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Frédéric Frézard - One of the best experts on this subject based on the ideXlab platform.
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mixed formulation of conventional and pegylated meglumine antimoniate containing liposomes reduces inflammatory process and parasite burden in leishmania infantum infected balb c mice
Antimicrobial Agents and Chemotherapy, 2017Co-Authors: Levi Eduardo Soares Reis, Frédéric Frézard, Rory Cristiane Fortes De Brito, Jamille Mirelle De Oliveira Cardoso, Fernando Augusto Siqueira Mathias, Rodrigo Dian De Oliveira Aguiar Soares, Claudia Martins Carneiro, Paula Melo De Abreu Vieira, Guilherme Santos Ramos, Bruno Mendes RoattAbstract:ABSTRACT Pentavalent Antimonial has been the first choice treatment for visceral leishmaniasis; however, it has several side effects that leads to low adherence to treatment. Liposome-encapsulated meglumine antimoniate (MA) arises as an important strategy for chemotherapy enhancement. We evaluated the immunopathological changes using the mixture of conventional and pegylated liposomes with MA. The mice were infected with Leishmania infantum and a single-dose treatment regimen. Comparison was made with groups treated with saline, empty liposomes, free MA, and a liposomal formulation of MA (Lipo MA). Histopathological analyses demonstrated that animals treated with Lipo MA showed a significant decrease in the inflammatory process and the absence of granulomas. The in vitro stimulation of splenocytes showed a significant increase of gamma interferon (IFN-γ) produced by CD8 + T cells and a decrease in interleukin-10 (IL-10) produced by CD4 + and CD8 + T cells in the Lipo MA. Furthermore, the Lipo MA group showed an increase in the IFN-γ/IL-10 ratio in both CD4 + and CD8 + T cell subsets. According to the parasite load evaluation using quantitative PCR, the Lipo MA group showed no L. infantum DNA in the spleen (0.0%) and 41.4% in the liver. In addition, we detected a low positive correlation between parasitism and histopathology findings (inflammatory process and granuloma formation). Thus, our results confirmed that Lipo MA is a promising antileishmanial formulation able to reduce the inflammatory response and induce a type 1 immune response, accompanied by a significant reduction of the parasite burden into hepatic and splenic compartments in treated animals.
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mixed antimony v complexes with different sugars to modulate the oral bioavailability of Pentavalent Antimonial drugs
Molecules, 2014Co-Authors: Weverson A Ferreira, Frédéric Frézard, Arshad Islam, Aretha P S Andrade, Flaviana R Fernandes, Cynthia DemicheliAbstract:Previous studies have shown that the association of the drug meglumine antimoniate (MA) with β-cyclodextrin can improve its bioavailability by the oral route. In this work, ribose and maltose were investigated for their ability to form mixed or association complexes with MA, release MA and modulate the serum levels of Sb after oral administration in mice. Analysis of the MA/ribose composition by high performance liquid chromatography coupled to mass spectrometry (LCMS-IT-TOF) revealed the presence of mixed meglumine-Sb-ribose and Sb-ribose complexes. Analysis of the MA/maltose composition suggested the formation of MA-maltose association compounds. Circular dichroism characterization of these compositions following dilution in water at 37 °C suggested a partial and slow dissociation of the association compounds. When the MA/ribose composition was administered orally and compared to MA, the serum concentration of Sb was significantly lower after 1 h and greater after 3 h. On the other hand, the MA/maltose composition showed similar serum Sb concentration after 1 h and higher level of Sb after 3 h, when compared to MA. In conclusion, the present study has demonstrated the formation of mixed or association complexes of MA with sugars, such as maltose and ribose, which promoted sustained serum level of Sb after oral administration.
