Artesunate

Artesunate (INN)

File:Artesunate.svg
Clinical data
AHFS/Drugs.com	International Drug Names
Legal status	Not licensed in UK or US
Routes of administration	oral, IV, IM
Identifiers
CAS Number	88495-63-0 N Template:CAS (sodium salt)
ATC code	P01BE03 (WHO)
PubChem	CID: 5464098
ChemSpider	16735675 Y
UNII	60W3249T9M Y
ChEMBL	CHEMBL258608 N
NIAID ChemDB	112081
Chemical data
Formula	C19H28O8
Molecular mass	384.421 g/mol
SMILES [H][C@@]12CC[C@@]3(C)OO[C@@]11[C@@]([H])(CC[C@H]2C)[C@@H](C)[C@H](OC(=O)CCC(O)=O)O[C@]1([H])O3
InChI InChI=1S/C19H28O8/c1-10-4-5-13-11(2)16(23-15(22)7-6-14(20)21)24-17-19(13)12(10)8-9-18(3,25-17)26-27-19/h10-13,16-17H,4-9H2,1-3H3,(H,20,21)/t10-,11-,12+,13+,16-,17-,18-,19-/m1/s1 N Key:FIHJKUPKCHIPAT-AHIGJZGOSA-N N
NY (what is this?)  (verify)

Artesunate (AS) is a medication used to treat malaria. It is water-soluble and may therefore be given by injection. It is a semi-synthetic derivative of artemisinin.

It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.

Medical uses

The World Health Organization recommends intramuscular or intravenous artesunate as the first line treatment for severe malaria. 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 beneficial effect to be consistent across all trials.

For severe malaria during pregnancy, there is less certainty about the safety of artesunate during the first trimester but artesunate is recommended as first-line therapy during the second and third trimesters.

Artesunate is also used to treat less severe forms of malaria when it can be given orally, but should always be taken with a second antimalarial such as mefloquine or amodiaquine to avoid the development 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 this needs confirming in large randomized trials.

Adverse effects

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

Delayed haemolysis (occurring around two weeks after treatment) has been observed in patients treated with artesunate for severe malaria. Whether or not this haemolysis is due to artesunate, or to the malaria itself is unclear.

The safety of artesunate in pregnancy is unclear. There is evidence of embryotoxicity in animal models (defects in long bones and ventricular septal defects in the heart in rats and monkeys). However, observational evidence from 123 human first-trimester pregnancies showed no evidence of damage to the fetus.

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).

Mechanisms of action

In a hematin dependent manner, artesunate has been shown to potently inhibit the essential Plasmodium falciparum exported protein 1 (EXP1), a membrane glutathione S-transferase.

Drug resistance

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