting the chemical
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constituents in A. annua including sesquiterpenes arteannuin A, arteannuin B, arteannuin C and flavone, coumarin,
essential oil and other chemical constituents in detail[12]. Youyou Tu served as the first author of these two articles.
article information was shown in Figure 4.
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The article published by Acta Pharmaceutica Sinica was selected as the key literature by the Nobel Committee. The
6. Journal of Traditional Chinese Medicine (in 1982) and Planta Medica (in 1982)
In October 1981, in the 4th meeting of the scientific working group on the chemotherapy of malaria, an international
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conference in the name of “special conference on qinghaosu” was held by the United Nations Development Programme/the World Bank/the World Health Organization (WHO) special programe for research and training in malaria chemotherapy group of tropical diseases in Beijing. The Chinese artemisinin research and development group made a systematic introduction of the related research at the meeting. After that, L. J. Bruce-Chwatt, a British expert,
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simply introduced the research development of artemisinin with an article “Qinghaosu: a new antimalarial” in British Medical Journal[13]. Related papers of Chinese specialists were published at the beginning of 1982 in the name of “China cooperative research group on qinghaosu and its derivatives as antimalarials” in Journal of Traditional
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Chinese Medicine[14], which included six papers: “Chemical studies on qinghaosu (artemisinine)”, “The chemistry and synthesis of qinghaosu derivatives”, “Antimalarial efficacy and mode of action of qinghaosu and its derivatives in experimental models”, “Metabolism and pharmacokinetics of qinghaosu and its derivatives”, “Studies on the toxicity of qinghaosu and its derivatives” and “Clinical studies on the treatment of malaria with qinghaosu and its derivatives”. As for the signature information of these papers, the Institute of Chinese Materia Medica of China Academy of Chinese Medical Sciences was presented to be the major unit of the discovery of artemisinin. After the international meeting, Planta Medica sent a manuscript invitation to Youyou Tu’s team[15]. In 1982, an article titled “Studies on the constituents of Artemisia annua L. Part II” was published and Youyou Tu is the first author. In this article, the related information of the extraction, separation and structural identification of the chemical constituents of sesquiterpenoids,
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flavonoids and coumarins which were isolated from Artemisia annua L. is introduced in English. The concrete article information was shown in Figure 5.
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7. General considerations
Ever since artemisinin and its derivatives came into being, which have played a key role in saving people from malaria. Artemisinin and its derivatives used in clinic mainly include artemisinin, dihydroartemisinin, artemether, arteether and artesunate. The International Pharmacopoeia (version 2003) has included the following artemisininbased drugs: artemether bulk drugs and injections, artemisinin bulk drugs, tablets and capsules, arteether
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bulk drugs and injections, dihydroartemisinin bulk drugs and tablets, as well as artesunate bulk drugs and tablets. The WHO has begun to recommend artemisinin-based combination therapies (ACTs) in 2001[16]. In 2006, ACTs
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combinatorial drugs were contained in the first version of Guidelines for the Treatment of Malaria made by WHO. In 2015, 5 ACTs were recommended in the third version. They were artemether + lumefantrine, artesunate + amodiaquine, artesunate + mefloquine, artesunate + sulfadoxine/pyrimethamine and dihydroartemisinin + piperaquine, respectively. In recent years, the value of ACTs becomes a highlighted topic. According to data of WHO, the global death rate of malaria from 2000 to 2013 decreased by 47%. The death rate in African areas
where the death toll of malaria accounted for 90% of the world’s total number also decreased by 54%[17].
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Artemisinin-based drugs have saved millions of malaria patients around the world.
The scientific research achievement of artemisinin was accomplished in a complicated social culture environment. There were many affiliations and people participating in it. Just like what Youyou Tu evaluated, artemisinin was a gift of traditional Chinese medicine to people around the world, which is of great importance to the prevention and treatment of infectious diseases such as malaria and the maintenance of people’s health.
