Tu Youyou: The scientist who discovered artemisinin

Vinitha Marimuthu*,

Clinical Pharmacist, Kauvery Hospitals, Trichy-Cantonment, Tamilnadu

*Correspondence: [email protected]

Tu Youyou is a Chinese Pharmaceutical Chemist and Malariologist, who is best known for discovering Artemisinin, a drug used to treat Malaria.

Discovery of Artemisinin

Malaria is a life-threatening tropical disease. It was effectively treated and controlled by chloroquine and quinolines for a long period of time until the development of drug-resistant malaria plasmodium parasites, especially plasmodium falciparum, in the late 1960s, following the catastrophic failure of a global attempt to eradicate malaria.

In the late 1960s, the Chinese government launched a secret project to find a cure for Malaria. Tu Youyou was part of a team tasked with finding a new antimalarial drug. She turned to Chinese medical texts and discovered, in 1972, a reference to a plant called Artemisia annua L. (Sweet Wormwood) which was used to treat fevers. She and her team extracted a compound from the plant, called Qinghaosu or Artemisinin.

They produced extracts from different herbs including Qinghao and tested those ethyl ether, ethanol and aqueous extracts on rodent malaria. On October 4, 1971, they observed that sample number 191 of the Qinghao ethyl ether extract showed 100% effectiveness in inhibiting malaria parasites in rodent malaria. In subsequent experiments, they separated the extracts into a neutral portion and a toxic acidic portion. The neutral portion showed the same effect when tested in malaria-infected monkeys between December 1971 and January 1972.

Dihydroartemisinin was discovered in September 1973 in an experiment where she tried to derivatize artemisinin for a structural activity relationship evaluation. The carboxyl group related peak disappeared and was replaced by the hydroxyl group related peak in the IR spectrum after a reduction reaction using sodium borohydride. This experimental result was verified in a repeat experiment carried out by team members. In a subsequent test in rodent malaria, they noticed that a significantly reduced dose was sufficient to achieve the same efficacy as artemisinin when dihydroartemisinin was administered.

They tested the compound on themselves and then on malarial infected mice, and found that artemisinin was highly effective in killing the malarial parasites.

  • Artemisinin has since become one of the world’s most effective malaria-fighting drugs. Tu Youyou’s discovery of Artemisinin has been called a breakthrough in twentieth-century tropical medicine.
  • Artemisinin and other Artemether- group drugs have been the main line of defense against drug-resistant malaria in many parts of Southeast Asia.
  • Combining an Artemisinin drug with partner drug that has a longer half-life was found to improve the efficacy of Artemisinin. Such companion drugs include lumefantrine, mefloquine, amodiaquine, sulfadoxine/pyrimethamine, piperaquine and chlorproguanil/dapsone.

Legacy

Tu Youyou’s discovery of Artemisinin has had a profound impact on global health.

  • Reduced Malaria Deaths: Artemisinin has helped to reduce the number of malaria deaths worldwide. It has saved millions of life in South China, Southeast Asia, Africa and South America.
  • Improved Treatment Options: Artemisinin-based combination therapies (ACTs) become the first line of treatment for malaria.
  • Inspiration of New Research: Tu Youyou’s discovery of Artemisinin has inspired other scientist to explore traditional medicine for new treatments. Tu Youyou’s work is a testament to the power of scientific curiosity and the importance of looking to the past for new solutions to modern problems.

Awards and Honors

Tu Youyou has received numerous awards and honor for her work, including:

  • Lasker- Debakey Clinical Medical Research Award (2011)
  • Warren Alpert Foundation Prize (2015)
  • Noble Prize in Physiology or Medicine (2015)
  • Highest Science and Technology Award, China (2016)
  • Medal of The Republic, China (2019)
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Artimisinin formulations

