artesunate

artesunate
IUPAC name	(3R,5aS,6R,8aS,9R,10S,12R,12aR)-Decahydro-3,6,9-trimethyl-3,12-epoxy-12H-pyrano[4,3-j]-1,2-benzodioxepin-10-ol hydrogen succinate
CAS number	88495-63-0
DrugBank	DB09274
ATC prefix	P01
ATC suffix	BE03

artesunate is a potent, water-soluble derivative of artemisinin, a natural compound extracted from the plant Artemisia annua. It is a cornerstone of modern antimalarial therapy, forming a key component of artemisinin-based combination therapies recommended by the World Health Organization for treating uncomplicated Plasmodium falciparum malaria. The drug is also used intravenously for the management of severe malaria and is under investigation for potential applications in oncology and other diseases.

Chemical properties

Artesunate is a semi-synthetic sesquiterpene lactone derived through chemical modification of dihydroartemisinin, itself a reduction product of artemisinin. Its defining structural feature is the incorporation of a succinic acid ester group, which confers high water solubility, distinguishing it from the parent compound and other derivatives like artemether. This molecular alteration allows for versatile formulation, including injectable solutions and oral tablets. The compound contains a crucial endoperoxide bridge within its 1,2,4-trioxane ring system, a pharmacophore essential for its potent biological activity against Plasmodium parasites.

Medical uses

The primary medical use is the treatment of malaria, specifically infections caused by Plasmodium falciparum and Plasmodium vivax. For uncomplicated cases, it is administered orally in fixed-dose combinations with longer-acting partner drugs such as amodiaquine, mefloquine, or sulfadoxine/pyrimethamine as part of artemisinin-based combination therapies. In severe malaria, intravenous or intramuscular artesunate is the treatment of choice, having demonstrated superior efficacy and reduced mortality compared to quinine in large trials like the SEAQUAMAT and AQUAMAT studies. Research is exploring its potential off-label use in cancers, viral infections, and autoimmune diseases.

Mechanism of action

The antimalarial activity is initiated by the iron-mediated cleavage of the essential endoperoxide bridge within the parasite's food vacuole. Heme or free ferrous iron from hemoglobin digestion generates reactive carbon-centered radicals and other reactive oxygen species. These highly reactive intermediates alkylate and damage critical parasite proteins, including the sarco/endoplasmic reticulum calcium ATPase ortholog, and induce widespread oxidative stress. This multifaceted assault disrupts essential cellular functions, leading to rapid parasite clearance from the bloodstream, typically within the first three days of treatment.

Pharmacokinetics

Following intravenous administration, artesunate is rapidly hydrolyzed in the plasma to its active metabolite, dihydroartemisinin, a process catalyzed by esterases. Oral formulations undergo extensive first-pass metabolism in the liver, also converting primarily to dihydroartemisinin. This active metabolite is highly protein-bound and has a very short elimination half-life of approximately one hour, necessitating its combination with longer-acting drugs. Metabolism occurs primarily via cytochrome P450 enzymes, notably CYP2A6 and CYP3A4, with excretion of metabolites via the bile and urine.

Adverse effects

When used for malaria, it is generally well-tolerated, with common adverse effects being mild and transient, including nausea, vomiting, anorexia, and dizziness. A notable concern is the risk of delayed hemolytic anemia following treatment for severe malaria, a phenomenon observed in the CARAMAL study. Rare but serious adverse events include allergic reactions and potential cardiotoxicity at very high doses. Its use in the first trimester of pregnancy is generally avoided due to embryotoxicity observed in animal studies, though the World Health Organization considers it a lifesaving option in later trimesters.

History and production

The development stems from the rediscovery of artemisinin by Chinese scientists during the Project 523 in the 1970s, led by researchers like Tu Youyou. To improve solubility and efficacy, chemists at the Institute of Microbiology and Epidemiology and the Guilin Pharmaceutical Factory developed artesunate in the late 1970s. Large-scale production now involves the extraction of artemisinin from cultivated Artemisia annua, followed by chemical synthesis steps to produce dihydroartemisinin and subsequent esterification. Major manufacturers include Sanofi and Guilin Pharmaceutical, with quality assurance monitored by the World Health Organization Prequalification of Medicines Programme.

Category:Antimalarial agents Category:World Health Organization essential medicines