Artesunate

Artesunate (AS) is a medication used to treat malaria.[3][4] The intravenous form is preferred to
quinidine for severe malaria.[3] Often it is used as part of combination therapy, such as artesunate plus
mefloquine.[4] It is not used for the prevention of malaria.[4] Artesunate can be given by injection into a
vein, injection into a muscle, by mouth, and by rectum.[4][5][6]

Artesunate is generally well tolerated.[5] Side effects may include a slow heartbeat, allergic reaction,
dizziness, and low white blood cell levels.[4] During pregnancy it appears to be a safer option, even
though animal studies have found harm to the baby.[7] Use is likely okay during breastfeeding.[8] It is in
the artemisinin class of medication.[3]

Artesunate is on the World Health Organization's List of Essential Medicines, the most effective and safe
medicines needed in a health system.[9] The wholesale cost in the developing world is US$2.09 to
US$2.57 a dose.[10] It is not commercially available in the United States; however, can be gotten from
the Centers for Disease Control.[3][11] It was originally made from the sweet wormwood plant.[3]

Medical uses

Artesunate is the first line treatment for children or adults with severe malaria,[12][11] 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.[13] 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.[3] Artesunate was shown
to prevent more deaths from severe malaria than quinine in two large multicentre randomized
controlled trials from Africa[14] and Asia.[15] A subsequent systematic review of seven randomized
controlled trials found this improvement in survival rates to be consistent across all trials.[16]

Artesunate is also used to treat less severe forms of malaria when it can be given orally.[12] It has
activity against P. ovale, P. malariae, and severe P. knowlesi.[12]

Artesunate + sulfadoxine/pyrimethamine for treatment of P. vivax is not recommended due to high

rates of resistance.[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,[17] but has not been evaluated in
large randomized trials.

Although not FDA-approved for use in the United States, artesunate is used as the treatment of choice
for severe malaria by the World Health Organization (WHO) over quinidine.[3]

Pregnancy

When given in the second or third trimesters of pregnancy, no artesunate-related adverse pregnancy
outcomes have been reported.[18] 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.[12] 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.[12] 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.

Adverse effects

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.[19] The best recognised adverse
effect of the artemisinins is that they lower reticulocyte counts.[20] This is not usually of clinical
relevance.

With increased use of I.V. artesunate, there have been reports of post-artesunate delayed haemolysis
(PADH).[21] Delayed haemolysis (occurring around two weeks after treatment) has been observed in
patients treated with artesunate for severe malaria.[22] It is unclear whether or not this haemolysis is
due to artesunate or to the malaria itself.[23]

Contraindications
Artesunate is typically a well tolerated medicine. Known contraindications include a previous severe
allergic reaction to artesunate.[24]

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.[25]

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.[26] 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.[26] In addition, Artesunate
potently inhibits the essential Plasmodium falciparum exported protein 1 (EXP1), a membrane
glutathione S-transferase.[27] 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.[28] There is evidence suggesting DHA inhibition of calcium-dependent ATPase on
endoplasmic membrane, which disrupts protein folding of parasites.[26]

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.[29] Because of its short half-life, its use in malaria prevention is limited.[26]

DHA is metabolized to an inactive metabolite by the liver enzymes CYP2B6, CYP2C19, and CYP3A4.[30]