Artesunate

Artesunate
Names
Pronunciationahr-tez′ŭ-nāt[1]
Trade namesmany[2]
Clinical data
Drug classArtemisinin
Main usesMalaria[3]
Routes of
use		By mouth, intravenous, intramuscular
Defined daily dose0.28 g (by mouth)
0.28 g (injection)
0.28 g (rectal) [4]
External links
AHFS/Drugs.comInternational Drug Names
US NLMArtesunate
Legal
License data
Legal status
Chemical and physical data
FormulaC19H28O8
Molar mass384.421 g·mol−1
3D model (JSmol)
SMILES
  • [H][C@@]12CC[C@@]3(C)OO[C@@]11[C@@]([H])(CC[C@H]2C)[C@@H](C)[C@H](OC(=O)CCC(O)=O)O[C@]1([H])O3
InChI
  • InChI=1S/C19H28O8/c1-10-4-5-13-11(2)16(23-15(22)7-6-14(20)21)24-17-19(13)12(10)8-9-18(3,25-17)26-27-19/h10-13,16-17H,4-9H2,1-3H3,(H,20,21)/t10-,11-,12+,13+,16-,17-,18-,19-/m1/s1 ☒N
  • Key:FIHJKUPKCHIPAT-AHIGJZGOSA-N ☒N

Artesunate (AS) is a medication used to treat malaria.[5][6] The intravenous form is preferred to quinine for severe malaria.[5] Often it is used as part of combination therapy, such as artesunate plus mefloquine.[6] It is not used for the prevention of malaria.[6] Artesunate can be given by injection into a vein, injection into a muscle, by mouth, and by rectum.[6][7][8]

Artesunate is generally well tolerated.[7] Side effects may include a slow heartbeat, allergic reaction, dizziness, and low white blood cell levels.[6] During pregnancy it appears to be a safer option, even though animal studies have found harm to the baby.[9] Use is likely fine during breastfeeding.[10] It is in the artemisinin class of medication.[5]

Artesunate was developed by Liu Xu in 1977.[11] It is on the World Health Organization's List of Essential Medicines.[12] It was approved for medical use in the United States in May 2020.[13] The wholesale cost in the developing world is US$2.09 to US$2.57 a dose.[14] It was approved for medical use in the United States in 2020.[15] It was originally made from the sweet wormwood plant.[5]

Medical uses

Artesunate is the first-line treatment for children or adults with severe malaria,[16][17][18] usually in combination with another antimalarial drug. There is moderate-quality evidence that treatment with artesunate plus mefloquine is superior to treatment with artesunate plus amodiaquine or artesunate plus sulfadoxine-pyrimethamine.[19] Artemisinin-based combination therapy may be used by mouth in persons that can tolerate it after 24 hours by injection. In facilities where long-term care is not appropriate, initial treatment with 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.[5] Artesunate was shown to prevent more deaths from severe malaria than quinine in two large multicentre randomized controlled trials from Africa[20] and Asia.[21] A subsequent systematic review of seven randomized controlled trials found this improvement in survival rates to be consistent across all trials.[22]

Artesunate's efficacy is comparable to that of artemether, another artemisinin derivative, in treating adults for severe malaria caused by Plasmodium falciparum, though artesunate clears more parasites initially.[23] Artesunate combination drugs have a number of advantages over artemether-based drugs in terms of its uptake and administration routes and may be more effective in treatment of severe and complicated malaria in children.[24]

Artesunate is also used to treat less severe forms of malaria when it can be given orally.[16] It has activity against P. ovale, P. malariae, and severe P. knowlesi.[16]

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,[25] but has not been evaluated in large randomized trials.

Artesunate is used as the treatment of choice for severe malaria by the World Health Organization (WHO) over quinine.[5][16]

Children

Artesunate is safe for use in children. Artesunate + sulfadoxine/pyrimethamine should be avoided in the newborns due to sulfadoxine/pyrmethamine effects on bilirubin.[16] 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.[16] 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.

Dosage

The defined daily dose is 280 mg by mouth, injection, or rectally.[4] In those over 20 kg it is given at a dose of 2.4 mg/kg while in those under 20 kg the dose is 3 mg/kg.[3] The medication is given at presentation, at 12 hours, at 24 hours, and than once per day for up to seven days.[3]

Side effects

Artesunate may cause serious side effects including hemolytic anemia (a condition in which red blood cells are destroyed), and severe allergic reactions.[26]

Artesunate is generally safe and well tolerated. Artesunate-based regimens are less likely to cause vomiting and tinnitus than quinine plus anti-malarial antibiotic therapy.[27] The best recognised adverse effect of the artemisinins is that they lower reticulocyte counts.[28] This is not usually of clinical relevance.

