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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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Related in: MedlinePlus

Histopathological analyses of the heart from L. infantum infected mice submitted to different treatment regimens.(A) Phosphate-buffered saline (PBS). (B) Empty liposomes (Empty Lipo). (C) Trivalent antimony (Sb). (D) Antimony entrapped liposomes (Sb Lipo). (E) Ascorbic acid (AA). (F) Ascorbic acid in association with antimony (AA+Sb). (G) Ascorbic acid in association with antimony entrapped liposomes (AA+Sb Lipo). Bar  = 50 µm. Insert  = 25 µm, representing an inflammatory infiltrate of lymphocytes (L) and macrophages (M). Dashed arrow  =  subendocardial inflammatory infiltrate composed of mononuclear cells. * Active hyperemia.
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pone-0104055-g005: Histopathological analyses of the heart from L. infantum infected mice submitted to different treatment regimens.(A) Phosphate-buffered saline (PBS). (B) Empty liposomes (Empty Lipo). (C) Trivalent antimony (Sb). (D) Antimony entrapped liposomes (Sb Lipo). (E) Ascorbic acid (AA). (F) Ascorbic acid in association with antimony (AA+Sb). (G) Ascorbic acid in association with antimony entrapped liposomes (AA+Sb Lipo). Bar  = 50 µm. Insert  = 25 µm, representing an inflammatory infiltrate of lymphocytes (L) and macrophages (M). Dashed arrow  =  subendocardial inflammatory infiltrate composed of mononuclear cells. * Active hyperemia.

Mentions: Analysis of the cardiac tissue revealed no architectural or cellular degeneration for any of the treatment groups. For infected animals treated with PBS, empty liposomes and ascorbic acid, a discrete and diffuse subendocardial inflammatory infiltrate, composed of mononuclear cells, was observed (Figure 5A, 5B and 5E, respectively). These tissue alterations were not detected for infected animals treated with free SbIII, liposome-entrapped SbIII, and the same treatments associated with ascorbic acid (Figure 5C, 5D, 5F and 5G). Notably, administration of SbIII, irrespective of its formulation, promotes an active hyperemia throughout the myocardium which was not reversed by co-administration of ascorbic acid (Figure 5C, 5D, 5F and 5G, asterisked areas).


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)

Histopathological analyses of the heart from L. infantum infected mice submitted to different treatment regimens.(A) Phosphate-buffered saline (PBS). (B) Empty liposomes (Empty Lipo). (C) Trivalent antimony (Sb). (D) Antimony entrapped liposomes (Sb Lipo). (E) Ascorbic acid (AA). (F) Ascorbic acid in association with antimony (AA+Sb). (G) Ascorbic acid in association with antimony entrapped liposomes (AA+Sb Lipo). Bar  = 50 µm. Insert  = 25 µm, representing an inflammatory infiltrate of lymphocytes (L) and macrophages (M). Dashed arrow  =  subendocardial inflammatory infiltrate composed of mononuclear cells. * Active hyperemia.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0104055-g005: Histopathological analyses of the heart from L. infantum infected mice submitted to different treatment regimens.(A) Phosphate-buffered saline (PBS). (B) Empty liposomes (Empty Lipo). (C) Trivalent antimony (Sb). (D) Antimony entrapped liposomes (Sb Lipo). (E) Ascorbic acid (AA). (F) Ascorbic acid in association with antimony (AA+Sb). (G) Ascorbic acid in association with antimony entrapped liposomes (AA+Sb Lipo). Bar  = 50 µm. Insert  = 25 µm, representing an inflammatory infiltrate of lymphocytes (L) and macrophages (M). Dashed arrow  =  subendocardial inflammatory infiltrate composed of mononuclear cells. * Active hyperemia.
Mentions: Analysis of the cardiac tissue revealed no architectural or cellular degeneration for any of the treatment groups. For infected animals treated with PBS, empty liposomes and ascorbic acid, a discrete and diffuse subendocardial inflammatory infiltrate, composed of mononuclear cells, was observed (Figure 5A, 5B and 5E, respectively). These tissue alterations were not detected for infected animals treated with free SbIII, liposome-entrapped SbIII, and the same treatments associated with ascorbic acid (Figure 5C, 5D, 5F and 5G). Notably, administration of SbIII, irrespective of its formulation, promotes an active hyperemia throughout the myocardium which was not reversed by co-administration of ascorbic acid (Figure 5C, 5D, 5F and 5G, asterisked areas).

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