Artemisinin may be administered orally, intramuscularly, or as a suppository. The drug reaches peak plasma levels within hours after administration and acts rapidly, significantly reducing malaria parasite burden in the first few days of treatment. Artesunate is unique among the artemisinin-derived agents because it can be administered intravenously, enabling the drug to take immediate effect. As a result, artesunate is used in the treatment of cerebral malaria, which is an acute form of the disease characterized by the rapid spread of parasites to the brain and by death within 72 hours if left untreated. Artemisinin appears to have few side effects in humans

Strandard Protocol Treatment

Table 1. Uncomplicated malaria: Plasmodium falciparum or unknown species (If later diagnosed as P. vivax or P. ovale, see Table 2 for antirelapse treatment)

<td”>IV artesunate: Commercially available from major distributors. 1 dose=2.4 mg/kg

IV doses (3 in total) at 0, 12 and 24 hours

PLUS follow-on treatment below

</td”>

Drug Susceptibility

(Based on where acquired)

 Recommended Adult Regimens Recommended Pediatric Regimens
Chloroquine resistant or unknown resistance

(All malaria-endemic regions except those in Central America west of Panama Canal, Haiti, and Dominican Republic)
  1. Artemether-lumefantrine (Coartem®) (1 tab: 20 mg artemether and 120 mg lumefantrine)

Adults: 4 tabs po per dose Three-day course:

Day 1: Initial dose and second dose 8 h

later

Days 2 and 3: 1 dose BID

  1. Atovaquone-proguanil (MalaroneTM) (Adult tab: 250 mg atovaquone and 100 mg proguanil)

4 adult tabs po QD x 3 days
  1. Artemether-lumefantrine (Coartem®) (1 tab: 20 mg artemether and 120 mg lumefantrine)

515 kg: 1 tab po per dose 1525 kg: 2 tabs po per dose 2535 kg: 3 tabs po per dose

35 kg: 4 tabs po per dose

Three-day course:

Day 1: Initial dose and second dose 8 h later

Days 2 and 3: 1 dose BID

  1. Atovaquone-proguanil (MalaroneTM) (Adult tab: 250 mg atovaquone and 100 mg proguanil; Peds tab: 62.5 mg atovaquone and 25 mg proguanil)

58 kg: 2 peds tabs po QD x 3 days 810 kg: 3 peds tabs po QD x 3 days 1020 kg: 1 adult tab po QD x 3 days 2030 kg: 2 adult tabs po QD x 3 days 3040 kg: 3 adult tabs po QD x 3 days

40 kg: 4 adult tabs po QD x 3 days
Drug Susceptibility

(Based on where acquired)

 Recommended Adult Regimens Recommended Pediatric Regimens4
Chloroquine resistant or unknown resistance

(All malaria- endemic regions except those in Central America west of Panama Canal, Haiti, and Dominican Republic)

 C. Quinine sulfate plus doxycycline, tetracycline, or clindamycin

Quinine sulfate: 542 mg base (650 mg salt) po TID x 3 or 7 days

Doxycycline: 100 mg po BID x 7 days Tetracycline: 250 mg po QID x 7 days Clindamycin: 20 mg/kg/day po divided TID x 7 days

D. Mefloquine

Dose 1: 684 mg base (750 mg salt) po

Dose 2 at 6 to 12 h: 456 mg base (500 mg salt) po

 C. Quinine sulfate plus doxycycline, tetracycline, or clindamycin

Quinine sulfate: 8.3 mg base/kg (10 mg salt/kg) po TID x 3 or 7 days7 Doxycycline: 2.2 mg/kg po BID x 7 days

Tetracycline: 25 mg/kg/day po divided QID x 7 days

Clindamycin: 20 mg /kg/day po divided TID x 7 days

D. Mefloquine

Dose 1: 13.7 mg base/kg (15 mg salt/kg) po

Dose 2 at 6 to 12 h: 9.1 mg base/kg (10 mg salt/kg) po
Chloroquine sensitive

(Central America west of Panama Canal, Haiti, and Dominican Republic)

 Chloroquine phosphate (Aralen and generics)

Dose 1: 600 mg base (1,000 mg salt) po

Doses 2 to 4 (3 additional doses) at 6, 24 and 48 h: 300 mg base (500 mg salt) po per dose; or

