In vitro and in vivo interactions between miltefosine and other antileishmanial drugs

Abstract

The interaction of miltefosine with amphotericin B, sodium stibogluconate, paromomycin, and sitamaquine was assessed in vitro and additionally for the first three combinations in vivo. In vitro interactions were indifferent for miltefosine combined with amphotericin B (mean sums of fractional inhibitory concentrations [mean summation operatorFICs] ranging from 1.22 to 1.51 at the 50% effective concentration [EC50] level and 1.08 to 1.38 at the EC90 level), sitamaquine (mean summation operatorFICs from 1.33 to 1.38 and 1.0 to 1.02, respectively), and paromomycin (mean summation operatorFICs from 0.79 to 0.93 at the EC50 and 0.77 to 1.35 at the EC90 level). Some synergy was observed for miltefosine combined with sodium stibogluconate (mean summation operatorFICs from 0.61 to 0.75 at EC50 and 0.49 to 0.97 at EC90). Different interactions were found in vivo, where the highest potentiation of miltefosine activity was achieved with amphotericin B (activity enhancement index [AEI] of up to 11.3). No significant interaction was observed when miltefosine was combined with sodium stibogluconate (AEI of up to 2.38). The potentiation of miltefosine in vivo was also achieved with the combination of miltefosine and paromomycin (AEI of up to 7.22).

FIG. 1.

Representative isobolograms of in vitro interactions against intracellular amastigotes. Interactions are given at the EC₅₀ (left) and EC₉₀ (right) levels. Numbers on the axes represent normalized FICs of miltefosine (x axis) and of the respective partner drugs (y axes). (a) Miltefosine-amphotericin B; (b) miltefosine-sodium stibogluconate; (c) miltefosine-sitamaquine; (d) miltefosine-paromomycin. Drugs were used in their salt forms as stated in the text.

FIG. 2.

Isobolograms of the in vivo interactions of (a) miltefosine-amphotericin B and (b) miltefosine-paromomycin. Triangles indicate ED₅₀s of miltefosine on the x axis when given with the dose of amphotericin B or paromomycin indicated on the y axis. Conversely, closed circles indicate ED₅₀s of amphotericin B or paromomycin on the y axis when given with the dose of miltefosine indicated on the x axis.