artesunate

Artesunate is the first-line treatment for children or adults with severe malaria,{{Cite book|vauthors=((World Health Organization))|title=Guidelines for treatment of malaria|series=WHO Guidelines Approved by the Guidelines Review Committee|publisher=World Health Organization|date=April 2015|isbn=9789241549127|edition=3rd|location=Geneva|url=https://www.ncbi.nlm.nih.gov/books/NBK294440/|pmid=26020088|hdl=10665/162441|hdl-access=free}}{{cite press release | title=CDC: Artesunate Now First-Line Treatment for Severe Malaria in the United States | website=U.S. Centers for Disease Control and Prevention (CDC) | access-date=6 April 2019 | url=https://www.cdc.gov/globalhealth/newsroom/artesunate.html | date=28 March 2019}}{{cite web | title=Treatment of Malaria: Guidelines For Clinicians (United States) | website=U.S. Centers for Disease Control and Prevention (CDC) | date=8 February 2009 | url=https://www.cdc.gov/malaria/diagnosis_treatment/clinicians1.html | access-date=30 May 2020}} 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.{{cite journal | vauthors = Peixoto HM, Marchesini PB, de Oliveira MR | title = Efficacy and safety of artesunate-mefloquine therapy for treating uncomplicated Plasmodium falciparum malaria: systematic review and meta-analysis | journal = Transactions of the Royal Society of Tropical Medicine and Hygiene | volume = 110 | issue = 11 | pages = 626–636 | date = November 2016 | pmid = 28039388 | doi = 10.1093/trstmh/trw077 | doi-access = free }} Artemisinin-based combination therapy may be used by mouth in persons that can tolerate it after 24 hours by injection.{{medcn|date=March 2022}}

Artesunate is preferred over parenteral quinine for severe malaria treatment. Artesunate was shown to prevent more deaths from severe malaria than quinine in two large multicentre randomized controlled trials from Africa{{cite journal | vauthors = Dondorp AM, Fanello CI, Hendriksen IC, Gomes E, Seni A, Chhaganlal KD, Bojang K, Olaosebikan R, Anunobi N, Maitland K, Kivaya E, Agbenyega T, Nguah SB, Evans J, Gesase S, Kahabuka C, Mtove G, Nadjm B, Deen J, Mwanga-Amumpaire J, Nansumba M, Karema C, Umulisa N, Uwimana A, Mokuolu OA, Adedoyin OT, Johnson WB, Tshefu AK, Onyamboko MA, Sakulthaew T, Ngum WP, Silamut K, Stepniewska K, Woodrow CJ, Bethell D, Wills B, Oneko M, Peto TE, von Seidlein L, Day NP, White NJ | display-authors = 6 | title = Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial | journal = Lancet | volume = 376 | issue = 9753 | pages = 1647–1657 | date = November 2010 | pmid = 21062666 | pmc = 3033534 | doi = 10.1016/S0140-6736(10)61924-1 }} and Asia.{{cite journal | vauthors = Dondorp A, Nosten F, Stepniewska K, Day N, White N | title = Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial | journal = Lancet | volume = 366 | issue = 9487 | pages = 717–725 | year = 2005 | pmid = 16125588 | doi = 10.1016/S0140-6736(05)67176-0 | s2cid = 173027 | doi-access = free }} A subsequent systematic review of seven randomized controlled trials found this improvement in survival rates to be consistent across all trials.{{cite journal | vauthors = Sinclair D, Donegan S, Isba R, Lalloo DG | title = Artesunate versus quinine for treating severe malaria | journal = The Cochrane Database of Systematic Reviews | volume = 6 | issue = 6 | pages = CD005967 | date = June 2012 | pmid = 22696354 | pmc = 6532684 | doi = 10.1002/14651858.CD005967.pub4 }}

