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1.
Rev Soc Bras Med Trop ; 53: e20180463, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32049198

RESUMO

INTRODUCTION: The therapeutic efficacy of daily amphotericin B infusion is related to its maximum concentration in blood; however, trough levels may be useful in intermittent regimens of this antifungal drug. METHODS: : High performance liquid chromatography (HPLC) was used to determine the minimum concentration (Cmin) of amphotericin B in the serum of patients receiving deoxycholate (D-Amph) or liposomal amphotericin B (L-AmB) for the treatment of cryptococcal meningitis (n=28), histoplasmosis (n=8), paracoccidioidomycosis (n=1), and leishmaniasis (n=1). RESULTS: Daily use of D-Amph 30 to 50 mg or L-AmB 50 mg resulted in a similar Cmin, but a significant increase ocurred with L-AmB 100 mg/day. The geometric mean Cmin tended to decrease with a reduction in the dose and frequency of intermittent L-AmB infusions: 357 ng/mL (100 mg 4 to 5 times/week) > 263 ng/mL (50 mg 4 to 5 times/week) > 227 ng/mL (50 mg 1 to 3 times/week). The impact on Cmin was variable in patients whose dose or therapeutic scheme was changed, especially when administered the intermittent infusion of amphotericin B. The mean Cmin for each L-AmB schedule of intermittent therapy was equal or higher than the minimum inhibitory concentration of amphotericin B against Cryptococcus isolates from 10/12 patients. The Cmin of amphotericin B in patients with cryptococcal meningitis was comparable between those that survived or died. CONCLUSIONS: By evaluating the Cmin of amphotericin B, we demonstrated the therapeutic potential of its intermittent use including in the consolidation phase of neurocryptococcosis treatment, despite the great variability in serum levels among patients.


Assuntos
Anfotericina B/sangue , Antifúngicos/sangue , Ácido Desoxicólico/sangue , Anfotericina B/administração & dosagem , Anfotericina B/farmacocinética , Antifúngicos/administração & dosagem , Antifúngicos/farmacocinética , Cromatografia Líquida de Alta Pressão , Ácido Desoxicólico/administração & dosagem , Ácido Desoxicólico/farmacocinética , Histoplasmose/tratamento farmacológico , Humanos , Leishmaniose/tratamento farmacológico , Meningite Criptocócica/tratamento farmacológico , Paracoccidioidomicose/tratamento farmacológico
2.
An Bras Dermatol ; 94(4): 470-472, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31644624

RESUMO

Paracoccidioidomycosis is a fungal infection that occurs in immunocompetent patients and are classified into two forms: the acute-subacute form, predominantly in young patients, and the chronic adult form that may present classic ulcerated lesions to rare sarcoid ones. We present the case of a boy whose infection began with sarcoid lesions but, after being mistakenly diagnosed with cutaneous sarcoidosis and treated (for three years) with prednisone, developed painful ulcerations throughout the body. After the correct diagnosis, with evidence of the fungus in histopathological and mycological examinations, the patient was properly treated with itraconazole for eight months and evolved with total remission of the disease.


Assuntos
Glucocorticoides/efeitos adversos , Paracoccidioidomicose/etiologia , Paracoccidioidomicose/patologia , Prednisona/efeitos adversos , Adolescente , Antifúngicos/uso terapêutico , Humanos , Itraconazol/uso terapêutico , Masculino , Paracoccidioidomicose/diagnóstico , Paracoccidioidomicose/tratamento farmacológico , Sarcoidose/diagnóstico , Sarcoidose/patologia , Resultado do Tratamento
3.
Artigo em Inglês | MEDLINE | ID: mdl-31618378

