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1.
Molecules ; 26(19)2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34641359

RESUMO

The increasing incidence of antifungal resistance represents a great challenge in the medical area and, for this reason, new therapeutic alternatives for the treatment of fungal infections are urgently required. Cold atmospheric plasma (CAP) has been proposed as a promising alternative technique for the treatment of superficial candidiasis, with inhibitory effect both in vitro and in vivo. However, little is known on the association of CAP with conventional antifungals. The aim of this study was to evaluate the effects of the association between CAP and conventional polyene antifungals on Candida albicans biofilms. C. albicans SC 5314 and a clinical isolate were used to grow 24 or 48 h biofilms, under standardized conditions. After that, the biofilms were exposed to nystatin, amphotericin B and CAP, separately or in combination. Different concentrations of the antifungals and sequences of treatment were evaluated to establish the most effective protocol. Biofilms viability after the treatments was compared to negative control. Data were compared by One-way ANOVA and post hoc Tukey (5%). The results demonstrate that 5 min exposure to CAP showed more effective antifungal effect on biofilms when compared to nystatin and amphotericin B. Additionally, it was detected that CAP showed similar (but smaller in magnitude) effects when applied in association with nystatin and amphotericin B at 40 µg/mL and 60 µg/mL. Therefore, it can be concluded that the application of CAP alone was more effective against C. albicans biofilms than in combination with conventional polyene antifungal agents.


Assuntos
Anfotericina B/farmacologia , Antifúngicos/farmacologia , Biofilmes/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Sinergismo Farmacológico , Nistatina/farmacologia , Gases em Plasma/farmacologia , Biofilmes/crescimento & desenvolvimento , Candida albicans/crescimento & desenvolvimento
2.
Appl Microbiol Biotechnol ; 105(16-17): 6355-6367, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34410437

RESUMO

Recently, the occurrence of candidiasis has increased dramatically, especially in immunocompromised patients. Additionally, their treatment is often ineffective due to the resistance of yeasts to antimycotics. Therefore, there is a need to search for new antifungals. A series of nine newly synthesized thiazole derivatives containing the cyclopropane system, showing promising activity against Candida spp., has been further investigated. We decided to verify their antifungal activity towards clinical Candida albicans isolated from the oral cavity of patients with hematological malignancies and investigate the mode of action on fungal cell, the effect of combination with the selected antimycotics, toxicity to erythrocytes, and lipophilicity. These studies were performed by the broth microdilution method, test with sorbitol and ergosterol, checkerboard technique, erythrocyte lysis assay, and reversed phase thin-layer chromatography, respectively. All derivatives showed very strong activity (similar and even higher than nystatin) against all C. albicans isolates with minimal inhibitory concentration (MIC) = 0.008-7.81 µg/mL Their mechanism of action may be related to action within the fungal cell wall structure and/or within the cell membrane. The interactions between the derivatives and the selected antimycotics (nystatin, chlorhexidine, and thymol) showed additive effect only in the case of combination some of them and thymol. The erythrocyte lysis assay confirmed the low cytotoxicity of these compounds as compared to nystatin. The high lipophilicity of the derivatives was related with their high antifungal activity. The present studies confirm that the studied thiazole derivatives containing the cyclopropane system appear to be a very promising group of compounds in treatment of infections caused by C. albicans. However, this requires further studies in vivo. KEY POINTS: • The newly thiazoles showed high antifungal activity and some of them - additive effect in combination with thymol. • Their mode of action may be related with the influence on the structure of the fungal cell wall and/or the cell membrane. • The low cytotoxicity against erythrocytes and high lipophilicity of these derivatives are their additional good properties.


Assuntos
Antifúngicos , Candida albicans , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Candida , Humanos , Testes de Sensibilidade Microbiana , Nistatina , Tiazóis
3.
Molecules ; 26(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34361779

RESUMO

Delivering nucleic acids into the endothelium has great potential in treating vascular diseases. However, endothelial cells, which line the vasculature, are considered as sensitive in nature and hard to transfect. Low transfection efficacies in endothelial cells limit their potential therapeutic applications. Towards improving the transfection efficiency, we made an effort to understand the internalization of lipoplexes into the cells, which is the first and most critical step in nucleic acid transfections. In this study, we demonstrated that the transient modulation of caveolae/lipid rafts mediated endocytosis with the cholesterol-sequestrating agents, nystatin, filipin III, and siRNA against Cav-1, which significantly increased the transfection properties of cationic lipid-(2-hydroxy-N-methyl-N,N-bis(2-tetradecanamidoethyl)ethanaminium chloride), namely, amide liposomes in combination with 1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) (AD Liposomes) in liver sinusoidal endothelial cells (SK-Hep1). In particular, nystatin was found to be highly effective with 2-3-fold enhanced transfection efficacy when compared with amide liposomes in combination with Cholesterol (AC), by switching lipoplex internalization predominantly through clathrin-mediated endocytosis and macropinocytosis.


