Artesunate

Artesunate (INN) is part of the artemisinin group of drugs that treat malaria. It is a semi-synthetic derivative of artemisinin that is water-soluble and may therefore be given by injection. It is sometimes abbreviated AS.

Uses

Artesunate is used primarily as treatment for malaria; it has also been shown to be >90% efficacious at reducing egg production in Schistosoma haematobium infection.^[1]

According to WHO intravenous AS is the drug of choice for severe malaria both in children and adults where there is low transmission.^[2] In regions where transmission is high, randomized trials among Asian adults and African children strongly advocates the use of artesunate over quinine as the treatment of choice for falciparum malaria.^{[3] [4]}

Dosing

There are no licensed forms of artesunate available in the U.S. or UK. In the UK, artesunate is available on a named patient basis only.

Intravenous dose of IV artesunate for treatment of severe malaria:

• 2.4 mg/kg loading dose over 5 minutes
• 2.4 mg/kg dose 12 hours later
• 2.4 mg/kg once daily after that

Artesunate must always be given with another antimalarial such as mefloquine^[5][6] or amodiaquine^[7] so as to avoid the development of resistance. The combination of artesunate/amodiaquine has been found to be equivalent to co-artemether.^[8]

For severe malaria during pregnancy, the WHO recommends artesunate or quinine during the first trimester and artesunate as the first-line therapy during the second and third trimesters.^[9]

Synthesis

Artesunate is prepared from dihydroartemisinin (DHA) by reacting it with succinic acid anhydride in basic medium. Pyridine as base/solvent, sodium bicarbonate in chloroform and catalyst DMAP (N,N-dimethylaminopyridine) and triethylamine in 1,2-dichloroethane have been used, with yields of up to 100%. A large scale process involves treatment of DHA in dichloromethane with a mixture of pyridine, a catalytic amount of DMAP and succinic anhydride. The dichloromethane mixture is stirred for 6–9 h to get artesunate in quantitative yield. The product is further re-crystallized from dichloromethane. alpha-Artesunate is exclusively formed (m.p 135–137˚C).

Drug resistance

Clinical evidence of drug resistance has appeared in Western Cambodia, where artemesinin monotherapy is common.^[10] There are as yet no reports of resistance emerging elsewhere.

References