Artemisinin

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Artemisinin
Systematic (IUPAC) name
(3R,5aS,6R,8aS,9R,12S,12aR)-
octahydro-3,6,9-trimethyl-3,12-
epoxy-12H-pyrano[4,3-j]-
1,2-benzodioxepin-10(3H)-one
Identifiers
CAS number 63968-64-9
ATC code P01BE01
PubChem 68827
ChemSpider 62060
Chemical data
Formula C15H22O5 
Mol. mass 282.332 g/mol
SMILES eMolecules & PubChem
Synonyms Artemisinine, Qinghaosu
Physical data
Density 1.24 ± 0.1 g/cm³
Melt. point 152–157 °C (306–315 °F)
Pharmacokinetic data
Bioavailability  ?
Metabolism  ?
Half life  ?
Excretion  ?
Therapeutic considerations
Pregnancy cat.

?
Legal status
Routes Oral

Artemisinin (pronounced /ɑrtɨˈmɪsɨnɨn/) is a drug used to treat multi-drug resistant strains of falciparum malaria. The compound (a sesquiterpene lactone) is isolated from the plant Artemisia annua. Not all plants of this species contain artemisinin. Apparently it is only produced when the plant is subjected to certain conditions, most likely biotic or abiotic stress. It can be synthesized from artemisinic acid.[1] The drug is derived from a herb used in Chinese traditional medicine, though it is usually chemically modified and combined with other medications.

Use of the drug by itself as a monotherapy is explicitly discouraged by the World Health Organization as there have been signs that malarial parasites are developing resistance to the drug. Combination therapies that include artemisinin are the preferred treatment for malaria and are both effective and well tolerated in patients. The drug is also being studied as a treatment for cancer.

Contents

[edit] History

Artemisia has been used by Chinese herbalists for more than a thousand years in the treatment of many illnesses, such as skin diseases and malaria. The earliest record dates back to 200 BC, in the "Fifty-two Prescriptions" unearthed from the Mawangdui Han Dynasty Tombs. Its antimalarial application was first described in Zhouhou Beji Fang ("The Handbook of Prescriptions for Emergencies"), edited in the middle of the fourth century by Ge Hong. In the 1960s a research program was set up by the Chinese army to find an adequate treatment for malaria. In 1972, in the course of this research, Tu Youyou (Chinese: 屠呦呦)[2] discovered artemisinin in the leaves of Artemisia annua (annual wormwood). The drug is named Qinghaosu (Chinese: 青蒿素) in Chinese. It was one of many candidates then tested by Chinese scientists from a list of nearly 200 traditional Chinese medicines for treating malaria. It was the only one that was effective, but it was found that it cleared malaria parasites from their bodies faster than any other drug in history. Artemisia annua is a common herb and has been found in many parts of the world, including along the Potomac River, in Washington, D.C.

Images of the original scientific papers are available online[3] and a book, Zhang Jianfang, "Late Report – Record of Project 523 and the Research and Development of Qinghaosu", Yangcheng Evening News Publisher 2007(張劍方. 遲到的報告五二三項目與青蒿素研發紀實. 羊城晚報出版社, 2007),[4] was published in 2006, which records the history of the discovery.

It remained largely unknown to the rest of the world for about ten years, until results were published in a Chinese medical journal. The report was met with skepticism at first, because the Chinese had made unsubstantiated claims about having found treatments for malaria before. In addition, the chemical structure of artemisinin, particularly the peroxide, appeared to be too unstable to be a viable drug.

[edit] Indications

Because artemisinin itself has physical properties such as poor bioavailability that limit its effectiveness, semi-synthetic derivatives of artemisinin, including artemether and artesunate, have been developed. However, their activity is not long lasting, with significant decreases in effectiveness after one to two hours. To counter this drawback, artemisinin is typically given with lumefantrine (also known as benflumetol) to treat uncomplicated falciparum malaria. Lumefantrine has a half-life of about 3 to 6 days and prevents the disease from returning. The treatments are called "ACT" (artemisinin-based combination therapy); other examples are artemether-lumefantrine, artesunate-mefloquine, artesunate-amodiaquine, and artesunate-sulfadoxine/pyrimethamine. Recent trials have shown that these therapies are more than 90% effective, with a recovery from symptoms after three days, especially for the chloroquine-resistant Plasmodium falciparum.

