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1.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(5): 1504-1509, 2021 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-34627431

RESUMO

OBJECTIVE: To investigate the effect of arsenic disulfide (AS2S2) combined with itraconazole on the proliferation, apoptosis and hedgehog pathway of diffuse large B-cell lymphoma (DLBCL) cells. METHODS: The human DLBCL cell OCI-LY3 was treated with different concentrations of AS2S2 and itraconazole. Cell proliferation inhibition was detected by CCK-8, cell apoptosis rate was determined by flow cytometry. The expression levels of BCL-2, BAX, SMO and GLi1 were detected by Western blot. RESULTS: The DLBCL cell viability was decreased significantly at 24, 48 or 72 h as cultured with itraconazole. Along with the increasing of itraconazole concentration, the DLBCL cell viability was significantly reduced as compared with that in control group, and the results showed statistically significant(r=-0.690,r=-0.639, r=-0.833, r=-0.808, r=-0.578). The inhibitory and apoptosis rates of the cells were significantly increased as compared with those of the single drug-treated group after treated by the combination of itraconazole and AS2S2(P<0.05). The protein levels of SMO and Glil were significantly down-regulated after treated by arsenic disulfide and itraconazole alone(P<0.01). The protein expression levels of SMO and Glil was down-regulated in the combined-treatment group(P<0.01). CONCLUSION: Itraconazole can inhibit proliferation of DLBCL cells in a concentration-and time-dependent manner. In addition, the combination of AS2S2 and itraconazole show a synergistic effects, which may be related with the down-regulated protein expression of SMO and Glil of Hedgehog signaling pathway.


Assuntos
Proteínas Hedgehog , Linfoma Difuso de Grandes Células B , Apoptose , Arsenicais , Humanos , Itraconazol/farmacologia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Sulfetos
2.
Anticancer Res ; 41(9): 4271-4276, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475046

RESUMO

BACKGROUND/AIM: The anticancer mechanism of itraconazole remains unsolved; therefore, we studied itraconazole-induced alterations in specialized pro-resolving mediators (SPMs) in cancer cells. MATERIALS AND METHODS: The human cervical squamous carcinoma cell line CaSki was cultured with or without 1 µM itraconazole. Liquid chromatography/mass spectrometry analysis was conducted to identify SPMs that were influenced by itraconazole. Cell growth experiments were conducted using itraconazole and inhibitors targeting the metabolic pathways of candidate SPMs. RESULTS: Resolvin E3, resolvin E2, prostaglandin J2 (PGJ2), delta-12-PGJ2, and maresin 2 were identified as candidate SPMs. The 12/15-lipoxygenase inhibitor, which is involved in the conversion of 18-hydroxy-eicosapentaenoic acid to resolvin E3, attenuated the inhibitory effect of itraconazole. Inhibition of the PGJ2 metabolic pathway did not interfere with itraconazole treatment. CONCLUSION: The metabolic pathway of SPMs, including resolving E3, could be proposed as an anticancer target of itraconazole.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Ácidos Graxos Insaturados/metabolismo , Itraconazol/farmacologia , Inibidores de Lipoxigenase/farmacologia , Neoplasias do Colo do Útero/metabolismo , Carcinoma de Células Escamosas/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Espectrometria de Massas , Redes e Vias Metabólicas/efeitos dos fármacos , Neoplasias do Colo do Útero/tratamento farmacológico
3.
J Vet Med Sci ; 83(7): 1090-1092, 2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34108335

RESUMO

We isolated ascomycetous yeasts including Candida species, that originally belonged to the genus Candida, from bulk milk in the Aichi area of Japan, and determined the minimum inhibitory concentrations (MICs) of antifungal drugs on these isolates by conducting E-tests. We isolated 7 human pathogenic species (14 isolates) from 14 bulk milk samples: 5 Candida species of yeasts, and 2 Candida-related species. Two isolates of C. albicans and C. inconspicua were resistant to fluconazole (MIC >32 mg/l). One isolate of C. krusei was resistant to both azoles (fluconazole: >256 mg/ml and itraconazole: 4 mg/l). One isolate of C. catenulata might be resistant to amphotericin B (>32 mg/l).


