Dogs are the primary urban reservoir of Leishmania infantum and play a crucial role in the transm... more Dogs are the primary urban reservoir of Leishmania infantum and play a crucial role in the transmission of this parasite to man via sandflies. The spleen and liver are the main target organs of L. infantum infection, but few studies have evaluated the immune response to this infection in the canine liver. To identify the immunological mediators involved in resistance and/or susceptibility to canine visceral leishmaniosis (CVL), we selected 21 dogs naturally infected by L. infantum and classified as asymptomatic or symptomatic. Immunological parameters were analysed and correlations with clinical signs were determined. Symptomatic dogs showed higher numbers of parasites and less leucocyte infiltration in the liver compared with asymptomatic dogs. The progression of this disease was characterized not only by the down regulation of T helper (Th) 1-related cytokines, such as interferon (IFN)-γ and tumour necrosis factor (TNF)-α, but also by the down regulation of genes encoding interleukin (IL)-17A, inducible nitric oxide synthase (iNOS) and IL-10 in the spleen and liver in symptomatic dogs compared with asymptomatic dogs. Importantly, IL-17A gene transcription level was positively correlated with mRNA expression for iNOS and IFN-γ. Th1- and Th17-related cytokines therefore appear to play a role in restricting parasite growth via iNOS activation and decrease susceptibility of dogs to CVL.
We investigated the in vitro activity and selectivity and in vivo efficacy of ravuconazole (RAV) ... more We investigated the in vitro activity and selectivity and in vivo efficacy of ravuconazole (RAV) in self-nanoemulsifying delivery system (SNEDDS) against Trypanosoma cruzi. Novel formulations of this poorly soluble C14-α-demethylase inhibitor may improve its efficacy in the experimental treatment. In vitro activity was determined in infected cardiomyocytes and efficacy in vivo evaluated in terms of parasitological cure induced in Y and Colombian strains of T. cruzi-infected mice. In vitro RAV-SNEDDS exhibited significantly higher potency of 1.9-fold at the IC50 level and 2-fold at IC90 level than free-RAV. No difference in activity with Colombian strain was observed. Oral treatment with a daily dose of 20 mg/kg for 30 days resulted in 70% of cure for RAV-SNEDDS versus 40% for free RAV and 50% for 100 mg/kg benznidazole in acute infection. Long-term treatment efficacy (40 days) was able to cure 100% of animals with both RAV preparations. Longer treatment time was also efficient to increase the cure rate with benznidazole. RAV-SNEDDS shows greater efficacy in a shorter time treatment regimen, it is safe and could be a promising formulation to be evaluated in other pre-clinical models to treat T. cruzi and fungi infections.
Mining existing agents that enhance the therapeutic potential of ergosterol biosynthesis inhibito... more Mining existing agents that enhance the therapeutic potential of ergosterol biosynthesis inhibitors (EBI) is a promising approach to improve Chagas disease chemotherapy. In this study, we evaluated the effect of ravuconazole, an EBI, combined with amlodipine, a calcium channel blocker, upon Trypanosoma cruzi experimental infection. In vitro assays confirmed the trypanocidal activity of both compounds in monotherapy and demonstrated an additive effect (sum of the fractional inhibitory concentration [ΣFIC] > 0.
In a previous work, an oleogel with cholesterol 3.5 wt% and mineral oil (Ch-LP) and another one o... more In a previous work, an oleogel with cholesterol 3.5 wt% and mineral oil (Ch-LP) and another one of sorbitan monostearate 19 wt% and sweet almond oil (SM-SAO) were obtained. In this work, the mechanical properties of the two oleogels were compared using textural and rheological measurements. The influence of the organogelator concentration on the texture of the gels was also evaluated. The texture parameters of the SM-SAO gel were nearly linearly dependent of the sorbitan monostearate concentration. In the Ch-LP gels, two regions were observed, as a linear relationship between cholesterol concentration and texture parameters was exhibited after a transition region. The SM-SAO gel presented higher hardness, higher adhesiveness and higher rigidity than the Ch-LP gel. From the rheological measurements, SM-SAO gel can be classified as "strong" gel, while the Ch-LP gel is a "weak"gel Further experimental results determined that the two oleogels were thermoreversible. T...
