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1.
Pharmaceuticals (Basel) ; 17(6)2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38931434

RESUMO

In the New World, dogs are considered the main reservoir of visceral leishmaniasis (VL). Due to inefficacies in existing treatments and the lack of an efficient vaccine, dog culling is one of the main strategies used to control disease, making the development of new therapeutic interventions mandatory. We previously showed that Tanespimycin (17-AAG), a Hsp90 inhibitor, demonstrated potential for use in leishmaniasis treatment. The present study aimed to test the safety of 17-AAG in dogs by evaluating plasma pharmacokinetics, dose-proportionality, and the tolerability of 17-AAG in response to a dose-escalation protocol and multiple administrations at a single dose in healthy dogs. Two protocols were used: Study A: four dogs received variable intravenous (IV) doses (50, 100, 150, 200, or 250 mg/m2) of 17-AAG or a placebo (n = 4/dose level), using a cross-over design with a 7-day "wash-out" period; Study B: nine dogs received three IV doses of 150 mg/m2 of 17-AAG administered at 48 h intervals. 17-AAG concentrations were determined by a validated high-performance liquid chromatographic (HPLC) method: linearity (R2 = 0.9964), intra-day precision with a coefficient of variation (CV) ≤ 8%, inter-day precision (CV ≤ 20%), and detection and quantification limits of 12.5 and 25 ng/mL, respectively. In Study A, 17-AAG was generally well tolerated. However, increased levels of liver enzymes-alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT)-and bloody diarrhea were observed in all four dogs receiving the highest dosage of 250 mg/m2. After single doses of 17-AAG (50-250 mg/m2), maximum plasma concentrations (Cmax) ranged between 1405 ± 686 and 9439 ± 991 ng/mL, and the area under the curve (AUC) plotting plasma concentration against time ranged between 1483 ± 694 and 11,902 ± 1962 AUC 0-8 h µg/mL × h, respectively. Cmax and AUC parameters were dose-proportionate between the 50 and 200 mg/m2 doses. Regarding Study B, 17-AAG was found to be well tolerated at multiple doses of 150 mg/m2. Increased levels of liver enzymes-ALT (28.57 ± 4.29 to 173.33 ± 49.56 U/L), AST (27.85 ± 3.80 to 248.20 ± 85.80 U/L), and GGT (1.60 ± 0.06 to 12.70 ± 0.50 U/L)-and bloody diarrhea were observed in only 3/9 of these dogs. After the administration of multiple doses, Cmax and AUC 0-48 h were 5254 ± 2784 µg/mL and 6850 ± 469 µg/mL × h in plasma and 736 ± 294 µg/mL and 7382 ± 1357 µg/mL × h in tissue transudate, respectively. In conclusion, our results demonstrate the potential of 17-AAG in the treatment of CVL, using a regimen of three doses at 150 mg/m2, since it presents the maintenance of high concentrations in subcutaneous interstitial fluid, low toxicity, and reversible hepatotoxicity.

2.
Parasit Vectors ; 17(1): 132, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38491526

RESUMO

BACKGROUND: Visceral leishmaniasis (VL), or kala-azar, is a common comorbidity in patients with AIDS in endemic areas. Many patients continue to experiences relapses of VL despite virological control, but with immunological failure. These patients remain chronically symptomatic with hypersplenism, for example with anemia, leukopenia, and thrombocytopenia, and are at risk of severe co-infection due to low CD4+ count. Therefore, in this study, splenectomized patients with VL and HIV infection were investigated to understand why the CD4+ count fails to recover in these patients, evaluating the importance of spleen mass for hypersplenism and immunological failure. METHODS: From a retrospective open cohort of 13 patients who had previously undergone splenectomy as salvage therapy for relapsing VL, 11 patients with HIV infection were investigated. This study compared the patients' complete blood cell count (CBC) and CD4+ and CD8+ cell counts before and after splenectomy with respect to spleen weight. RESULTS: CBC was substantially improved after splenectomy, indicating hypersplenism. However, to the best of our knowledge, this is the first study to show that spleen mass is strongly and negatively correlated with CD4+ cell count (ρ = -0.71, P = 0.015). CONCLUSIONS: This finding was unexpected, as the spleen is the most extensive lymphoid tissue and T-lymphocyte source. After reviewing the literature and reasoning, we hypothesized that the immunological failure was secondary to CD4+ loss initially by apoptosis in the spleen induced by productive HIV infection and, subsequently, by pyroptosis sustained by parasitic infection in spleen macrophages.


