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Background  Quinine (QN) remains the first line anti-malarial drug for the treatment of complicated malaria in Europe and Africa. The emergence of QN resistance has been documented. QN resistance is not yet a significant problem, but there is an urgent need to discover partners for use in combination with QN. The aim of the study was to assess the in vitro potentiating effects of atorvastatin (AVA), a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, in combination with QN against  Plasmodium falciparum  and to evaluate whether the effects of AVA could be associated with gene copy number or mutations in genes involved in QN resistance, such as  pfcrt ,  pfmdr1 ,  pfmrp  and  pfnhe .    Methods  The susceptibilities to combination of AVA with QN were assessed against 21 parasite strains using the  in vitro  isotopic microtest. Genotypes and gene copy number were assessed for  pfcrt ,  pfmdr1 ,  pfmdr2 ,  pfmrp  genes. In addition, the number of DNNND, DDNHNDNHNN repeats in  pfnhe-1  ms4760 and the ms4760 profile were determined for each strains of  P. falciparum .    Results  AVA demonstrated synergistic effects in combination with QN against 21  P. falciparum  strains. The QN IC 50  was reduced by 5% (0% to 15%; 95%CI: 1%-8%), 10% (3% to 23%; 95%CI: 7%-14%) and 22% (14% to 40%; 95%CI: 19%-25%) in presence of AVA at concentrations of 0.1, 0.5 and 1.0 μM, respectively. These reductions were all significant (p < 0.009). The reduction in the QN IC 50  in presence of AVA was not significantly correlated with the QN IC 50  (r = 0.22,  P  = 0.3288) or the AVA IC 50  (r = 0.03, P = 0.8946). The synergistic effect of AVA in combination with QN was not significantly associated with polymorphisms in the  pfcrt ,  pfmdr1 ,  pfmrp , and  pfnhe-1  genes that could be involved in QN resistance. The synergistic effect of AVA on QN responses was not significantly associated with  pfmdr1  copy number ( P  = 0.0428).    Conclusion  The synergistic effect of AVA in combination with QN was found to be unrelated to mutations occurring in transport protein genes involved in QN drug resistance. The different mechanisms of drug uptake and/or mode of action for AVA compared to the other anti-malarial drugs, as well as the AVA-mediated synergy of the anti-malarial effect of QN, suggests that AVA will be a good candidate for combinatorial malaria treatment. All of these observations support calls for both an in vivo evaluation with pharmacokinetic component and clinical trials of AVA as an anti-malarial therapy.

Atorvastatin as a potential anti-malarial drug: in vitro synergy in combinational therapy with quinine against Plasmodium falciparum