With increased use of I.V. artesunate, there have been reports of post-artesunate delayed haemolysis (PADH).[29] Delayed haemolysis (occurring around two weeks after treatment) has been observed in people treated with artesunate for severe malaria.[30]

Artesunate is typically a well tolerated medicine. Known contraindications include a previous severe allergic reaction to artesunate.[31]

Pregnancy and breastfeeding

When given in the second or third trimesters of pregnancy, no artesunate-related adverse pregnancy outcomes have been reported.[32] 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.

Interactions

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.[33]

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.[34] 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.[34] In addition, Artesunate potently inhibits the essential Plasmodium falciparum exported protein 1 (EXP1), a membrane glutathione S-transferase.[35] 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.[36] There is evidence suggesting DHA inhibition of calcium-dependent ATPase on endoplasmic membrane, which disrupts protein folding of parasites.[34]

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.[37] Because of its short half-life, its use in malaria prevention is limited.[34]

DHA is metabolized to an inactive metabolite by the liver enzymes CYP2B6, CYP2C19, and CYP3A4.[38]

History

In May 2020, artesunate was approved for medical use in United States.[13][39] Prior to this approval, intravenous (IV) artesunate was only available through the Expanded Access program of the U.S. Food and Drug Administration (FDA), which allowed the Centers for Disease Control and Prevention (CDC) to provide IV artesunate to people in the U.S. with severe malaria and to people with uncomplicated malaria who are unable to take oral medications under an investigational new drug (IND) protocol.[13] There has been no FDA-approved drug for treatment of severe malaria in the United States since the marketing of quinidine was discontinued by the manufacturer in March 2019.[13]

The safety and efficacy of IV artesunate for the treatment of severe malaria was primarily evaluated in a randomized controlled trial in Asia (Trial 1) and a supportive published randomized controlled trial in Africa (Trial 2).[13][26] Trial 1 was conducted at 10 sites in Myanmar, Bangladesh, India, and Indonesia.[26]

Trial 1 enrolled 1,461 participants who received either IV artesunate or the comparator drug quinine and included 202 pediatric participants younger than 15 years.[13] Trial 2 included 5,425 randomized pediatric participants younger than 15 years of age with severe malaria who were treated with artesunate or quinine.[13] In both trials, the number of participants treated with artesunate who died in the hospital was significantly lower than the number who died in the control group treated with quinine.[13] Trial 2 was conducted during 2005–2010 in nine African countries.[26] A third trial, Trial 3, was conducted during 2007–2008 in Gabon and Malawi.[26]

In Trial 1, the most common adverse reactions in participants with malaria treated with IV artesunate were acute renal failure requiring dialysis, hemoglobinuria and jaundice.[13] The safety profile in Trial 2 was generally similar to Trial 1.[13]

One trial was used to evaluate both, safety and benefits of artesunate.[26] The trial enrolled participants with severe malaria who needed hospitalization because of their condition.[26] Participants received at random either artesunate or a medicine used to treat malaria (quinine).[26] Participants and the health care providers knew which treatment was being given.[26]

The benefit of artesunate in comparison to quinine was evaluated by comparing the number of participants who died while in the hospital (in-hospital mortality).[26]

The benefit of artesunate was supported by the data from Trial 2 in which pediatric participants younger than 15 years of age with severe malaria were randomly assigned treatment with artesunate or quinine.[26]

The application for IV artesunate was granted priority review and orphan drug designations.[13][40] The FDA granted approval of artesunate for injection to Amivas.[13]

Manufacture

Artesunate is made from dihydroartemisinin (DHA) by reacting it with succinic acid anhydride in a basic medium. It is one of few semi-synthetic derivatives from artemisinin that is water-soluble.[37][41]

Research

In 2007, the FDA approved an Investigational New Drug (IND) protocol for intravenous artesunate.