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Hepatotoxicity of Pentavalent Antimonial Drug: Possible Role of Residual Sb(III) and Protective Effect of Ascorbic Acid
Antimicrobial agents and chemotherapy, 2013Co-Authors: Kelly Cristina Kato, Cynthia Demicheli, Eliane De Morais-teixeira, Priscila G. Reis, Neila M. Silva-barcellos, Pascal Salaün, Paula Peixoto Campos, José D. Corrêa-junior, Ana Rabello, Frédéric FrézardAbstract:Pentavalent Antimonial drugs such as meglumine antimoniate (Glucantime [Glu; Sanofi-Aventis, Sao Paulo, Brazil]) produce severe side effects, including cardiotoxicity and hepatotoxicity, during the treatment of leishmaniasis. We evaluated the role of residual Sb(III) in the hepatotoxicity of meglumine antimoniate, as well as the protective effect of the antioxidant ascorbic acid (AA) during Antimonial chemotherapy in a murine model of visceral leishmaniasis. BALB/c mice infected with Leishmania infantum were treated intraperitoneally at 80 mg of Sb/kg/day with commercial meglumine antimoniate (Glu) or a synthetic meglumine antimoniate with lower Sb(III) level (MA), in association or not with AA (15 mg/kg/day), for a 20-day period. Control groups received saline or saline plus AA. Livers were evaluated for hepatocytes histological alterations, peroxidase activity, and apoptosis. Increased proportions of swollen and apoptotic hepatocytes were observed in animals treated with Glu compared to animals treated with saline or MA. The peroxidase activity was also enhanced in the liver of animals that received Glu. Cotreatment with AA reduced the extent of histological changes, the apoptotic index, and the peroxidase activity to levels corresponding to the control group. Moreover, the association with AA did not affect the hepatic uptake of Sb and the ability of Glu to reduce the liver and spleen parasite loads in infected mice. In conclusion, our data supports the use of Pentavalent Antimonials with low residue of Sb(III) and the association of Pentavalent Antimonials with AA, as effective strategies to reduce side effects in Antimonial therapy.
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unexpectedly high levels of antimony iii in the Pentavalent Antimonial drug glucantime insights from a new voltammetric approach
Analytical and Bioanalytical Chemistry, 2013Co-Authors: Pascal Salaün, Frédéric FrézardAbstract:Glucantime, a Pentavalent Antimonial drug, is commonly used for the treatment of leishmaniasis but the presence of residual trivalent antimony, Sb(III), is thought to be responsible for toxic side-effects observed in patients. Numerous analytical studies have focused on determining Sb(III) concentrations in Glucantime but without reaching a consensus: results span over 3 orders of magnitude. In this study, we present a detailed new analytical approach showing that: (1) Sb(III) levels are much higher than previously reported and represent more than 30 % of total Sb; (2) determination of Sb(III) concentrations in acidic conditions is hampered by fast oxidation rates. This latter point explains the large variations in previously reported results of Sb(III) concentrations in Glucantime. Measurements were made here at a vibrated gold microwire electrode by stripping voltammetry enabling measurement of Sb(III) in acidic, neutral or alkaline conditions. The developed methods are sensitive (e.g., detection limits of 19 pM for 120 s deposition at pH 4.5), stable (<6 %, N = 100), precise (5 %, N = 5) and robust (same electrode used for weeks) at all pH values. In diluted solutions of Glucantime, Sb(III) levels were strongly dependent both on pH and ionic strength. At pH < 3, Sb(III) is oxidized with oxidation rates that increase as pH is decreased. At high pH, Sb(III) forms electro-inactive complexes. Highest Sb(III) levels were detected at pH ∼3 and at low ionic strength. The presence of several Sb(III) and Sb(V) species was demonstrated by different reduction waves obtained by stripping scanned voltammetry. As an implication of these unexpectedly high Sb(III) concentrations, an alternative model can be proposed for the mode of action of Pentavalent Antimonials against leishmaniasis, in which antimony complexes may act as molecular carrier of Sb(III) and release it specifically in the acidic intracellular compartment where the Leishmania parasites reside.
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New delivery strategies for the old Pentavalent Antimonial drugs.
Expert opinion on drug delivery, 2010Co-Authors: Frédéric Frézard, Cynthia DemicheliAbstract:Importance of the field: Pentavalent Antimonials are the first-line drugs for treatment of the major tropical disease leishmaniasis. However, their use is limited by the need for daily parenteral administration, their severe side effects and treatment failures. As leishmaniasis belongs to the group of neglected diseases, the improvement of old drugs through new delivery approaches has more support than the development of new chemical entities. Areas covered in this review: The review covers, from 1977 to the present, the progress achieved towards pharmaceutically acceptable liposome-based formulations of Antimonials, identification of specific ligands for improved targeting of infected macrophages and new approaches for oral and topical delivery of Antimonial drugs. What the reader will gain: Insights into the most promising delivery strategies to improve Antimonial therapy and the chemical basis and future directions for achieving innovative orally and topically effective formulations. Take home message:...
