title: Augmentation of antileishmanial efficacy of miltefosine in combination with tuftsin against experimental visceral leishmaniasis.
abstract: 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.
authors.affiliation: Division of Parasitology, Central Drug Research Institute (CSIR), Chattar Manzil Palace, M.G. Road, Lucknow, 226001 Uttar Pradesh, India.
authors.forename: Nishi
authors.initials: N
authors.lastname: Shakya
authors.forename: Shraddha A
authors.initials: SA
authors.lastname: Sane
authors.forename: Wahajul
authors.initials: W
authors.lastname: Haq
authors.forename: Suman
authors.initials: S
authors.lastname: Gupta
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D006861:Hydrogen Peroxide; D007111:Immunity, Cellular / Q000187:drug effects; D007893:Leishmania donovani; D007898:Leishmaniasis, Visceral / Q000188:drug therapy*; D008081:Liposomes; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D010587:Phagocytosis / Q000187:drug effects; D010767:Phosphorylcholine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D014405:Tuftsin / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000981:Antiprotozoal Agents; D008081:Liposomes; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D010767:Phosphorylcholine; C039128:miltefosine; D006861:Hydrogen Peroxide; D014405:Tuftsin