Assuntos
Cavéolas/efeitos dos fármacos , Colesterol/química , Células Endoteliais/efeitos dos fármacos , Lipossomos/química , Microdomínios da Membrana/efeitos dos fármacos , Transfecção/métodos , Animais , Cavéolas/química , Cavéolas/metabolismo , Caveolina 1/antagonistas & inibidores , Caveolina 1/genética , Caveolina 1/metabolismo , Linhagem Celular Transformada , Colesterol/metabolismo , Clatrina/metabolismo , DNA/química , DNA/metabolismo , Endocitose/efeitos dos fármacos , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Filipina/química , Filipina/farmacologia , Expressão Gênica , Lipossomos/metabolismo , Microdomínios da Membrana/química , Microdomínios da Membrana/metabolismo , Nistatina/química , Nistatina/farmacologia , Fosfatidiletanolaminas/química , Fosfatidiletanolaminas/farmacologia , Pinocitose/efeitos dos fármacos , Plasmídeos/química , Plasmídeos/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ratos
4.
Molecules ; 26(12)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200814

RESUMO

Multi-drug resistant pathogens are a rising danger for the future of mankind. Iodine (I2) is a centuries-old microbicide, but leads to skin discoloration, irritation, and uncontrolled iodine release. Plants rich in phytochemicals have a long history in basic health care. Aloe Vera Barbadensis Miller (AV) and Salvia officinalis L. (Sage) are effectively utilized against different ailments. Previously, we investigated the antimicrobial activities of smart triiodides and iodinated AV hybrids. In this work, we combined iodine with Sage extracts and pure AV gel with polyvinylpyrrolidone (PVP) as an encapsulating and stabilizing agent. Fourier transform infrared spectroscopy (FT-IR), Ultraviolet-visible spectroscopy (UV-Vis), Surface-Enhanced Raman Spectroscopy (SERS), microstructural analysis by scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS), and X-Ray-Diffraction (XRD) analysis verified the composition of AV-PVP-Sage-I2. Antimicrobial properties were investigated by disc diffusion method against 10 reference microbial strains in comparison to gentamicin and nystatin. We impregnated surgical sutures with our biohybrid and tested their inhibitory effects. AV-PVP-Sage-I2 showed excellent to intermediate antimicrobial activity in discs and sutures. The iodine within the polymeric biomaterial AV-PVP-Sage-I2 and the synergistic action of the two plant extracts enhanced the microbial inhibition. Our compound has potential for use as an antifungal agent, disinfectant and coating material on sutures to prevent surgical site infections.


Assuntos
Antibacterianos/química , Antibacterianos/síntese química , Aloe/química , Antifúngicos/química , Gentamicinas/química , Testes de Sensibilidade Microbiana , Microscopia Eletrônica de Varredura/métodos , Nistatina/química , Extratos Vegetais/química , Povidona/química , Salvia/química , Salvia officinalis/química , Espectrometria por Raios X/métodos , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Difração de Raios X/métodos
6.
An Acad Bras Cienc ; 93(2): e20190366, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33950151

RESUMO

Candida spp. are naturally opportunistic and can promote infections. These yeasts can form biofilm, after penetration and adhesion to the biotic or abiotic surfaces. Preexisting diseases, treatments with drugs and radiation therapy, medical procedures, and parafunctional habits favor the installation of a fungal infection. Increased resistance to the available antifungals has become a concern. Therefore, alternative methods to control them have been evaluated, including the use of plant substances. In this study, the antibiofilm effect of R. officinalis L. extract was analyzed on C. albicans, C. dubliniensis, C. glabrata, C. krusei, and C. tropicalis. A phytochemical analysis of the extract was performed. Biofilms were formed for 48 h and exposed to the different concentrations of the extract (50, 100, and 200 mg/mL) for 5 min or 24 h. The effect of the plant extract was compared to the antifungal nystatin. Rosmarinus officinalis L. extract was constituted of phenols and flavonoids, highlighting the presence of chlorogenic acid derivatives in its composition. Biofilm reductions were observed after exposure to the plant extract for both periods. The plant extract provided a reduction similar to the antifungal. Thus, R. officinalis L. extract showed antibiofilm effect on Candida spp. comparable to the nystatin.