Cynthia Demicheli - One of the best experts on this subject based on the ideXlab platform.
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mixed antimony v complexes with different sugars to modulate the oral bioavailability of Pentavalent Antimonial drugs
Molecules, 2014Co-Authors: Weverson A Ferreira, Frédéric Frézard, Arshad Islam, Aretha P S Andrade, Flaviana R Fernandes, Cynthia DemicheliAbstract:Previous studies have shown that the association of the drug meglumine antimoniate (MA) with β-cyclodextrin can improve its bioavailability by the oral route. In this work, ribose and maltose were investigated for their ability to form mixed or association complexes with MA, release MA and modulate the serum levels of Sb after oral administration in mice. Analysis of the MA/ribose composition by high performance liquid chromatography coupled to mass spectrometry (LCMS-IT-TOF) revealed the presence of mixed meglumine-Sb-ribose and Sb-ribose complexes. Analysis of the MA/maltose composition suggested the formation of MA-maltose association compounds. Circular dichroism characterization of these compositions following dilution in water at 37 °C suggested a partial and slow dissociation of the association compounds. When the MA/ribose composition was administered orally and compared to MA, the serum concentration of Sb was significantly lower after 1 h and greater after 3 h. On the other hand, the MA/maltose composition showed similar serum Sb concentration after 1 h and higher level of Sb after 3 h, when compared to MA. In conclusion, the present study has demonstrated the formation of mixed or association complexes of MA with sugars, such as maltose and ribose, which promoted sustained serum level of Sb after oral administration.
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Hepatotoxicity of Pentavalent Antimonial Drug: Possible Role of Residual Sb(III) and Protective Effect of Ascorbic Acid
Antimicrobial agents and chemotherapy, 2013Co-Authors: Kelly Cristina Kato, Cynthia Demicheli, Eliane De Morais-teixeira, Priscila G. Reis, Neila M. Silva-barcellos, Pascal Salaün, Paula Peixoto Campos, José D. Corrêa-junior, Ana Rabello, Frédéric FrézardAbstract:Pentavalent Antimonial drugs such as meglumine antimoniate (Glucantime [Glu; Sanofi-Aventis, Sao Paulo, Brazil]) produce severe side effects, including cardiotoxicity and hepatotoxicity, during the treatment of leishmaniasis. We evaluated the role of residual Sb(III) in the hepatotoxicity of meglumine antimoniate, as well as the protective effect of the antioxidant ascorbic acid (AA) during Antimonial chemotherapy in a murine model of visceral leishmaniasis. BALB/c mice infected with Leishmania infantum were treated intraperitoneally at 80 mg of Sb/kg/day with commercial meglumine antimoniate (Glu) or a synthetic meglumine antimoniate with lower Sb(III) level (MA), in association or not with AA (15 mg/kg/day), for a 20-day period. Control groups received saline or saline plus AA. Livers were evaluated for hepatocytes histological alterations, peroxidase activity, and apoptosis. Increased proportions of swollen and apoptotic hepatocytes were observed in animals treated with Glu compared to animals treated with saline or MA. The peroxidase activity was also enhanced in the liver of animals that received Glu. Cotreatment with AA reduced the extent of histological changes, the apoptotic index, and the peroxidase activity to levels corresponding to the control group. Moreover, the association with AA did not affect the hepatic uptake of Sb and the ability of Glu to reduce the liver and spleen parasite loads in infected mice. In conclusion, our data supports the use of Pentavalent Antimonials with low residue of Sb(III) and the association of Pentavalent Antimonials with AA, as effective strategies to reduce side effects in Antimonial therapy.
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New delivery strategies for the old Pentavalent Antimonial drugs.
