Augmentation of antileishmanial efficacy of miltefosine in combination with tuftsin against experimental Visceral Leishmaniasis

Abstract

Current drugs for the treatment of Visceral Leishmaniasis (VL), are inadequate and their efficacies are also compromised due to suppression of immune function associated during the course of infection. Miltefosine is the only promising orally active antileishmanial drug but due to its long half life there is risk of development of resistance. To overcome these problems, efforts are needed to develop combination therapy of miltefosine with effective immunostimulating agent where decrease of parasitic burden and simultaneous enhancement of adaptive immunity can be achieved. In the present study we have explored the antileishmanial efficacy of sub-curative dose of miltefosine in combination with free as well as liposomal p-tuftsin using L. donovani/BALB/c mouse model. When miltefosine (2.5mg/kg for 5 days) was given with free p-tuftsin, the inhibitory effect was significantly increased from 49.6% to 66% (P<0.01), which was further enhanced up to 81% (P<0.001) when given after liposomal encapsulation of p-tuftsin. Significant enhancement in parasitic inhibition (93%, P<0.01) was witnessed when animals were co-administered with liposomal p-tuftsin + 5 mg/kg x 5 days dose of miltefosine (72.1%). Enhancement in the production of Th1 cytokines (IL-12, TNF-α, IFN-γ), reactive oxygen and nitrogen metabolites was witnessed in the combination group. Remarkable increase in phagocytosis index was also observed indicating overall immunological support to antileishmanial activity of miltefosine by p-tuftsin.