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.{{cite journal | vauthors = Phu NH, Tuan PQ, Day N, Mai NT, Chau TT, Chuong LV, Sinh DX, White NJ, Farrar J, Hien TT | display-authors = 6 | title = Randomized controlled trial of artesunate or artemether in Vietnamese adults with severe falciparum malaria | journal = Malaria Journal | volume = 9 | issue = 1 | pages = 97 | date = April 2010 | pmid = 20398339 | pmc = 2873528 | doi = 10.1186/1475-2875-9-97 | doi-access = free }} 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.{{cite journal | vauthors = Li Q, Weina P | title = Artesunate: The Best Drug in the Treatment of Severe and Complicated Malaria | journal = Pharmaceuticals | volume = 3 | issue = 7 | pages = 2322–2332 | date = July 2010 | pmid = 27713355 | pmc = 4036668 | doi = 10.3390/ph3072322 | doi-access = free }}

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

Artesunate + sulfadoxine/pyrimethamine for treatment of P. vivax is not recommended due to high rates of resistance.{{citation needed|date=February 2017}}

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,{{cite journal | vauthors = Boulanger D, Dieng Y, Cisse B, Remoue F, Capuano F, Dieme JL, Ndiaye T, Sokhna C, Trape JF, Greenwood B, Simondon F | display-authors = 6 | title = Antischistosomal efficacy of artesunate combination therapies administered as curative treatments for malaria attacks | journal = Transactions of the Royal Society of Tropical Medicine and Hygiene | volume = 101 | issue = 2 | pages = 113–116 | date = February 2007 | pmid = 16765398 | doi = 10.1016/j.trstmh.2006.03.003 | s2cid = 1675813 | url = https://hal.ird.fr/ird-00177064/file/Boulanger_artesunate_2007.pdf }} 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.

When given in the second or third trimesters of pregnancy, no artesunate-related adverse pregnancy outcomes have been reported.WHO (2007). [http://malaria.who.int/docs/mip/artemisinin_compounds_pregnancy.pdf Assessment of the safety of artemisinin compounds in pregnancy] {{webarchive|url=https://web.archive.org/web/20100414125450/http://malaria.who.int/docs/mip/artemisinin_compounds_pregnancy.pdf |date=14 April 2010}}. World Health Organization, Geneva. 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.{{medcn|date=February 2020}}

Artesunate is safe for use in children. Artesunate + sulfadoxine/pyrimethamine should be avoided in the newborns due to sulfadoxine/pyrmethamine effects on bilirubin. 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. 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.{{medcn|date=February 2020}}

Artesunate may cause serious side effects including hemolytic anemia (a condition in which red blood cells are destroyed), and severe allergic reactions.{{citation-attribution|1={{cite web | title=Drug Trials Snapshots: Artesunate | website=U.S. Food and Drug Administration (FDA) | date=26 May 2020 | url=https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-artesunate | access-date=5 June 2020}} }}

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.{{cite journal | vauthors = Song T, Chen J, Huang L, Gan W, Yin H, Jiang J, He T, Huang H, Hu X | display-authors = 6 | title = Should we abandon quinine plus antibiotic for treating uncomplicated falciparum malaria? A systematic review and meta-analysis of randomized controlled trials | journal = Parasitology Research | volume = 115 | issue = 3 | pages = 903–912 | date = March 2016 | pmid = 26661109 | doi = 10.1007/s00436-015-4842-z | s2cid = 18501106 }} The best recognised adverse effect of the artemisinins is that they lower reticulocyte counts.{{cite journal | vauthors = Clark RL | title = Effects of artemisinins on reticulocyte count and relationship to possible embryotoxicity in confirmed and unconfirmed malarial patients | journal = Birth Defects Research. Part A, Clinical and Molecular Teratology | volume = 94 | issue = 2 | pages = 61–75 | date = February 2012 | pmid = 22125126 | doi = 10.1002/bdra.22868 }} This is not usually of clinical relevance.{{medcn|date=February 2020}}