RESUMO

The largest endemic areas of paracoccidioidomycosis (PCM) in Brazil comprise the humid agricultural regions of the Southeast, South, and, recently, the Midwest and North regions. The Ceara State, located in the Brazilian Northeast region, presents semi-arid climate in most of its territory, characterized by high temperatures, scarce vegetation and low humidity. The objective of the present study was to describe a new autochthonous case of paracoccidioidomycosis from a distinct area of Ceara and review the characteristics of PCM occurrence in Northeastern Brazil. The patient was a 65-year-old male farmer who denied traveling outside the Ceara State or living in other locations. He was born and lived in the rural area known as Camara, bordering the municipalities of Itapaje and Itapipoca. Camara is one of the highest areas (around 720 m of altitude) of the Uruburetama mountains that exhibits tropical forests and is located in Northern Ceara, distant 139 km from the capital, Fortaleza. The patient sought for care, complaining of an oral lesion that appeared over the past three years. The hard palate lesion biopsy revealed multinucleated cells with cytoplasmic inclusions, compatible with PCM. After culture, P. brasiliensis was identified by polymerase chain reaction. Serological testing for PCM was reagent. The patient was treated with itraconazole for approximately 17 months, persisting free of symptoms after 15 months of follow-up. Regarding this new autochthonous case in the Ceara State, PCM should be considered in the differential diagnosis of patients with suggestive clinical manifestations, proceeding from the mountainous areas of Ceara.


Assuntos
Antifúngicos/uso terapêutico , Itraconazol/uso terapêutico , Paracoccidioidomicose/diagnóstico , Idoso , Humanos , Masculino , Paracoccidioidomicose/tratamento farmacológico
4.
Mycoses ; 62(11): 999-1005, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31408548

RESUMO

The acute-subacute form of paracoccidioidomycosis (PCM) is a severe systemic mycosis that affects children and adolescents from endemic regions, leading to generalised lymphadenopathy, fever, weight loss, anaemia, eosinophilia, hypoalbuminemia and hypergammaglobulinemia. The objective of this study is to describe the clinical and laboratorial characteristics of acute-subacute PCM, to determine a mortality risk factor and to propose a test for non-survival hazard related to the disease. Children and adolescents diagnosed with PCM, under 15 years were included in the study. Their epidemiological, clinical and laboratorial data were obtained from the hospital records. Descriptive analysis, comparison of means, univariate logistic regression, multivariate logistic regression and a ROC curve were performed in order to identify significant information (P < .05). Through a period of 38 years, 141 children and adolescents were diagnosed with acute-subacute PCM. The main antifungal agent used for the treatment was sulfamethoxazole-trimethoprim (SMX-TMP). The complication rate was 17%, the relapse rate was 7.8% and the mortality rate was 5.7%. A low albumin dosage was identified as a predictor factor for mortality. The cut-off for serum albumin was 2.18 g/dL, above which, the survival rate is 99.1%. Thus, simple clinical and laboratorial examinations may lead to the diagnosis of acute-subacute PCM, and the beginning of the treatment is encouraged even before the isolation of the fungus in biological samples, preventing unfavourable outcomes. Patients with an albumin dosage ≤ 2.18g/dL must receive special attention, preferably hospitalised, during the first four weeks of treatment for presenting an elevated mortality hazard.


Assuntos
Paracoccidioidomicose/diagnóstico , Doença Aguda , Adolescente , Brasil , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Paracoccidioides/isolamento & purificação , Paracoccidioidomicose/tratamento farmacológico , Paracoccidioidomicose/mortalidade , Pesquisa Qualitativa , Estudos Retrospectivos , Fatores de Risco , Albumina Sérica/análise , Combinação Trimetoprima e Sulfametoxazol/uso terapêutico
5.
An. bras. dermatol ; 94(4): 470-472, July-Aug. 2019. graf
Artigo em Inglês | LILACS | ID: biblio-1038288

RESUMO

Abstract: Paracoccidioidomycosis is a fungal infection that occurs in immunocompetent patients and are classified into two forms: the acute-subacute form, predominantly in young patients, and the chronic adult form that may present classic ulcerated lesions to rare sarcoid ones. We present the case of a boy whose infection began with sarcoid lesions but, after being mistakenly diagnosed with cutaneous sarcoidosis and treated (for three years) with prednisone, developed painful ulcerations throughout the body. After the correct diagnosis, with evidence of the fungus in histopathological and mycological examinations, the patient was properly treated with itraconazole for eight months and evolved with total remission of the disease.


