Efficacious treatment of experimental leishmaniasis with amphotericin B-arabinogalactan water-soluble derivatives

In this study, we tested the efficacy of amphotericin B (AmB)-arabinogalact an (AmB-AG) conjugates for the treatment of experimental leishmaniasis. Che mical conjugation of AmB to a water-soluble, biodegradable, and biocompatib le polymer could present many advantages over presently available AmB formu lations, Two conjugates were tested, a reduced (rAmB-AG) form and an unredu ced (uAmB-AG) form. In vitro, the drug concentrations which lower the value s of parasites (for promastigotes) or infected macrophages (for amastigotes ) to 50% of the untreated values ED(50)s of uAmB-AG and rAmB-AG were 0.19 a nd 0.34 mu g/ml, respectively, for Leishmania major promastigotes and 0.17 and 0.31 mu g/ml, respectively, for amastigotes. The effect on Leishmania i nfantum-infected macrophages was more marked, with ED(50)s of 0.035 mu g/ml for rAmB-AG and 0.027 mu g/ml for uAmB-AG, In in vivo experiments, BALB/c mice injected with L. major were treated from day 2 onwards on alternate da ys for 2 weeks, Both conjugates, as well as liposomal AmB tall at 6 mg/kg o f body weight and Fungizone (I mg/kg), significantly delayed the appearance of lesions compared to that in untreated mice. In addition, both conjugate s, but not liposomal AmB, were significantly more effective than Fungizone, Subcutaneous injection of the conjugates (6 mg/kg) was significantly more effective than liposomal AmB in delaying the appearance of lesions. Higher AmB concentrations of up to 12 mg/kg could be administered by this route. W hen an established infection was treated, uAmB-AG was somewhat more effecti ve than liposomal AmB, In summary, water-soluble polymeric AmB derivatives were found effective and safe for the treatment of leishmanial infections. The conjugates, which are stable and can be produced relatively cheaply (co mpared to lipid formulations), can be used in the future for the treatment of leishmaniasis infections.