Assuntos
Antifúngicos , Leite , Animais , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Candida , Farmacorresistência Fúngica , Fluconazol/farmacologia , Itraconazol/farmacologia , Japão , Testes de Sensibilidade Microbiana/veterinária , Leveduras
4.
Antimicrob Agents Chemother ; 65(9): e0043321, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34181477

RESUMO

For many fungal infections, in vitro susceptibility testing is used to predict if an isolate is resistant or susceptible to the antifungal agent used to treat the infection. For Madurella mycetomatis, the main causative agent of mycetoma, in vitro susceptibility testing currently is not performed on a routine basis. The current in vitro susceptibility testing method is labor-intensive, and sonication must be done to generate a hyphal inoculum. For endpoint visualization, expensive viability dyes are needed. Here, we investigated if the currently used in vitro susceptibility method could be adapted to make it amendable for use in a routine setting which can be used in low-income countries, where mycetoma is endemic. First, we developed a methodology in which hyphal fragments can be generated without the need for sonication, by comparing different bead beating methodologies. Next, in vitro susceptibility was assessed using standard broth microdilution assays as well as disc diffusion, Etest, and VIPcheck methodologies. We demonstrate that after a hyphal suspension is generated by glass bead beating, disc diffusion, Etest, and VIPcheck can be used to determine susceptibility of Madurella mycetomatis to itraconazole, posaconazole, and voriconazole. The MICs found with Etest were comparable to those obtained with our modified CLSI-based broth microdilution in vitro susceptibility assay for itraconazole and posaconazole. Furthermore, we found an inverse relationship between the zones of inhibition and MICs obtained with the Etest and those obtained by the modified CLSI broth microdilution technique.


Assuntos
Itraconazol , Madurella , Antifúngicos/farmacologia , Testes de Sensibilidade a Antimicrobianos por Disco-Difusão , Itraconazol/farmacologia , Testes de Sensibilidade Microbiana , Triazóis , Voriconazol/farmacologia
5.
Antimicrob Agents Chemother ; 65(8): e0054621, 2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-33972246

RESUMO

Chromoblastomycosis (CBM) is a chronic subcutaneous infection caused by genera of melanized fungi: Fonsecaea, Cladophialophora, Phialophora, Exophiala, and Rhinocladiella. Melanin is a virulence factor known to influence antifungal susceptibility. A specific inhibitor of melanin biosynthesis is tricyclazole. The aim of this study was to evaluate the effect of melanin inhibition on antifungal susceptibility of chromoblastomycosis agents and describe the susceptibility profiles of some unusual CBM agents. Seventy-six clinical isolates, representing 13 species of the five main genera of CBM agents, were studied. The antifungal susceptibility testing was performed according to the M38-A2 protocol of CLSI (Reference Method for Broth Dilution Antifungal Susceptibility Testing of Filamentous Fungi, 3rd ed., CLSI Standard M38, 2017). In the melanin inhibition test, 16 mg/liter of tricyclazole was added to the medium used in the inoculum preparation and the susceptibility assay. CBM agents were less susceptible to amphotericin B than azoles and terbinafine. The unusual species showed similar susceptibility profiles to those of other species of the same genera. With tricyclazole exposure, MICs of terbinafine, posaconazole, and itraconazole for Fonsecaea spp. significantly decreased (P < 0.05). For Phialophora spp., this reduction was significant for posaconazole and itraconazole. For the other genera, there was a reduction in MICs of terbinafine and itraconazole; however, the statistical tests were not significant. Melanin inhibition can increase the antifungal susceptibility of most CBM agents to itraconazole and terbinafine, the main drugs used in the disease treatment. This increased susceptibility may open up new possibilities for therapy in refractory cases of CBM and/or cases caused by resistant fungal strains. Further studies are needed to confirm the same results in vivo.


Assuntos
Ascomicetos , Cromoblastomicose , Antifúngicos/farmacologia , Cromoblastomicose/tratamento farmacológico , Humanos , Itraconazol/farmacologia , Melaninas , Testes de Sensibilidade Microbiana , Terbinafina
6.
ACS Appl Mater Interfaces ; 13(15): 18128-18141, 2021 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-33840187