Assuntos
Síndrome da Imunodeficiência Adquirida , Infecções por HIV , Hiperesplenismo , Leishmaniose Visceral , Humanos , Leishmaniose Visceral/epidemiologia , Infecções por HIV/complicações , Hiperesplenismo/complicações , Estudos Retrospectivos , Cemitérios , Síndrome da Imunodeficiência Adquirida/complicações , Recidiva Local de Neoplasia/complicações , Linfócitos T CD4-Positivos
3.
Stem Cell Res Ther ; 10(1): 146, 2019 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-31113444

RESUMO

BACKGROUND: Survival and therapeutic actions of bone marrow-derived mesenchymal stem cells (BMMSCs) can be limited by the hostile microenvironment present during acute spinal cord injury (SCI). Here, we investigated whether BMMSCs overexpressing insulin-like growth factor 1 (IGF-1), a cytokine involved in neural development and injury repair, improved the therapeutic effects of BMMSCs in SCI. METHODS: Using a SCI contusion model in C57Bl/6 mice, we transplanted IGF-1 overexpressing or wild-type BMMSCs into the lesion site following SCI and evaluated cell survival, proliferation, immunomodulation, oxidative stress, myelination, and functional outcomes. RESULTS: BMMSC-IGF1 transplantation was associated with increased cell survival and recruitment of endogenous neural progenitor cells compared to BMMSC- or saline-treated controls. Modulation of gene expression of pro- and anti-inflammatory mediators was observed after BMMSC-IGF1 and compared to saline- and BMMSC-treated mice. Treatment with BMMSC-IGF1 restored spinal cord redox homeostasis by upregulating antioxidant defense genes. BMMSC-IGF1 protected against SCI-induced myelin loss, showing more compact myelin 28 days after SCI. Functional analyses demonstrated significant gains in BMS score and gait analysis in BMMSC-IGF1, compared to BMMSC or saline treatment. CONCLUSIONS: Overexpression of IGF-1 in BMMSC resulted in increased cell survival, immunomodulation, myelination, and functional improvements, suggesting that IGF-1 facilitates the regenerative actions of BMMSC in acute SCI.


Assuntos
Fator de Crescimento Insulin-Like I/genética , Transplante de Células-Tronco Mesenquimais , Células-Tronco Neurais/transplante , Traumatismos da Medula Espinal/terapia , Animais , Células da Medula Óssea/citologia , Diferenciação Celular/genética , Modelos Animais de Doenças , Humanos , Células-Tronco Mesenquimais/citologia , Camundongos , Bainha de Mielina/genética , Bainha de Mielina/patologia , Células-Tronco Neurais/citologia , Recuperação de Função Fisiológica , Regeneração/genética , Traumatismos da Medula Espinal/genética , Traumatismos da Medula Espinal/patologia
4.
J. bras. nefrol ; 39(4): 376-383, Oct.-Dec. 2017. tab, graf
Artigo em Inglês | LILACS | ID: biblio-893801

RESUMO

Abstract Introduction: A report on the prevalence of glomerular disease diagnosed via renal biopsy in Salvador, BA, Brazil was published in 1973 and showed a predominance of membranoproliferative glomerulonephritis, which was frequently associated with hepatosplenic schistosomiasis. Objective: In this study, we investigate the potential changes in the distribution of glomerular diseases after a period of important epidemiological transition in Brazil. Methods: Pathology reports of all patients subjected to kidney biopsy from 2003 to 2015 in a referral nephrology service were reviewed. Clinical, laboratorial and pathological diagnoses were collected for analysis. Histological slides of the biopsies performed between 2003 and 2006 were reviewed to examine the accuracy of the estimates based on the pathology reports. Results: Among the biopsies performed during the time period, 1,312 met the inclusion criteria for the study. Focal and segmental glomerulosclerosis was the most prevalent diagnosis, followed by lupus nephritis. However, a trend toward a decrease in the prevalence of focal and segmental glomerulosclerosis was detected (p < 0.05), and an increase in lupus (p < 0.0001) and membranous glomerulonephritis (p < 0.005) was observed. Conclusion: The data presented herein suggest the occurrence of changes in the distribution of nephrological diseases in Salvador, Brazil. The disease that was most prevalent shifted from membranoproliferative glomerulonephritis to focal and segmental glomerulosclerosis from 1975 to 2006 and from focal and segmental glomerulosclerosis to lupus nephritis from 2006 to 2015.


