2. History
2nd century BC Traditional Chinese
Medicine Doctors
Empirical usage
of sweet wormwood
(Artemisia annua) for fever
23/05/1967 Chinese government (Mao
Tse-toung)
Launch of the 523 malaria
research programme
1971 AMMS (academy of
military medical science);
Shanghai Institute of
Materia medica
Isolation of artemisinin
(quinghaosu) from sweet
wormwood
1980 Welcome Trust Information to the world
2006 WHO ACT recommended as gold
standard treatment
worldwide11/08/14 2
3. MECHANISM OF ACTION
• Unique structure bearing
endoperoxide lactone (1,2,4 –
trioxane)
• High selectivity due to its
interaction with haem which
accumulates in parasitized
RBC’s as byproduct of
haemoglobin lysis
• This endoperoxide lactone
moiety form a complex with
Fe(II) of haem & generate highly
reactive free radicals which
causes lysis of the parasite
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4. Source:
It is the active principle of the plant Artemisia annua used in
chinese traditional medicine as quinghaosu
Derivatives marketed in India:
• Artemether (oil soluble)
• Artesunate (water soluble)
• Arteether (developed in India)
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5. Problem
Price and Availability
• Difficulty in distribution in remote areas, which are
most affected with malaria
• Volatile crop- grows commercially in just a small
slice of the world and fluctuates drastically in supply
and price
• Yield and quality vary depending on weather, region,
growing practices, and market conditions
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6. • Concentration of the active ingredient in
wormwood is low- vast acres of land are needed to
produce sufficient quantities of the Active
Pharmaceutical Ingredient (API)
• Only China & Vietnam provide enough fields to grow
plant in large scale
• Experimental cultivation- Kenya, Tanzania,
Madagascar
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7. Breakthrough
• 2001 – University of California, Berkeley, professor of
chemical engineering Jay Keasling- implanted a
combination of wormwood and yeast (Saccharomyces
cerevisiae) genes into bacteria produceing a chemical that
could be chemically converted to artemisinin
• Further research turned up another gene in 2006 that,
when inserted into yeast with the earlier genes,
synthesize small amounts of artemisinic acid
11/08/14 7
8. • Using synthetic biology techniques from Keasling’s
lab, Amyris added that gene to yeast along with
other plant genes to boost artemisinic acid
production by a factor of 15
• Sanofi developed its own proprietary photochemical
process to convert artemisinic acid to artemisinin
• On April 11, 2013, Sanofi launched the large-scale
production of this partially synthetic version of
artemisinin
11/08/14 8
11. • Production of artemisinic acid through fermentation-
performed by Huvepharma, Bulgaria
• Synthetic transformation of the artemisinic acid into
artemisinin via photochemistry- performed at
Sanofi’s Garessio site at Italy
• Sanofi planned to produce 35 tons of artemisinin in
2013 and, on average, 50 to 60 tons a year on & from
2014, which corresponds to between 80 and 150
million ACT treatments
11/08/14 11
12. Advantage
• low price for developing countries (UCB- royalty-free
licensing of the process, Sanofi’s no-profit, no-loss
production model
• Though the price of ACTs will vary from product to
product, the new source for its key ingredient, in
addition to the plant- derived supply, should lead to
a stable cost and steady supply of artemisinin
• ultimately ensuring greater availability of treatment
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13. The Partnership
• Keasling's UC Berkeley research lab- initial discovery
• Amyris, biotechnology firm in California- refined the
process to enable industrialization
• Sanofi- large scale production and marketing
• OneWorld Health, the drug development program for
PATH, an international nonprofit organization aiming to
transform global health through innovation
• Two grants totaling $53.3 million from the Bill & Melinda
Gates Foundation
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16. • Faiz MA, Rahman E, Hossain MA, Rahman MR, Yunus EB, Samad R, Hossain MA; “A
randomized controlled trial comparing artemether and quinine in the treatment of
cerebral malaria in Bangladesh”; Indian J Malariol. 2001 Mar-Jun;38(1-2):9-18
• Mohanty AK, Rath BK, Mohanty R, Samal AK, Mishra K; “Randomized control trial of
quinine and artesunate in complicated malaria”; Indian J Pediatr. 2004 Apr;71(4):291-5
• Dondorp A, Nosten F, Stepniewska K, Day N, White N; “Artesunate versus quinine for
treatment of severe falciparum malaria: a randomised trial”; The Lancet; 2005,
366(9487):717-725
• Tran Tinh Hien, M.D., Nicholas P.J. Day, B.M., B.ch., Nguyen Hoan Phu, M.D., Nguyen Thi
Hoang Mai, M.D., Tran Thi Hong Chau, M.D., Pham Phu Loc, M.D. et al; “A Controlled
Trial of Artemether or Quinine in Vietnamese Adults with Severe Falciparum Malaria”; N
Engl J Med 1996; 335:76-83
11/08/14 16
Notes de l'éditeur
Pre-qualification programme (WHO) has encouraged to decrease the price of these drugs in public tenders. Affordable Medicines Facility – malaria (AMFm), is under experimentation to decrease the price in the private market
Yeast strain engineering. S. cerevisiae codon-optimized synthetic genes of A. annua ADS, CYP71AV1 and CPR1