ARTEMISININ & ITS DERIVATIVES
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 over 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; useful for oral, intravenous, intramuscular, and rectal administration), artemether (lipid-soluble; useful for oral, intramuscular, and rectal administration), and dihydroartemisinin (water-soluble; useful for oral administration).
Artemisinin and its analogs are rapidly absorbed, with peak plasma levels occurring in 1–2 hours and half-lives of 1–3 hours after oral administration. Artemisinin, artesunate, and artemether are rapidly metabolized to the active metabolite dihydroartemisi-nin. Drug levels appear to decrease after a number of days of therapy.
The artemisinins are now widely available around the world. However, artemisinin monotherapy for the treatment of uncompli-cated malaria is now 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 Food and Drug Administration (FDA) in 2009, and may be considered the new first-line therapy in the USA for uncomplicated falciparum malaria, although the drug may not be widely available. Intravenous artesunate was made available by the CDC in 2007; use of the drug can be initi-ated by contact with the CDC, which will release the drug 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 sch-izonticides against all human malaria parasites. Artemisinins have no effect on hepatic stages. The antimalarial activity of artemisinins may result from the production of free radicals that follows the iron-catalyzed cleavage of the artemisinin endoperoxide bridge in the parasite food vacuole or from inhibition of a parasite calcium ATPase. Artemisinin resistance is not yet an important problem, but P falciparum isolates with diminished in vitro susceptibility to arte-mether have recently been described. In addition, increasing rates of treatment failure and increases in parasite clearance times after use of artesunate or artesunate-mefloquine in parts of Cambodia may be early signs of a worrisome decrease in artesunate efficacy.
Artemisinin-based combination therapy is now the standard for treatment of uncomplicated falciparum malaria in nearly all areas endemic for falciparum malaria. These regimens were developed because the short plasma half-lives of the artemisinins led to unac-ceptably 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.
The WHO recommends five artemisinin-based combinations for the treatment of uncomplicated falciparum malaria (Table 52–4). One of these, artesunate-sulfadoxine-pyrimethamine is not rec-ommended in many areas owing to unacceptable levels of resis-tance to sulfadoxine-pyrimethamine, but it is the first-line therapy in some countries in Asia, South America, and North Africa. The other four recommended regimens are now all available as combi-nation formulations, although manufacturing standards may vary. Artesunate-mefloquine is highly effective in Southeast Asia, where resistance to many antimalarials is common; it is the first-line therapy in some countries in Southeast Asia and South America. This regimen is less practical for other areas, particularly Africa, because of its relatively high cost and poor tolerability. Either artesunate-amodiaquine or artemether-lumefantrine is now thestandard treatment for uncomplicated falciparum malaria in most countries in Africa and some additional endemic countries on other continents. Dihydroartemisinin-piperaquine is a newer regi-men that has shown excellent efficacy; it is the first-line therapy for falciparum malaria in Vietnam.
The relative efficacy and safety of artemisinin-based combina-tion therapies are now under active investigation. In general, the leading regimens are highly efficacious, safe, and well tolerated, and they are the new standard of care for the treatment of uncom-plicated falciparum malaria.
Artemisinins are also proving to have outstanding efficacy in the treatment of complicated falciparum malaria. Large random-ized trials and meta-analyses have shown that intramuscular artemether has an efficacy equivalent to that of quinine and that intravenous artesunate is superior to intravenous quinine in terms of parasite clearance time and—most important—patient sur-vival. Intravenous artesunate also has a superior side-effect profile compared with that of intravenous quinine or quinidine. Thus, intravenous artesunate will likely replace quinine as the standard of care for the treatment of severe falciparum malaria, although it is not yet widely available in most areas. Artesunate and arte-mether have also been effective in the treatment of severe malaria when administered rectally, offering a valuable treatment modality when parenteral therapy is not available.
Artemisinins are generally very well tolerated. The most commonly reported adverse effects are nausea, vomiting, diarrhea, and dizzi-ness, and these may often be due to underlying malaria rather than the medications. Rare serious toxicities include neutropenia, ane-mia, hemolysis, elevated liver enzymes, and allergic reactions. Irreversible neurotoxicity has been seen in animals, but only after doses much higher than those used to treat malaria. Artemisinins have been embryotoxic in animal studies, but rates of congenital abnormalities, stillbirths, and abortions were not elevated, com-pared with those of controls, in women who received artemisinins during pregnancy. Based on this information and the significant risk of malaria during pregnancy, the WHO recommends artemisinin-based combination therapies for the treatment of uncomplicated falciparum malaria during the second and third trimesters of preg-nancy, intravenous artesunate or quinine for the treatment of severe malaria during the first trimester, and intravenous artesunate for treatment of severe malaria during the second and third trimesters.