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Association of liposome-encapsulated trivalent antimonial with ascorbic acid: an effective and safe strategy in the treatment of experimental visceral leishmaniasis.

Castro RA, Silva-Barcellos NM, Licio CS, Souza JB, Souza-Testasicca MC, Ferreira FM, Batista MA, Silveira-Lemos D, Moura SL, Frézard F, Rezende SA - PLoS ONE (2014)

Bottom Line: Considering the lack of an effective vaccine the afflicted population must rely on both, an accurate diagnosis and successful treatment to combat the disease.Treatment with liposome-encapsulated SbIII significantly reduced the parasite burden in the liver, spleen and bone marrow.Of particular importance, reduction of parasite burden in the bone marrow attested to the ability of SbIII-carrying liposomes to efficiently reach this body compartment.

View Article: PubMed Central - PubMed

Affiliation: Programa de Pós-Graduação em Ciências Farmacêuticas - Cipharma, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brasil.

ABSTRACT

Background: Visceral leishmaniasis (VL) is a chronic debilitating disease endemic in tropical and subtropical areas, caused by protozoan parasites of the genus Leishmania. Annually, it is estimated the occurrence of 0.2 to 0.4 million new cases of the disease worldwide. Considering the lack of an effective vaccine the afflicted population must rely on both, an accurate diagnosis and successful treatment to combat the disease. Here we propose to evaluate the efficacy of trivalent antimonial encapsulated in conventional liposomes, in association with ascorbic acid, by monitoring its toxicity and efficacy in BALB/c mice infected with Leishmania infantum.

Methodology/principal findings: Infected mice were subjected to single-dose treatments consisting in the administration of either free or liposome-encapsulated trivalent antimony (SbIII), in association or not with ascorbic acid. Parasite burden was assessed in the liver, spleen and bone marrow using the serial limiting dilution technique. After treatment, tissue alterations were examined by histopathology of liver, heart and kidney and confirmed by serum levels of classic biomarkers. The phenotypic profile of splenocytes was also investigated by flow cytometry. Treatment with liposome-encapsulated SbIII significantly reduced the parasite burden in the liver, spleen and bone marrow. Co-administration of ascorbic acid, with either free SbIII or its liposomal form, did not interfere with its leishmanicidal activity and promoted reduced toxicity particularly to the kidney and liver tissues.

Conclusions/significance: Among the evaluated posological regimens treatment of L. infantum-infected mice with liposomal SbIII, in association with ascorbic acid, represented the best alternative as judged by its high leishmanicidal activity and absence of detectable toxic effects. Of particular importance, reduction of parasite burden in the bone marrow attested to the ability of SbIII-carrying liposomes to efficiently reach this body compartment.

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Parasite burden associated to different organs from L. infantum infected mice submitted to treatment regimens.(A) Liver, (B) Spleen and (C) Bone marrow. (PBS) phosphate-buffered saline, (Sb) trivalent antimony, (Empty Lipo) empty liposomes, (Sb Lipo) antimony entrapped liposomes, (AA) ascorbic acid, (AA+Sb) ascorbic acid in association with antimony, (AA+Sb Lipo) ascorbic acid in association with antimony entrapped liposomes. Parasite burden is expressed as log10 (number of parasites) +1 for each individual organ (n = 4, per experimental group) and represented as median ± interquartile range of two independent experiments. Statistically significant differences were assumed when p<0,05 in relation to (a) PBS; (b) Sb; (c) Empty Lipo; (d) Sb Lipo; (e) AA and (f) AA+Sb.
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pone-0104055-g002: Parasite burden associated to different organs from L. infantum infected mice submitted to treatment regimens.(A) Liver, (B) Spleen and (C) Bone marrow. (PBS) phosphate-buffered saline, (Sb) trivalent antimony, (Empty Lipo) empty liposomes, (Sb Lipo) antimony entrapped liposomes, (AA) ascorbic acid, (AA+Sb) ascorbic acid in association with antimony, (AA+Sb Lipo) ascorbic acid in association with antimony entrapped liposomes. Parasite burden is expressed as log10 (number of parasites) +1 for each individual organ (n = 4, per experimental group) and represented as median ± interquartile range of two independent experiments. Statistically significant differences were assumed when p<0,05 in relation to (a) PBS; (b) Sb; (c) Empty Lipo; (d) Sb Lipo; (e) AA and (f) AA+Sb.

Mentions: On the 14th day following the administration of the different treatment regimens, parasite quantification in the liver, spleen and bone marrow revealed reduction in parasitism only for animals treated with SbIII entrapped in liposomes. Characterization of such liposomes showed median size of 222.5 nm, 0.214 polydispersion index and 15% encapsulation efficiency for a preparation containing 4 mg SbIII/mL. Administration of the SbIII liposomal formulation, as a single dose, resulted in 47%, 33% and 47% reduction in parasite burden associated with the liver, spleen and bone marrow, respectively (Figure 2). Parallel administration of ascorbic acid with either free SbIII or SbIII entrapped in liposomes did not alter the parasite burden for the investigated organs. At the employed dose, reductions in parasite levels following treatment with free SbIII were not observed.


