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Chinese Annals of History of Science and Technology, Volume 4 , Issue 2 : 73-134(2020) https://doi.org/10.3724/SP.J.1461.2020.02073

The Search for Antimalarial Drugs and the Discovery of Artemisinin

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  • ReceivedAug 3, 2020
  • AcceptedOct 25, 2020
  • PublishedApr 7, 2021

Abstract


Acknowledgment

The author would like to thank Zeng Meiyi 曾美怡, Wu Yulin 吴毓林, Liu Tianwei 刘天伟, and Su Jingjing 苏静静 for their valuable suggestions.

The paper was translated from Chinese into English by Yu Yueyuan 俞月圆 and copyedited by John Moffett.


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  • Figure 1

    : Tu Youyou receiving her Nobel Prize on December 10, 2015. Photo from Guangming Daily (Guangming ribao 光明日报), 5; December 11, 2015.

  • Figure 2

    : “The Effect of Qinghao in Treating Malaria” written by Li Weipu in 1954 (Li 1954).

  • Figure 3

    : Collection on Malaria published in May 1965, compiled by the Shanghai Literature Institute of Traditional Chinese Medicine (Shanghai Literature Institute of Traditional Chinese Medicine 1965). Photo by Li Runhong.

  • Figure 4

    : References for Research on Effective Recipes for Common Diseases published in May 1970, compiled by the CACMS “Revolutionary Committee.” Photo by Li Runhong.

  • Figure 5

    : The second research subject in the three-year research plan for Project 523, which included qinghao as one important targets of the research.

  • Figure 6

    : Transcript of a 1977 speech by Zhang Guozhen 章国镇, vice-director of the CACMS ICMM at the time. The transcript was provided by Li Zelin 李泽琳.

  • Figure 7

    : Tu Youyou in the 1950s (right). On the left was Associate Professor Lou Zhicen 楼之岑. Photo courtesy of Xinhua News Agency.

  • Figure 8

    : Graduation photo taken on November 5, 1960, of all the classmates from the third Off-the-Job Training Program of Traditional Chinese Medicine for Doctors Trained in Western Medicine, held by the Research Institute of Chinese Medical Sciences. Both Tu Youyou (second row, sixth from the left) and Yu Yagang (fourth row, fourth from the left) were there. Photo from the Editorial Group of Tu Youyou zhuan (2015, 48–49).

  • Figure 9

    : The cover, preface (Kongfz.com), and page 15 (The Editorial Group of Tu Youyou zhuan 2015, 64) of Collection of Antimalarial Recipes and Prescriptions, edited by the Special Group in Charge of Daily Work of the CACMS “Revolutionary Committee.”

  • Figure 10

    : The cover, preface, and page 15 of Collection of Antimalarial Recipes and Prescriptions of the copy kept by Tu Youyou. Photo by Li Runhong.

  • Figure 11

    : One of the tables made by Yu Yagang in June 1970. Photo by Li Runhong.

  • Figure 12

    : The screening plan composed by Yu Yagang. Photo by Li Runhong.

  • Figure 13

    : The list of materia medica for screening. This was provided by Tu Youyou for Yu Yagang in 1970 and was preserved by Yu. Photo by Yu Yagang.

  • Figure 14

    : The list of materia medica for screening preserved by the CACMS ICMM. The photo was shown by the ICMM during the Shantou meeting of 2012.35)

  • Figure 15

    : A photocopy of the picture provided by the CACMS ICMM during the 2012 Shantou Meeting (the first line has the date “9.14,” while the fifth line from the bottom has “9.23”).

  • Figure 16

    : Tu Youyou’s presentation on March 8, 1972, titled “Using Mao Zedong Thought to Guide the Exploration of Antimalarial Chinese Herbal Medicines.”

  • Figure 17

    : Summary of the clinical experiment using neutral ethyl ether qinghao extract in Changjiang, Hainan Province, in October 1972 (the main part was written by somebody else, while the note at the end is in Tu Youyou’s handwriting).

