Artesunate

Abstract

Artesunate is an antimalarial agent, available in oral, rectal and parenteral formulations, that provides a rapid clinical effect in patients with Plasmodium falciparum malaria. The rapidity of effect, availability of an intravenous and intramuscular formulation and convenient dosage regimen make artesunate an ideal candidate for the treatment of severe malaria, including cerebral disease. While some results have been promising, there is no clear evidence to date that artesunate reduces mortality in patients with cerebral malaria to any greater extent than standard quinine therapy. When given as monotherapy, treatment should be continued for at least 5 to 7 days to prevent recrudescence. Combination therapy with mefloquine allows artesunate to be administered over 3 days or less, with a satisfactory clinical outcome maintained. Although optimal dosages remain to be determined, this combination continues to provide the rapid onset of clinical effect observed with artesunate monotherapy, but decreases the rate of recrudescence to 2% (i.e. radical cure rate of 98%) when used as treatment in patients with uncomplicated malaria from areas with a high risk of multidrug-resistant falciparum malaria. Although assessment of tolerability is complicated by the difficulty of distinguishing between disease- and treatment-related events, artesunate and artesun-ate-mefloquine combinations appear to be well tolerated in adults and children. Indeed, it is possible that prior administration of artesunate may reduce the incidence of mefloquine-induced vomiting. Clinical findings to date have not revealed any pattern of resistance to artesunate after use of the drug. However, given the history of the development of resistance to other antimalarial drugs, the use of artesunate should be restricted to areas of multidrug resistance, the drug should be used in combination with a longer acting agent such as mefloquine, and it should be used in regimens that provide radical cure rates of 90 to 100%. If used according to these treatment principles, artesunate will provide a well tolerated and valuable addition to the current extremely limited treatment options for multidrug-resistant falciparum malaria, a widespread parasitic disease associated with considerable mortality. Artesunate is an antimalarial agent which acts by increasing the oxidant stress on the intra-erythrocytic plasmodia. Although the thresholds for in vitro sensitivity and resistance of Plasmodium falciparum have not been determined, artesunate is active against chloroquine- and mefloquine-resistant strains of P. falciparum. Compared with other qinghao derivatives (arteether, artemisinin and artemether), artesunate is the most potent in vitro. The results of in vitro experiments using erythrocytes from individuals with genetic variants of α-thalassaemia indicate that artesunate is likely to be less effective in the treatment of malaria in these populations than in other patient groups; however, this has not yet been demonstrated clinically. Animal models have demonstrated the efficacy of artesunate in the treatment of experimental P. berghei infection in mice and cerebral malaria caused by P. coatneyi in rhesus monkeys. Paired isolates from patients who had a recrudescence of infection after treatment with artesunate monotherapy, or mefloquine- or doxycycline-containing combination regimens, did not demonstrate any pattern of increased resistance in vitro to artesunate. The difficulty in finding an assay reliable enough to determine the plasma concentrations of the drug has limited the availability of pharmacokinetic data. In addition, interpretation of the plasma concentration-time profile for artesunate is complicated because the drug is rapidly hydrolysed to its principal active metabolite, dihydroartemisinin, and binds tightly to erythrocyte membranes. Peak plasma concentrations of artesunate and dihydroartemisinin in vivo are orders of magnitude greater than the minimum inhibitory concentration of the drug against P. falciparum in vitro. Dihydroartemisinin has a plasma elimination half-life of less than 2 hours, which may slow the development of resistance to artesunate. Artesunate has a minimal effect on hepatic cytochrome P450 activity and does not appear to influence the metabolism of mefloquine, a drug likely to be used in combination with artesunate. Artesunate causes a rapid reduction in parasitaemia and fever in patients with falciparum malaria and is associated with an acceptable radical cure rate (i.e. >90%) if given in doses of 600mg or more (initial dose of 200mg) for 5 to 7 days. Compared with other standard antimalarial agents (mefloquine, quinine plus tetracycline and intravenous quinine), artesunate