With increased use of I.V. artesunate, there have been reports of post-artesunate delayed haemolysis (PADH).{{cite journal | vauthors = Boillat O, Spechbach H, Chalandon Y, Eperon G | title = Post-artesunate delayed haemolysis ‒ report of four cases and review of the literature | journal = Swiss Medical Weekly | volume = 145 | issue = 4546 | pages = w14181 | year = 2015 | pmid = 26524733 | doi = 10.4414/smw.2015.14181 | doi-access = free }} Delayed haemolysis (occurring around two weeks after treatment) has been observed in people treated with artesunate for severe malaria.{{cite journal | vauthors = Rolling T, Agbenyega T, Issifou S, Adegnika AA, Sylverken J, Spahlinger D, Ansong D, Löhr SJ, Burchard GD, May J, Mordmüller B, Krishna S, Kremsner PG, Cramer JP | display-authors = 6 | title = Delayed hemolysis after treatment with parenteral artesunate in African children with severe malaria--a double-center prospective study | journal = The Journal of Infectious Diseases | volume = 209 | issue = 12 | pages = 1921–1928 | date = June 2014 | pmid = 24376273 | doi = 10.1093/infdis/jit841 | doi-access = free }}

Artesunate is typically a well tolerated medicine. Known contraindications include a previous severe allergic reaction to artesunate.{{cite journal | vauthors = Hess KM, Goad JA, Arguin PM | title = Intravenous artesunate for the treatment of severe malaria | journal = The Annals of Pharmacotherapy | volume = 44 | issue = 7–8 | pages = 1250–1258 | date = 1 January 2010 | pmid = 20551300 | doi = 10.1345/aph.1M732 | url = https://works.bepress.com/goad/3/ | url-status = live | s2cid = 23946665 | archive-url = https://web.archive.org/web/20161110043829/https://works.bepress.com/goad/3/ | archive-date = 10 November 2016 }}

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 and tranylcypromine.{{Cite web|url=http://www.wipo.int/export/sites/www/research/en/data/sanofi/marketed_products/Artesunate_and_Amodiquine.pdf|title=Artesunate Amodiaquine Winthrop (artesunate, amodiaquine) [summary of product characteristics]|publisher=Sanofi-Aventis|url-status=live|archive-url=https://web.archive.org/web/20161024090154/http://www.wipo.int/export/sites/www/research/en/data/sanofi/marketed_products/Artesunate_and_Amodiquine.pdf|archive-date=24 October 2016}}

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.{{cite journal | vauthors = Cui L, Su XZ | title = Discovery, mechanisms of action and combination therapy of artemisinin | journal = Expert Review of Anti-Infective Therapy | volume = 7 | issue = 8 | pages = 999–1013 | date = October 2009 | pmid = 19803708 | pmc = 2778258 | doi = 10.1586/eri.09.68 }} 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. In addition, Artesunate potently inhibits the essential Plasmodium falciparum exported protein 1 (EXP1), a membrane glutathione S-transferase.{{cite journal | vauthors = Lisewski AM, Quiros JP, Ng CL, Adikesavan AK, Miura K, Putluri N, Eastman RT, Scanfeld D, Regenbogen SJ, Altenhofen L, Llinás M, Sreekumar A, Long C, Fidock DA, Lichtarge O | display-authors = 6 | title = Supergenomic network compression and the discovery of EXP1 as a glutathione transferase inhibited by artesunate | journal = Cell | volume = 158 | issue = 4 | pages = 916–928 | date = August 2014 | pmid = 25126794 | pmc = 4167585 | doi = 10.1016/j.cell.2014.07.011 }} As a result, the amount of glutathione in the parasite is reduced.{{medcn|date=February 2020}}

In 2016, artemisinin has been shown to bind to a large number targets, suggesting that it acts in a promiscuous manner.{{cite journal | vauthors = 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 | display-authors = 6 | title = Haem-activated promiscuous targeting of artemisinin in Plasmodium falciparum | journal = Nature Communications | volume = 6 | pages = 10111 | date = December 2015 | pmid = 26694030 | pmc = 4703832 | doi = 10.1038/ncomms10111 | bibcode = 2015NatCo...610111W }} There is evidence suggesting DHA inhibition of calcium-dependent ATPase on endoplasmic membrane, which disrupts protein folding of parasites.

