Visceral leishmaniasis (VL) caused by the parasite Leishmania donovani is a potentially fatal disease. Available limited drugs are toxic, require prolonged
treatment duration, and are costly. A low-cost parenteral formulation of
paromomycin sulfate (PM) has recently been approved for the treatment of VL. Monotherapy with PM runs the risk of development of resistance. Hence, efforts are needed to develop a combination
therapy of PM with other drugs to shorten the
duration of treatment and prolong the effective life of the
drug. PM was formulated with leishmanicidal
stearylamine (SA)-bearing
phosphatidylcholine (PC)
liposomes for low-dose
therapy. In vitro and in vivo antileishmanial effects of the
combination drug were determined. The immunomodulatory role of PC-SA-PM was determined using
enzyme-linked
immunosorbent assay (ELISA) and flow cytometry. Excluding the spleen, for which the
therapeutic effect was additive, a remarkable synergistic activity toward cure and prophylaxis with a single-shot low-dose treatment with PC-SA-associated PM was achieved with BALB/c mice. PC-SA-PM showed an immunomodulatory effect on CD4(+) and CD8(+) T cells for
gamma interferon (IFN-γ) production and downregulated disease-associated
interleukin-10 (IL-10) and
transforming growth factor β (TGF-β) to almost negligible levels. Such
combination chemotherapy may provide a promising alternative for the cure of
leishmaniasis, with a plausible conversion of the host immune response from a disease-promoting pattern to a Th1-biased response indicative of long-term resistance.