monotherapy causes a more rapid reduction in parasitaemia and fever, but actual radical cure rates have been similar in most trials. Courses of artesunate therapy of less than 5 days commonly result in unacceptably high recrudescence rates. However, the combination of rapidly acting artesunate with mefloquine, a drug with a long elimination half-life, has been shown to be effective in preventing recrudescence. Sequential administration of various different combinations of artesunate and mefloquine has provided a rapid clinical effect, but has not always provided acceptable radical cure rates if artesunate is given over less than 2 days. This appears to be largely due to inadequate duration of artesunate treatment. Importantly, when oral artesunate 10 mg/kg was given over 3 days (initial dose of 4 mg/kg) followed by mefloquine 25 mg/kg, the regimen achieved radical cure rates of 98% in Karen patients displaced to the Myanmar-Thai border (individuals who typically are at a high risk of contracting multidrug-resistant disease). Similar sequential combination regimens were effective in patients with falciparum malaria that was unresponsive to standard therapeutic regimens. Artesunate has also been used in combination with other antimalarial agents, but to date they have all been associated with a high level of recrudescence after an initial rapid clinical effect. Preliminary data indicate that rectal administration of artesunate combined with mefloquine is effective in the treatment of both adults and children. Because artesunate has a rapid effect and can be administered parenterally, it is an excellent choice for the treatment of cerebral malaria or other forms of severe P. falciparum malaria. Although results have been equivocal, artesunate-mefloquine combinations may reduce mortality compared with standard quinine regimens in patients with cerebral malaria. However, further clinical trials are required to substantiate these findings. Clinically, the development of resistance to antimalarial therapy is of concern worldwide. The short elimination half-life of artesunate may favour slow development of resistance to this drug. However, general treatment principles for avoidance of resistance, such as restriction of the newer drugs to the treatment of resistant disease only and the use of regimens that provide a radical cure rate of 90 to 100%, should be applied to the use of artesunate. Artesunate and other related artemisinin derivatives have been widely used in China, with no reports of any serious adverse reactions. In healthy volunteers, a reversible reduction in reticulocyte counts was the dose-limiting adverse effect of artesunate, occurring with doses of 16.88 mg/kg. Overviews of clinical studies from Thailand and China indicate that the drug is remarkably well tolerated. Possible drug-related adverse effects include dizziness, itching, vomiting and other gastrointestinal effects, reduction in neutrophil counts and convulsions. However, it is likely that many of these effects are disease-related rather than drug-induced. When given in combination with mefloquine, artesunate has also been well tolerated. The incidence of mefloquine-induced vomiting has been variously reported to be slightly increased or markedly decreased during combination therapy: differences in the incidence of adverse effects following combination therapy may actually reflect the more rapid resolution of malarial symptoms in patients receiving the drug combination. Of some concern is the finding that artemisinin and its derivatives cause neurotoxicity in animals; however, to date, there is no evidence of neurotoxicity occurring clinically. The World Health Organization (WHO) recommends that artesunate be given for a minimum of 3 days, followed sequentially by a single dose of mefloquine. If mefloquine cannot be given, then artesunate monotherapy should be given for at least 5, but preferably 7, days. A total oral artesunate dose of 600mg is recommended by some investigators for uncomplicated disease: 100 or 200mg initially then 100 mg/day for at least 4 days. If artesunate is given for less than 7 days, treatment should be followed by a therapeutic dose of mefloquine (in doses of up to 25 mg/kg depending on the degree of multidrug resistance). For the treatment of severe disease, it is suggested that artesunate be administered intravenously or intramuscularly at an initial dose of 2 mg/kg, followed by 1 mg/kg every 12 hours until oral treatment can begin. A total administration period of 7 days is recommended. To ensure radical cure, artesunate therapy should be followed by a therapeutic dose of mefloquine. Artesunate has shown clinical efficacy when administered rectally, but no dosage recommendations are available.