High-level chloroquine resistance of Plasmodium berghei is associated with multiple drug resistance and loss of reversal by calcium antagonists.

The chloroquine resistance of Plasmodium falciparum is reversed in vitro by numerous compounds, including calcium antagonists, which could enhance the accumulation of the drug in the parasite food vacuole. However, this mechanism of resistance could be insufficient when the resistance level increases. Using in vitro drug trials on strains of Plasmodium berghei displaying various chloroquine-resistance levels, we confirmed previous results obtained in vivo in the chloroquine-resistant strains of P. berghei are cross-resistant to related drugs (amodiaquine, quinine and mefloquine), the resistance levels to these drugs being related to their analogy to chloroquine. Furthermore, we showed that high-level resistant lines were associated with a loss of drug potentiation by verapamil and nicardipine in vivo, but that the reversal rates obtained in vitro are of low significance. We conclude that the parasite is able to escape the activity of these reversing agents.