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The discovery of artemisinin is a successful example for collective exploration of traditional Chinese medicine. Therefore, the award is a collective honor for those Chinese scientists. The achievement of artemisinin belongs
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to every person of the scientific team. A simple summary of the related work was shown in Figure 6. Terms in boxes in blue background were accomplished by the anti-malaria team of Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, terms in boxes in white background were accomplished by other
cooperative teams, and terms in boxes in transiting from blue to white were finished by the institute and other cooperative groups. The invention right of artemisinin has remained disputable for years. From the aspect of literature publications, the Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences should be the main research unit and Youyou Tu should be the main creator. There are also some indirect evidences supporting the idea, such as, the order and specific illustration of the certificate of the invention. The concrete information was shown in Figure 7. Also, the article titled “The development of the antimalarial drugs with new type of chemical structure: qinghaosu and dihydroqinghaosu” was published in Southeast Asian
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Journal of Tropical Medicine and Public Health in 2004 by Youyou Tu herself [18]. With the increasing globalization of scientific researches, how to estimate scientific research achievement has raised more and more attentions in the international scientific community at present. In general, scientific researchers disseminate their research achievement by issuing research papers, which can not only be an
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effective way to promote the application of the achievement by communicating with their counterparts, but also be an academic honor for those authors. Artemisinin drugs have been widely used for over ten years in the
whole world, and their research, social value and the achievement of their creators have been agreed by many academic communities and scientific workers. However, the research achievement of artemisinin project is limited by specific social historical conditions and divorced from the paradigm and course of the publications of
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mainstream scientific researches, which makes it difficult to be estimated. The author held an idea that the
difficulty, to a certain degree, delayed the Nobel Prize of Youyou Tu. Australian scientists Barry J. Marshall
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and J. Robin Warren were honored with the Nobel Prize in physiology or medicine in 2005 for the discovery of Helicobacter pylori and its pathogenesis for peptic ulcer disease. Their study was originating from 1979. The related research papers were all published gradually in academic journals with personal signatures by classic route transmissions of academic achievements, which further transmits and expands the research achievements. The author insists that the reason why they won Nobel Price 10 years earlier than Youyou Tu must have something to do with this mode which is conductive to achievement evaluation.
Ever since Youyou Tu started studying anti-malarial drugs from 1969, she has studied the reasonable application
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of artemisinin-based drugs, development of drug resistance, expansion of indications and development of new ACTs drugs. Besides, she has been honored with six certificates for new drugs, one clinical approval document for
her new drug and two invention patents. In the field of traditional Chinese medicine, the study of A. annua L. was conducted systematically, and its medicinal varieties are normalized. “Medicines without confusing names benefit
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people”, the work conducted by her team improves the control level of the qualities of original crude drugs and decoction pieces and corrects the long-used mistake of Chinese Pharmacopoeia. For over 40 years, Youyou Tu has
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worked hard in her field and obtained great achievements, so the Nobel Prize in Physiology or Medicine she won is a fully deserved recognition of her achievements.
Conflict of interest statement
I declare that I have no conflict of interest.
Acknowledgments
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Thanks go to Professor Youyou Tu for the permit of the reference material.
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References
[1]
Ergonul O, Yalcin CE, Erkent MA, Demirci M, Uysal SP, Ay NZ, et al. Who can get the next Nobel Prize in infectious diseases. Int J Infect Dis 2016; 45: 88-91.
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[2]
White NJ, Hien TT, Nosten FH. A brief history of qinghaosu. Trends Parasitol 2015; 31(12): 607-10. [3]
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Kong LY, Tan RX. Artemisinin, a miracle of traditional Chinese medicine. Nat Prod Rep 2015; 32(12): 1617-21. [4]
Miller LH, Su XZ. Artemisinin: discovery from the Chinese herbal garden. Cell 2011; 146(6): 855-8. [5]
Tu YY. The discovery of artemisinin (qinghaosu) and gifts from Chinese medicine. Nat Med 2011; 17(10): 1217-20. [6]
[7]
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Klayman DL. Qinghaosu (artemisinin): an antimalarial drug from China. Science 1985; 228(4703): 1049-55.
Collaboration Research Group for Qinghaosu. [A new sesquiterpene lactone–Qinghaosu]. Kexue Tongbao 1977; 3: 142. Chinese. [8]
Chinese. [9]
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Collaboration Research Group for Qinghaosu. [Studies on new antimalarial drug qinghaosu]. Yao Xue Tong Bao 1979; 14: 49-53.
Liu JM, Ni MY, Fan JF, Tu YY, Wu ZH, Wu YL, et al. [Structure and reaction of arteannuin]. Acta Chim Sin 1979; 37(2): 129-
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43. Chinese. [10]
Qinghaosu Antimalaria Coordinating Research Group. Antimalaria studies on qinghaosu. Chin Med J (Engl) 1979; 92(12): 811-6.
