Artemisinin (qinghaosu) is a sesquiterpene lactone endoperoxide (Figure 52–2), the active component of an herbal medicine that has been used as an antipyretic in China for more than 2000 years. Artemisinin is insoluble and can only be used orally. Analogs have been synthesized to increase solubility and improve antimalarial efficacy. The most important of these analogs are artesunate (water-soluble; oral, intravenous, intramuscular, and rectal administration), artemether (lipid-soluble; oral, intramuscular, and rectal administration), and dihydroartemisinin (water-soluble; oral administration).
Artemisinin and its analogs are complex 3and 4-ring structures (Figure 52-2). They are rapidly absorbed, with peak plasma levels occurring promptly. Half-lives after oral administration are 30–60 minutes for artesunate and dihydroartemisinin, and 2–3 hours for artemether. Artemisinin, artesunate, and artemether are rapidly metabolized to the active metabolite dihydroartemisinin. Drug levels appear to decrease after a number of days of therapy.
The artemisinins are now widely available, but monotherapy for the treatment of uncomplicated malaria is strongly discouraged. Rather, co-formulated artemisinin-based combination therapies are recommended to improve efficacy and prevent the selection of artemisinin-resistant parasites. The oral combination regimen Coartem (artemether-lumefantrine) was approved by the U.S. Food and Drug Administration (FDA) in 2009, and it may be considered the new first-line therapy in the USA for uncomplicated falciparum malaria, although it may not be widely available. Intravenous artesunate is available from the CDC; use is initiated by contacting the CDC, which will release it for appropriate indications (falciparum malaria with signs of severe disease or inability to take oral medications) from stocks stored around the USA.
Artemisinin and its analogs are very rapidly acting blood schizonticides against all human malaria parasites. Artemisinins have no effect on hepatic stages. They are active against young, but not mature gametocytes. The antimalarial activity of artemisinins appears to result from the production of free radicals that follows the iron-catalyzed cleavage of the artemisinin endoperoxide bridge. Artemisinin resistance is not yet a widespread problem, but delayed clearance of P falciparum infections and decreased treatment efficacy in parts of Southeast Asia demonstrate a worrisome focus of resistance.
Artemisinin-based combination therapy is now the standard of care for treatment of uncomplicated falciparum malaria in nearly all endemic areas. The leading regimens are highly efficacious, safe, and well tolerated. These regimens were developed because the short plasma half-lives of the artemisinins led to unacceptably high recrudescence rates after short-course therapy, which were reversed by inclusion of longer-acting drugs. Combination therapy also helps to protect against the selection of artemisinin resistance. However, with completion of dosing after 3 days, the artemisinin components are rapidly eliminated, and so selection of resistance to partner drugs is of concern.