Artesunate

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Artesunate
Artesunate.svg
Clinical data
AHFS/Drugs.com International Drug Names
Legal status
  • Not licensed in UK or US
Routes oral, IV, IM
Identifiers
CAS number 88495-63-0 N
80155-81-3 (sodium salt)
ATC code P01BE03
PubChem CID 5464098
ChemSpider 16735675 YesY
UNII 60W3249T9M YesY
ChEMBL CHEMBL258608 N
NIAID ChemDB 112081
Chemical data
Formula C19H28O8 
Mol. mass 384.421 g/mol
 N (what is this?)  (verify)

Artesunate (INN) is part of the artemisinin group of drugs that treat malaria. It is a semi-synthetic derivative of artemisinin that is water-soluble and may therefore be given by injection. It is sometimes abbreviated AS.

It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.[1]

Medical uses[edit]

The World Health Organization recommends intramuscular or intravenous artesunate as the first line treatment for severe malaria.[2] Artesunate was shown to prevent more deaths from severe malaria than quinine in two large multicentre randomized controlled trials from Africa[3] and Asia.[4] A subsequent systematic review of seven randomized controlled trials found this beneficial effect to be consistent across all trials.[5]

For severe malaria during pregnancy, there is less certainty about the safety of artesunate during the first trimester but artesunate is recommended as first-line therapy during the second and third trimesters.[6]

Artesunate is also used to treat less severe forms of malaria when it can be given orally, but should always be taken with a second antimalarial such as mefloquine or amodiaquine to avoid the development of resistance.[2]

While artesunate is used primarily as treatment for malaria, there is some evidence that it may also have some beneficial effects in Schistosoma haematobium infection,[7] but this needs confirming in large randomized trials.

Adverse effects[edit]

Artesunate is generally safe and well-tolerated. The best recognised side effect of the artemesinins that they lower reticulocyte counts.[8] This is not usually of clinical relevance.

Delayed haemolysis (occurring around two weeks after treatment) has been observed in patients treated with artesunate for severe malaria.[9] Whether or not this haemolysis is due to artesunate, or to the malaria itself is unclear.[10]

The safety of artesunate in pregnancy is unclear. There is evidence of embryotoxicity in animal models (defects in long bones and ventricular septal defects in the heart in rats and monkeys). However, observational evidence from 123 human first-trimester pregnancies showed no evidence of damage to the fetus.[11]

Synthesis[edit]

Artesunate is prepared from dihydroartemisinin (DHA) by reacting it with succinic acid anhydride in basic medium. Pyridine as base/solvent, sodium bicarbonate in chloroform and catalyst DMAP (N,N-dimethylaminopyridine) and triethylamine in 1,2-dichloroethane have been used, with yields of up to 100%. A large scale process involves treatment of DHA in dichloromethane with a mixture of pyridine, a catalytic amount of DMAP and succinic anhydride. The dichloromethane mixture is stirred for 6–9 h to get artesunate in quantitative yield. The product is further re-crystallized from dichloromethane. alpha-Artesunate is exclusively formed (m.p 135–137˚C).

Mechanisms of action[edit]

In a hematin dependent manner, artesunate has been shown to potently inhibit the essential Plasmodium falciparum exported protein 1 (EXP1), a membrane glutathione S-transferase.[12]

Drug resistance[edit]

Clinical evidence of drug resistance has appeared in Western Cambodia, where artemisinin monotherapy is common.[13] There are as yet no reports of resistance emerging elsewhere.

References[edit]

  1. ^ "WHO Model List of EssentialMedicines". World Health Organization. October 2013. Retrieved 22 April 2014. 
  2. ^ a b World Health Organization. "Guidelines for the treatment of malaria; Second edition 2010". World Health Organization. Retrieved 10 January 2014. 
  3. ^ Dondorp AL, et al. (2010). "Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial". The Lancet 376 (9753): 1647–1657. doi:10.1016/S0140-6736(10)61924-1. PMC 3033534. PMID 21062666. 
  4. ^ South East Asian Quinine Artesunate Malaria Trial (SEAQUAMAT) (2005). "Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial". The Lancet 366 (9487): 717–725. doi:10.1016/S0140-6736(05)67176-0. PMID 16125588. 
  5. ^ Sinclair, D; Donegan, S; Isba, R; Lalloo, DG (Jun 13, 2012). "Artesunate versus quinine for treating severe malaria.". The Cochrane database of systematic reviews 6: CD005967. doi:10.1002/14651858.CD005967.pub4. PMID 22696354. 
  6. ^ WHO (2007). Assessment of the safety of artemisinin compounds in pregnancy. World Health Organization, Geneva.
  7. ^ Boulangier D, Dieng Y, Cisse B, et al. (2007). "Antischistosomal efficacy of artesunate combination therapies administered as curative treatments for malaria attacks". Trans R Soc Trop Med Hyg 101 (2): 113–16. doi:10.1016/j.trstmh.2006.03.003. PMID 16765398. 
  8. ^ Clark RL (2012). "Effects of artemisinins on reticulocyte count and relationship to possible embryotoxicity in confirmed and unconfirmed malarial patients". Birth defects research. Part A, Clinical and molecular teratology 94 (2): 61–75. doi:10.1002/bdra.22868. 
  9. ^ Rolling T, Agbenyega T, Issifou S, et al. (2013). "Delayed hemolysis after treatment with parenteral artesunate in African children with severe malaria—a double-center prospective study.". J Infect Dis 209 (12): 1921–8. doi:10.1093/infdis/jit841. PMID 24376273. 
  10. ^ Clark RL (2013). "Hypothesized cause of delayed hemolysis associated with intravenous artesunate.". Med Hypotheses 82 (2): 167–70. doi:10.1016/j.mehy.2013.11.027. PMID 24370269. 
  11. ^ Clark RL (2009). "Embryotoxicity of the artemisinin antimalarials and potential consequences for use in women in the first trimester.". Reprod Toxicol 28 (3): 285–96. doi:10.1016/j.reprotox.2009.05.002. PMID 19447170. 
  12. ^ Lisewski, A. M.; Quiros, J. P.; Ng, C. L.; Adikesavan, A. K.; Miura, K; Putluri, N; Eastman, R. T.; Scanfeld, D; Regenbogen, S. J.; Altenhofen, L; Llinás, M; Sreekumar, A; Long, C; Fidock, D. A.; Lichtarge, O (2014). "Supergenomic Network Compression and the Discovery of EXP1 as a Glutathione Transferase Inhibited by Artesunate". Cell 158 (4): 916–28. doi:10.1016/j.cell.2014.07.011. PMID 25126794.  edit
  13. ^ White NJ (2008). "Qinghaosu (Artemisinin): The price of success". Science 320 (5874): 330–334. doi:10.1126/science.1155165. PMID 18420924.