Analyses of the interactions between HU and antimalarial drugs. (A) Isobologram analyses of the interaction between HU and indicated antimalarial drugs against Pf3D7: lumefantrine (LUM), amodiaquine (AQ), chloroquine (CQ), and primaquine (PQ). FIC of HU vs FIC of antimalarial drugs were plotted. Isobolograms were constructed from EC50 or EC90 values. For each drug combination, the FIC was calculated by dividing the measured “apparent” EC values for individual drugs in the different combinations of HU and antimalarial drugs EC values obtained when the drugs were used alone. Colors represent independent experiments. (B) Sum of 50% and 90% fractional inhibitory concentration (∑FIC50, 90) of the interaction of HU and indicated antimalarial drugs against Pf3D7 and PfDd2 strains, carried out in 2 to 5 independent experiments. In panel B, ∑FIC values are presented as median (range). α, ADD-SLANT; β, ADD-SYN; γ, ADD-SYN-SLANT. ADD, additive; ND, not determine; SLANT, slightly antagonistic; SYN, synergistic, based on well-established criteria of ∑FIC <0.5, substantial synergism, ∑FIC <1 moderate synergism, ∑FIC ≥1 and <2 additive interaction; ∑FIC ≥2 and <4 slight antagonism and ∑FIC >4 marked antagonism.33