Hydroxychloroquine (PlaquenilTM and generics)

Dose 1: 620 mg base (800 mg salt) po

Doses 2 to 4 (3 additional doses) at 6, 24 and 48 h: 310 mg base (400 mg salt) po per dose

 Chloroquine phosphate (Aralen and generics)

Dose 1: 10 mg base/kg (16.7 mg salt/kg) po

Doses 2 to 4 (3 additional doses) at 6, 24 and 48 h: 5 mg base/kg (8.3 mg salt/kg) po per dose; or

Hydroxychloroquine (PlaquenilTM and generics)

Dose 1: 10 mg base/kg (12.9 mg salt/kg) po

Doses 2 to 4 (3 additional doses) at 6, 24 and 48 h: 5 mg base/kg (6.5 mg salt/kg) po per dose
Drug Susceptibility

(Based on where acquired)

 Recommended Adult Regimens

(BOTH acute and antirelapse treatments

recommended)

 Recommended Pediatric Regimens

(BOTH acute and antirelapse treatments recommended)
Chloroquine resistant

(Papua New Guinea and Indonesia)

Chloroquine sensitive

(All malaria- endemic regions except Papua New Guinea and Indonesia)

 Acute treatment:

  1. Artemether-lumefantrine (Coartem®) (1 tab: 20 mg artemether and 120 mg lumefantrine)

Adults: 4 tabs po per dose Three-day course:

Day 1: Initial dose and second dose 8 h

later

Days 2 and 3: 1 dose BID

  1. Atovaquone-proguanil (MalaroneTM) (Adult tab: 250 mg atovaquone and 100 mg proguanil)

4 adult tabs po QD x 3 days

Acute treatment :

Chloroquine phosphate (Aralen and generics)

Dose 1: 600 mg base (1,000 mg salt) po

Doses 2 to 4 (3 additional doses) at 6, 24 and 48 h: 300 mg base (500 mg salt) po per dose; or

Hydroxychloroquine (PlaquenilTM and generics)

Dose 1: 620 mg base (800 mg salt) po

Doses 2 to 4 (3 additional doses) at 6, 24 and 48 h: 310 mg base (400 mg salt) po per dose

AND Antirelapse treatments: Primaquine phosphate

30 mg base po qd x 14 days; or

Tafenoquine (KrintafelTM)

300 mg po x 1 dose

 Acute treatment:

  1. Artemether-lumefantrine (Coartem®) (1 tab: 20 mg artemether and 120 mg lumefantrine)

515 kg: 1 tab po per dose 1525 kg: 2 tabs po per dose 2535 kg: 3 tabs po per dose

35 kg: 4 tabs po per dose

Three-day course:

Day 1: Initial dose and second dose 8 h later

Days 2 and 3: 1 dose BID

  1. Atovaquone-proguanil (MalaroneTM) (Adult tab: 250 mg atovaquone and 100 mg proguanil; peds tab: 62.5 mg atovaquone and 25 mg proguanil)

58 kg: 2 peds tabs po QD x 3 days 810 kg: 3 peds tabs po QD x 3 days 1020 kg: 1 adult tab po QD x 3 days 2030 kg: 2 adult tabs po QD x 3 days 3040 kg: 3 adult tabs po QD x 3 days

40 kg: 4 adult tabs po QD x 3 days

Acute treatment :

Chloroquine phosphate (Aralen and generics)

Dose 1: 10 mg base/kg (16.7 mg salt/kg) po

Doses 2 to 4 (3 additional doses) at 6, 24 and 48 h: 5 mg base/kg (8.3 mg salt/kg) po per dose; or

Hydroxychloroquine (PlaquenilTM and generics)

Dose 1: 10 mg base/kg (12.9 mg salt/kg) po

Doses 2 to 4 (3 additional doses) at 6, 24 and 48 h: 5 mg base/kg (6.5 mg salt/kg) po per dose