Expert opinion on drug delivery, 2010Co-Authors: Frédéric Frézard, Cynthia DemicheliAbstract:Importance of the field: Pentavalent Antimonials are the first-line drugs for treatment of the major tropical disease leishmaniasis. However, their use is limited by the need for daily parenteral administration, their severe side effects and treatment failures. As leishmaniasis belongs to the group of neglected diseases, the improvement of old drugs through new delivery approaches has more support than the development of new chemical entities. Areas covered in this review: The review covers, from 1977 to the present, the progress achieved towards pharmaceutically acceptable liposome-based formulations of Antimonials, identification of specific ligands for improved targeting of infected macrophages and new approaches for oral and topical delivery of Antimonial drugs. What the reader will gain: Insights into the most promising delivery strategies to improve Antimonial therapy and the chemical basis and future directions for achieving innovative orally and topically effective formulations. Take home message:...
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new insights into the chemical structure and composition of the Pentavalent Antimonial drugs meglumine antimonate and sodium stibogluconate
Journal of Inorganic Biochemistry, 2008Co-Authors: Frédéric Frézard, Adriano Monteiro De Castro Pimenta, Patricia S Martins, Millen C M Barbosa, Weverson A Ferreira, Juliane E De Melo, John B Mangrum, Cynthia DemicheliAbstract:The chemical structures of the Pentavalent Antimonial drugs, meglumine antimonate (MA) and sodium stibogluconate (SSG), were re-evaluated using electrospray ionization mass spectrometry (ESI-MS) and osmolarity measurements. Both MA and SSG were found to contain 1:1, 1:2, 2:2 and 2:3 Sb(V)-ligand complexes. ESI-MS analysis of MA showed negatively-charged 1:1 (m/z 364) and 2:2 (m/z 765) Sb(V)-meglumine complexes, supporting the predominance of zwitterionic species in solution. Our data are consistent with a structure for the 1:2 Sb(V)-meglumine, which differs from that previously postulated, with two positively-charged amino groups and one negatively-charged antimonate group. Instead of the commonly hypothesized structure for SSG, in which two Sb atoms are linked by an oxygen, an alternative structure is proposed, based on the ability of Sb(V)-gluconate complexes to polymerize. MA (or SSG) in concentrated aqueous solutions, such as of MA (or SSG) in its commercial form, is expected to consist mainly of a mixture of 2:2, 2:3 and 2:1 Sb(V)-ligand complexes, as suggested by the 2:1 Sb-to-particle ratio found by osmometry. 1:1 Sb(V)-ligand complexes in MA and SSG are expected to play an important pharmacological role, as suggested by the slow increase of osmolarity of MA solution upon dilution at 37 degrees C (half-time of 20min).
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kinetics of antimony v reduction by l cysteine pharmacological implications and application to the determination of antimony in Pentavalent Antimonial drugs
Journal of the Brazilian Chemical Society, 2006Co-Authors: Fernanda B. De Oliveira, Claudio S Ferreira, Frédéric Frézard, Dante A Schettini, Breno Rates, Olguita G F Rocha, Cynthia DemicheliAbstract:Since antimony is the active species in the antileishmanial drug meglumine antimoniate (MA), the knowledge of the exact metal concentration is critical for its experimental and clinical use. On the other hand, the involvement of thiols, such as cysteine (Cys), in the metabolism of this drug remains to be clarified. In the present work, the reduction reaction of SbV by Cys was kinetically characterized. The reaction orders with respect to Sb and Cys were equal to 1.0 and 3.3, respectively. The rate constant for the reduction reaction was pH-dependent. This reaction was exploited to effectively reduce SbV in MA, for the subsequent photometric determination of SbIII using the chromogen bromopyrogallol red. Reduction efficiencies of 100% were achieved at pH 3. Solutions with Sb concentration as low as 0.5 mmol L-1 were successfully assayed. The method was also applied to the determination of Sb in liposomal formulations of MA.
Eli Schwartz - One of the best experts on this subject based on the ideXlab platform.