Artesunate is under study for the treatment of cancer.[42]

References

  1. ↑ "Artesunate definition". Drugs.com. Archived from the original on 20 December 2016. Retrieved 7 December 2016.
  2. ↑ "Artesunate". Drugs.com. Archived from the original on 20 December 2016. Retrieved 7 December 2016.
  3. 1 2 3 "ARTESUNATE injectable - Essential drugs". medicalguidelines.msf.org. Archived from the original on 27 August 2021. Retrieved 1 September 2020.
  4. 1 2 "WHOCC - ATC/DDD Index". www.whocc.no. Archived from the original on 26 July 2020. Retrieved 1 September 2020.
  5. 1 2 3 4 5 6 Prevention, CDC - Centers for Disease Control and. "CDC - Malaria - Diagnosis & Treatment (United States) - Treatment (U.S.) - Artesunate". www.cdc.gov. Archived from the original on 2016-10-29. Retrieved 2016-10-28.
  6. 1 2 3 4 5 "Artesunate" (PDF). World Health Organization. March 2013. Archived (PDF) from the original on 28 December 2013. Retrieved 7 December 2016.
  7. 1 2 Rosenthal, Philip J. (24 April 2008). "Artesunate for the Treatment of Severe Falciparum Malaria". New England Journal of Medicine. 358 (17): 1829–1836. doi:10.1056/NEJMct0709050. PMID 18434652. Archived from the original on 27 August 2021. Retrieved 21 September 2020.
  8. ↑ World Health Organization (2017). "Rectal artesunate for pre-referral treatment of severe malaria". World Health Organization. hdl:10665/259356. WHO/HTM/GMP/2017.19; License: CC BY-NC-SA 3.0 IGO. {{cite journal}}: Cite journal requires |journal= (help)
  9. ↑ Kovacs, SD; Rijken, MJ; Stergachis, A (February 2015). "Treating severe malaria in pregnancy: a review of the evidence". Drug Safety. 38 (2): 165–81. doi:10.1007/s40264-014-0261-9. PMC 4328128. PMID 25556421.
  10. ↑ "Artesunate use while Breastfeeding | Drugs.com". www.drugs.com. Archived from the original on 20 December 2016. Retrieved 7 December 2016.
  11. ↑ Li, Guoqiao; Li, Ying; Li, Zelin; Zeng, Meiyi (2017-11-28). Artemisinin-Based and Other Antimalarials: Detailed Account of Studies by Chinese Scientists Who Discovered and Developed Them. Academic Press. ISBN 9780128132111. Archived from the original on 2020-07-26. Retrieved 2020-06-03.
  12. ↑ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  13. 1 2 3 4 5 6 7 8 9 10 11 12 "FDA Approves Only Drug in U.S. to Treat Severe Malaria". U.S. Food and Drug Administration (FDA) (Press release). 26 May 2020. Archived from the original on 29 May 2020. Retrieved 26 May 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  14. ↑ "Artesunate". International Drug Price Indicator Guide. Archived from the original on 22 January 2018. Retrieved 1 January 2016.
  15. ↑ Commissioner, Office of the (27 May 2020). "FDA Approves Only Drug in U.S. to Treat Severe Malaria". FDA. Archived from the original on 29 May 2020. Retrieved 30 May 2020.
  16. 1 2 3 4 5 6 World Health Organization (April 2015). Guidelines for treatment of malaria. WHO Guidelines Approved by the Guidelines Review Committee (3rd ed.). Geneva: World Health Organization. hdl:10665/162441. ISBN 9789241549127. PMID 26020088. Archived from the original on 2021-08-27. Retrieved 2016-11-06.
  17. ↑ "CDC: Artesunate Now First-Line Treatment for Severe Malaria in the United States". U.S. Centers for Disease Control and Prevention (CDC) (Press release). 28 March 2019. Archived from the original on 16 June 2019. Retrieved 6 April 2019.
  18. ↑ "Treatment of Malaria: Guidelines For Clinicians (United States)". U.S. Centers for Disease Control and Prevention (CDC). 8 February 2009. Archived from the original on 11 June 2020. Retrieved 30 May 2020.
  19. ↑ Peixoto HM, Marchesini PB, de Oliveira MR (December 2016). "Efficacy and safety of artesunate-mefloquine therapy for treating uncomplicated Plasmodium falciparum malaria: systematic review and meta-analysis". Trans. R. Soc. Trop. Med. Hyg. 110 (11): 626–636. doi:10.1093/trstmh/trw077. PMID 28039388.
  20. ↑ 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. Archived from the original on 2011-04-29. Retrieved 2011-04-13.