Assuntos
Humanos , Masculino , Adolescente , Paracoccidioidomicose/etiologia , Paracoccidioidomicose/patologia , Glucocorticoides/efeitos adversos , Paracoccidioidomicose/diagnóstico , Paracoccidioidomicose/tratamento farmacológico , Sarcoidose/diagnóstico , Sarcoidose/patologia , Prednisona/efeitos adversos , Resultado do Tratamento , Itraconazol/uso terapêutico , Antifúngicos/uso terapêutico
6.
Future Microbiol ; 14: 587-598, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31148472

RESUMO

Aim: 17 new 4-methoxynaphthalene-N-acylhydrazones were synthesized in order to evaluate their biological action against important pathogens. Methods: In vitro susceptibility assays of compounds were performed against Paracoccidioides brasiliensis and Mycobacterium tuberculosis. Results: Compounds 4a, 4b and 4k were the most potent against P. brasiliensis, two with minimum inhibitory concentrations of ≤1 µg ml-1 and exhibited pharmacological synergy with amphotericin B. The compounds also showed activity against M. tuberculosis, with 4c and 4k being the more promising. Compound 4k showed good synergistic antimycobacterium activity with ethambutol. None of the compounds tested showed toxicity. Conclusion: We highlight the compound 4k, as a potential agent for the treatment of patients co-infected with paracoccidioidomycosis and tuberculosis.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Coinfecção/tratamento farmacológico , Mycobacterium tuberculosis/efeitos dos fármacos , Paracoccidioides/efeitos dos fármacos , Paracoccidioidomicose/tratamento farmacológico , Tuberculose/tratamento farmacológico , Anfotericina B/farmacologia , Antibacterianos/síntese química , Antifúngicos/síntese química , Combinação de Medicamentos , Descoberta de Drogas , Sinergismo Farmacológico , Etambutol/farmacologia , Humanos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/patogenicidade , Paracoccidioides/patogenicidade
7.
PLoS Negl Trop Dis ; 13(6): e0007441, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31163021

RESUMO

Paracoccidioidomycosis (PCM) is a neglected disease present in Latin America with difficulty in treatment and occurrence of serious sequelae. Thus, the development of alternative therapies is imperative. In the current work, two oxadiazole compounds (LMM5 and LMM11) presented fungicidal activity against Paracoccidioides spp. The minimum inhibitory and fungicidal concentration values ranged from 1 to 32 µg/mL, and a synergic effect was observed for both compounds when combined with Amphotericin B. LMM5 and LMM11 were able to reduce CFU counts (≥2 log10) on the 5th and 7th days of time-kill curve, respectively. The fungicide effect was confirmed by fluorescence microscopy (FUN-1/FUN-2). The hippocratic screening and biochemical analysis were performed in Balb/c male mice that received a high dose of each compound, and the compounds showed no in vivo toxicity. The treatment of experimental PCM with the new oxadiazoles led to significant reduction in CFU (≥1 log10). Histopathological analysis of the groups treated exhibited control of inflammation, as well as preserved lung areas. These findings suggest that LMM5 and LMM11 are promising hits structures, opening the door for implementing new PCM therapies.


