Atorvastatin (AVA) is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. AVA exposure resulted in reduced in vitro growth of 22 P. falciparum strains with IC50s ranging from 2.5 microM to 10.8 microM. A significant positive correlation was found between the strains' responses to AVA and mefloquine (r = 0.553; P = 0.008). The authors found no correlation between the responses to AVA and chloroquine, quinine, monodesethylamodiaquine, lumefantrine, dihydroartemisinin, atovaquone or doxycycline. These data could suggest different mechanisms of drug uptake and/or mode of action for AVA from other antimalarial drugs. IC50 values for AVA were unrelated to mutations occurring in transport protein genes involved in quinoline antimalarial drug resistance, such as pfcrt, pfmdr1, pfmrp and pfnhe-1. Therefore, AVA can be ruled out as a substrate for these transport proteins (PfCRT, Pgh1 and PfMRP) and is not subject to pH modification induced by PfNHE-1. The absence of in vitro cross-resistance between AVA and chloroquine, quinine, mefloquine, monodesethylamodiaquine, lumefantrine, dihydroartemisinin, atovaquone or doxycycline argues that these antimalarial drugs could potentially be paired with AVA as a malaria treatment strategy. In conclusion, the present observations suggest that AVA is a good candidate for further studies on the use of statins in association known antimarial drugs.

Artesunate (AS) plus amodiaquine (AQ) is one artemisinin-based combination (ACT) recommended by the WHO for treating Plasmodium falciparum malaria. Fixed-dose AS/AQ is new, but its safety and efficacy are hitherto untested. A randomized, open-label trial was conducted comparing the efficacy (non-inferiority design) and safety of fixed (F) dose AS (25 mg)/AQ (67.5 mg) to loose (L) AS (50 mg) + AQ (153 mg) in 750, P. falciparum-infected children from Burkina Faso aged 6 months to 5 years. Dosing was by age. Primary efficacy endpoint was Day (D) 28, PCR-corrected, parasitological cure rate. Recipients of rescue treatment were counted as failures and new infections as cured. Documented, common toxicity criteria (CTC) graded adverse events (AEs) defined safety. Recruited and evaluable children numbered 750 (375/arm) and 682 (90.9%), respectively. There were 8 (AS/AQ) and 6 (AS+AQ) early treatment failures and one D7 failure (AS+AQ). Sixteen (AS/AQ) and 12 (AS+AQ) patients had recurrent parasitaemia (PCR new infections 10 and 6, respectively). Fourteen patients per arm required rescue treatment for vomiting/spitting out study drugs. Efficacy rates were 92.1% in both arms: AS/AQ = 315/342 (95% CI: 88.7-94.7) vs. AS+AQ = 313/340 (95% CI: 88.6-94.7). Non-inferiority was demonstrated at two-sided alpha = 0.05: Delta (AS+AQ - AS/AQ) = 0.0% (95% CI: -4.1% to 4.0%). D28, Kaplan Meier PCR-corrected cure rates (all randomized children) were similar: 93.7% (AS/AQ) vs. 93.2% (AS+AQ) Delta = -0.5 (95% CI -4.2 to 3.0%). By D2, both arms had rapid parasite (F & L, 97.8% aparasitaemic) and fever (97.2% [F], 96.0% [L] afebrile) clearances. Both treatments were well tolerated. Drug-induced vomiting numbered 8/375 (2.1%) and 6/375 (1.6%) in the fixed and loose arms, respectively (p = 0.59). One patient developed asymptomatic, CTC grade 4 hepatitis (AST 1052, ALT 936). Technical difficulties precluded the assessment and risk of neutropaenia for all patients. Fixed dose AS/AQ was efficacious and well tolerated. These data support the use of this new fixed dose combination for treating P. falciparum malaria with continued safety monitoring.