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liposomal amphotericin b in comparison to sodium stibogluconate for leishmania braziliensis cutaneous leishmaniasis in travelers
Journal of The American Academy of Dermatology, 2013Co-Authors: Michal Solomon, Aviv Barzilai, Felix Pavlotzky, Eli SchwartzAbstract:Background New World cutaneous leishmaniasis is mostly acquired in the Amazon Basin of Bolivia where L viannia (V) braziliensis is endemic. Treatment with systemic Pentavalent Antimonial compounds has been shown to be effective in achieving clinical cure in only 75% of cases. Objective We sought to assess the efficacy and safety of liposomal amphotericin B (L-AmB) treatment for primary infection of cutaneous L (V) braziliensis. Methods A prospective observational evaluation was performed for cutaneous leishmaniasis due to L (V) braziliensis which was treated with L-AmB, 3 mg/kg, for 5 consecutive days, and a sixth dose on day 10. This therapy regimen was compared with the treatment regimen of sodium stibogluconate (SSG) 20 mg/kg for 3 weeks. Results Our study was divided into two groups; 34 patients received L-AmB and 34 received SSG treatment. Almost all patients were infected in Bolivia. In the L-AmB group, 29 patients (85%) had complete cure compared with 70% in the SSG group ( P = not significant), 4 other patients were slow healers, and only one patient needed additional treatment with SSG. No relapses were seen during a mean 29-month follow-up period. Failure rate was 3% in the L-AmB versus 29% in the SSG group ( P = .006). Treatment was interrupted in 65% of patients taking SSG because of adverse events, whereas all patients receiving L-AmB completed treatment. Limitations This was a non-blinded comparative study. Conclusions Comparison of L-Amb to SSG treatment for L (V) braziliensis shows that the former is effective, better tolerated, and more cost effective. L-AmB should therefore be considered as the first-line treatment option for cutaneous L (V) braziliensis infection.
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liposomal amphotericin b in comparison to sodium stibogluconate for cutaneous infection due to leishmania braziliensis
Journal of The American Academy of Dermatology, 2007Co-Authors: Michal Solomon, Sharon Baum, Aviv Barzilai, Alon Scope, Henry Trau, Eli SchwartzAbstract:Background New World cutaneous leishmaniasis among Israeli travelers is mostly acquired in the Amazon Basin of Bolivia where Leishmania viannia (V.) braziliensis is endemic. Treatment with systemic Pentavalent Antimonial compounds is effective in achieving clinical cure in only 75% of cases. In this study, we assessed liposomal amphotericin B (AmBisome) as an alternative treatment for cutaneous L (V.) braziliensis infection. Methods A prospective evaluation was performed for cutaneous leishmaniasis due to L (V.) braziliensis , proven by polymerase chain reaction. A 3-mg/kg AmBisome dose was given for 5 consecutive days, and a sixth dose on day 10, all in an outpatient setting. This therapy was compared with a series of historical patients who were treated with sodium stibogluconate (SSG). Results Seven consecutive patients, 5 males and 2 females, received AmBisome treatment. All were returned travelers infected in Bolivia; their mean age was 23.1 years; 5 had failed to respond to a full course of SSG; two had a primary lesion; none had mucosal lesions. All achieved complete clinical cure within less than 1 month. Mean follow-up of 12 months revealed no relapses. Side effects were mild, and none had to terminate treatment prematurely. Comparison of AmBisome to SSG treatment shows that the former is safer, with fewer recurrence rates. Additionally, the expense of the total care with AmBisome is less than with SSG: 45% less if SSG was given in an inpatient setting; 15% less when SSG was given in an outpatient setting. Limitations This was a nonrandomized study, with relatively few patients. Conclusion AmBisome treatment for L (V.) braziliensis appears to be effective, better tolerated, and to have more cost benefit in countries where hospital-care costs are significant.
Ana Rabello - One of the best experts on this subject based on the ideXlab platform.