Assuntos
Candida , Rosmarinus , Antifúngicos/farmacologia , Biofilmes , Candida albicans , Testes de Sensibilidade Microbiana , Nistatina/farmacologia , Extratos Vegetais/farmacologia
8.
Drug Dev Ind Pharm ; 47(5): 825-837, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34033502

RESUMO

OBJECTIVE: The objective of this work was to prepare mucoadhesive buccal tablets containing nystatin and purified cashew gum for the treatment of oral candidiasis. SIGNIFICANCE: Mucoadhesive buccal tablets containing the drug nystatin are an alternative to oral suspensions, which cause low therapeutic adherence to the treatment of oral candidiasis. Purified cashew gum has been studied as a diluent and mucoadhesive agent in tablets. METHODS: Two batches of mucoadhesive tablets were produced, MT1 and MT 2, containing purified cashew gum, nystatin (500,000 IU), flavoring agent and with or without the presence of lubricant agent. The average weight, mechanical properties, dose uniformity, drug release profile, mucoadhesive properties and antimicrobial activity against Candida albicans were evaluated. RESULTS: Tablets presented average weight of 329.1 ± 3.1 mg (MT1) and 334.6 ± 1.5 mg (MT2), hardness of 9.8 ± 0.8 KgF (MT1) and 8.3 ± 0.4 KgF (MT2), friability of 0.2% (MT1 and MT2), and dose uniformity of 102.20 ± 1.17% (MT1) and 99.06 ± 7.40% (MT2). MT1 and MT2 were able to swell, erode, release the drug and remain adhered to the pig's cheek up to 3 h for batch MT1 and 4 h for batch MT2, and the amount of nystatin released since the beginning of the test in both batches was sufficient to inhibit the growth of the fungus. CONCLUSIONS: Therefore, the proposed formulation proved to be very promising and met all the studied criteria, showing to be ideal for the treatment of oral candidiasis.


Assuntos
Anacardium , Candidíase Bucal , Candidíase Bucal/tratamento farmacológico , Preparações de Ação Retardada/uso terapêutico , Mucosa Bucal , Nistatina/uso terapêutico , Solubilidade , Comprimidos/uso terapêutico
9.
Photodiagnosis Photodyn Ther ; 35: 102292, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33857598

RESUMO

The study evaluated the effect of antimicrobial photodynamic therapy (aPDT) and nystatin (NYS) in the expression of genes (ACT1, ALS1, CAP1, CAT1, EFG1, HWP1, LIP3, PLB1, SAP1, and SOD1) involved in the virulence of Candida albicans strains recovered from patients with denture stomatitis (DS). These strains were isolated from the patients before (initial) and after treatment (final), and 45 days after the treatments (follow-up). For gene expression analyses, RNA was isolated from the clinical strains, followed by cDNA synthesis and qPCR using specific primers for each target gene. The samples that present integrity were pooled to increase the RNA yield. In the end, four patients treated with aPDT and five patients treated with NYS had the clinical isolates of C. albicans submitted to gene expression evaluation. The data demonstrated a statistical difference in the expression of PLB1 and ACT1 for the different therapies (aPDT versus NYS). Also, there was a statistical difference in the expression of CAT1, SOD1, and LIP3 at the time intervals assessed (initial, final, and follow-up). In contrast, no statistical difference was found in the expression of ALS1, HWP1, EFG1, CAP1, CAT1, SOD1, LIP3, and SAP1 between the therapies, while no significant difference was detected at the time intervals evaluated for ALS1, HWP1, EFG1, CAP1, and SAP1. Therefore, the topical treatments for DS with aPDT or NYS did not effect the expression of most C. albicans virulence genes evaluated.


Assuntos
Fotoquimioterapia , Estomatite sob Prótese , Candida albicans/genética , Expressão Gênica , Humanos , Nistatina/uso terapêutico , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/uso terapêutico , Estomatite sob Prótese/tratamento farmacológico
10.
Rev. Asoc. Odontol. Argent ; 109(1): 59-63, ene.-abr. 2021. ilus
Artigo em Espanhol | LILACS | ID: biblio-1281778

