Current drugs for the treatment of
visceral leishmaniasis are inadequate, and their efficacies are also compromised due to suppression of immune function 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 agents where a decrease of parasitic burden and simultaneous enhancement of adaptive immunity can be achieved. In the present study, we have explored the antileishmanial efficacy of a subcurative dose of
miltefosine in combination with free as well as liposomal palmitoyl
tuftsin (p-
tuftsin) using a Leishmania donovani/BALB/c mouse model. When
miltefosine (2.5 mg/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 × 5 days dose of
miltefosine (72.1%). Enhancement in the production of Th1
cytokines (IL-12, TNF-α, and IFN-γ), reactive
oxygen, and
nitrogen metabolites was witnessed in the combination group. A remarkable increase in phagocytosis index was also observed indicating overall immunological enhancement to antileishmanial activity of
miltefosine by p-
tuftsin.