Assuntos
Antifúngicos/farmacologia , Oxidiazóis/farmacologia , Paracoccidioides/efeitos dos fármacos , Anfotericina B/farmacologia , Animais , Antifúngicos/administração & dosagem , Contagem de Colônia Microbiana , Modelos Animais de Doenças , Sinergismo Farmacológico , Histocitoquímica , Pulmão/microbiologia , Pulmão/patologia , Masculino , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Viabilidade Microbiana/efeitos dos fármacos , Oxidiazóis/administração & dosagem , Paracoccidioidomicose/tratamento farmacológico , Paracoccidioidomicose/microbiologia , Paracoccidioidomicose/patologia , Resultado do Tratamento
9.
J Bras Pneumol ; 45(2): e20180167, 2019 Apr 18.
Artigo em Inglês, Português | MEDLINE | ID: mdl-31017226

RESUMO

OBJECTIVE: To evaluate the treatment compliance of patients with paracoccidioidomycosis. METHODS: We studied 188 patients with paracoccidioidomycosis admitted to a tertiary referral hospital in the Central-West Region of Brazil from 2000 to 2010, to assess their compliance to treatment. In order to be considered compliant, patients needed to present two established criteria: (1) receive medicines from the pharmacy, and (2) achieve a self-reported utilization of at least 80% of the dispensed antifungal compounds prescribed since their previous appointment. RESULTS: Most patients were male (95.7%), had the chronic form of the disease (94.2%), and were treated with cotrimoxazole (86.2%). Only 44.6% of patients were treatment compliant. The highest loss to follow-up was observed in the first 4 months of treatment (p < 0.02). Treatment compliance was higher for patients with than for those without pulmonary involvement (OR: 2.986; 95%CI 1.351-6.599), and higher for patients with than without tuberculosis as co-morbidity (OR: 2.763; 95%CI 1.004-7.604). CONCLUSIONS: Compliance to paracoccidioidomycosis treatment was low, and the period with the highest loss to follow-up corresponds to the first four months. Pulmonary paracoccidioidal involvement or tuberculosis comorbidity predicts a higher compliance to paracoccidioidomycosis therapy.


Assuntos
Antifúngicos/uso terapêutico , Adesão à Medicação/estatística & dados numéricos , Paracoccidioidomicose/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Brasil , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
11.
Future Microbiol ; 14: 235-245, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30663901

RESUMO

AIM: Novel 4-methoxy-naphthalene derivatives were synthesized based on hits structures in order to evaluate the antifungal activity against Paracoccidioides spp. METHODS: Antifungal activity of compounds was evaluated against P. brasiliensis and most promising compounds 2 and 3 were tested against eight clinically important fungal species. RESULTS: Compound 3 was the more active compound with MIC 8 to 32 µg.ml-1 for Paracoccidioides spp without toxicity monkey kidney and murine macrophagecells. Carbohydrazide 3 showed good synergistic antifungal activity with amphotericin B against P. brasiliensis specie. Titration assay of carbohydrazide 3 with PbHSD enzyme demonstrates the binding ligand-protein. Molecular dynamics simulations show that ligand 3 let the PbHSD protein more stable. CONCLUSION: New carbohydrazide 3 is an attractive lead for drug development to treat paracoccidioidomycoses.


Assuntos
Antifúngicos/farmacologia , Naftalenos/farmacologia , Paracoccidioides/efeitos dos fármacos , Paracoccidioidomicose/tratamento farmacológico , Anfotericina B/farmacologia , Animais , Antifúngicos/uso terapêutico , Combinação de Medicamentos , Sinergismo Farmacológico , Homosserina Desidrogenase/metabolismo , Hidrazinas/farmacologia , Macrófagos/efeitos dos fármacos , Camundongos , Testes de Sensibilidade Microbiana , Simulação de Dinâmica Molecular , Naftalenos/síntese química , Naftalenos/uso terapêutico , Paracoccidioides/patogenicidade , Estabilidade Proteica , Células Vero/efeitos dos fármacos
12.
Med Mycol ; 57(3): 332-339, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-29945180