RESUMO

Objetivo: Describir el diagnóstico y el tratamiento interdisciplinario de un caso clínico de histoplasmosis. Caso clínico: Un paciente masculino de 39 años, con antecedentes de consumo de drogas, alcohol, tabaquismo crónico y VIH+ sin adherencia al tratamiento, acudió al Servicio de Odontología por una interconsulta del Servicio de Clínica Médica para la evaluación de lesiones erosivas en paladar duro y blando, reborde alveolar anterior, dorso lingual y lesión tumoral en encía anterosuperior. El diagnóstico definitivo se obtuvo por medio del análisis de muestras de biopsia transbronquial, lavado broncoalveolar y biopsia de lesión en piel. El paciente recibió tratamiento sistémico con antimicóticos (anfotericina B e itraconazol según esquema) y tratamiento local con colutorio de clorhexidina al 0,12% y 100.000 UI de nistatina en suspensión. Al momento del alta, presentaba una considerable mejoría de su estado general y de las lesiones orales, con disminución de sintomatología dolorosa. Se indicó turno para control a los 7 días de forma ambulatoria, al cual el paciente no asistió. El abordaje interdisciplinario y el análisis de los diferentes aspectos socioeconómicos, culturales, ambientales y sistémicos del paciente facilitaron el diagnóstico temprano de la enfermedad (AU)


Aim: To describe the diagnosis and interdisciplinary treatment of a clinical case of histoplasmosis. Clinical case: 39-year-old male patient with a history of drug abuse, alcohol, and chronic smoking, HIV+ without treatment compliance, attends the dental department referred by the medical department for the diagnosis of erosive lesions in the hard and soft palate, anterior alveolar ridge, lingual dorsum and tumor lesion in the anterosuperior gingiva. The definitive diagnosis was obtained by the analysis of transbronchial biopsy, bronchoalveolar lavage and skin lesion biopsy. The patient received systemic treatment with antifungals (amphotericin b, itraconazole according to protocol), and local treatment with 0.12% chlorhexidine mouthwash and 100,000 IU nystatin suspension. At the time of medical discharge, the patient presented a considerable improvement in his general condition and of the oral lesions with a reduced pain. A 7 days recall was prescribed, however the patient failed to attend. The interdisciplinary approach to the patient and the analysis of the different socio-economic, cultural, environmental and systemic aspects of the patient facilitates the early diagnosis of the disease (AU)


Assuntos
Humanos , Masculino , Adulto , Manifestações Bucais , HIV , Assistência Odontológica para Doentes Crônicos , Histoplasmose , Argentina , Biópsia , Anfotericina B , Nistatina , Imunossupressão/efeitos adversos , Itraconazol , Lavagem Broncoalveolar , Unidade Hospitalar de Odontologia , Diagnóstico Precoce , Mucosa Bucal/lesões , Antifúngicos
11.
J Appl Oral Sci ; 28: e20200639, 2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33656098

RESUMO

OBJECTIVE: To evaluate the surface morphology and in vitro leachability of temporary soft linings modified by the incorporation of antifungals in minimum inhibitory concentrations (MIC) for Candida albicans biofilm. METHODOLOGY: Specimens of soft lining materials Softone and Trusoft were made without (control) or with the addition of nystatin (Ny), miconazole (Mc), ketoconazole (Ke), chlorhexidine diacetate (Chx), or itraconazole (It) at their MIC for C. albicans biofilm. The surface analyses were performed using Confocal laser scanning microscopy after 24 h, 7 days, or 14 days of immersion in distilled water at 37ºC. In vitro leachability of Chx or Ny from the modified materials was also measured using Ultraviolet visible spectroscopy for up to 14 days of immersion in distilled water at 37ºC. Data (µg/mL) were submitted to ANOVA 1-factor/Bonferroni (α=0.05). RESULTS: Softone had a more irregular surface than Trusoft. Morphological changes were noted in both materials with increasing immersion time, particularly, in those containing drugs. Groups containing Chx and It presented extremely porous and irregular surfaces. Both materials had biexponential release kinetics. Softone leached a higher concentration of the antifungals than Trusoft (p=0.004), and chlorhexidine was released at a higher concentration than nystatin (p<0.001). CONCLUSIONS: The surface of the soft lining materials changed more significantly with the addition of Chx or It. Softone released a higher concentration of drugs than Trusoft did, guiding the future treatment of denture stomatitis.