Resumo Introdução: um relatório sobre a prevalência de glomerulopatia diagnosticada por biópsia renal em Salvador foi publicado em 1973, demonstrando o predomínio de glomerulonefrite membranoproliferativa, frequentemente associada a esquistossomose hepatoesplênica. Objetivo: no presente estudo, investigamos as possíveis mudanças na distribuição das glomerulopatias após um período de importantes transições epidemiológicas no Brasil. Métodos: foram revisados todos os relatos de pacientes submetidos a biópsia renal de 2003 a 2015 em um serviço de referência em nefrologia. Diagnósticos clínicos, laboratoriais e patológicos foram colhidos para análise. Lâminas histológicas das biópsias executadas entre 2003 e 2006 foram revisadas para avaliar a precisão das estimativas baseadas nos laudos anatomopatológicos. Resultados: entre as biópsias realizadas durante o período em questão, 1.312 satisfizeram os critérios de inclusão do estudo. Glomeruloesclerose segmentar e focal foi o diagnóstico mais prevalente, seguido de nefrite lúpica. Entretanto, foi detectada tendência de queda na prevalência da glomeruloesclerose segmentar e focal (p < 0,05) e de elevação nos casos de lúpus (p < 0,0001) e glomerulonefrite membranosa (p < 0,005). Conclusão: os dados apresentados neste estudo sugerem a ocorrência de mudanças na distribuição das doenças nefrológicas em Salvador. A doença mais prevalente passou de glomerulonefrite membranoproliferativa para glomeruloesclerose segmentar e focal de 1975 a 2006 e de glomeruloesclerose segmentar e focal para nefrite lúpica de 2006 a 2015.


Assuntos
Humanos , Masculino , Feminino , Lactente , Pré-Escolar , Criança , Adolescente , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Adulto Jovem , Nefropatias/patologia , Nefropatias/epidemiologia , Glomérulos Renais , Fatores de Tempo , Biópsia , Brasil/epidemiologia , Prevalência
5.
Sci Rep ; 7(1): 15914, 2017 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-29162847

RESUMO

Canine Visceral Leishmaniasis (CVL) is caused by Leishmania infantum, which in the New World is transmitted by Lutzomyia longipalpis. While prospective clinical and immunological assessments of dogs experimentally challenged with L. infantum have been previously reported over a relatively short follow-up period, the long-term characterization of infected animals has not been performed to date. We evaluated dogs in a subclinical state for six years following experimental infection with L. infantum and Lu. longipalpis saliva, via an intradermal route, to characterize clinical, parasitological and immunological parameters arising from L. infantum experimental infection. We also assess these parameters in a group of naturally infected animals. The immune profiles of the experimentally and naturally infected animals exhibited increases of IFN-γ, IL-6 and IL-18, and decreases in TNF, IL-2, IL-8 and CXCL1, compared to controls. Our results indicate that over a six-year follow-up post-challenge, subclinically infected dogs presented low CVL clinical scores despite the persistence of Leishmania parasites in the lymph nodes, spleen and skin. Similarities observed among immune profiles in the context of experimental and natural infection seem to suggest that an enduring activation of the host immune response may lead to the control of parasite growth, thereby limiting disease severity.


Assuntos
Doenças do Cão/imunologia , Doenças do Cão/parasitologia , Leishmania infantum/fisiologia , Leishmaniose Visceral/imunologia , Leishmaniose Visceral/parasitologia , Animais , Quimiocinas/sangue , Doenças do Cão/sangue , Doenças do Cão/patologia , Cães , Feminino , Seguimentos , Leishmaniose Visceral/sangue , Leishmaniose Visceral/patologia , Masculino , Fatores de Tempo
6.
J Bras Nefrol ; 39(4): 376-383, 2017.
Artigo em Inglês, Português | MEDLINE | ID: mdl-29319763

