Artesunate

Artesunate
Clinical data
AHFS/Drugs.com International Drug Names
Routes of
administration		 oral, intravenous, intramuscular
ATC code P01BE03 (WHO)
Legal status
Legal status
  • Not licensed in UK or US
Identifiers
CAS Number 88495-63-0 N
80155-81-3 (sodium salt)
PubChem (CID) 5464098
ChemSpider 16735675 YesY
UNII 60W3249T9M YesY
ChEMBL CHEMBL258608 N
NIAID ChemDB 112081
Chemical and physical data
Formula C19H28O8
Molar mass 384.421 g/mol
3D model (Jmol) Interactive image
 NYesY (what is this?)  (verify)

Artesunate (AS) is a medication used to treat severe cases of malaria. Although not FDA-approved for use in the United States, artesunate is indicated as the treatment of choice for severe malaria by the World Health Organization (WHO) over quinidine.[1] Artesunate is available as a solution for intravenous or intramuscular injection as well as a salt form for oral use. It is an arteminisin-based medication derived from the sweet wormwood plan (Artemisia annua).[1]

Artesunate is listed on the WHO's List of Essential Medicines, which lists the most important medications needed in a basic health system.[2] Artesunate is not licensed in the United States. In 2007, the FDA approved an Investigational New Drug (IND) protocol for intravenous artesunate. Until license approval, medical providers may obtain artesunate from the Centers for Disease Control and Prevention (CDC)'s malaria hotline.[1]

Medical uses

Artesunate is the first line treatment for children or adults with severe malaria.[3] The recommendation is to treat with at least 24 hours of parenteral artesunate at a dose of 2.4 mg/kg, or 3 mg/kg in children weighing less than 20 kg. Oral artemisinin-based combination therapy may be used in persons that can tolerate it after this 24 hour parenteral treatment window. In facilities where long-term care is not appropriate, artesunate may be given as a single intramuscular injection or by rectal route (children < 6 years) prior to transferring care to a higher level facility.

Artesunate is preferred over parenteral quinine for severe malaria treatment.[1] Artesunate was shown to prevent more deaths from severe malaria than quinine in two large multicentre randomized controlled trials from Africa[4] and Asia.[5] A subsequent systematic review of seven randomized controlled trials found this improvement in survival rates to be consistent across all trials.[6]

Artesunate is also used to treat less severe forms of malaria when it can be given orally.[3] It has activity against P. ovale, P. malariae, and severe P. knowlesi.[3] Artesunate + sulfadoxine/pyrimethamine for treatment of P. vivax is not recommended due to high rates of resistance.

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 has not been evaluated in large randomized trials.

Special Populations

Pregnancy

When given in the second or third trimesters of pregnancy, no artesunate-related adverse pregnancy outcomes have been reported.[8] However, there is insufficient evidence regarding the safety of artesunate use in the first trimester of pregnancy. The WHO recommends that artesunate use for severe malaria in the first trimester should be based on the individual risks versus benefits. In absence of other viable treatment options, artesunate may be used.

Children

Artesunate is safe for use in children. Artesunate + sulfadoxine/pyrimethamine should be avoided in the newborns due to sulfadoxine/pyrmethamine effects on bilirubin.[3] Parenteral artesunate dosing for treatment of severe malaria in children less than 20 kg should be higher than that of adults in order to increase exposure.[3] When artesunate cannot be given orally or intramuscularly due to an individual's weakness or inability to swallow, rectal administration may be given as pre-referral treatment as long as parenteral administration is initiated after transfer to a more advanced facility.

Mechanisms of action

The mechanisms of action of artesunate remains unclear and debatable. Artesunate is a prodrug that is rapidly converted to its active form dihydroartemisinin (DHA). This process involves hydrolysis of the 4-carbon ester group via plasma esterase enzyme.[9] It is hypothesized that the cleavage of endoperoxide bridge in the pharmacophore of DHA generates reactive oxygen species (ROS), which increases oxidative stress and causes malarial protein damage via alkylation.[9] In addition, Artesunate potently inhibits the essential Plasmodium falciparum exported protein 1 (EXP1), a membrane glutathione S-transferase.[10] As a result, the amount of glutathione in the parasite is reduced.

In 2016, artemisinin has been shown to bind to a large number targets, suggesting that it acts in a promiscuous manner.[11] There is evidence suggesting DHA inhibition of calcium-dependent ATPase on endoplasmic membrane, which disrupts protein folding of parasites.[9]

Pharmacokinetics

In infected individuals, the elimination half-life of artesunate is about 0.22 hours. Its active metabolite, DHA, has a slightly longer half-life of 0.34 hours. Overall, the average half-life ranges from 0.5 to 1.5 hours.[12] Because of its short half-life, its use in malaria prevention is limited.[9]

DHA is metabolized to an inactive metabolite by the liver enzymes CYP2B6, CYP2C19, and CYP3A4.[13]

Adverse effects

Artesunate is generally safe and well-tolerated. The best recognised side effect of the artemesinins is that they lower reticulocyte counts.[14] This is not usually of clinical relevance.

