Artesunate

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Artesunate (AS) is a medication used to treat malaria.<ref name="FDA label" /><ref name="CDC2012" /><ref name="WHO2013" /> The intravenous form is preferred to quinine for severe malaria.<ref name="CDC2012" /> Often it is used as part of combination therapy, such as artesunate plus mefloquine.<ref name="WHO2013" /> It is not used for the prevention of malaria.<ref name="WHO2013" /> Artesunate can be given by injection into a vein, injection into a muscle, by mouth, and by rectum.<ref name="WHO2013">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="NEJM2008" /><ref>Template:Cite report</ref>

The most common side effects include kidney failure requiring dialysis, hemoglobinuria (the presence of hemoglobin in urine) and jaundice.<ref name="FDA snapshot" />

Artesunate is generally well tolerated.<ref name="NEJM2008">Template:Cite journal</ref> Side effects may include a slow heartbeat, allergic reaction, dizziness, and low white blood cell levels.<ref name="WHO2013" /> During pregnancy it appears to be a safer option, even though animal studies have found harm to the baby.<ref>Template:Cite journal</ref> Use is likely fine during breastfeeding.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> It is in the artemisinin class of medication.<ref name="CDC2012" />

Artesunate was developed by Liu Xu in 1977.<ref>Template:Cite book</ref> It is on the World Health Organization's List of Essential Medicines.<ref name="WHO21st">Template:Cite book</ref> It was approved for medical use in the United States in May 2020.<ref name="FDA PR" /> It is in the class of medications known as artemisinins, which are derivatives from "qinghao," or sweet wormwood plant (Artemisia annua).<ref>Template:Citation-attribution</ref><ref name="CDC2012">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Medical uses

Artesunate is the first-line treatment for children or adults with severe malaria,<ref name="WHO Malaria">Template:Cite book</ref><ref name="CDC2019">Template:Cite press release</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref>Template:Cite journal</ref> Artemisinin-based combination therapy may be used by mouth in persons that can tolerate it after 24 hours by injection.Template:Medcn

Artesunate is preferred over parenteral quinine for severe malaria treatment.<ref name="CDC2012" /> Artesunate was shown to prevent more deaths from severe malaria than quinine in two large multicentre randomized controlled trials from Africa<ref>Template:Cite journal</ref> and Asia.<ref>Template:Cite journal</ref> A subsequent systematic review of seven randomized controlled trials found this improvement in survival rates to be consistent across all trials.<ref>Template:Cite journal</ref>

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.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref>

Artesunate is also used to treat less severe forms of malaria when it can be given orally.<ref name="WHO Malaria" /> It has activity against P. ovale, P. malariae, and severe P. knowlesi.<ref name="WHO Malaria" />

Artesunate + sulfadoxine/pyrimethamine for treatment of P. vivax is not recommended due to high rates of resistance.Template:Citation needed

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,<ref>Template:Cite journal</ref> 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.<ref name="CDC2012" /><ref name="WHO Malaria" />

Pregnancy

When given in the second or third trimesters of pregnancy, no artesunate-related adverse pregnancy outcomes have been reported.<ref>WHO (2007). Assessment of the safety of artemisinin compounds in pregnancy Template:Webarchive. World Health Organization, Geneva.</ref> 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.Template:Medcn

Children

Artesunate is safe for use in children. Artesunate + sulfadoxine/pyrimethamine should be avoided in the newborns due to sulfadoxine/pyrmethamine effects on bilirubin.<ref name="WHO Malaria" /> 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.<ref name="WHO Malaria" /> 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.Template:Medcn

Adverse effects

Artesunate may cause serious side effects including hemolytic anemia (a condition in which red blood cells are destroyed), and severe allergic reactions.<ref name="FDA snapshot">Template:Citation-attribution</ref>

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.<ref>Template:Cite journal</ref> The best recognised adverse effect of the artemisinins is that they lower reticulocyte counts.<ref>Template:Cite journal</ref> This is not usually of clinical relevance.Template:Medcn

With increased use of I.V. artesunate, there have been reports of post-artesunate delayed haemolysis (PADH).<ref>Template:Cite journal</ref> Delayed haemolysis (occurring around two weeks after treatment) has been observed in people treated with artesunate for severe malaria.<ref>Template:Cite journal</ref>

Contraindications

Artesunate is typically a well tolerated medicine. Known contraindications include a previous severe allergic reaction to artesunate.<ref>Template:Cite journal</ref>

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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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.<ref name="Cui2009">Template:Cite journal</ref> 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.<ref name="Cui2009" /> In addition, Artesunate potently inhibits the essential Plasmodium falciparum exported protein 1 (EXP1), a membrane glutathione S-transferase.<ref>Template:Cite journal</ref> As a result, the amount of glutathione in the parasite is reduced.Template:Medcn

In 2016, artemisinin has been shown to bind to a large number targets, suggesting that it acts in a promiscuous manner.<ref>Template:Cite journal</ref> There is evidence suggesting DHA inhibition of calcium-dependent ATPase on endoplasmic membrane, which disrupts protein folding of parasites.<ref name="Cui2009" />

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.<ref name="Morris2011">Template:Cite journal</ref> Because of its short half-life, its use in malaria prevention is limited.<ref name="Cui2009" />

DHA is metabolized to an inactive metabolite by the liver enzymes CYP2B6, CYP2C19, and CYP3A4.<ref>Template:Cite journal</ref>

Chemical synthesis

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.<ref name="Morris2011" /><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Research

Artesunate is under study for the treatment of COVID-19.<ref>Template:Cite journal</ref>

History

In May 2020, artesunate was approved for medical use in United States.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="FDA PR">Template:Citation-attribution</ref> 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.<ref name="FDA PR" /> 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.<ref name="FDA PR" />

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).<ref name="FDA PR" /><ref name="FDA snapshot" /> Trial 1 was conducted at 10 sites in Myanmar, Bangladesh, India, and Indonesia.<ref name="FDA snapshot" />

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

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.<ref name="FDA PR" /> The safety profile in Trial 2 was generally similar to Trial 1.<ref name="FDA PR" />

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

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).<ref name="FDA snapshot" />

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.<ref name="FDA snapshot" />

The application for IV artesunate was granted priority review and orphan drug designations.<ref name="FDA PR" /><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The FDA granted approval of artesunate for injection to Amivas.<ref name="FDA PR" />