RESUMO

INTRODUCTION: A report on the prevalence of glomerular disease diagnosed via renal biopsy in Salvador, BA, Brazil was published in 1973 and showed a predominance of membranoproliferative glomerulonephritis, which was frequently associated with hepatosplenic schistosomiasis. OBJECTIVE: In this study, we investigate the potential changes in the distribution of glomerular diseases after a period of important epidemiological transition in Brazil. METHODS: Pathology reports of all patients subjected to kidney biopsy from 2003 to 2015 in a referral nephrology service were reviewed. Clinical, laboratorial and pathological diagnoses were collected for analysis. Histological slides of the biopsies performed between 2003 and 2006 were reviewed to examine the accuracy of the estimates based on the pathology reports. RESULTS: Among the biopsies performed during the time period, 1,312 met the inclusion criteria for the study. Focal and segmental glomerulosclerosis was the most prevalent diagnosis, followed by lupus nephritis. However, a trend toward a decrease in the prevalence of focal and segmental glomerulosclerosis was detected (p < 0.05), and an increase in lupus (p < 0.0001) and membranous glomerulonephritis (p < 0.005) was observed. CONCLUSION: The data presented herein suggest the occurrence of changes in the distribution of nephrological diseases in Salvador, Brazil. The disease that was most prevalent shifted from membranoproliferative glomerulonephritis to focal and segmental glomerulosclerosis from 1975 to 2006 and from focal and segmental glomerulosclerosis to lupus nephritis from 2006 to 2015.


Assuntos
Nefropatias/epidemiologia , Nefropatias/patologia , Glomérulos Renais , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Brasil/epidemiologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de Tempo , Adulto Jovem
7.
PLoS One ; 9(7): e103635, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25076494

RESUMO

Host tissues affected by Leishmania infantum have differing degrees of parasitism. Previously, the use of different biological tissues to detect L. infantum DNA in dogs has provided variable results. The present study was conducted to evaluate the accuracy of molecular diagnostic testing (qPCR) in dogs from an endemic area for canine visceral leishmaniasis (CVL) by determining which tissue type provided the highest rate of parasite DNA detection. Fifty-one symptomatic dogs were tested for CVL using serological, parasitological and molecular methods. Latent class analysis (LCA) was performed for accuracy evaluation of these methods. qPCR detected parasite DNA in 100% of these animals from at least one of the following tissues: splenic and bone marrow aspirates, lymph node and skin fragments, blood and conjunctival swabs. Using latent variable as gold standard, the qPCR achieved a sensitivity of 95.8% (CI 90.4-100) in splenic aspirate; 79.2% (CI 68-90.3) in lymph nodes; 77.3% (CI 64.5-90.1) in skin; 75% (CI 63.1-86.9) in blood; 50% (CI 30-70) in bone marrow; 37.5% (CI 24.2-50.8) in left-eye; and 29.2% (CI 16.7-41.6) in right-eye conjunctival swabs. The accuracy of qPCR using splenic aspirates was further evaluated in a random larger sample (n = 800), collected from dogs during a prevalence study. The specificity achieved by qPCR was 76.7% (CI 73.7-79.6) for splenic aspirates obtained from the greater sample. The sensitivity accomplished by this technique was 95% (CI 93.5-96.5) that was higher than those obtained for the other diagnostic tests and was similar to that observed in the smaller sampling study. This confirms that the splenic aspirate is the most effective type of tissue for detecting L. infantum infection. Additionally, we demonstrated that LCA could be used to generate a suitable gold standard for comparative CVL testing.


Assuntos
Doenças do Cão/diagnóstico , Leishmaniose Visceral/veterinária , Técnicas de Diagnóstico Molecular , Reação em Cadeia da Polimerase em Tempo Real , Animais , Brasil/epidemiologia , Doenças do Cão/epidemiologia , Doenças do Cão/parasitologia , Cães , Doenças Endêmicas , Feminino , Leishmania donovani/genética , Leishmaniose Visceral/diagnóstico , Leishmaniose Visceral/epidemiologia , Leishmaniose Visceral/parasitologia , Masculino , Carga Parasitária , Prevalência , Sensibilidade e Especificidade
8.
Ren Fail ; 35(5): 776-81, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23560558