[edit] Chemically modified analogues

There are a number of derivatives and analogues within the artemisinin family:

There are also simplified analogs in preclinical research.[5]

[edit] Purely synthetic analogues

To counter the present shortage in leaves of Artemisia annua, researchers have been searching for a way to develop artemisinin artificially in the laboratory. A 2006 paper in Nature[6] presented a genetically engineered yeast that can synthesize a precursor called artemisinic acid which can be chemically converted to artemisinin. The compound called OZ-277 (also known as RBx11160), developed by Jonathan Vennerstrom at the University of Nebraska, has proved to be even more effective than the natural product in test-tube trials. A six month trial of the drug on human subjects in Thailand was started in January 2005. There are also plans to have the plant grow in other areas of the world outside Vietnam and China (Kenya, Tanzania, Madagascar).

[edit] Cancer treatment

Artemisinin is under early research and testing for treatment of cancer, primarily by researchers at the University of Washington.[7][8] Artemisinin has a peroxide lactone group in its structure. It is thought that when the peroxide comes into contact with high iron concentrations (common in cancerous cells), the molecule becomes unstable and releases reactive oxygen species. It has been shown to reduce angiogenesis and the expression of vascular endothelial growth factor in some tissue cultures.

[edit] Contraindications

The artemesinins are not used for malaria prophylaxis (prevention) because of the extremely short activity of the drug. To be effective, it would have to be administered multiple times each day.

Artemisinin can be used by itself, but is almost always chemically modified to artesunate or artemether and combined with another antimalarial drug. Artemisinin and its derivatives are fast-acting, but other drugs are often required to clear the body of all parasites and prevent recrudescence.

The World Health Organization is pressuring manufacturers to stop making the pure drug, saying it would be a loss if the parasites would build up resistance for the only known drug the parasites have not developed resistance to.[9] In vitro experiments have been able to generate a resistant strain of the parasite and resistant strains have been found from field samples. Artemisinin is widely used in China and Southeast Asia for treatment of malaria.

The World Health Organisation has recommended that a switch to ACT should be made in all countries where the malaria parasite has developed resistance to chloroquine. Artemisinin and its derivatives are now standard components of malaria treatment in China, Vietnam, and some other countries in Asia and Africa, where they have proved to be safe and effective anti-malarial drugs. They have minimal adverse side effects. Currently, artemisinin is not widely available in the United States or Canada, but is easy to find in Africa and Asia. There have been some concerns about the quality of some products on offer in Africa,[10] where so-called "Artemisinin Combination Treatments" are sold, having cheaper ineffective substitutes in place of artemisinin, the most expensive ingredient.

A study published in 2008 by Noedl and colleagues in the New England Journal of Medicine suggests a consensus amongst researchers that artemisinin is losing its potency in Cambodia and increased efforts are required to prevent drug-resistant malaria from spreading across the globe.[11]

[edit] Adverse effects

Artemisinins are generally well tolerated in the doses used to treat malaria. The drugs that are used in combination therapies sometimes add to these effects. Adverse effects in patients with acute falciparum malaria treated with artemisinin derivatives tend to be higher.[12] The side effects from the artemsinins themselves are similar to the symptoms of malaria: nausea, vomiting, anorexia, and dizziness. The combination drugs may have additional side effects.

[edit] Pharmacokinetics and pharmacodynamics

The specific mechanism of action of artemisinin is not well understood, and there is ongoing research directed at elucidating it. When the parasite that causes malaria infects a red blood cell, it consumes hemoglobin and liberates free heme, an iron-porphyrin complex. The iron reduces the peroxide bond in artemisinin generating high-valent iron-oxo species, resulting in a cascade of reactions that produce reactive oxygen radicals which damage the parasite leading to its death.[13]

Numerous studies have investigated the type of damage that these oxygen radicals may induce. For example, Pandey et al. have observed inhibition of digestive vacuole cysteine protease activity of malarial parasite by artemisinin.[14] These observations were further confirmed by ex vivo experiments showing accumulation of hemoglobin in the parasites treated with artemisinin, suggesting inhibition of hemoglobin degradation. They found artemisinin to be a potent inhibitor of hemozoin formation activity of malaria parasite.

A 2005 study investigating the mode of action of artemisinin using a yeast model demonstrated that the drug acts on the electron transport chain, generates local reactive oxygen species, and causes the depolarization of the mitochondrial membrane.[15]

[edit] Mechanism of action

Artemisinins have also been shown to inhibit PfATP6, a SERCA-type enzyme (calcium transporter) and artemisinin has been shown to compete with thapsigargin for SERCA binding, though artemesinin is much less toxic to mammalian cells. These experiments however, have only been conducted in a recombinant system (Xenopus oocytes), and it remains to be verified within P. falciparum parasites. Resistance to artemisinin is conferred by a single mutation in the calcium transporter (PfATP6). This mutation has been studied in the laboratory but recently a study from French Guiana in field isolates of malaria parasites has identified a different mutation in the calcium transporter (PfATP6) that is associated with resistance to artemether, lending support to the idea that PfATP6 is the target for artemisinins.[16]