RESUMO

The poor solubility of itraconazole (ITZ) has limited its efficacy in the treatment of vaginal candidiasis. Accordingly, the improvement of ITZ solubility using a solid dispersion technique was important to enhance its antifungal activity. Besides, as the purpose of this research was to develop local-targeting formulations, bioadhesive-thermosensitive in situ vaginal gel combined with the gel-flake system was found to be the most suitable choice. To obtain optimum solubility, entrapment efficiency, and drug-loading capacity, optimization of solid dispersion (SD) and gel-flake formulations of ITZ was performed using a composite central design. The results showed that the optimized formulation of SD-ITZ was able to significantly enhance its solubility in both water and simulated vaginal fluid to reach the values of 4.211 ± 0.23 and 4.291 ± 0.21 mg/mL, respectively. Additionally, the optimized formulation of SD-ITZ gel flakes possessed desirable entrapment efficiency and drug-loading capacity. The in situ vaginal gel containing SD-ITZ gel flakes was prepared using PF-127 and PF-68, as the gelling agents, with the addition of hydroxypropyl methylcellulose (HPMC) as the mucoadhesive polymer. It was found that the obtained in situ vaginal gel provided desirable physicochemical properties and was able to retain an amount of more than 4 mg of ITZ in the vaginal tissue after 8 h. Importantly, according to the in vivo antifungal activity using infection animal models, the incorporation of the solid dispersion technique and gel-flake system in the formulation of the bioadhesive-thermosensitive in situ vaginal gel led to the most significant decrease of the growth of Candida albicans reaching <1 log colony-forming units (CFU)/mL or equivalent to <10% of the total colony after 14 days, indicating the improvement of ITZ antifungal activity compared to other treated groups. Therefore, these studies confirmed a great potential to enhance the efficacy of ITZ in treating vaginal candidiasis. Following these findings, several further experiments need to be performed to ensure acceptability and usability before the research reaches the clinical stage.


Assuntos
Antifúngicos/farmacologia , Candidíase/tratamento farmacológico , Itraconazol/farmacologia , Temperatura , Vagina/microbiologia , Adesividade , Animais , Antifúngicos/química , Antifúngicos/uso terapêutico , Feminino , Itraconazol/química , Itraconazol/uso terapêutico , Ratos , Solubilidade , Cremes, Espumas e Géis Vaginais/química , Cremes, Espumas e Géis Vaginais/farmacologia , Cremes, Espumas e Géis Vaginais/uso terapêutico
7.
Br J Pharmacol ; 178(11): 2339-2350, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33825201

RESUMO

BACKGROUND AND PURPOSE: The SARS-COV-2 pandemic and the global spread of coronavirus disease 2019 (COVID-19) urgently call for efficient and safe antiviral treatment strategies. A straightforward approach to speed up drug development at lower costs is drug repurposing. Here, we investigated the therapeutic potential of targeting the interface of SARS CoV-2 with the host via repurposing of clinically licensed drugs and evaluated their use in combinatory treatments with virus- and host-directed drugs in vitro. EXPERIMENTAL APPROACH: We tested the antiviral potential of the antifungal itraconazole and the antidepressant fluoxetine on the production of infectious SARS-CoV-2 particles in the polarized Calu-3 cell culture model and evaluated the added benefit of a combinatory use of these host-directed drugs with the direct acting antiviral remdesivir, an inhibitor of viral RNA polymerase. KEY RESULTS: Drug treatments were well-tolerated and potently impaired viral replication. Importantly, both itraconazole-remdesivir and fluoxetine-remdesivir combinations inhibited the production of infectious SARS-CoV-2 particles > 90% and displayed synergistic effects, as determined in commonly used reference models for drug interaction. CONCLUSION AND IMPLICATIONS: Itraconazole-remdesivir and fluoxetine-remdesivir combinations are promising starting points for therapeutic options to control SARS-CoV-2 infection and severe progression of COVID-19.


Assuntos
COVID-19 , Hepatite C Crônica , Preparações Farmacêuticas , Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/farmacologia , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Fluoxetina/farmacologia , Hepatite C Crônica/tratamento farmacológico , Humanos , Itraconazol/farmacologia , SARS-CoV-2
8.
Artigo em Inglês | MEDLINE | ID: mdl-33820768

RESUMO

Aspergillus niger is an opportunistic pathogen commonly found in a variety of indoor and outdoor environments. An environmental isolate of A. niger from a pig farm was resistant to itraconazole, and in-depth investigations were conducted to better understand cellular responses that occur during growth when this pathogen is exposed to an antifungal. Using a combination of cultivation techniques, antibiotic stress testing, and label-free proteomics, this study investigated the physiological and metabolic responses of A. niger to sublethal levels of antifungal stress. Challenging A. niger with itraconazole inhibited growth, and the MIC was estimated to be > 16 mg · liter-1 Through the proteome analysis, 1,305 unique proteins were identified. During growth with 2 and 8 mg · liter-1 itraconazole, a total of 91 and 50 proteins, respectively, were significantly differentially expressed. When challenged with itraconazole, A. niger exhibited decreased expression of peroxidative enzymes, increased expression of an ATP-binding cassette (ABC) transporter most likely involved as an azole efflux pump, and inhibited ergosterol synthesis; however, several ergosterol biosynthesis proteins increased in abundance. Furthermore, reduced expression of proteins involved in the production of ATP and reducing power from both the tricarboxylic acid (TCA) and glyoxylate cycles was observed. The mode of action of triazoles in A. niger therefore appears more complex than previously anticipated, and these observations may help highlight future targets for antifungal treatment.