The benefits of mucoadhesive systems are related to the increased in situ residence and intimate ... more The benefits of mucoadhesive systems are related to the increased in situ residence and intimate contact of the delivery vehicle with the mucosa. The recent emergence of nanomedicine and the properties of nanoparticulate systems have created new challenges in understanding the nature and mechanisms of nanoscale mucoadhesion and in the development of methodologies for measuring its mucoadhesive potential. Even when usually regarded as an advantageous property, mucoadhesion can be an inconvenience for nanosystems, and strategies have been developed for minimizing interactions with the mucosal tissues/fluids. This article summarizes the basic concepts of mucoadhesion at the nanoscale, different techniques used for measuring the mucoadhesive potential of nanosystems and strategies for increasing/decreasing mucoadhesive interactions. The mucoadhesion behavior of materials in bulk and at the nanoscale can significantly differ. Advances in the methodology used for studying the mucoadhesion phenomenon have contributed to its better understanding and, more importantly, the development of strategies to increase/decrease mucoadhesion. However, development of new methodologies for studying mucoadhesion at the nanoscale and the refinement of existing methodologies are still required. Also, a substantial amount of information is still lacking, particularly related to formulation issues, on how to translate lessons learnt at the bench top to the bed side.
ABSTRACTWe performed a critical study of conventional serology, followed by supplementary serolog... more ABSTRACTWe performed a critical study of conventional serology, followed by supplementary serological, parasitological, and molecular tests, to assess the response to etiologic treatment of Chagas' disease. A group of 94 Chagas' disease patients treated with benznidazole at least 10 years earlier were evaluated from the laboratory and clinical points of view. When conventional serology (enzyme-linked immunosorbent assay [ELISA], indirect immunofluorescence [IIF], and indirect hemagglutination [IHA]) and classic criteria (consistent results with any two of the three tests) or more rigorous criteria (consistent results from the three tests) were used, 10.6% and 8.5% of patients were considered treated and cured (TC) by classic and rigorous criteria, respectively. Patients were then evaluated using supplementary (recombinant ELISA andTrypanosoma cruziexcreted-secreted antigen blotting [TESA-blot]), parasitological (hemoculture), and molecular (PCR) tests. The results of recombi...
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Dogs are the primary urban reservoir of Leishmania infantum and play a crucial role in the transm... more Dogs are the primary urban reservoir of Leishmania infantum and play a crucial role in the transmission of this parasite to man via sandflies. The spleen and liver are the main target organs of L. infantum infection, but few studies have evaluated the immune response to this infection in the canine liver. To identify the immunological mediators involved in resistance and/or susceptibility to canine visceral leishmaniosis (CVL), we selected 21 dogs naturally infected by L. infantum and classified as asymptomatic or symptomatic. Immunological parameters were analysed and correlations with clinical signs were determined. Symptomatic dogs showed higher numbers of parasites and less leucocyte infiltration in the liver compared with asymptomatic dogs. The progression of this disease was characterized not only by the down regulation of T helper (Th) 1-related cytokines, such as interferon (IFN)-γ and tumour necrosis factor (TNF)-α, but also by the down regulation of genes encoding interleukin (IL)-17A, inducible nitric oxide synthase (iNOS) and IL-10 in the spleen and liver in symptomatic dogs compared with asymptomatic dogs. Importantly, IL-17A gene transcription level was positively correlated with mRNA expression for iNOS and IFN-γ. Th1- and Th17-related cytokines therefore appear to play a role in restricting parasite growth via iNOS activation and decrease susceptibility of dogs to CVL.
We investigated the in vitro activity and selectivity and in vivo efficacy of ravuconazole (RAV) ... more We investigated the in vitro activity and selectivity and in vivo efficacy of ravuconazole (RAV) in self-nanoemulsifying delivery system (SNEDDS) against Trypanosoma cruzi. Novel formulations of this poorly soluble C14-α-demethylase inhibitor may improve its efficacy in the experimental treatment. In vitro activity was determined in infected cardiomyocytes and efficacy in vivo evaluated in terms of parasitological cure induced in Y and Colombian strains of T. cruzi-infected mice. In vitro RAV-SNEDDS exhibited significantly higher potency of 1.9-fold at the IC50 level and 2-fold at IC90 level than free-RAV. No difference in activity with Colombian strain was observed. Oral treatment with a daily dose of 20 mg/kg for 30 days resulted in 70% of cure for RAV-SNEDDS versus 40% for free RAV and 50% for 100 mg/kg benznidazole in acute infection. Long-term treatment efficacy (40 days) was able to cure 100% of animals with both RAV preparations. Longer treatment time was also efficient to increase the cure rate with benznidazole. RAV-SNEDDS shows greater efficacy in a shorter time treatment regimen, it is safe and could be a promising formulation to be evaluated in other pre-clinical models to treat T. cruzi and fungi infections.