RESUMO

Paracoccidioidomycosis (PCM) is the most prevalent systemic mycosis in Latin American countries. Amphotericin B, sulfonamides, and azoles may be used in the treatment of PCM. However, the high toxicity, prolonged course of treatment, and significant frequency of disease relapse compromise their use. Therefore, there is a need to seek new therapeutic options. We conducted tests with thiosemicarbazone of lapachol (TSC-lap) to determine the antifungal activity and phenotypic effects against several isolates of Paracoccidioides spp. In addition, we evaluated the toxicity against murine macrophages and the ability to enhance phagocytosis. Further, we verified that TSC-lap was active against yeasts but did not show any interaction with the drugs tested. The TSC-lap showed no toxicity at the concentration of 40 µg/ml in macrophages, and at 15.6 µg/ml it could increase the phagocytic index. We observed that this compound induced in vitro ultrastructural changes manifested as withered and broken cells beyond a disorganized cytoplasm with accumulation of granules. We did not observe indications of activity in the cell wall, although membrane damages were noted. We observed alterations in the membrane permeability, culminating in a significant increase in K+ efflux and a gradual loss of the cellular content with increase in the concentration of TSC-lap. In addition, we showed a significant reduction of ergosterol amount in the Pb18 membrane. These data reinforce the possible mechanism of action of this compound to be closely associated with ergosterol biosynthesis and reaffirms the antifungal potential of TSC-lap against Paracoccidioides spp.


Assuntos
Antifúngicos/farmacologia , Membrana Celular/efeitos dos fármacos , Naftoquinonas/farmacologia , Paracoccidioides/efeitos dos fármacos , Tiossemicarbazonas/farmacologia , Animais , Ergosterol/biossíntese , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Paracoccidioidomicose/tratamento farmacológico , Paracoccidioidomicose/microbiologia , Fagocitose/efeitos dos fármacos
13.
Bioorg Chem ; 84: 87-97, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30496872

RESUMO

Drug repositioning is the process of discovery, validation and marketing of previously approved drugs for new indications. Our aim was drug repositioning, using ligand-based and structure-based computational methods, of compounds that are similar to two hit compounds previously selected by our group that show promising antifungal activity. Through the ligand-based method, 100 compounds from each of three databases (MDDR, DrugBank and TargetMol) were selected by the Tanimoto coefficient, as similar to LMM5 or LMM11. These compounds were analyzed by the scaffold trees, and up to 10 compounds from each database were selected. The structure-based method (molecular docking) using thioredoxin reductase as the target drug was performed as a complementary approach, resulting in six compounds that were tested in an in vitro assay. All compounds, particularly raltegravir, showed antifungal activity against the genus Paracoccidioides. Raltegravir, an antiviral drug, showed promising antifungal activity against the experimental murine paracoccidioidomycosis, with significant reduction of the fungal burden and decreased alterations in the lung structure of mice treated with 1 mg/kg of raltegravir. In conclusion, the combination of two in silico methods for drug repositioning was able to select an antiviral drug with promising antifungal activity for treatment of paracoccidioidomycosis.


Assuntos
Antifúngicos/farmacologia , Antivirais/farmacologia , Infecções Fúngicas Invasivas/tratamento farmacológico , Paracoccidioidomicose/tratamento farmacológico , Animais , Antifúngicos/síntese química , Antifúngicos/química , Antivirais/síntese química , Antivirais/química , Candida/efeitos dos fármacos , Cryptococcus neoformans/efeitos dos fármacos , Relação Dose-Resposta a Droga , Reposicionamento de Medicamentos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Estrutura Molecular , Paracoccidioides/efeitos dos fármacos , Relação Estrutura-Atividade
14.
Artigo em Inglês | MEDLINE | ID: mdl-30348661