Assuntos
Aspergillus niger , Itraconazol , Animais , Antifúngicos/farmacologia , Azóis , Farmacorresistência Fúngica/genética , Itraconazol/farmacologia , Testes de Sensibilidade Microbiana , Suínos
9.
Braz J Microbiol ; 52(2): 491-501, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33651333

RESUMO

Filamentous fungus Purpureocillium lilacinum is an emerging pathogen that infects immunocompromised and immunocompetent individuals and is resistant to several azole molecules. Although azole resistance mechanisms are well studied in Aspergillus sp. and Candida sp., there are no studies to date reporting P. lilacinum molecular response to these molecules. The aim of this study was to describe P. lilacinum molecular mechanisms involved in antifungal response against fluconazole and itraconazole. Transcriptomic analyses showed that gene expression modulation takes place when P. lilacinum is challenged for 12 h with fluconazole (64 µg/mL) or itraconazole (16 µg/mL). The antifungals acted on the ergosterol biosynthesis pathway, and two homologous genes coding for cytochrome P450 51 enzymes were upregulated. Genes coding for efflux pumps, such as the major facilitator superfamily transporter, also displayed increased expression in the treated samples. We propose that P. lilacinum develops antifungal responses by raising the expression levels of cytochrome P450 enzymes and efflux pumps. Such modulation could confer P. lilacinum high levels of target enzymes and could lead to the constant withdrawal of antifungals, which would force an increase in the administration of antifungal medications to achieve fungal morbidity or mortality. The findings in this work could aid in the decision-making for treatment strategies in cases of P. lilacinum infection.


Assuntos
Antifúngicos/farmacologia , Fluconazol/farmacologia , Hypocreales/efeitos dos fármacos , Hypocreales/genética , Itraconazol/farmacologia , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Farmacorresistência Fúngica , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Regulação Fúngica da Expressão Gênica/efeitos dos fármacos , Humanos , Hypocreales/metabolismo , Testes de Sensibilidade Microbiana , Micoses/tratamento farmacológico , Micoses/microbiologia , Transcriptoma/efeitos dos fármacos
10.
J Med Virol ; 93(7): 4454-4460, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33666253

RESUMO

Although vaccination campaigns are currently being rolled out to prevent coronavirus disease (COVID-19), antivirals will remain an important adjunct to vaccination. Antivirals against coronaviruses do not exist, hence global drug repurposing efforts have been carried out to identify agents that may provide clinical benefit to patients with COVID-19. Itraconazole, an antifungal agent, has been reported to have activity against animal coronaviruses. Using cell-based phenotypic assays, the in vitro antiviral activity of itraconazole and 17-OH itraconazole was assessed against clinical isolates from a German and Belgian patient infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Itraconazole demonstrated antiviral activity in human Caco-2 cells (EC50 = 2.3 µM; 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay). Similarly, its primary metabolite, 17-OH itraconazole, showed inhibition of SARS-CoV-2 activity (EC50 = 3.6 µM). Remdesivir inhibited viral replication with an EC50 = 0.4 µM. Itraconazole and 17-OH itraconazole resulted in a viral yield reduction in vitro of approximately 2-log10 and approximately 1-log10 , as measured in both Caco-2 cells and VeroE6-eGFP cells, respectively. The viral yield reduction brought about by remdesivir or GS-441524 (parent nucleoside of the antiviral prodrug remdesivir; positive control) was more pronounced, with an approximately 3-log10 drop and >4-log10 drop in Caco-2 cells and VeroE6-eGFP cells, respectively. Itraconazole and 17-OH itraconazole exert in vitro low micromolar activity against SARS-CoV-2. Despite the in vitro antiviral activity, itraconazole did not result in a beneficial effect in hospitalized COVID-19 patients in a clinical study (EudraCT Number: 2020-001243-15).