  • Figure 18

    : Artemisia annua L. f. macrocephala Pamp in the 1980 paper by Luo Kaijun 罗开均 from the Yunnan Institute of Materia Medica (Luo 1980).

  • Figure 19

    : One page of the slide that Tu Youyou used in 2015 during her Nobel lecture (The Nobel Prize Organization 2015, page 4 of the PDF attachment titled “Artemisinin–A Gift from Traditional Chinese Medicine to the World: Lecture slides”).

  • Figure 20

    : The article published in Chinese Science Bulletin in 1977, under the name of “The Cooperation Group on Research of Artemisinin’s Structure.”

  • Figure 21

    : The absolute configuration of artemisinin (The Cooperation Group on Artemisinin of the Institute of Biophysics, CAS 1979, 1114).

  • Figure 22

    : The certificate of artemisinin’s State Technological Invention Award, which was won in September 1979. Provided by Tu Youyou; photo by Li Runhong.

  • Figure 23

    : The medal that came with the State Technological Invention Award won by artemisinin. Provided by Tu Youyou; photo by Li Runhong.

  • Figure 24

    : The article titled “Antimalarial Activity of Mefloquine and Qinghaosu” published in The Lancet (Jiang et al. 1982, 285).

  • Table 1   : New antimalarial drugs developed through original research in China during the period of Project 523 (1967–1981)

    Drug name

    R&D institution and manufacturer

    Time of evaluation (in China)*

    Pyronaridine

    The National Institute of Parasitic Diseases of Chinese Center for Disease Control and Prevention, Hangzhou Minsheng Pharmaceutical Factory

    1975

    Artemisinin

    CACMS ICMM, Shandong Institute of Chinese Medicine, Yunnan Institute of Materia Medica, Guangzhou College of Chinese Medicine

    1978

    Piperaquine phosphate

    State Institute of Pharmaceutical Industry in Shanghai, Second Military Medical University

    1978**

    Artesunate injection

    Guilin Pharmaceutical Factory (nowadays Guilin Pharmaceutical Corporation [Fosun]), Guilin No. 2 Pharmaceutical Factory (nowadays Guilin Pharmaceutical Corporation [Fosun]), Guangxi Medical College, Guangxi College of Chinese Medicine

    1980

    Artemether injection

    Shanghai Institute of Materia Medica, Kunming Pharmaceutical Factory (nowadays Kunming Pharmaceutical Inc. [Holley])

    1981

    Lumefantrine

    AMMS Institute of Microbiology and Epidemiology (hereafter “the AMMS IME”). R&D started in 1976.

    Unevaluated

    * In the 1970s and the 1980s, the R&D and regulation system for drugs in China was not as rigorous as the present day, and international standards, such as those of FDA, GMP, or GLP, were not enforced. Many drugs would be put into production having only been evaluated by invited professionals in the province or institute from which they originated, and then put into use. Such remedies were accepted as “drugs” in the Chinese context.

    ** Piperaquine phosphate (PQP) was first developed by China. It was used for long-term malaria prevention in the late 1960s and had wholly replaced chloroquine by 1978 in regions throughout the country where malaria p.f. was endemic. Hydroxypiperquine phosphate was evaluated in 1975 (in the Meeting for the Evaluation and Certification of Chemically-Synthesized Drugs in Project 523, held on December 24, 1975).