  21. ↑ 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. Archived from the original on 2011-06-08. Retrieved 2011-04-13.
  22. ↑ 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. PMC 6532684. PMID 22696354.
  23. ↑ Phu, Nguyen H; Tuan, Phung Q; Day, Nicholas; Mai, Nguyen TH; Chau, Tran TH; Chuong, Ly V; Sinh, Dinh X; White, Nicholas J; Farrar, Jeremy; Tran, Hien T (2010). "Randomized controlled trial of artesunate or artemether in Vietnamese adults with severe falciparum malaria". Malaria Journal. 9 (1): 97. doi:10.1186/1475-2875-9-97. PMC 2873528. PMID 20398339.
  24. ↑ Li, Qigui; Weina, Peter (2010). "Artesunate: The Best Drug in the Treatment of Severe and Complicated Malaria". Pharmaceuticals. 3 (7): 2322–2332. doi:10.3390/ph3072322. PMC 4036668. PMID 27713355.
  25. ↑ Boulangier D, Dieng Y, Cisse B, et al. (2007). "Antischistosomal efficacy of artesunate combination therapies administered as curative treatments for malaria attacks" (PDF). Trans R Soc Trop Med Hyg. 101 (2): 113–16. doi:10.1016/j.trstmh.2006.03.003. PMID 16765398. Archived (PDF) from the original on 2018-07-21. Retrieved 2018-07-26.
  26. 1 2 3 4 5 6 7 8 9 10 11 "Drug Trials Snapshots: Artesunate". U.S. Food and Drug Administration (FDA). 26 May 2020. Archived from the original on 6 June 2020. Retrieved 5 June 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  27. ↑ Song T, Chen J, Huang L, Gan W, Yin H, Jiang J, He T, Huang H, Hu X (March 2016). "Should we abandon quinine plus antibiotic for treating uncomplicated falciparum malaria? A systematic review and meta-analysis of randomized controlled trials". Parasitol. Res. 115 (3): 903–12. doi:10.1007/s00436-015-4842-z. PMID 26661109.
  28. ↑ 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. PMID 22125126.
  29. ↑ Boillat O, Spechbach H, Chalandon Y, Eperon (2015). "Post-artesunate delayed haemolysis ‒ report of four cases and review of the literature". Swiss Medical Weekly. 145 (4546): w14181. doi:10.4414/smw.2015.14181. PMID 26524733.
  30. ↑ 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. Archived from the original on 2021-08-27. Retrieved 2014-01-06.
  31. ↑ Hess, Karl M.; Goad, Jeffery A.; Arguin, Paul M. (2010-01-01). "Intravenous Artesunate for Severe Malaria". Ann Pharmacother. 44 (7–8): 1250–1258. doi:10.1345/aph.1M732. PMID 20551300. Archived from the original on 2016-11-10.
  32. ↑ WHO (2007). Assessment of the safety of artemisinin compounds in pregnancy Archived 2010-04-14 at the Wayback Machine. World Health Organization, Geneva.
  33. ↑ "Artesunate Amodiaquine Winthrop (artesunate, amodiaquine) [summary of product characteristics]" (PDF). Sanofi-Aventis. Archived (PDF) from the original on 2016-10-24.
  34. 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 2778258. PMID 19803708.
  35. ↑ 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. PMC 4167585. PMID 25126794.
  36. ↑ 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. Bibcode:2015NatCo...610111W. doi:10.1038/ncomms10111. PMC 4703832. PMID 26694030.
  37. 1 2 Morris, Carrie A; Duparc, Stephan; Borghini-Fuhrer, Isabelle; Jung, Donald; Shin, Chang-Sik; Fleckenstein, Lawrence (2011-09-13). "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 3180444. PMID 21914160.
  38. ↑ 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. S2CID 23946665.
  39. ↑ "Artesunate: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Archived from the original on 26 July 2020. Retrieved 27 May 2020.
  40. ↑ "Artesunate Orphan Drug Designation and Approval". U.S. Food and Drug Administration (FDA). 5 September 2017. Archived from the original on 26 July 2020. Retrieved 27 May 2020.
  41. ↑ "World of Chemicals – online chemical directory, chemistry portal, articles, news". www.worldofchemicals.com. Archived from the original on 2016-11-10. Retrieved 2016-11-10.
  42. ↑ "Intervention Dynamic Trial Listing Page". National Cancer Institute. 2017-06-13. Archived from the original on 2018-07-25. Retrieved 2018-07-31.
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