ABSTRACT
BACKGROUND: Leishmaniasis is a neglected tropical disease caused by protozoa of the genus Leishmania. Current treatments are restricted to a small number of drugs that display both severe side effects and a potential for parasites to develop resistance. A new N-(3,4-methylenedioxyphenyl)-N'- (2-phenethyl) thiourea compound (thiourea 1) has shown promising in vitro activity against Leishmania amazonensis with an IC50 of 54.14 µM for promastigotes and an IC50 of 70 µM for amastigotes. OBJECTIVE: To develop a formulation of thiourea 1 as an oral treatment for leishmaniasis, it was incorporated into Nanoparticles (NPs), a proven approach to provide long-acting drug delivery systems. METHODS: Poly (D,L-Lactic-co-Glycolic Acid) (PLGA) polymeric NPs containing thiourea 1 were obtained through a nanoprecipitation methodology associated with solvent evaporation. The NPs containing thiourea 1 were characterized for Encapsulation Efficiency (EE%), reaction yield (% w/w), surface charge, particle size and morphology by Transmission Electron Microscopy (TEM). RESULTS: NPs with thiourea 1 showed an improved in vitro leishmanicidal activity with a reduction in its cytotoxicity against macrophages (CC50>100 µg/mL) while preserving its IC50 against intracellular amastigotes (1.46 ± 0.09 µg/mL). This represents a parasite Selectivity Index (SI) of 68.49, which is a marked advancement from the reference drug pentamidine (SI = 30.14). CONCLUSION: The results suggest that the incorporation into NPs potentiated the therapeutic effect of thiourea 1, most likely by improving the selective delivery of the drug to the phagocytic cells that are targeted for infection by L. amazonensis. This work reinforces the importance of nanotechnology in the acquisition of new therapeutic alternatives for oral treatments.
Subject(s)
Antiprotozoal Agents/administration & dosage , Drug Carriers/chemistry , Leishmania mexicana/drug effects , Leishmaniasis, Cutaneous/drug therapy , Thiourea/administration & dosage , Animals , Antiprotozoal Agents/pharmacokinetics , Antiprotozoal Agents/toxicity , Disease Models, Animal , Drug Liberation , Humans , Leishmaniasis, Cutaneous/parasitology , Macrophages/parasitology , Mice , Nanoparticles/chemistry , Parasitic Sensitivity Tests , Particle Size , Polylactic Acid-Polyglycolic Acid Copolymer/chemistry , Primary Cell Culture , Thiourea/analogs & derivatives , Thiourea/pharmacokinetics , Thiourea/toxicity , Toxicity Tests, AcuteABSTRACT
The neural histaminergic system innervates the cerebellum, with a high density of fibers in the vermis and flocculus. The cerebellum participates in motor functions, but the role of the histaminergic system in this function is unclear. In the present study, we investigated the effects of intracerebellar histamine injections and H1, H2 and H3 receptor antagonist injections (chlorpheniramine, ranitidine, and thioperamide, respectively) and H4 receptor agonist (VUF-8430) on locomotor and exploratory behaviors in mice. The cerebellar vermis of male mice was implanted with guide cannula. After three days of recovery,the animals received microinjections of saline or histamine (experiment1), saline or chlorpheniramine (experiment 2), saline or ranitidine(experiment 3), saline or thioperamide (experiment 4), and saline or VUF-8430 (experiment 5) in different concentrations. Five minutes postinjection,the open field test was performed. The data were analyzed using one-way ANOVA and Duncan's post hoc test. The microinjections of histamine, ranitidine or thioperamide did not lead any behavioral effects at the used doses. In contrast, animals that received chlorpheniramine at the highest dose (0.16 nmol) and VUF-8430 at the highest dose (1.48 nmol)were more active in the open field apparatus, with an increase in the number of crossed quadrants, number of rearings and time spent in the central area of the arena, suggesting that chlorpheniramine and VUF-8430 modulates locomotor and exploratory behaviors in mice.