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The Cure Rate after Placebo or No Therapy in American Cutaneous Leishmaniasis: A Systematic Review and Meta-Analysis
2016Co-Authors: Gláucia Fernandes Cota, Marcos Roberto De Sousa, Tatiani Oliveira Fereguetti, Priscila Said Saleme, Thais Kawagoe Alvarisa, Ana RabelloAbstract:IntroductionThere are few drugs with proven efficacy in cutaneous leishmaniasis (CL), and Pentavalent Antimonial derivatives are still the main first-line therapeutic agents worldwide, despite their recognized high toxicities. Randomized controlled clinical trials assessing the efficacy and safety of new therapeutic modalities are of high priority, and the definition of the design of such trials raises debate about the use of placebo as a comparator. To support the use of placebo as a comparator, two main points need to be addressed: 1- the cure rate without any therapeutic intervention and 2- the damage caused by CL and its impact on patients.ObjectiveThe aim of this study was to systematically assess the spontaneous cure rate for American CL and to broaden the discussion about placebo use in CL trials.MethodsThe PRISMA guidelines for systematic reviews and the Cochrane manual were followed. The sources used were the PubMed and LILACS databases. Studies were included if they reported cure rates using placebo or no treatment in American CL.ResultsThirteen studies of a total of 352 patients were ultimately included in this review. The summarized global cure rates for all Leishmania species according to the intention-to-treat analyses performed at approximately three (“initial cure”) and nine (“definitive cure”) months after “no treatment” or placebo use were 26% (CI95%: 16 to 40%) and 26% (CI95%:16 to 38%), respectively. Notably, a significantly lower cure rate was observed for L. braziliensis infection (6.4%, CI95%:0.2 to 20%) than for L. mexicana infection (44%, CI95%:19 to 72%), p = 0.002. Of note, relapse occurred in 20% of patients with initial healing (CI95%:9.2 to 38.9%).ConclusionThese results clearly demonstrate a low spontaneous cure rate following no-treatment or placebo use, confirming that this strategy for the control group in CL studies expose patients to greater morbidity, especially for CL caused by L. braziliensis. Therefore, from this point, the crucial questionto consider regarding placebo use isthe seriousness of the suffering caused by this disease.
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Hepatotoxicity of Pentavalent Antimonial Drug: Possible Role of Residual Sb(III) and Protective Effect of Ascorbic Acid
Antimicrobial agents and chemotherapy, 2013Co-Authors: Kelly Cristina Kato, Cynthia Demicheli, Eliane De Morais-teixeira, Priscila G. Reis, Neila M. Silva-barcellos, Pascal Salaün, Paula Peixoto Campos, José D. Corrêa-junior, Ana Rabello, Frédéric FrézardAbstract:Pentavalent Antimonial drugs such as meglumine antimoniate (Glucantime [Glu; Sanofi-Aventis, Sao Paulo, Brazil]) produce severe side effects, including cardiotoxicity and hepatotoxicity, during the treatment of leishmaniasis. We evaluated the role of residual Sb(III) in the hepatotoxicity of meglumine antimoniate, as well as the protective effect of the antioxidant ascorbic acid (AA) during Antimonial chemotherapy in a murine model of visceral leishmaniasis. BALB/c mice infected with Leishmania infantum were treated intraperitoneally at 80 mg of Sb/kg/day with commercial meglumine antimoniate (Glu) or a synthetic meglumine antimoniate with lower Sb(III) level (MA), in association or not with AA (15 mg/kg/day), for a 20-day period. Control groups received saline or saline plus AA. Livers were evaluated for hepatocytes histological alterations, peroxidase activity, and apoptosis. Increased proportions of swollen and apoptotic hepatocytes were observed in animals treated with Glu compared to animals treated with saline or MA. The peroxidase activity was also enhanced in the liver of animals that received Glu. Cotreatment with AA reduced the extent of histological changes, the apoptotic index, and the peroxidase activity to levels corresponding to the control group. Moreover, the association with AA did not affect the hepatic uptake of Sb and the ability of Glu to reduce the liver and spleen parasite loads in infected mice. In conclusion, our data supports the use of Pentavalent Antimonials with low residue of Sb(III) and the association of Pentavalent Antimonials with AA, as effective strategies to reduce side effects in Antimonial therapy.
