Semi synthetic artemisinin_Dr. Mansij Biswas
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Transcript of Semi synthetic artemisinin_Dr. Mansij Biswas
History
2nd century BC Traditional Chinese Medicine Doctors
Empirical usageof 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 goldstandard treatment worldwide11/08/14 2
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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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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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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• 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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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
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• Using synthetic biology techniques from Keasling’slab, 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
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• 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
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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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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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• 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 ThiHoang 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
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