AND

Antirelapse treatment: Primaquine phosphate

0.5 mg base/kg po qd x 14 days; or

Tafenoquine (KrintafelTM)

300 mg po x 1 dose, only for patients 16

years old
Drug Susceptibility

(Based on where

acquired)

 Recommended Adult Regimens Recommended Pediatric Regimens
Chloroquine sensitive

(All malaria- endemic regions, no known resistance)

Chloroquine sensitive

(All malaria- endemic regions, no known resistance)
  1. Chloroquine phosphate (Aralen and generics)

Dose 1: 600 mg base (1,000 mg salt) po

Doses 2 to 4 (3 additional doses) at 6, 24 and 48 h: 300 mg base (500 mg salt) po per dose; or

Hydroxychloroquine (PlaquenilTM and generics)

Dose 1: 620 mg base (800 mg salt) po

Doses 2 to 4 (3 additional doses) at 6, 24 and 48 h: 310 mg base (400 mg salt) po per dose

  1. Artemether-lumefantrine (Coartem®)4 (1 tab: 20 mg artemether and 120 mg lumefantrine)

course:

Day 1: Initial dose and second dose 8 h later

Days 2 and 3: 1 dose BID

C. Atovaquone-proguanil (MalaroneTM) (Adult tab: 250 mg atovaquone and 100 mg proguanil)

4 adult tabs po QD x 3 days

D. Quinine sulfate plus doxycycline, tetracycline, or clindamycin

Quinine sulfate: 542 mg base (650 mg salt) po TID x 3 days

Doxycycline: 100 mg po BID x 7 days Tetracycline: 250 mg po QID x 7 days Clindamycin: 20 mg/kg/day po divided TID x 7 days

E. Mefloquine

Dose 1: 684 mg base (750 mg salt) po

Dose 2 at 6 to 12 h: 456 mg base (500 mg salt) po
  1. Chloroquine phosphate (Aralen and generics)

Dose 1: 10 mg base/kg (16.7 mg salt/kg) po

Doses 2 to 4 (3 additional doses) at 6, 24 and 48 h: 5 mg base/kg (8.3 mg salt/kg) po per dose; or

Hydroxychloroquine (PlaquenilTM and generics)

Dose 1: 10 mg base/kg (12.9 mg salt/kg) po

Doses 2 to 4 (3 additional doses) at 6, 24 and 48 h: 5 mg base/kg (6.5 mg salt/kg) po per dose

  1. Artemether-lumefantrine (Coartem®) (1 tab: 20 mg artemether and 120 mg lumefantrine)

515 kg: 1 tab po per dose 1525 kg: 2 tabs po per dose 2535 kg: 3 tabs po per dose

35 kg: 4 tabs po per dose

Three-day course:

Day 1: Initial dose and second dose 8 h later Days 2 and 3: 1 dose BID

  1. Atovaquone-proguanil (MalaroneTM) (Adult tab: 250 mg atovaquone and 100 mg proguanil; peds tab: 62.5 mg atovaquone and 25 mg proguanil)

58 kg: 2 peds tabs po QD x 3 days 810 kg: 3 peds tabs po QD x 3 days 1020 kg: 1 adult tab po QD x 3 days 2030 kg: 2 adult tabs po QD x 3 days 3040 kg: 3 adult tabs po QD x 3 days

40 kg: 4 adult tabs po QD x 3 days

  1. Quinine sulfate6 plus doxycycline7, tetracycline7, or clindamycin8

Quinine sulfate: 8.3 mg
Species and Drug Susceptibility

(Based on where acquired)

 Recommended Adult Regimen Recommended Pediatric Regimen
All species, drug susceptibility not relevant for acute treatment of severe malaria

If P. vivax or P. ovale infections, in addition to acute treatment listed here, antirelapse treatment needed (Table 2)
If IV artesunate not readily available, give oral antimalarials while obtaining IV artesunate. When IV artesunate arrives, discontinue oral antimalarial and initiate IV treatment. Interim treatment options (Table 1 for dosing):