Assuntos
Reembasadores de Dentadura , Estomatite sob Prótese , Antifúngicos , Candida albicans , Humanos , Cetoconazol , Teste de Materiais , Nistatina , Estomatite sob Prótese/tratamento farmacológico , Propriedades de Superfície
12.
Nat Commun ; 12(1): 1140, 2021 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-33602902

RESUMO

Clostridioides difficile spores produced during infection are important for the recurrence of the disease. Here, we show that C. difficile spores gain entry into the intestinal mucosa via pathways dependent on host fibronectin-α5ß1 and vitronectin-αvß1. The exosporium protein BclA3, on the spore surface, is required for both entry pathways. Deletion of the bclA3 gene in C. difficile, or pharmacological inhibition of endocytosis using nystatin, leads to reduced entry into the intestinal mucosa and reduced recurrence of the disease in a mouse model. Our findings indicate that C. difficile spore entry into the intestinal barrier can contribute to spore persistence and infection recurrence, and suggest potential avenues for new therapies.


Assuntos
Clostridioides difficile/fisiologia , Infecções por Clostridium/microbiologia , Células Epiteliais/microbiologia , Células Epiteliais/patologia , Intestinos/microbiologia , Intestinos/patologia , Esporos Bacterianos/fisiologia , Animais , Aderência Bacteriana/efeitos dos fármacos , Proteínas de Bactérias/metabolismo , Linhagem Celular , Clostridioides difficile/efeitos dos fármacos , Clostridioides difficile/ultraestrutura , Colágeno/metabolismo , Endocitose , Células Epiteliais/ultraestrutura , Feminino , Fibronectinas/metabolismo , Humanos , Integrinas/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Masculino , Camundongos Endogâmicos C57BL , Nistatina/farmacologia , Ligação Proteica/efeitos dos fármacos , Recidiva , Esporos Bacterianos/efeitos dos fármacos , Esporos Bacterianos/ultraestrutura , Ácido Taurocólico/farmacologia , Vitronectina/metabolismo
13.
Int J Nanomedicine ; 16: 1157-1174, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33623380

RESUMO

Introduction: Candida albicans is a major opportunistic pathogen that causes a wide range of human infections. Currently available therapeutic agents are limited for treating these fungal infections due to multidrug resistance as well as their nonbiodegradability, poor biocompatibility and toxicity. In order to battle these limitations, we have synthesized a polymeric system as microcarriers to deliver the antifungal drug. The objective of the present study was to immobilize MgO/CuO nanocomposite and nystatin-loaded MgO/CuO nanocomposites in nontoxic, nonimmunogenic, biodegradable and biocompatible sodium alginate microspheres for the first time. Materials and Methods: Nanoparticle-loaded sodium alginate microspheres were prepared by ionotropic gelation technique using calcium chloride as a cross-linker. Synthesized microspheres were characterized using standard characterization techniques and were evaluated for biological activity against MDR strain of C. albicans. Results: Characterization of microspheres by Fourier-transform infrared spectroscopy confirmed loading of Nys-MgO/CuO NPs, scanning electron microscopy (SEM) revealed rough spherical beads with a highly porous surface having an average size in the range of 8-10 µm. X-ray diffraction (XRD) analyzed its semicrystalline structure. Entrapment efficiency of Nys-MgO/CuO NPs was 80% and release kinetic study revealed sustained and prolonged release of drug in pH 5.5. Flow cytometry analysis showed yeast cell death caused by Nys-MgO/CuO MS exhibits late apoptotic features. In cytotoxicity assay 5-14 mg of microspheres did not cause hemolysis. Microspheres reduced virulence traits of C. albicans such as germ tube and biofilm formation were compromised at concentration of 5 mg/mL. Antimicrobial assessment results revealed a pronounced inhibitory effect against C. albicans. Conclusion: The in vitro experiments have shown promising results based on good stability, Nys-MgO/CuO NP-encapsulated microspheres can be used as a prolonged controlled release system against MDR pathogenic C. albicans.


Assuntos
Alginatos/química , Candida albicans/patogenicidade , Cobre/química , Resistência a Múltiplos Medicamentos , Óxido de Magnésio/química , Microesferas , Nanocompostos/química , Nistatina/farmacologia , Anti-Infecciosos/farmacologia , Biofilmes/efeitos dos fármacos , Liberação Controlada de Fármacos , Eritrócitos/efeitos dos fármacos , Hemólise/efeitos dos fármacos , Humanos , Cinética , Testes de Sensibilidade Microbiana , Tamanho da Partícula , Fenótipo , Espectroscopia de Infravermelho com Transformada de Fourier , Virulência/efeitos dos fármacos , Fatores de Virulência/metabolismo , Difração de Raios X
14.
Spec Care Dentist ; 41(3): 349-357, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33475184

