Artesunate

Medical uses

Artesunate is the first line treatment for children or adults with severe malaria. The recommendation is to treat with at least 24 hours of artesunate by injection. 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, 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. Artesunate was shown to prevent more deaths from severe malaria than quinine in two large multicentre randomized controlled trials from Africa and Asia. A subsequent systematic review of seven randomized controlled trials found this improvement in survival rates to be consistent across all trials.

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.

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, 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.

Pregnancy

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

Adverse effects

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

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

Contraindications

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

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.

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. 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. 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. There is evidence suggesting DHA inhibition of calcium-dependent ATPase on endoplasmic membrane, which disrupts protein folding of parasites.

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. 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.

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.

Research

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