RESUMO

Paracoccidioidomycosis (PCM), caused by Paracoccidioides, is a systemic mycosis with granulomatous character and a restricted therapeutic arsenal. The aim of this work was to search for new alternatives to treat largely neglected tropical mycosis, such as PCM. In this context, the enzymes of the shikimate pathway constitute excellent drug targets for conferring selective toxicity because this pathway is absent in humans but essential for the fungus. In this work, we have used a homology model of the chorismate synthase (EC 4.2.3.5) from Paracoccidioides brasiliensis (PbCS) and performed a combination of virtual screening and molecular dynamics testing to identify new potential inhibitors. The best hit, CP1, successfully adhered to pharmacological criteria (adsorption, distribution, metabolism, excretion, and toxicity) and was therefore used in in vitro experiments. Here we demonstrate that CP1 binds with a dissociation constant of 64 ± 1 µM to recombinant chorismate synthase from P. brasiliensis and inhibits enzymatic activity, with a 50% inhibitory concentration (IC50) of 47 ± 5 µM. As expected, CP1 showed no toxicity in three cell lines. On the other hand, CP1 reduced the fungal burden in lungs from treated mice, similar to itraconazole. In addition, histopathological analysis showed that animals treated with CP1 displayed less lung tissue infiltration, fewer yeast cells, and large areas with preserved architecture. Therefore, CP1 was able to control PCM in mice with a lower inflammatory response and is thus a promising candidate and lead structure for the development of drugs useful in PCM treatment.


Assuntos
Antifúngicos/farmacologia , Descoberta de Drogas/métodos , Paracoccidioides/efeitos dos fármacos , Paracoccidioidomicose/tratamento farmacológico , Fósforo-Oxigênio Liases/antagonistas & inibidores , Quinolinas/farmacologia , Sequência de Aminoácidos , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Células HeLa , Células Endoteliais da Veia Umbilical Humana , Humanos , Itraconazol/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Microscopia Eletrônica de Varredura , Simulação de Dinâmica Molecular , Paracoccidioides/classificação , Paracoccidioides/isolamento & purificação , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/microbiologia , Análise de Sequência de Proteína
15.
Med Mycol ; 57(1): 30-37, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29346653

RESUMO

Argentina has two endemic areas of paracoccidioidomycosis (PCM). Bordering Paraguay and Brazil, Northeast Argentina (NEA) comprises the area with the highest incidence where the chronic adult clinical form has historically been reported. Juvenile form in children and adolescents is rare in this area since only one case was reported in the last 10 years. Despite this, between 2010 and 2012, several cases of acute/subacute clinical forms in children aged 10 to 16 (median 12) were detected. In the last decade, the NEA region has been exposed to ecological variations as consequences of certain climatic and anthropogenic changes, including El Niño-Southern Oscillation phenomenon during 2009, and deforestation. The region has also suffered from the significant ecological effects of the construction of one of the biggest hydroelectric dams of South America. This study aims to describe clinical and epidemiological aspects of acute/subacute PCM cases detected in children from NEA and to discuss climatic and anthropogenic changes as possible contributing factors in the emergence of this disease in children. This acute/subacute PCM cluster was characterized by severe disseminated and aggressive presentations to localized form, with a high spectrum of clinical manifestations uncommonly observed. Due to the lack of experience in acute/subacute PCM in children in the studied area and the atypical clinical manifestations observed, the diagnosis was delayed. In order to avoid misdiagnosis, a higher level of suspicion is now required in NEA and countries bordering the southern part of the endemic area, which are affected by the changes discussed in this article.


Assuntos
Clima , Meio Ambiente , Paracoccidioidomicose/epidemiologia , Adolescente , Antifúngicos/uso terapêutico , Argentina/epidemiologia , Criança , Doenças Transmissíveis Emergentes/diagnóstico , Doenças Transmissíveis Emergentes/tratamento farmacológico , Doenças Transmissíveis Emergentes/epidemiologia , Doenças Transmissíveis Emergentes/patologia , Feminino , Humanos , Incidência , Masculino , Paracoccidioides/efeitos dos fármacos , Paracoccidioides/isolamento & purificação , Paracoccidioidomicose/diagnóstico , Paracoccidioidomicose/tratamento farmacológico , Paracoccidioidomicose/patologia , Estudos Retrospectivos , Testes Sorológicos , Resultado do Tratamento
16.
An. bras. dermatol ; 93(6): 902-904, Nov.-Dec. 2018. graf
Artigo em Inglês | LILACS | ID: biblio-1038284