[edit] Dosing

The WHO approved adult dose of co-artemether (artemether-lumefantrine) for malaria is 4 tablets at 0, 8, 24, 36, 48 and 60 hours (six doses).[17][18] This has been proven to be superior to regimens based on amodiaquine.[19] Artemesinin is not soluble in water and therefore Artemisia annua tea was postulated not to contain pharmacologically significant amounts of artemesinin.[20] However, this conclusion was rebuked by several experts who stated that hot water (85 oC), and not boiling water, should be used to prepare the tea. Although Artemisia tea is not recommended as a substitute for the ACT (artemisinin combination therapies) more clinical studies on artemisia tea preparation have been suggested.[21]

[edit] Synthesis

In 2006 a team from Berkeley published an article claiming that they had engineered Saccharomyces cerevisiae microbes that can produce the precursor artemisinic acid. The synthesized artemisinic acid can then be transported out, purified and turned into a drug that they claim will cost roughly 0.25 cents per dose. Details of the formation of artemisinic acid involves a mevalonate pathway, expression of amorphadiene synthase, a novel cytochrome P450 monooxygenase (CYP71AV1) and its redox partner from A. annua. A three-step oxidation of amorpha-4,11-diene gives the resulting artemisinic acid.[22] Amyris Biotechnologies is collaborating with UC Berkeley and the Institute for One World Health to further develop this technology.[23]

Using seed supplied by Action for Natural Medicine (ANAMED), the World Agroforestry Centre (ICRAF) has developed a hybrid, dubbed A3, which can grow to a height of 3 m and which produces 20 times more artemisinin than wild varieties. In northwestern Mozambique, ICRAF is working together with a medical organisation, Médecins sans frontières (MSF), ANAMED and the Ministry of Agriculture and Rural Development to train farmers on how to grow the shrub from cuttings, and to harvest and dry the leaves to make artemisia tea. Cultivation of this crop may well prove a valuable niche market for Africa, given the strong demand for the plant from pharmaceutical laboratories.

The biosynthesis of artemisinin is expected to involve the mevalonate pathway (MVA) and the cyclization of FDP (farnesyl diphosphate). Although it is not clear whether the DXP (deoxyxylulose phosphate)pathway can also contribut 5-carbon precurosrs (IPP or/and DMAPP), as occurs in other sesquiterpene biosynthetic system. The routes from artemisinic alcohol to artemisinin remain controversial and they differ mainly in when the reduction step takes place. Both routes suggested dihydroartemisinic acid as the final precursor to artemisinin. Dihydroartemisinic acid then undergoes photoxidation to produce dihydroartemisinic acid hydroperoxide. Ring expansion by the cleavage of hydroeroxide and a second oxygen-mediated hydroperoxidation furnish the biosynthesis of artemisinin.

Figure 1. Biosynthesis of Artemisinin.

The total synthesis of artemisinin can also be performed using basic organic reagents. In 1982, G. Schmid and W. Hofheinz published a paper showing the complete synthesis of artemisinin. Their starting material was (-)-Isopulegol (2) which as converted to methoxymethyl ether (3). The ether was hydroborated and then underwent oxidative workup to give (4). The primary hydroxyl group was then benzylated and the methoxymethyl ether was cleaved resulting in (5) which would be oxidized to (6). Next, the compound was protonated and treated with (E)-(3-iodo-1-methyl-1-propenyl)-trimethylsilane to give (7). This resulting ketone was reacted with lithium methoxy(trimethylsily)methylide to obtain two diastereomeric alcohols, (8a) and (8b). 8a was then debenzylated using (Li, NH3) to give lactone (9). The vinylsilane was then oxidized to ketone (10). The ketone was then reacted with fluoride ion that caused it to undergo desilylation, enol ether formation and carboxylic acid formation to give (11). An introduction of a hydroperoxide function at C(3) of 11 gives rise to (12). Finally, this underwent photooxygenation and then treated with acid to produce artemisinin.[24]

[edit] The Artemisinin Project

The Artemisinin Project is an program by Sanofi-Aventis, Amyris Biotechnologies, the Institute for OneWorld Health, and Jay Keasling, a researcher from the University of California, to combat malaria by producing artemisinin at low cost.[25] Naturally derived artemisinin is expensive and Keasling's proposal for its production by biotechnology is expected to reduce its price. With the help of the Gates Foundation, Keasling, OneWorld Health and Amyris developed a lab process for the production of artemisinin. Sanofi-Aventis was chosen to put the process into mass-production.