Mining existing agents that enhance the therapeutic potential of ergosterol biosynthesis inhibito... more Mining existing agents that enhance the therapeutic potential of ergosterol biosynthesis inhibitors (EBI) is a promising approach to improve Chagas disease chemotherapy. In this study, we evaluated the effect of ravuconazole, an EBI, combined with amlodipine, a calcium channel blocker, upon Trypanosoma cruzi experimental infection. In vitro assays confirmed the trypanocidal activity of both compounds in monotherapy and demonstrated an additive effect (sum of the fractional inhibitory concentration [ΣFIC] > 0.
In a previous work, an oleogel with cholesterol 3.5 wt% and mineral oil (Ch-LP) and another one o... more In a previous work, an oleogel with cholesterol 3.5 wt% and mineral oil (Ch-LP) and another one of sorbitan monostearate 19 wt% and sweet almond oil (SM-SAO) were obtained. In this work, the mechanical properties of the two oleogels were compared using textural and rheological measurements. The influence of the organogelator concentration on the texture of the gels was also evaluated. The texture parameters of the SM-SAO gel were nearly linearly dependent of the sorbitan monostearate concentration. In the Ch-LP gels, two regions were observed, as a linear relationship between cholesterol concentration and texture parameters was exhibited after a transition region. The SM-SAO gel presented higher hardness, higher adhesiveness and higher rigidity than the Ch-LP gel. From the rheological measurements, SM-SAO gel can be classified as "strong" gel, while the Ch-LP gel is a "weak"gel Further experimental results determined that the two oleogels were thermoreversible. T...
The benefits of mucoadhesive systems are related to the increased in situ residence and intimate ... more The benefits of mucoadhesive systems are related to the increased in situ residence and intimate contact of the delivery vehicle with the mucosa. The recent emergence of nanomedicine and the properties of nanoparticulate systems have created new challenges in understanding the nature and mechanisms of nanoscale mucoadhesion and in the development of methodologies for measuring its mucoadhesive potential. Even when usually regarded as an advantageous property, mucoadhesion can be an inconvenience for nanosystems, and strategies have been developed for minimizing interactions with the mucosal tissues/fluids. This article summarizes the basic concepts of mucoadhesion at the nanoscale, different techniques used for measuring the mucoadhesive potential of nanosystems and strategies for increasing/decreasing mucoadhesive interactions. The mucoadhesion behavior of materials in bulk and at the nanoscale can significantly differ. Advances in the methodology used for studying the mucoadhesion phenomenon have contributed to its better understanding and, more importantly, the development of strategies to increase/decrease mucoadhesion. However, development of new methodologies for studying mucoadhesion at the nanoscale and the refinement of existing methodologies are still required. Also, a substantial amount of information is still lacking, particularly related to formulation issues, on how to translate lessons learnt at the bench top to the bed side.
ABSTRACTWe performed a critical study of conventional serology, followed by supplementary serolog... more ABSTRACTWe performed a critical study of conventional serology, followed by supplementary serological, parasitological, and molecular tests, to assess the response to etiologic treatment of Chagas' disease. A group of 94 Chagas' disease patients treated with benznidazole at least 10 years earlier were evaluated from the laboratory and clinical points of view. When conventional serology (enzyme-linked immunosorbent assay [ELISA], indirect immunofluorescence [IIF], and indirect hemagglutination [IHA]) and classic criteria (consistent results with any two of the three tests) or more rigorous criteria (consistent results from the three tests) were used, 10.6% and 8.5% of patients were considered treated and cured (TC) by classic and rigorous criteria, respectively. Patients were then evaluated using supplementary (recombinant ELISA andTrypanosoma cruziexcreted-secreted antigen blotting [TESA-blot]), parasitological (hemoculture), and molecular (PCR) tests. The results of recombi...
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
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