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efficacy of anti leishmania therapy in visceral leishmaniasis among hiv infected patients a systematic review with indirect comparison
PLOS Neglected Tropical Diseases, 2013Co-Authors: Gláucia Fernandes Cota, Marcos Roberto De Sousa, Tatiani Oliveira Fereguetti, Ana RabelloAbstract:Objective We conducted a systematic literature review with indirect comparison of studies evaluating therapeutic efficacy and toxicity associated to visceral leishmaniasis (VL) therapy among HIV infected individuals. Main outcome measurements The outcomes of interest were clinical and parasitological cure, mortality, and adverse events. Methods PRISMA guidelines for systematic reviews and Cochrane manual were followed. Sources were MEDLINE, LILACS, EMBASE, Web of Knowledge databases and manual search of references from evaluated studies. We included all studies reporting outcomes after VL treatment, regardless of their design. Study quality was evaluated systematically by using the Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomized studies in meta-analyses. Comprehensive Meta-Analysis software v.2.2.048 was used to perform one-group meta-analysis of study arms with the same drug to estimate global rates of success and adverse events with each drug. These estimates were used, when possible, to indirectly compare treatment options, adjusted for CD4 count. Direct comparison was pooled when available. Results Seventeen studies reporting five treatment regimens and outcome of 920 VL episodes occurring in HIV infected individuals were included. The main outstanding difference in outcome among the treatment regimens was observed in mortality rate: it was around 3 times higher with high-dose antimony use (18.4%, CI 95% 13.3–25%), indirectly compared to lipid formulations of amphotericin B treatment (6.1%, CI 95% 3.9–9.4%). It was observed, also by indirect comparison, higher rates of clinical improvement in study arms using amphotericin B than in study arms using Pentavalent Antimonial therapy (Sbv). The parasitological cure, an outcome that presented some degree of risk of selection and verification bias, had rates that varied widely within the same treatment arm, with high heterogeneity, hampering any formal comparison among drugs. One direct comparison of amphotericin and antimoniate was possible combining results of two studies and confirming the superiority of amphotericin. Conclusions Available evidence suggests that amphotericin is superior to antimony treatment. Death rate using antimoniate high dose is unacceptably high. Randomized controlled trials are necessary to compare different formulations and doses of amphotericin, alternative therapies and drug combinations.
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rapid clearance of circulating leishmania kinetoplast dna after treatment of visceral leishmaniasis
Acta Tropica, 2004Co-Authors: Jolande Disch, Maria C Oliveira, Marcela Orsini, Ana RabelloAbstract:With the aim of evaluating the utility of the detection of Leishmania kDNA in peripheral blood for the cure assessment of visceral leishmaniasis (VL), a PCR based method was performed in patients with confirmed VL at three follow-up periods after specific chemotherapy with Pentavalent Antimonial. In 16 out of 17 (94.1%) patients with pre-treatment detectable kDNA that were clinically cured, the PCR turned negative up to 37 days after the initiation of treatment, remaining negative over 90 days after treatment. The clearance of Leishmania kDNA from peripheral blood of patients with VL hints to occur during or shortly after treatment concurring or preceding clinical recovery.
Edgar M. Carvalho - One of the best experts on this subject based on the ideXlab platform.
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in situ cellular response underlying successful treatment of mucosal leishmaniasis with a combination of Pentavalent Antimonial and pentoxifylline
American Journal of Tropical Medicine and Hygiene, 2019Co-Authors: Edgar M. Carvalho, Daniela R Faria, Luiza Cenizio Barbieri, Carolina Cattoni Koh, Paulo R L Machado, Carolina Cincura Barreto, Clara Monica Figueiredo De Lima, Marcus Miranda Lessa, Kenneth J GollobAbstract:Mucosal leishmaniasis (ML) is characterized by high production of inflammatory cytokines. Administration of pentoxifylline (PTX), an inhibitor of TNF-alpha, with Pentavalent antimony (Sbv), has been successfully used as alternative treatment for refractory ML. Our study aims to investigate the in situ cellular response underlying the effectiveness of this therapy, by evaluating the intensity of the inflammatory infiltrate, cellular composition, and expression of cytokines and granzyme A in lesions from ML before and after treatment with Sbv alone or in combination with PTX. Our data showed no differences in the intensity of inflammatory infiltrate comparing before and after treatment, and comparing between different treatments. However, although the number and frequency of CD4+ and CD8+ cells were not different before and after treatments or comparing different treatments, frequency of CD68+ cells decreased after treatment with Sbv + PTX, but not with Sbv. This was due to a reduction in CD68+ TNF-alpha+ and not in CD68+ IL-10+ cells. The frequency of TNF-alpha+ cells was correlated with the intensity of the inflammatory infiltrate before treatment, but this correlation was lost after treatment with Sbv + PTX. Although the total expression of granzyme A did not significantly change after treatments, a clear trend of decrease was observed after treatment with Sbv + PTX. Interestingly, patients who took longer to heal, regardless of the treatment, displayed a higher frequency of granzyme A+ cells. Our data suggest that treatment with Sbv + PTX acts in CD68+ cells reducing the expression of TNF-alpha but not IL-10, resulting in more efficient modulation of the inflammatory response, accelerating the healing process.
