Artemether (ATM) cardiotoxicity, its short half-life and low oral bioavailability are the major limiting factors for its use to treat malaria. The purposes of this work were to study free-ATM and ATM-loaded poly-ε-caprolactone nanocapules (ATM-NC) cardiotoxicity and oral efficacy on Plasmodium berghei-infected mice. ATM-NC was obtained by interfacial polymer deposition and ATM was associated with polymeric NC oily core. For cardiotoxicity evaluation, male black C57BL6 uninfected or P. berghei-infected mice received, by oral route twice daily/4 days, vehicle (sorbitol/carboxymethylcellulose), blank-NC, free-ATM or ATM-NC at doses 40, 80 or 120 mg kg−1. Electrocardiogram (ECG) lead II signal was obtained before and after treatment. For ATM efficacy evaluation, female P. berghei-infected mice were treated the same way. ATM-NC improved antimalarial in vivo efficacy and reduced mice mortality. Free-ATM induced significantly QT and QTc intervals prolongation. ATM-NC (120 mg kg−1) given to uninfected mice reduced QT and QTc intervals prolongation 34 and 30%, respectively, compared with free-ATM. ATM-NC given to infected mice also reduced QT and QTc intervals prolongation, 28 and 27%, respectively. For the first time, the study showed a nanocarrier reducing cardiotoxicity of ATM given by oral route and it was more effective against P. berghei than free-ATM as monotherapy.

Using an age-fractionated RBC model, we investigated the in vitro sensitivity of artemether in β-thalassaemic RBC infected with the K1 and FC27 strains of Plasmodium falciparum and, to study the role of oxidant stress in modulating the sensitivity pattern, pro-oxidant (riboflavin) and antioxidant (vitamin E) agents were added to cultures in the presence of artemether. With the FC27 strain, the artemether IC50 doses in thalassaemic samples (whole blood and fractions) were significantly higher compared to equivalent normal RBC samples (P<0·05). However, with the K1 strain, such a significant difference was not demonstrable. The addition of vitamin E reduced the antimalarial effect of artemether in both the FC27 and K1 strains (P<0·0001). In contrast, the addition of riboflavin resulted in a significant increase in antimalarial activity (P<0·0001). This effect of the drug combinations was not influenced by the red cell type (P<0·0001) and there was no interaction between red cell type and drug type (P<0·0001). These findings show that reduced sensitivity to artemether occurs in whole blood and age-fractionated β-thalassaemic trait RBC. It appears that the RBC redox status does not influence the sensitivity to artemether.

The in vitro activity of artemether against 63 African isolates of Plasmodium falciparum from Libreville, Gabon was evaluated using an isotopic drug susceptibility semi-microtest. The 50% inhibitory concentration (IC50) values for artemether were in a narrow range from 0·8 to 34·8 nm (mean IC50 5·0 nm) and the 95% confidence interval (CI95%) was 3·6–6·3 nm. In vitro decreased susceptibility or resistance were observed with artemether (14%), to chloroquine (90%), to quinine (32%). Isolate susceptibility to amodiaquine and halofantrine was high i.e. 100% and 98%, respectively. There was a significant positive correlation between responses to artemether and amodiaquine (r2=0·45, P<0·001), artemether and chloroquine (r2=0·36, P<0·001), artemether and quinine (r2=0·31, P<0·001), and artemether and halofantrine r2=0·19, P<0·01). Positive correlation between these drugs suggests in vitro cross-resistance or at least common features in drug uptake and/or mode of action or resistance.