title: Combination therapy with paromomycin-associated stearylamine-bearing liposomes cures experimental visceral leishmaniasis through Th1-biased immunomodulation.
abstract: 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.
authors.affiliation: Infectious Diseases and Immunology Division, Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata 700032, India.
authors.forename: Antara
authors.initials: A
authors.lastname: Banerjee
authors.forename: Manjarika
authors.initials: M
authors.lastname: De
authors.forename: Nahid
authors.initials: N
authors.lastname: Ali
mesh_terms: D000588:Amines / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D002478:Cells, Cultured; D006224:Cricetinae; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D056724:Immunity, Humoral / Q000187:drug effects; D007155:Immunologic Factors / Q000008:administration & dosage / Q000627:therapeutic use*; D016753:Interleukin-10 / Q000378:metabolism; D007898:Leishmaniasis, Visceral / Q000188:drug therapy*; D008081:Liposomes / Q000737:chemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D010303:Paromomycin / Q000008:administration & dosage / Q000627:therapeutic use*; D010713:Phosphatidylcholines / Q000737:chemistry; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D000588:Amines; D000900:Anti-Bacterial Agents; D007155:Immunologic Factors; D008081:Liposomes; D010713:Phosphatidylcholines; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D010303:Paromomycin; C009317:stearylamine