RESUMO

OBJECTIVE: Recent studies have demonstrated the therapeutic effects of bone marrow-derived cells in tissue regeneration. The aim of this study was to investigate the effects of bone marrow mononuclear cell (BMMC) transplantation in a mouse model of acute renal failure (ARF) induced by mercuric chloride. METHODS: BMMC was isolated from male BALB/c mice and injected into female mice treated with a lethal dose (LD90) of mercuric chloride. Survival rate, histopathological analysis, and assessment of urea, creatinine, sodium, potassium, and mercury levels were carried out. RESULTS: Cellular therapy with BMMC significantly reduced the mortality induced by mercuric chloride (p < 0.05). This finding correlated with a decrease in serum levels of urea (p = 0.04) and potassium (p < 0.01). However, no differences in renal morphology were observed when BMMC-treated and control group were compared. CONCLUSION: Transplanted BMMC improve renal function and reduce mortality and, therefore, may represent a new therapeutic alternative to treat ARF.


Assuntos
Injúria Renal Aguda/terapia , Transplante de Medula Óssea , Monócitos/transplante , Injúria Renal Aguda/induzido quimicamente , Animais , Modelos Animais de Doenças , Feminino , Masculino , Cloreto de Mercúrio , Camundongos , Camundongos Endogâmicos BALB C
9.
Ren Fail ; 34(10): 1252-7, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23002699

RESUMO

Renal failure is common in patients with glomerular disease. Although renal failure may result from the glomerular lesion itself, it is also observed in patients with minimal glomerular alterations. Degenerative changes and necrosis of the tubular epithelium are common findings in kidney biopsies from these patients. The aim of this work is to examine the association between acute tubular necrosis (ATN) and renal failure in patients with glomerulopathy and to estimate the relationship between the degree of ATN and renal failure in these patients. Data on age, sex, presence of nephrotic syndrome, and renal failure were recorded for 149 patients, who underwent a renal biopsy for the diagnosis of glomerulopathy. The biopsies were reviewed, and ATN, when present, was classified as one of four grades depending on its intensity. The mean age of the patients was 21 ± 16 years. Eighty patients (54%) were male, 43 (42%) had renal failure, 104 (72%) had nephrotic syndrome, and 66 (45%) had minimal change disease or focal segmental glomerulosclerosis. ATN was present in 115 (77%) patients. The frequency of renal failure was directly correlated with the intensity of ATN [odds ratio (OR) of 26.0 for patients with grade 2 lesions and OR of 45.5 for patients with grade 3 lesions]. ATN is a common finding in the biopsies of patients with glomerulopathy. The severity of ATN is directly associated with the frequency of renal failure in these patients.


Assuntos
Glomerulonefrite/complicações , Glomerulosclerose Segmentar e Focal/complicações , Necrose Tubular Aguda/complicações , Insuficiência Renal/complicações , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Necrose Tubular Aguda/epidemiologia , Necrose Tubular Aguda/patologia , Masculino , Pessoa de Meia-Idade , Insuficiência Renal/epidemiologia , Adulto Jovem
10.
Rev Col Bras Cir ; 39(3): 207-10, 2012.
Artigo em Inglês, Português | MEDLINE | ID: mdl-22836569

RESUMO

OBJECTIVE: To develop an experimental model of global normothermic ischemia able to demonstrate the transient ischemia and reperfusion periods required for development of ischemia/reperfusion injury in the small intestines of Wistar rats by clamping the abdominal aorta. METHODS: Twenty adult male Wistar rats weighing 250-350g were randomly divided into five groups with four rats each and submitted to increasing times of ischemia (0 - 30 - 45 - 60 - 90 minutes). Within each group, except the control one, two rats underwent 60 minutes of reperfusion and two 90 minutes. After the procedures, histological analysis was conducted by measurement of areas of necrosis. RESULTS: The degree of intestinal necrosis ranged from 15% to 54% (p = 0.0004). There was progressive increase in the degree of injury related to increase in ischemic time. However, greater degrees of injury were observed in the lowest times of reperfusion. The analysis of the coefficient of variation of necrosis among the ten groups of ischemia/reperfusion showed a statistically significant difference in 15 areas, 13 related to the control group. CONCLUSION: The model was able to show the periods required for the occurrence of ischemia/reperfusion injury by aortic clamping and can serve as a basis to facilitate the development of studies that aim at understanding this kind of injury.


Assuntos
Modelos Animais de Doenças , Isquemia , Mesentério/irrigação sanguínea , Animais , Aorta Abdominal , Constrição , Masculino , Ratos , Ratos Wistar , Reperfusão/métodos
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