RESUMO

Abstract: Molecular studies have shown more than one species of the genus Paracoccidioides to be the causal agent of paracoccidioidomycosis. Efforts have been made to correlate the identified species with epidemiological and clinical data of patients, aiming to determine the real meaning and impact of new species. Bearing this objective in mind, the authors report a clinical case of paracoccidioidomycosis, from São Paulo state, Brazil, that manifested as uncommon sarcoid-like cutaneous lesions and was caused by Paracoccidioides brasiliensis sensu stricto (S1a). The patient was treated with itraconazole 200mg/day for 12 months, with complete clinical remission.


Assuntos
Humanos , Masculino , Pessoa de Meia-Idade , Paracoccidioides/classificação , Paracoccidioidomicose/diagnóstico , Paracoccidioidomicose/microbiologia , Sarcoidose/diagnóstico , Paracoccidioides/isolamento & purificação , Paracoccidioidomicose/tratamento farmacológico , Itraconazol/uso terapêutico , Diagnóstico Diferencial , Antifúngicos/uso terapêutico
17.
An Bras Dermatol ; 93(6): 902-904, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30484542

RESUMO

Molecular studies have shown more than one species of the genus Paracoccidioides to be the causal agent of paracoccidioidomycosis. Efforts have been made to correlate the identified species with epidemiological and clinical data of patients, aiming to determine the real meaning and impact of new species. Bearing this objective in mind, the authors report a clinical case of paracoccidioidomycosis, from São Paulo state, Brazil, that manifested as uncommon sarcoid-like cutaneous lesions and was caused by Paracoccidioides brasiliensis sensu stricto (S1a). The patient was treated with itraconazole 200mg/day for 12 months, with complete clinical remission.


Assuntos
Paracoccidioides/classificação , Paracoccidioidomicose/diagnóstico , Paracoccidioidomicose/microbiologia , Sarcoidose/diagnóstico , Antifúngicos/uso terapêutico , Diagnóstico Diferencial , Humanos , Itraconazol/uso terapêutico , Masculino , Pessoa de Meia-Idade , Paracoccidioides/isolamento & purificação , Paracoccidioidomicose/tratamento farmacológico
18.
J Diabetes Res ; 2018: 6209694, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30426021

RESUMO

Paracoccidioidomycosis, a key issue for Brazilian health service, can be aggravated in patients with impaired immunological responses, such as diabetic patients. We evaluated the role of insulin in inflammatory parameters in diabetic and nondiabetic mice using a systemic mycosis Paracoccidioides brasiliensis (Pb) model. Diabetic C57BL-6 mice and controls were infected with Pb18 and treated with insulin for 12 days prior to experiments. After 55 days, infected diabetic mice exhibited fewer leukocytes in both peritoneal lavage fluid (PeLF) and bronchoalveolar lavage fluid and reduced secretion of interleukin- (IL-) 6 in lungs. In addition, diabetic mice presented a reduced influx of TCD4+ cells, TCD8+ cells, B lymphocytes, NK cells, and dendritic cells compared to control infected groups. Insulin treatment restored the leukocyte number in PeLF and restored the presence of B lymphocytes, dendritic cells, and NK cells in lungs of diabetic animals. The data suggest that diabetic mice present impaired immunological response to Pb18 infection and insulin modulates inflammation by reducing IL-6 levels in lung and CINC-1 levels in spleen and liver homogenates, restoring leukocyte concentrations in PeLF and also restoring populations of dendritic cells and B lymphocytes in lungs of diabetic mice, permitting the host to better control the infection.