With increased use of I.V. artesunate, there have been reports of post-artesunate delayed haemolysis (PADH).[15] Delayed haemolysis (occurring around two weeks after treatment) has been observed in patients treated with artesunate for severe malaria.[16] It is unclear whether or not this haemolysis is due to artesunate or to the malaria itself.[17]

Warnings/Contraindications

Artesunate is typically a well tolerated medicine. Known contraindications include a severe allergic reaction or anaphylactic response upon receiving artesunate.[18]

Drugs that should be avoided while on artesunate are the drugs that inhibit the liver enzyme CYP2A6. These drugs include amiodarone, desipramine, isoniazid, ketoconazole, letrozole, methoxsalen, tranylcypromine.[19]

Chemical synthesis

Artesunate is made from dihydroartemisinin (DHA) by reacting it with succinic acid anhydride in a basic medium. It is one of many semi-synthetic derivatives from Artemisinin that is water-soluble.[20]

References

  1. 1 2 3 4 Prevention, CDC - Centers for Disease Control and. "CDC - Malaria - Diagnosis & Treatment (United States) - Treatment (U.S.) - Artesunate". www.cdc.gov. Retrieved 2016-10-28.
  2. ↑ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
  3. 1 2 3 4 5 Guidelines for treatment of malaria. (3 ed.). Geneva: World Health Organization. 2015 – via https://www.ncbi.nlm.nih.gov/books/NBK294440/.
  4. ↑ 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 3033534Freely accessible. PMID 21062666.
  5. ↑ 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.
  6. ↑ 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 (6): CD005967. doi:10.1002/14651858.CD005967.pub4. PMID 22696354.
  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. ↑ WHO (2007). Assessment of the safety of artemisinin compounds in pregnancy. World Health Organization, Geneva.
  9. 1 2 3 4 Cui, Liwang; Su, Xin-zhuan (2009-10-01). "Discovery, mechanisms of action and combination therapy of artemisinin". Expert Review of Anti-infective Therapy. 7 (8): 999–1013. doi:10.1586/eri.09.68. ISSN 1478-7210. PMC 2778258Freely accessible. PMID 19803708.
  10. ↑ 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.
  11. ↑ Wang J, Zhang CJ, Chia WN, Loh CC, Li Z, Lee YM, He Y, Yuan LX, Lim TK, Liu M, Liew CX, Lee YQ, Zhang J, Lu N, Lim CT, Hua ZC, Liu B, Shen HM, Tan KS, Lin Q (2015). "Haem-activated promiscuous targeting of artemisinin in Plasmodium falciparum". Nature Communications. 6: 10111. doi:10.1038/ncomms10111. PMC 4703832Freely accessible. PMID 26694030.
  12. ↑ Morris, Carrie A.; Duparc, Stephan; Borghini-Fuhrer, Isabelle; Jung, Donald; Shin, Chang-Sik; Fleckenstein, Lawrence (2011-01-01). "Review of the clinical pharmacokinetics of artesunate and its active metabolite dihydroartemisinin following intravenous, intramuscular, oral or rectal administration". Malaria Journal. 10: 263. doi:10.1186/1475-2875-10-263. ISSN 1475-2875. PMC 3180444Freely accessible. PMID 21914160.
  13. ↑ Hess, Karl M.; Goad, Jeffery A.; Arguin, Paul M. (2010-07-01). "Intravenous Artesunate for the Treatment of Severe Malaria". Annals of Pharmacotherapy. 44 (7-8): 1250–1258. doi:10.1345/aph.1M732. ISSN 1060-0280. PMID 20551300.
  14. ↑ 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.
  15. ↑ Boillat O, Spechbach H, Chalandon Y, Eperon. "Post-artesunate delayed haemolysis ‒ report of four cases and review of the literature". Swiss Medical Weekly. Retrieved 2016-11-09.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ Hess, Karl M.; Goad, Jeffery A.; Arguin, Paul M. (2010-01-01). "Intravenous Artesunate for Severe Malaria". doi:10.1345/aph.1M732.
  19. ↑ "Artesunate Amodiaquine Winthrop (artesunate, amodiaquine) [summary of product characteristics]" (PDF). Sanofi-Aventis.
  20. ↑ "World of Chemicals – online chemical directory,chemistry portal,aricles,news". www.worldofchemicals.com. Retrieved 2016-11-10.
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