RESUMO

AIM: It was analyzed the efficacy of mouthwash and spray containing essential oil (EO) of Cinnamomum zeylanicum Blume for the treatment of oral candidiasis. METHODS AND RESULTS: A randomized, controlled, and blinded clinical trial was conducted with 36 individuals (probabilistic sample) with oral candidiasis who were divided into two treatment groups: C. zeylanicum (0.5 mg/mL), n = 18; nystatin (100,000IU/mL), n = 18. The efficacy of the products was evaluated by two parameters: (a) clinical evolution recorded by calibrated examiners (Kappa = 0.822) according to Newton's classification and (b) reduction of colony-forming units/mL. Mycological and clinical parameters were analyzed before and at 15 days after treatment. Clinical examination of the mucosa showed that C. zeylanicum (p < 0.0339) and nystatin (p < .0139) had efficacy, resulting in a reduction of signs and symptoms (Mann-Whitney test). Mycological analysis showed that C. zeylanicum caused a reduction of 61% and 33% of Candida spp., isolates oral mucosa and dentures, respectively. Candida tropicalis strains were eliminated after C. zeylanicum, in both sites. The participants reported a pleasant taste and few product-related complaints. CONCLUSION: C. zeylanicum EO and nystatin exhibited clinical efficacy, according to the Newton classification, and reducing in Candida spp. The clinical trial has been registered (Registration number: NBR-33s6 × 5, ensaiosclinicos.gov.br).


Assuntos
Candidíase Bucal , Óleos Voláteis , Antifúngicos/uso terapêutico , Candidíase Bucal/tratamento farmacológico , Cinnamomum zeylanicum , Humanos , Nistatina/uso terapêutico , Óleos Voláteis/uso terapêutico
15.
Photodiagnosis Photodyn Ther ; 33: 102155, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33444787

RESUMO

This investigation assessed the effect of five consecutive daily topical treatments of antimicrobial photodynamic therapy (aPDT), nystatin (NYS), and an association of treatments on a fluconazole-resistant strain of Candida albicans colonizing the tongues of mice. After the last treatments application, colonies of C. albicans were recovered from the tongues and used to determine their fluconazole susceptibility. After 24 hours of the last treatment, the mice tongues were processed to evaluate the expression of C. albicans genes related to the virulence and ergosterol production. The fluconazole susceptibility test yielded a resistance profile similar for all treatment groups and the control group (no treatment). The treatments aPDT, NYS, NYS+aPDT, and aPDT+NYS promoted a reduction in ALS1, EFG1, CAP1, SOD1, SAP1, and LIP3 expression. The expression of HWP1 was higher in the three groups containing nystatin. In contrast, the treatments produced a significative increase in CAT1 gene expression, mainly in the groups in which aPDT was performed. The expression of genes related to ergosterol production was significantly reduced by the treatments evaluated (aPDT, NYS, NYS+aPDT, and aPDT+NYS). Thus, the consecutive topical treatments performed on mice tongues promoted a reduction in the expression of virulence and ergosterol biosynthesis genes of a fluconazole-resistant C. albicans.


Assuntos
Fluconazol , Fotoquimioterapia , Animais , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Candida albicans/genética , Ergosterol , Fluconazol/farmacologia , Camundongos , Nistatina/farmacologia , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Virulência
16.
Proteins ; 89(5): 558-568, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33389775

RESUMO

Polyene polyketides amphotericin B (AMB) and nystatin (NYS) are important antifungal drugs. Thioesterases (TEs), located at the last module of PKS, control the release of polyketides by cyclization or hydrolysis. Intrigued by the tiny structural difference between AMB and NYS, as well as the high sequence identity between AMB TE and NYS TE, we constructed four systems to study the structural characteristics, catalytic mechanism, and product release of AMB TE and NYS TE with combined MD simulations and quantum mechanics/molecular mechanics calculations. The results indicated that compared with AMB TE, NYS TE shows higher specificity on its natural substrate and R26 as well as D186 were proposed to a key role in substrate recognition. The energy barrier of macrocyclization in AMB-TE-Amb and AMB-TE-Nys systems were calculated to be 14.0 and 22.7 kcal/mol, while in NYS-TE-Nys and NYS-TE-Amb systems, their energy barriers were 17.5 and 25.7 kcal/mol, suggesting the cyclization with their natural substrates were more favorable than that with exchanged substrates. At last, the binding free energy obtained with the MM-PBSA.py program suggested that it was easier for natural products to leave TE enzymes after cyclization. And key residues to the departure of polyketide product from the active site were highlighted. We provided a catalytic overview of AMB TE and NYS TE including substrate recognition, catalytic mechanism and product release. These will improve the comprehension of polyene polyketide TEs and benefit for broadening the substrate flexibility of polyketide TEs.