Assuntos
Linfócitos B/efeitos dos fármacos , Células Dendríticas/efeitos dos fármacos , Hipoglicemiantes/uso terapêutico , Inflamação/tratamento farmacológico , Insulina/uso terapêutico , Células Matadoras Naturais/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Paracoccidioidomicose/tratamento farmacológico , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Paracoccidioides
19.
Curr Top Med Chem ; 18(15): 1333-1348, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30277157

RESUMO

The thermally-dimorphic systemic fungal group includes several important human pathogens: Blastomyces dermatitides, Coccidioides immitis and C. posadasii, Histoplasma capsulatum, Paracoccidioides brasiliensis, P. lutzii, and Talaromyces (Penicillium) marneffei. They usually are geographically restricted and have natural habitats in soil or in plants, and when fungal propagules invade mammalian host by inhalation, they initiate an inflammatory reaction that can result in self-resolution of the infection or cause an acute or chronic disease. In the setting of the AIDS pandemic and the developments in modern medicine, such as immunosuppressive therapy in cancer surgery patients and in transplantation and autoimmune diseases, the incidence of endemic mycoses has progressively increased. Another important factor of the increased incidence of systemic mycoses in certain regions is the progressive devastation of tropical and subtropical forests. In this review, we focus on two of the most important systemic mycoses: paracoccidioidomycosis and histoplasmosis, and their major characteristics in epidemiology, clinical aspects and laboratorial diagnosis.


Assuntos
Antifúngicos/farmacologia , Histoplasma/efeitos dos fármacos , Histoplasmose/diagnóstico , Histoplasmose/tratamento farmacológico , Paracoccidioides/efeitos dos fármacos , Paracoccidioidomicose/diagnóstico , Paracoccidioidomicose/tratamento farmacológico , Antifúngicos/química , Histoplasma/isolamento & purificação , Histoplasmose/epidemiologia , Humanos , Testes de Sensibilidade Microbiana , Paracoccidioides/isolamento & purificação , Paracoccidioidomicose/epidemiologia
20.
Artigo em Inglês | MEDLINE | ID: mdl-30150478

RESUMO

Paracoccidioidomycosis (PCM) is the cause of many deaths from systemic mycoses. The etiological agents of PCM belong to the Paracoccidioides genus, which is restricted to Latin America. The infection is acquired through the inhalation of conidia that primarily lodge in the lungs and may disseminate to other organs and tissues. The treatment for PCM is commonly performed via the administration of antifungals such as amphotericin B, co-trimoxazole, and itraconazole. The antifungal toxicity and side effects, in addition to their long treatment times, have stimulated research for new bioactive compounds. Argentilactone is a compound that was isolated from the Brazilian savanna plant Hyptis ovalifolia, and it has been suggested to be a potent antifungal, inhibiting the dimorphism of P. brasiliensis and the enzymatic activity of isocitrate lyase, a key enzyme of the glyoxylate cycle. This work was developed due to the importance of elucidating the putative mode of action of argentilactone. The chemoproteomics approach via affinity chromatography was the methodology used to explore the interactions between P. brasiliensis proteins and argentilactone. A total of 109 proteins were identified and classified functionally. The most representative functional categories were related to amino acid metabolism, energy, and detoxification. Argentilactone inhibited the enzymatic activity of malate dehydrogenase, citrate synthase, and pyruvate dehydrogenase. Furthermore, argentilactone induces the production of reactive oxygen species and inhibits the biosynthesis of cell wall polymers.


Assuntos
Antifúngicos/farmacologia , Lactonas/farmacologia , Paracoccidioides/efeitos dos fármacos , Paracoccidioidomicose/tratamento farmacológico , Células A549 , Anfotericina B/farmacologia , Brasil , Linhagem Celular Tumoral , Parede Celular/efeitos dos fármacos , Humanos , Itraconazol/farmacologia
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