[edit] Legal Status

For many years, access to the purified drug and the plant it was extracted from were restricted by the Chinese government. It was not until the late 1970s and early 80s that news of the discovery reached scientists outside China. The World Health Organisation (WHO) tried to contact Chinese scientists and officials to find out more, but drew a blank. Dr Ying Lee, one of the scientists involved in the research into artemisinin, said the Chinese distrusted the West. The Chinese suspected the West just wanted to exploit the drug and sell it around the world slightly altered and repatented. The fact that there were several Americans on the WHO's steering board on malaria and that some were from the military did not help clear the distrust. It can be noted Americans had just invested a lot into mefloquine, an analogue of chloroquine.

[edit] References

  1. ^ Acton, N. & Roth, R.J. On the conversion of dihydroartemisinic acid into artemisinin. J. Org. Chem. 57, 3610-3614 (1992)
  2. ^ ChinaVitae: Tu Youyou
  3. ^ Qinghaosu Project
  4. ^ ycwb.com
  5. ^ Gary H. Posner; Michael H. Parker; Northrop, John; Elias, Jeffrey S.; Ploypradith, Poonsakdi; Xie, Suji; Shapiro, Theresa A. (1999). "Orally Active, Hydrolytically Stable, Semisynthetic, Antimalarial Trioxanes in the Artemisinin Family". J. Med. Chem. 42 (2): 300-304. 
  6. ^ Ro DK, Paradise EM et al. Production of the antimalarial drug precursor artemisinic acid in engineered yeast. Nature. (2006) 440: 940-943.
  7. ^ University of Washington: News
  8. ^ University of Washington: Artemisinin
  9. ^ "WHO ultimatum on artemisinin monotherapy is showing results". British Medical Journal. http://www.bmj.com/cgi/content/full/332/7551/1176-b. Retrieved on 2008-11-14. 
  10. ^ BBC news
  11. ^ Noedl H, Se Y, Schaecher K, Smith BL, Socheat D, Fukuda MM (December 2008). "Evidence of artemisinin-resistant malaria in western Cambodia". N. Engl. J. Med. 359 (24): 2619–20. doi:10.1056/NEJMc0805011. PMID 19064625. 
  12. ^ R. Price et al. (1999). American Journal of Tropical Medicine and Hygiene 60: 547-555. http://www.ajtmh.org/cgi/content/abstract/60/4/547. 
  13. ^ Cumming, Jared N.; Ploypradith, Poonsakdi; Gary H. Posner Antimalarial activity of artemisinin (qinghaosu) and related trioxanes: mechanism(s) of action. Advances in Pharmacology (San Diego) (1997), 37 253-297.
  14. ^ Pandey et al.
  15. ^ Li et al., PLOS Genetics, September 2005, Volume 1, Issue 3
  16. ^ A.-C. Uhlemann et al. Nature Struct. Mol. Biol. 12, 628-629;2005
  17. ^ Vugt MV, Wilairatana P, Gemperli B, et al. (1999). "Efficacy of six doses of artemether-lumefantrine (benflumetol) in multidrug-resistant Plasmodium falciparum malaria". Am J Trop Med Hyg 60 (6): 936–42. PMID 10403324. 
  18. ^ Lefevre G, Looareesuwan S, Treeprasertsuk S, et al. (2001). "A clinical and pharmacokinetic trial of six doses of artemether-lumefantrine for multidrug-resistant Plasmodium falciparum malaria in Thailand". Am J Trop Med Hyg 64 (5–6): 247–56. PMID 11463111. 
  19. ^ Mutabingwa TK, Anthony D, Heller A, et al. (2005). "Amodiaquine alone, amodiaquine+sulfadoxine-pyrimethamine, amodiaquine+artesunate, and artemether-lumefantrine for outpatient treatment of malaria in Tanzanian children: a four-arm randomised effectiveness trial". Lancet 365 (9469): 1474–80. doi:10.1016/S0140-6736(05)66417-3. PMID 15850631. 
  20. ^ Jansen FH (2006). "The herbal tea approach for artemesinin as a therapy for malaria?". Trans R Soc Trop Med Hyg 100 (3): 285–6. doi:10.1016/j.trstmh.2005.08.004. 
  21. ^ Bioline
  22. ^ Richmond Sarpong, Jay D. Keasling. "Production of the antimalarial drug precursor artemisinic acid in engineered yeast" Nature 440, 940-943 (13 April 2006)
  23. ^ Amyris Biotechnologies
  24. ^ G. Schmid, W. Hofheinz. "Total Synthesis of qinghaosu" J. Am. Chem. Soc.; 1983; 105 (3); 624-625
  25. ^ Steve Hamm (January 26, 2009). "'Crative Capitalism' versus Malaria". Business Week: 083. 

[edit] External links

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