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/farmacologia , COVID-19/tratamento farmacológico , Furanos/farmacologia , Itraconazol/farmacologia , Pirróis/farmacologia , SARS-CoV-2/efeitos dos fármacos , Triazinas/farmacologia , Monofosfato de Adenosina/farmacologia , Alanina/farmacologia , Animais , Células CACO-2 , Linhagem Celular Tumoral , Chlorocebus aethiops , Reposicionamento de Medicamentos , Humanos , Células Vero , Replicação Viral/efeitos dos fármacos
11.
EBioMedicine ; 66: 103288, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33752127

RESUMO

BACKGROUND: The antifungal drug itraconazole exerts in vitro activity against SARS-CoV-2 in Vero and human Caco-2 cells. Preclinical and clinical studies are required to investigate if itraconazole is effective for the treatment and/or prevention of COVID-19. METHODS: Due to the initial absence of preclinical models, the effect of itraconazole was explored in a clinical, proof-of-concept, open-label, single-center study, in which hospitalized COVID-19 patients were randomly assigned to standard of care with or without itraconazole. Primary outcome was the cumulative score of the clinical status until day 15 based on the 7-point ordinal scale of the World Health Organization. In parallel, itraconazole was evaluated in a newly established hamster model of acute SARS-CoV-2 infection and transmission, as soon as the model was validated. FINDINGS: In the hamster acute infection model, itraconazole did not reduce viral load in lungs, stools or ileum, despite adequate plasma and lung drug concentrations. In the transmission model, itraconazole failed to prevent viral transmission. The clinical trial was prematurely discontinued after evaluation of the preclinical studies and because an interim analysis showed no signal for a more favorable outcome with itraconazole: mean cumulative score of the clinical status 49 vs 47, ratio of geometric means 1.01 (95% CI 0.85 to 1.19) for itraconazole vs standard of care. INTERPRETATION: Despite in vitro activity, itraconazole was not effective in a preclinical COVID-19 hamster model. This prompted the premature termination of the proof-of-concept clinical study. FUNDING: KU Leuven, Research Foundation - Flanders (FWO), Horizon 2020, Bill and Melinda Gates Foundation.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , Itraconazol/farmacologia , Animais , Antivirais/administração & dosagem , Antivirais/farmacocinética , Antivirais/uso terapêutico , COVID-19/etiologia , COVID-19/transmissão , Chlorocebus aethiops , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Itraconazol/administração & dosagem , Itraconazol/farmacocinética , Itraconazol/uso terapêutico , Masculino , Mesocricetus , Pessoa de Meia-Idade , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Estudo de Prova de Conceito , SARS-CoV-2/efeitos dos fármacos , Resultado do Tratamento , Células Vero
12.
Biosci Biotechnol Biochem ; 85(3): 722-727, 2021 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-33624784

RESUMO

There are only a few combinations of antifungal drugs with known resistance marker genes in the Aspergillus species; therefore, the transformation of their wild-type strains is limited. In this study, to develop the novel dominant selectable marker for itraconazole, a fungal cell membrane synthesis inhibitor, we focused on Aspergillus luchuensis cyp51A (Alcyp51A), which encodes a 14-α-sterol demethylase related to the steroid synthesis pathway. We found that the G52R mutation in AlCyp51A and the replacement of the native promoter with a high-expression promoter contributed to itraconazole resistance in Aspergillus oryzae, designated as itraconazole resistant gene (itrA). The random integration in the A. luchuensis genome of the itrA marker cassette gene also allowed for transformation using itraconazole. Therefore, we succeed in developing a novel itraconazole resistance marker as a dominant selectable marker for transformation in A. oryzae and A. luchuensis.


Assuntos
Antifúngicos/farmacologia , Aspergillus oryzae/efeitos dos fármacos , Aspergillus/efeitos dos fármacos , Farmacorresistência Fúngica/genética , Marcadores Genéticos , Itraconazol/farmacologia , Aspergillus/genética , Aspergillus oryzae/genética , Genes Fúngicos
13.
Chem Biol Interact ; 338: 109426, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33617800