[11]
Tu YY, Ni MY, Zhong YR, Li LN. [Studies on the constituents of Artemisia annua L. and derivatives of artemisinin]. Zhong Yao Tong Bao 1981; 6(2): 31. Chinese. [12] Tu YY, Ni MY, Zhong YR, Li LN, Cui SL, Zhang MQ, et al. [Studies on the constituents of Artemisia annua L]. Acta Pharmaceutica Sinica 1981; 16(5): 366-70. Chinese. [13] Bruce-Chwatt LJ. Qinghaosu: a new antimalarial. Br Med J 1982; 284(6318): 767-8.
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[14] China Cooperative Research Group on Qinghaosu and Its Derivatives as Antimalarials. Chemical studies on qinghaosu (artemisinine). J Tradit Chin Med 1982; 2(1): 3-8. [15]
1982; 44(3): 143-5. [16]
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Tu YY, Ni MY, Zhong YR, Li LN, Cui SL, Zhang MQ, et al. Studies on the constituents of Artemisia annua Part II. Planta Med
World Health Organization. Antimalarial drug combination therapy: report of a WHO technical consultation. Geneva: World Health
Organization;
2001.
[Online]
Available
from:
http://apps.who.int/iris/bitstream/10665/66952/1/WHO_CDS_RBM_2001.35.pdf [Accessed on 25th March, 2016]
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[17]
World Health Organization. World malaria report 2014. Geneva: World Health Organization; 2014. [Online] Available from: http://www.who.int/malaria/publications/world_malaria_report_2014/en/ [Accessed on 25th March, 2016]
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[18] Tu YY. The development of the antimalarial drugs with new type of chemical structure: qinghaosu and dihydroqinghaosu. Southeast Asian J Trop Med Public Health 2004; 35(2): 250-1.
Figure legends:
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Figure 1. A copy of a paragraph of Communication on Malaria Controlling Research issued by the National Leading Group Office for Malaria Controlling on 5th November 1972. Figure 2. A copy of the publication information on “A new sesquiterpene lactone–qinghaosu” (Kexue Tongbao) 1977; 22(3): 142)[7]. Figure 3. A copy of the publication information on “Studies on new antimalarial drug qinghaosu”(Yao Xue Tong Bao 1979; 14(2): 49-53)[8], “Chemical structure and reaction of arteannuin” (Acta Chimica Sinica 1979; 37(2): 129-143)[9], “Antimalaria studies on qinghaosu” (Chinese Medical Journal 1979; 92(12): 811-816)[10]. Figure 4. A copy of the publication information on “Studies on the constituents of Artemisia annua L. and derivatives of qinghaosu (concise report)”(Zhong Yao Tong Bao 1981; 6(2): 31)[11], “Studies on the constituents of Artemisia annua L. I ”(Acta Pharmaceutica Sinica 1981; 16(5): 366-370)[12]. Figure 5. A copy of the publication information on “Chemical studies on qinghaosu (artemisinine)” (Meeting reports of the 4th meeting of the scientific working group on the chemotherapy of malaria in Beijing in 1981 and Journal of Traditional Chinese Medicine 1982; 2(1): 3-8)[14], “Studies on the constituents of Artemisia annua L. Part II” (Planta Medica 1982; 44(3): 143-5)[15]. Figure 6. Summary of the work done mainly by the research team in China Academy of Traditional Chinese Medicine (boxes in blue background), the work completed by the collaboration between the Institute of Chinese Materia Medica and other units (boxes in transitioning from blue to white), and the work completed by the collaboration between Other Research Teams across the Nation (boxes in white). Figure 7. A copy of the invention certificate for artemisinin and Youyou Tu.
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Figure 2.
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Figure 1.
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Figure 3.
Figure 4.
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Clinical trial for No. 191 Aug-Oct, 1972
Screening for Artemisia annua L.
The finding of neutral extract No. 191 Oct 4th, 1971
First clinical trail for artemisinin Sept-Oct, 1973
Determination of stero-structure for artemisinin
New drug approval of dihydroartemisinin 1992
Optimization of manufacturing techniques
Synthesization of artemisinin 1983
Research for new indications of dihydroartemisinin 2003
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Figure 6.
The finding of dihydroartemisinin Sept, 1973
New drug approval of artemisinin 1986
Studies on resources
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Artemether 1987
Dihydroartemisinin derivatives
The discovery of artemisinin Nov 8th, 1972
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Artesunate 1987
Extended clinical trails 1974-
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Screening for herbal extracts
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Figure 5.
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Figure 7.