  • Table 2   : The efficacy of various drugs based on artemisinin and its derivatives90)

    Dosage form

    Daily dose

    (grams per day)

    Cases

    Hours until

    Cure rate

    The fever abated

    The Plasmodium cleared

    Artemisinin tablet

    3.2

    43

    34

    41

    22%

    Artemisinin tablet

    5.0

    14

    36

    27

    55%

    Artemisinin suppository

    0.9

    68

    32

    30

    89%

    Artemether

    0.6

    180

    22

    38

    94%

    Artesunate

    0.4

    159

    26

    29

    48%

  • Table 3   : New antimalarial drugs developed through original research in China that received financial aid from the Steering Committee on Artemisinin between 1982 and 1988

    Drug name

    R&D institution and manufacturer

    Year of certification

    Pyronaridine phosphate tablets and injection

    National Institute of Parasitic Diseases of Chinese Center for Disease Control and Prevention, Hangzhou Minsheng Pharmaceutical Factory

    1985

    API (Active pharmaceutical ingredient) of artemisinin

    CACMS ICMM*

    1986

    Artemisinin suppository

    CACMS ICMM, Guangzhou Baiyunshan Pharmaceutical Factory, Guangzhou College of Chinese Medicine

    1986

    API of artesunate

    Guilin Pharmaceutical Factory (nowadays Guilin Pharmaceutical Corporation [Fosun]), State Institute of Pharmaceutical Industry in Shanghai, AMMS IME, CACMS ICMM, CAMS IMM, Shanghai Institute of Materia Medica, Guangxi Medical College, Guangxi College of Chinese Medicine

    1987

    Artesunate for injection

    State Institute of Pharmaceutical Industry in Shanghai, Guilin No. 2 Pharmaceutical Factory (nowadays Guilin Pharmaceutical Corporation [Fosun]), Guangzhou College of Chinese Medicine

    1987 (2010**)

    Artesunate tablets

    Guilin Pharmaceutical Factory

    1988

    API of artemether

    Shanghai Institute of Materia Medica, Kunming Pharmaceutical Factory

    1987

    Artemether for injection

    Kunming Pharmaceutical Factory

    1987

    API and gel pills of lumefantrine

    AMMS IME, Kunming Pharmaceutical Factory

    1987

    API and tablets of dihydroartemisinin

    CACMS ICMM, Beijing No. 6 Pharmaceutical Factory

    1992

    Tablets of compound artemether (Lumefantrine + Artemether)

    AMMS IME, Kunming Pharmaceutical Factory

    1992

    Naphthoquine phosphate tablets

    AMMS IME

    1993

    * The application documents for the active pharmaceutical ingredient (API) of artemisinin included the work accomplished by many institutions during Project 523. The certification for the new drug, however, was given exclusively to the CACMS ICMM, which is now regarded as a mistake of the government. Permissions to produce artemisinin were only granted to the Guangzhou Baiyunshan Pharmaceutical Factory, which never actually produced any artemisinin, and the Kunming Pharmaceutical Factory. Control over the production of artemisinin was lifted after 2000; as a consequence, the number of manufacturers of artemisinin in China reached over eighty at one time. In contrast, less than five enterprises have permission to produce the API of artemisinin.

    ** Guilin Pharmaceutical Corporation [Fosun] passed the WHO’s prequalification for suppliers in 2010.

  • Table 4   : ACTs currently in use throughout the world that contain new chemical antimalarial drugs developed through original research in China

    ACT name

    Brand

    Manufacturer

    Year of international registration

    Lumefantrine-Artemether

    Coartem, Riamet

    Novartis AG

    1998

    Piperaquine (PO4)-Dihydroartemisinin

    Duo-Cotecxin (Artekin)

    Kunming Pharmaceutical Inc. (Holley)

    2002*

    Naphthoquine (PO4)-Artemisinin

    Arco

    Kunming Pharmaceutical Inc. (Holley)

    2003*

    Piperaquine-Artemisinin

    Artequick

    Artepharm Co., Ltd.

    2006*

    Piperaquine (PO4)-Dihydroartemisinin

    Eurartesim

    Alfasigma S.p.A (Sigma-Tau)

    2011

    Pyronaridine-Artesunate

    Pyramax

    Shin Poong Pharmaceutical Co., Ltd. (South Korea)

    2012

    * Time of new drug certification in China.

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