Association of liposome-encapsulated trivalent antimonial with ascorbic acid: an effective and safe strategy in the treatment of experimental visceral leishmaniasis.

Castro RA, Silva-Barcellos NM, Licio CS, Souza JB, Souza-Testasicca MC, Ferreira FM, Batista MA, Silveira-Lemos D, Moura SL, Frézard F, Rezende SA - PLoS ONE (2014)

Parasite burden associated to different organs from L. infantum infected mice submitted to treatment regimens.(A) Liver, (B) Spleen and (C) Bone marrow. (PBS) phosphate-buffered saline, (Sb) trivalent antimony, (Empty Lipo) empty liposomes, (Sb Lipo) antimony entrapped liposomes, (AA) ascorbic acid, (AA+Sb) ascorbic acid in association with antimony, (AA+Sb Lipo) ascorbic acid in association with antimony entrapped liposomes. Parasite burden is expressed as log10 (number of parasites) +1 for each individual organ (n = 4, per experimental group) and represented as median ± interquartile range of two independent experiments. Statistically significant differences were assumed when p<0,05 in relation to (a) PBS; (b) Sb; (c) Empty Lipo; (d) Sb Lipo; (e) AA and (f) AA+Sb.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4126701&req=5

pone-0104055-g002: Parasite burden associated to different organs from L. infantum infected mice submitted to treatment regimens.(A) Liver, (B) Spleen and (C) Bone marrow. (PBS) phosphate-buffered saline, (Sb) trivalent antimony, (Empty Lipo) empty liposomes, (Sb Lipo) antimony entrapped liposomes, (AA) ascorbic acid, (AA+Sb) ascorbic acid in association with antimony, (AA+Sb Lipo) ascorbic acid in association with antimony entrapped liposomes. Parasite burden is expressed as log10 (number of parasites) +1 for each individual organ (n = 4, per experimental group) and represented as median ± interquartile range of two independent experiments. Statistically significant differences were assumed when p<0,05 in relation to (a) PBS; (b) Sb; (c) Empty Lipo; (d) Sb Lipo; (e) AA and (f) AA+Sb.
Mentions: On the 14th day following the administration of the different treatment regimens, parasite quantification in the liver, spleen and bone marrow revealed reduction in parasitism only for animals treated with SbIII entrapped in liposomes. Characterization of such liposomes showed median size of 222.5 nm, 0.214 polydispersion index and 15% encapsulation efficiency for a preparation containing 4 mg SbIII/mL. Administration of the SbIII liposomal formulation, as a single dose, resulted in 47%, 33% and 47% reduction in parasite burden associated with the liver, spleen and bone marrow, respectively (Figure 2). Parallel administration of ascorbic acid with either free SbIII or SbIII entrapped in liposomes did not alter the parasite burden for the investigated organs. At the employed dose, reductions in parasite levels following treatment with free SbIII were not observed.

Bottom Line: Considering the lack of an effective vaccine the afflicted population must rely on both, an accurate diagnosis and successful treatment to combat the disease.Treatment with liposome-encapsulated SbIII significantly reduced the parasite burden in the liver, spleen and bone marrow.Of particular importance, reduction of parasite burden in the bone marrow attested to the ability of SbIII-carrying liposomes to efficiently reach this body compartment.

View Article: PubMed Central - PubMed

Affiliation: Programa de Pós-Graduação em Ciências Farmacêuticas - Cipharma, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brasil.

ABSTRACT

Background: Visceral leishmaniasis (VL) is a chronic debilitating disease endemic in tropical and subtropical areas, caused by protozoan parasites of the genus Leishmania. Annually, it is estimated the occurrence of 0.2 to 0.4 million new cases of the disease worldwide. Considering the lack of an effective vaccine the afflicted population must rely on both, an accurate diagnosis and successful treatment to combat the disease. Here we propose to evaluate the efficacy of trivalent antimonial encapsulated in conventional liposomes, in association with ascorbic acid, by monitoring its toxicity and efficacy in BALB/c mice infected with Leishmania infantum.

Methodology/principal findings: Infected mice were subjected to single-dose treatments consisting in the administration of either free or liposome-encapsulated trivalent antimony (SbIII), in association or not with ascorbic acid. Parasite burden was assessed in the liver, spleen and bone marrow using the serial limiting dilution technique. After treatment, tissue alterations were examined by histopathology of liver, heart and kidney and confirmed by serum levels of classic biomarkers. The phenotypic profile of splenocytes was also investigated by flow cytometry. Treatment with liposome-encapsulated SbIII significantly reduced the parasite burden in the liver, spleen and bone marrow. Co-administration of ascorbic acid, with either free SbIII or its liposomal form, did not interfere with its leishmanicidal activity and promoted reduced toxicity particularly to the kidney and liver tissues.

Conclusions/significance: Among the evaluated posological regimens treatment of L. infantum-infected mice with liposomal SbIII, in association with ascorbic acid, represented the best alternative as judged by its high leishmanicidal activity and absence of detectable toxic effects. Of particular importance, reduction of parasite burden in the bone marrow attested to the ability of SbIII-carrying liposomes to efficiently reach this body compartment.

Show MeSH
Related in: MedlinePlus