To review the pharmacodynamics and pharmacotherapeutic use of intravenous artesunate for the treatment of severe malaria. Literature was retrieved through PubMed (1999-March 2010), MEDLINE (1996-March 2010), and the Centers for Disease Control and Prevention (CDC), using the search terms artemisinin, artesunate, malaria, and severe malaria. In addition, reference citations from publications identified were reviewed. All articles in English that were identified from the data sources were reviewed. Focus was placed on postmarketing trials examining the safety and efficacy of artesunate in comparison with other regimens. The treatment of severe malaria requires prompt, safe, and effective intravenous antimalarials. Many oral and intravenous agents are available worldwide for the treatment of malaria; however, quinidine has been the only option for parenteral therapy in the US. Furthermore, this product's lack of availability as well as its adverse safety profile have created a treatment option gap. Recently, intravenous artesunate was approved by the Food and Drug Administration (FDA) for investigational drug use and distribution by the CDC. Three major studies regarding the use of intravenous artesunate are reviewed, in addition to the World Health Organization's malaria treatment guidelines. While there are no published head-to-head trials of intravenous artesunate versus intravenous quinidine for severe malaria, several international studies comparing intravenous quinine and artesunate concluded that artesunate has the highest treatment success, with lower incidence of adverse events. In addition, other literature is reviewed regarding counterfeit and other issues associated with artesunate. Artesunate, a new antimalarial currently available through the CDC, appears to be highly effective, better tolerated than quinidine, and not hampered by accessibility issues. If it were to be FDA approved and commercially available, it would be the preferred agent for the treatment of severe malaria in the US.

The aim of the study was to assess the in vitro potentiating effects of atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, in combination with mefloquine, chloroquine or monodesethylamodiaquine against Plasmodium falciparum and to evaluate whether the effects of atorvastatin could be associated with mutations or gene copy number in multidrug resistance (MDR)-like protein genes. The susceptibilities of 21 parasite strains to combinations of atorvastatin with mefloquine, chloroquine or monodesethylamodiaquine were assessed using the in vitro isotopic microtest. Genotypes and gene copy number were assessed for pfmdr1, pfmdr2 and pfmrp genes. Atorvastatin demonstrated synergistic effects in combination with mefloquine. The mefloquine IC(50) (50% inhibitory concentration) was reduced by 7%, 24% and 37% in the presence of atorvastatin at concentrations of 0.1, 0.5 and 1.0 microM, respectively. The synergistic effect of atorvastatin on the response to mefloquine was significantly associated with pfmdr1 copy number. The concentration of atorvastatin that could reduce the IC(50) of mefloquine by 50% was 2.4 + 1.3 microM for the 12 strains that contained one copy of pfmdr1 and 5.8 + 2.1 microM for the 9 strains that contained two copies or more. The synergistic effect of atorvastatin in combination with mefloquine was found to be significantly unrelated to mutations in pfmdr1, pfmdr2 or pfmrp genes. The synergy of the effect of mefloquine at concentrations relevant to its achievable plasma concentrations in patients taking 80 mg of atorvastatin daily suggests that atorvastatin will be a good candidate in combination with mefloquine for malaria treatment.