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The miRNA 361-3p, a Regulator of GZMB and TNF Is Associated With Therapeutic Failure and Longer Time Healing of Cutaneous Leishmaniasis Caused by L. (viannia) braziliensis
Frontiers Media S.A., 2018Co-Authors: Edgar M. Carvalho, Tainã S. Lago, Juliana Almeida Silva, Ednaldo L. Lago, Dalila L. Zanette, Léa Cristina CastellucciAbstract:L. (viannia) braziliensis infection causes American Tegumentary Leishmaniasis (ATL), with prolonged time to healing lesions. The potent inflammatory response developed by the host is important to control the parasite burden and infection however an unbalanced immunity may cooperate to the tissue damage observed. The range of mechanisms underlying the pathological responses associated with ATL still needs to be better understood. That includes epigenetic regulation by non-coding MicroRNAs (miRNAs), non-coding sequences around 22 nucleotides that act as post-transcriptional regulators of RNAs encoding proteins. The miRNAs have been associated with diverse parasitic diseases, including leishmaniasis. Here we evaluated miRNAs that targeted genes expressed in cutaneous leishmaniasis lesions (CL) by comparing its expression in both CL and normal skin obtained from the same individual. In addition, we evaluated if the miRNAs expression would be correlated with clinical parameters such as therapeutic failure, healing time as well as lesion size. The miR-361-3p and miR-140-3p were significantly more expressed in CL lesions compared to normal skin samples (p = 0.0001 and p < 0.0001, respectively). In addition, the miR-361-3p was correlated with both, therapeutic failure and healing time of disease (r = 0.6, p = 0.003 and r = 0.5, p = 0.007, respectively). In addition, complementary analysis shown that miR-361-3p is able to identify with good sensitivity (81.2%) and specificity (100%) patients who tend to fail initial treatment with Pentavalent Antimonial (Sbv). Finally, the survival analysis considering “cure” as the endpoint showed that the higher the expression of miR-361-3p, the longer the healing time of CL. Overall, our data suggest the potential of miR-361-3p as a prognostic biomarker in CL caused by L. braziliensis
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Oxidative burst production before and after therapy and cure of CL patients.
2016Co-Authors: Pedro Paulo Carneiro, Jacilara Conceição, Michael Macedo, Viviane Magalhães, Edgar M. Carvalho, Olivia BacellarAbstract:Production of burst oxidative, NO and ROS by monocytes from CL patients (n = 6) after infection with L.braziliensis promastigotes or upon PMA stimulus, were determined before and after therapy (i.v. Pentavalent Antimonial, 20mg/kg body weight daily for 20 days) and cure of cutaneous leishmaniasis. The data represent the median of mean intensity of fluorescence (MIF) of oxidative burst production (A), frequency of NO production (B) and frequency of ROS production (C). Statistical analysis was performed using Wilcoxon test and results were considered significant (p
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effect of Pentavalent Antimonial treatment on the histopathologic and ultrastructural aspects of diffuse cutaneous leishmaniasis due to leishmania amazonensis
European Journal of Dermatology, 1996Co-Authors: Achilea L Bittencourt, Roberto Badaro, J M L Costa, Aldina Barral, F Badaro, Edgar M. CarvalhoAbstract:The histopathological and ultrastructural aspects of six patients with diffuse cutaneous leishmaniasis (three with the polar form and three with the sub-polar and borderline forms) during and after treatment with Pentavalent antimony associated with IFN-γ is presented. In most of the biopsies a marked decrease or disappearence of the parasitism and of the macrophagic aspect associated with an increase in the intensity of the lymphoplasmacytic infiltration and appearance of granulomas was observed in two cases. These aspects indicated a cell-mediated immune response that in two cases were enough to produce clearing of parasitism and healing of the lesions demonstrating the effectiveness of the treatment associating Pentavalent antimony with IFN-γ.