Assuntos
Anfotericina B/química , Proteínas de Bactérias/química , Nistatina/química , Streptomyces/enzimologia , Tioléster Hidrolases/química , Anfotericina B/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Sítios de Ligação , Biocatálise , Domínio Catalítico , Ciclização , Ligação de Hidrogênio , Hidrólise , Interações Hidrofóbicas e Hidrofílicas , Isoenzimas/química , Isoenzimas/genética , Isoenzimas/metabolismo , Cinética , Modelos Moleculares , Simulação de Dinâmica Molecular , Mutação , Nistatina/metabolismo , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Teoria Quântica , Streptomyces/química , Especificidade por Substrato , Termodinâmica , Tioléster Hidrolases/genética , Tioléster Hidrolases/metabolismo
17.
Transpl Infect Dis ; 23(3): e13559, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33387388

RESUMO

OBJECTIVE: To compare the incidence of oropharyngeal candidiasis (OC), or thrush, in renal transplant recipients receiving nystatin versus no antifungal prophylaxis. METHODS: This was a single-center, retrospective, non-inferiority study of adult renal transplant recipients (RTRs) who received nystatin for 30 days for OC prophylaxis (nystatin group) or no antifungal prophylaxis therapy (No PPX group). The primary outcome was the incidence of OC within 3 months post-transplant. Secondary outcomes included time to OC occurrence and severity of OC. The pre-specified non-inferiority margin was 10%. RESULTS: The incidence of OC within 3 months post-transplant among 257 RTRs was 7.8% (10/128) in the No PPX group and 4.7% (6/129) RTRs in the nystatin group, a risk difference of 3.2% (95% CI, -2.7% to 9.1%, non-inferiority P = .04). The median time to OC was 7.5 days (IQR 6.3-34.3 days) in the nystatin group and 9.5 days (IQR 5.3-30.5 days) in the No PPX group (P = .64). Esophageal candidiasis was observed in 10% (1/10) of RTRs with OC in the No PPX group compared to 16.7% (1/6) RTRs in the nystatin group (P = 1.00). All RTRs with OC achieved symptom resolution with fluconazole and/or nystatin. Two patients in the No PPX group required readmission for decreased oral intake, and OC was diagnosed and treated during their hospital day. CONCLUSIONS: In this retrospective study of adult RTRs, the absence of antifungal prophylaxis demonstrated non-inferiority to 30-day nystatin prophylaxis at reducing the incidence of OC within 3 months of transplant. OC prophylaxis may not be warranted after renal transplant.


Assuntos
Candidíase Bucal , Transplante de Rim , Nistatina/uso terapêutico , Antifúngicos/uso terapêutico , Candidíase Bucal/tratamento farmacológico , Candidíase Bucal/prevenção & controle , Humanos , Estudos Retrospectivos , Transplantados
18.
Laryngoscope ; 131(5): E1640-E1646, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33141477

RESUMO

OBJECTIVES/HYPOTHESIS: To compare the efficacy and adverse effects of triamcinolone acetonide econazole cream and nystatin suspension in the treatment of otomycosis, and to determine the clinical features, predisposing factors, and etiology of otomycosis. STUDY DESIGN: A prospective study. METHODS: A prospective clinical trial was conducted on 786 patients diagnosed with otomycosis. The study population was randomly divided into two treatment groups of triamcinolone acetonide econazole cream (TAEC) and nystatin suspension in a 1:1 ratio. After clearing all fungal deposits in the external auditory canal, the antimycotic drugs were locally applied for at least 2 weeks. The efficacy and adverse effects were compared between the two antifungal reagents by statistical analysis. Meanwhile, patient clinical data were collected to find out the clinical features, predisposing factors, and etiology. RESULTS: Pruritis was the most common symptom and Aspergillus niger was the leading fungal pathogen. There was high association (44.5%) of otomycosis with a history of unclean ear picking. The cure rate was 97.6% in the TAEC group and 73.5% in the nystatin group (P < .01). Treatment with TAEC resulted in 2.4% of patients complaining of discomforts (irritant dermatitis, otalgia, or headache) versus 59.8% of patients complaining discomforts treated with nystatin (P < .01). The residue rate of antifungals was 1.9% in the TAEC group and 89.9% in the nystatin group (P < .01) at the end of treatment. CONCLUSIONS: Thoroughly cleaning of the external auditory canal followed by local use of TAEC under endotoscope is an effective, convenient, and well-tolerated treatment for otomycosis. LEVEL OF EVIDENCE: 1 Laryngoscope, 131:E1640-E1646, 2021.


