Comparison of the Efficacy of Free and Non-ionic-surfactant Vesicular Formulations of Paromomycin in a Murine Model of Visceral Leishmaniasis

Abstract

Non-ionic-surfactant vesicular (NIV) formulations of paromomycin have been tested in-vitro and in-vivo for their activity against Leishmania donovani. Production of NIV was dependent both on the surfactant used and on the concentration of paromomycin; only two of the surfactants studied formed vesicles at the highest paromomycin concentration (9 mg mL(-1)). At surfactant-lipid concentrations > or = 1.5 mM, suspensions of NIV (drug- or glucose-loaded) were cytotoxic to macrophages infected with L. donovani; high levels of nitrite were produced in cell supernatants. At surfactant-lipid concentrations < 1.5 mM, drug-loaded NIV were more effective than the same dose of free drug, in terms of the percentage of cells infected and the number of parasites/cell. At surfactant-lipid concentrations < or = 0.15 mM, drug-loaded NIV were ineffective in-vitro. In-vivo, treatment with decaethylene glycol mono n-hexadecyl ether paromomycin NIV was more effective than hexaethylene glycol mono n-hexadecyl ether paromomycin NIV, in terms of suppression of liver and spleen parasite burdens. Against liver parasites, both types of paromomycin-loaded NIV were more effective than free drug. Neither the NIV nor free forms of paromomycin caused significant suppression of bone-marrow parasites. The study shows that entrapment of paromomycin in NIV can be used to increase its antileishmanial activity in-vitro and in-vivo.

Efficacies of Vesicular and Free Sodium Stibogluconate Formulations against Clinical Isolates of Leishmania donovani

“…Studies are under way to The results of this study showed that the SSG-NIV was more effective than free SSG both in vitro and in vivo. In vitro studies showed that PBS-NIV did have antileishmanial properties, which confirms results of previous studies (21). However, treatment with PBS-NIV did not significantly suppress parasite burdens in vivo, a finding which was obtained in previous studies (22).…”

Combination Therapy with Paromomycin-Associated Stearylamine-Bearing Liposomes Cures Experimental Visceral Leishmaniasis through Th1-Biased Immunomodulation

“…Williams et al (47) strated parasite clearance only from the liver of L. donovaniinfected mice, with single-or double-dose treatment with nonionic-surfactant vesicular formulations of PM (47). Recently, liposomal formulations of PM were used as a topical treatment against CL to show the enhanced skin permeation and retention capacity of PM (10,24).…”

“…Unentrapped drug was washed with PBS through ultracentrifugation at 1,00,000 ϫ g for 1 h. PC-SA (22 mg) with entrapped PM was finally resuspended in PBS. The entrapped PM concentration was determined by an agar diffusion inhibition assay of the growth of Staphylococcus aureus (ATCC 6571) on sensitivity test agar as described previously (47). A straight-line relationship was obtained between PM concentration and zone of inhibition (mm).…”

The In Vivo Susceptibility of Leishmania donovani to Sodium Stibogluconate Is Drug Specific and Can Be Reversed by Inhibiting Glutathione Biosynthesis

“…Mice treated intravenously were dosed on day 7 with one of the following: PBS (controls), paromomycin (20 mg/kg), SSG solution (300 mg of Sb v /kg), AMB deoxycholate (Fungizone; 0.375 mg of AMB/kg), or liposomal AMB (AmBisome; 8 mg of AMB/kg). A dose of 20 mg of paromomycin/kg was chosen, since previous studies have shown that this dose causes 50% suppression of liver L. donovani parasite burdens (29). AmBisome and Fungizone were prepared in accordance with the manufacturer's instructions and were diluted prior to use with 5% dextrose to give a final AMB concentration of 1 mg/ml.…”