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.{{cite journal | vauthors = Morris CA, Duparc S, Borghini-Fuhrer I, Jung D, Shin CS, Fleckenstein L | title = Review of the clinical pharmacokinetics of artesunate and its active metabolite dihydroartemisinin following intravenous, intramuscular, oral or rectal administration | journal = Malaria Journal | volume = 10 | pages = 263 | date = September 2011 | pmid = 21914160 | pmc = 3180444 | doi = 10.1186/1475-2875-10-263 | name-list-style = vanc | doi-access = free }} Because of its short half-life, its use in malaria prevention is limited.

DHA is metabolized to an inactive metabolite by the liver enzymes CYP2B6, CYP2C19, and CYP3A4.{{cite journal | vauthors = Hess KM, Goad JA, Arguin PM | title = Intravenous artesunate for the treatment of severe malaria | journal = The Annals of Pharmacotherapy | volume = 44 | issue = 7–8 | pages = 1250–1258 | date = 1 July 2010 | pmid = 20551300 | doi = 10.1345/aph.1M732 | s2cid = 23946665 }}

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.{{Cite web|url=http://www.worldofchemicals.com/chemicals/chemical-properties/artesunate.html|title=World of Chemicals – online chemical directory, chemistry portal, articles, news|website=www.worldofchemicals.com|access-date=10 November 2016|url-status=live|archive-url=https://web.archive.org/web/20161110114544/http://www.worldofchemicals.com/chemicals/chemical-properties/artesunate.html|archive-date=10 November 2016}}

Artesunate is under study for the treatment of COVID-19.{{cite journal | vauthors = Krishna S, Augustin Y, Wang J, Xu C, Staines HM, Platteeuw H, Kamarulzaman A, Sall A, Kremsner P | display-authors = 6 | title = Repurposing Antimalarials to Tackle the COVID-19 Pandemic | journal = Trends in Parasitology | volume = 37 | issue = 1 | pages = 8–11 | date = January 2021 | pmid = 33153922 | pmc = 7572038 | doi = 10.1016/j.pt.2020.10.003 | author-link = Sanjeev Krishna }}

In May 2020, artesunate was approved for medical use in United States.{{cite web | title=Drug Approval Package: Artesunate | website=U.S. Food and Drug Administration (FDA) | date=25 June 2020 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213036Orig1s000TOC.cfm | access-date=24 September 2020}}{{citation-attribution|1={{cite press release | title=FDA Approves Only Drug in U.S. to Treat Severe Malaria | website=U.S. Food and Drug Administration (FDA) | date=26 May 2020 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-only-drug-us-treat-severe-malaria | access-date=26 May 2020}} }} 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. 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.

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). Trial 1 was conducted at 10 sites in Myanmar, Bangladesh, India, and Indonesia.

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. Trial 2 included 5,425 randomized pediatric participants younger than 15 years of age with severe malaria who were treated with artesunate or quinine. 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. Trial 2 was conducted during 2005–2010 in nine African countries. A third trial, Trial 3, was conducted during 2007–2008 in Gabon and Malawi.

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. The safety profile in Trial 2 was generally similar to Trial 1.

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

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).

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.

The application for IV artesunate was granted priority review and orphan drug designations.{{cite web | title=Artesunate Orphan Drug Designation and Approval | website=U.S. Food and Drug Administration (FDA) | date=5 September 2017 | url=https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=598517 | access-date=27 May 2020}} The FDA granted approval of artesunate for injection to Amivas.

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