Assuntos
Antifúngicos/administração & dosagem , Aspergilose/tratamento farmacológico , Econazol/administração & dosagem , Nistatina/administração & dosagem , Otomicose/tratamento farmacológico , Triancinolona Acetonida/administração & dosagem , Administração Tópica , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antifúngicos/efeitos adversos , Aspergilose/diagnóstico , Aspergilose/microbiologia , Aspergillus niger/isolamento & purificação , Criança , Pré-Escolar , Dermatite Irritante/epidemiologia , Dermatite Irritante/etiologia , Combinação de Medicamentos , Meato Acústico Externo/efeitos dos fármacos , Meato Acústico Externo/microbiologia , Dor de Orelha/induzido quimicamente , Dor de Orelha/epidemiologia , Econazol/efeitos adversos , Feminino , Cefaleia/induzido quimicamente , Cefaleia/epidemiologia , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Nistatina/efeitos adversos , Otomicose/microbiologia , Estudos Prospectivos , Suspensões , Resultado do Tratamento , Triancinolona Acetonida/efeitos adversos , Adulto Jovem
19.
Biochim Biophys Acta Biomembr ; 1863(2): 183528, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33279513

RESUMO

Nystatin is an antifungal polyene macrolide which is widely applied to treat yeast infections. Nystatin has also been used as a laboratory tool to inhibit endocytic processes in mammalian cells. The interaction of nystatin with model membranes has been studied thoroughly by various spectroscopic methods, making use of its weak fluorescence in the ultraviolet (UV). Studying its interaction with cells would require direct imaging, which, so far, required attachment of a fluorophore to nystatin. Using UV-sensitive microscopy, we show here how to visualize the interaction of nystatin with the plasma membrane (PM) directly. We find that nystatin forms micron-sized aggregates in buffer, and molecular dynamics simulations confirm that nystatin rapidly self-assembles into aggregates in aqueous solution. Using UV-sensitive microscopy, we find that large nystatin aggregates adhere to the surface of Chinese Hamster Ovarian (CHO) cells, causing slow spreading of nystatin fluorescence into the PM. Binding of nystatin to CHO cells does not interfere with cellular uptake or lateral membrane diffusion of the cholesterol analogue TopFluor-cholesterol (TF-Chol). Nystatin binds extensively to the PM of yeast cells as inferred from a strong UV signal in this membrane. Loading a yeast mutant unable to synthesize ergosterol with cholesterol gave much less nystatin membrane staining compared to loading such cells with ergosterol. These results explain the selective fungicidal effect of nystatin by differential interaction of nystatin with yeast membranes containing ergosterol compared to the mammalian cholesterol. Our combined experimental and computational approach provides a toolset for future design of new polyene macrolides.


Assuntos
Antifúngicos , Membrana Celular/metabolismo , Nistatina , Saccharomyces cerevisiae/metabolismo , Animais , Antifúngicos/farmacocinética , Antifúngicos/farmacologia , Células CHO , Cricetulus , Nistatina/farmacocinética , Nistatina/farmacologia , Saccharomyces cerevisiae/citologia
20.
Methods Mol Biol ; 2188: 93-108, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33119848

RESUMO

The automated patch clamp (APC) technology is used for increasing the data throughput of electrophysiological measurements, especially in safety pharmacology and drug discovery. Typically, electrical access to the cells are obtained using standard whole-cell formation by rupturing the membrane, thereby causing a rapid washout of cytosolic components. In contrast the perforated whole-cell configuration provides electrical access to the cell interior while limiting intracellular wash-out. This method allows for recordings of ion channels that are gated by intracellular modulators (e.g., ATP, cyclic nucleotides, or Ca2+), prevents channel current "run down," and maintains a physiological membrane potential for action potential recordings. Here we present some practical approaches to the use of perforated patch clamp for APC recordings. Our findings from these high-throughput, data-rich measurements (e.g., defining optimized concentrations and practical recommendations for four different perforating agents) can be more broadly applied to perforated patch clamp experiments in general (automated and manual), improving success rates, experimental conditions, and applications.


Assuntos
Técnicas de Patch-Clamp/métodos , Potenciais de Ação , Anfotericina B/química , Animais , Células CHO , Técnicas de Cultura de Células/métodos , Linhagem Celular , Cricetulus , Fenômenos Eletrofisiológicos , Desenho de Equipamento , Humanos , Canais Iônicos/metabolismo , Potenciais da Membrana , Nistatina/química , Técnicas de Patch-Clamp/instrumentação
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