  • Artemether-lumefantrine (Coartem®) (preferred); or
  • Atovaquone-proguanil (Malarone); or
  • Quinine sulfate; or
  • Mefloquine (only if no other options available)

If oral therapy not tolerated, consider administration via nasogastric (NG) tube or after an antiemetic.
Reassess parasite density at least 4 hours after the third dose:

Parasite density ≤1% and patient able to tolerate oral medications: Give a complete follow-on oral regimen. Options include (Table 1 for dosing):

  • Artemether-lumefantrine (Coartem®) (preferred), or
  • Atovaquone-proguanil (Malarone), or
  • Quinine plus doxycycline or, in children <8 years old and pregnant women, clindamycin, or
  • Mefloquine (only if no other options available)

Parasite density >1%: Continue IV artesunate, same dose, QD up to 6 more days (for a total of 7 days of IV artesunate) until parasite density ≤1%. When parasite density ≤1%, give complete follow-on oral regimen (Table 1 for options and dosing).

Parasite density ≤1% but patient unable to take oral medication: Continue IV artesunate, same dose, QD up to 6 more days (for a total of 7 days of IV artesunate)

until patient able to take oral therapy.
Chloroquine resistant

P. falciparum (All malaria- endemic regions except Central America west of Panama Canal, Haiti, and Dominican Republic)

P. vivax or P. ovale (Papua New Guinea and Indonesia)

 All trimesters: Artemether-lumefantrine (Coartem®)

(1 tab: 20 mg artemether and 120 mg lumefantrine) Adults: 4 tabs po per dose

Three-day course:

Day 1: Initial dose and second dose 8 h later Days 2 and 3: 1 dose BID

All trimesters: Quinine sulfate plus clindamycin

Quinine sulfate: 542 mg base (650 mg salt) po TID x 3 or 7 days Clindamycin: 20 mg/kg/day po divided TID x 7 days

If no other options, all trimesters: Mefloquine

Dose 1: 684 mg base (750 mg salt) po

Dose 2 at 6 to 12 h: 456 mg base (500 mg salt) po

AND if P. vivax or P.ovale:

Chloroquine 500 mg salt (300 mg base) weekly until delivery, then consider antirelapse treatment (Table 2 for options and dosing)

Antirelapse treatment with either primaquine or tafenoquine contraindicated during pregnancy
Chloroquine sensitive

P. falciparum (Central America west of Panama Canal, Haiti, and Dominican Republic)

P. vivax or P. ovale

(All malaria-endemic regions except Papua New Guinea and Indonesia)

P. malariae or P. knowlesi

 A. Chloroquine phosphate (Aralen and generics)

Dose 1: 600 mg base (1,000 mg salt) po

Doses 2 to 4 (3 additional doses) at 6, 24 and 48 h: 300 mg base (500 mg salt) po per

Hydroxychloroquine (PlaquenilTM and generics)

Dose 1: 620 mg base (800 mg salt) po

Doses 2 to 4 (3 additional doses) at 6, 24 and 48 h: 310 mg base (400 mg salt) po per dose

Options above for chloroquine-resistant malaria parasites AND if P. vivax or P.ovale:

Chloroquine 500 mg salt (300 mg base) weekly until delivery, then consider antirelapse treatment (Table 2 for options and dosing)

Antirelapse treatment with either primaquine or tafenoquine contraindicated during pregnancy

Post Script

Unfortunately resistance has emerged, especially in south east Asia .

Indiscriminate usage of the drugs in Africa, for non – malarial fevers, has also encouraged development of resistance

References

  • Xin-zhuan S., Miller LH. The discovery of artemisinin and Nobel Prize in Physiology or Medicine. Sci China Life Sci. 2015;58(11):1175–9.
  • Xiao Z., Qijin W., Ming L. Tu Youyou’s Nobel Prize and the academic evaluation system in China. 2016;387(10029):P1722.
vinitha-marimuthu2023-08-01-07:55:20am

Ms. Vinitha Marimuthu

Clinical Pharmacist

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