RESUMO

Sunitinib is a small molecule inhibitor of multiple receptor tyrosine kinases such as platelet derived growth factor receptor, vascular endothelial growth factor receptor, kit receptor and other receptors. The US Food and Drug Administration (FDA) has approved sunitinib for the treatment of advanced renal cell carcinoma and gastrointestinal stromal tumors. It has been reported that sunitinib was mainly metabolized by CYP3A but its pharmacokinetic interactions have not been revealed. In this study, we investigated whether CYP3A inhibitors (ketoconazole, voriconazole, and itraconazole) could influence the pharmacokinetics of sunitinib and its equipotent metabolite N-desethyl sunitinib in a drug-drug interaction study in Sprague Dawley (SD) rats. The results showed that ketoconazole and voriconazole significantly increased the exposure of sunitinib, decreased the exposure of N-desethyl sunitinib, and inhibited the metabolism of sunitinib in rats. However, itraconazole showed only a weak effect on pharmacokinetics and metabolism. Coadministration of sunitinib with ketoconazole and voriconazole should be avoided if possible or if not, there should be therapeutic drug monitoring of the levels of sunitinib and N-desethyl sunitinib. Therefore, drug-drug interaction should be considered when sunitinib is administered in conjunction with CYP3A inhibitors, which might lead to toxicity.


Assuntos
Inibidores do Citocromo P-450 CYP3A/farmacologia , Itraconazol/farmacologia , Cetoconazol/farmacologia , Sunitinibe/farmacocinética , Voriconazol/farmacologia , Administração Oral , Animais , Masculino , Ratos Sprague-Dawley , Sunitinibe/administração & dosagem
14.
Lett Appl Microbiol ; 72(6): 688-697, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33550599

RESUMO

Candida albicans is one of the most common clinical pathogenic microorganisms and it is becoming a serious health threat, particularly to immunocompromised populations. Drug resistance of Candida species has also frequently emerged, and combination therapy for fungal infections has attracted considerable attention. In this study, we established the Qinling Mountains myxobacterial secondary metabolites library and a synergic assay in combination with ketoconazole against C. albicans was introduced for metabolites screening. Two active compounds with synergic anticandidal activities were obtained, which were identified as trans-resveratrol and cis-resveratrol. According to our study, resveratrol can reduce the dosage to 1/64 of ketoconazole as well as itraconazole. Furthermore, synergistic anticandidal activity of resveratrol combined with azoles was verified against a panel of clinical C. albicans isolates, and the combination strategy enhanced the azoles susceptibility of three fluconazole-resistant isolates. These findings suggest that resveratrol enhances the efficacy of azoles and provides a promising application in therapy of C. albicans infection.


Assuntos
Antifúngicos/farmacologia , Azóis/farmacologia , Candida albicans/efeitos dos fármacos , Micoses/tratamento farmacológico , Resveratrol/farmacologia , Farmacorresistência Fúngica/fisiologia , Sinergismo Farmacológico , Quimioterapia Combinada , Fluconazol/farmacologia , Humanos , Itraconazol/farmacologia , Testes de Sensibilidade Microbiana
15.
ABCS health sci ; 46: e021203, 09 fev. 2021. tab
Artigo em Inglês | LILACS | ID: biblio-1147180

RESUMO

INTRODUCTION: The resistance of fungal species to drugs usually used in clinics is of great interest in the medical field. OBJECTIVE: To evaluate susceptibility and in vitro response of species of Trichophyton spp. to antifungal drugs of interest in clinical medicine. METHODS: 12 samples of clinical isolates from humans were used, nine of T. mentagrophytes and three of T. tonsurans. Susceptibility tests were performed according to the agar diffusion (AD) and broth microdilution (BM) methods. RESULTS: In the AD method, the species T. tonsurans presented a percentage of sensitivity of 33% in relation to amphotericin B and 66% to itraconazole, with 100% resistance to ketoconazole and fluconazole. T. mentagrophytes also showed 100% resistance to ketoconazole in this technique, with 11% sensitivity to ketoconazole, 22% to itraconazole and 22% of samples classified as sensitive dose dependent. In the MC method, the species T. tonsurans presented a sensitivity percentage of 66%, 55% and 33% in relation to ketoconazole, fluconazole and itraconazole, respectively. The T. mentagrophytes species presented sensitivity percentages of 11%, 11%, 33% and 55% for amphotericin B, itraconazole, ketoconazole and fluconazole, respectively. CONCLUSION: There was resistance in vitro of the species of T. mentagrophytes and T. tonsurans against the antifungal fluconazole and relative resistance against ketoconazole in the AD method. In BM, however, important percentages of sensitivity were observed for the two species analyzed in relation to the antifungals fluconazole and ketoconazole when compared to itraconazole and amphotericin B.


INTRODUÇÃO: A resistência de espécies fúngicas às drogas usualmente empregadas no meio clínico é motivo de grande interesse na área médica. OBJETIVO: Avaliar susceptibilidade e resposta in vitro de espécies de Trichophyton spp. a drogas antifúngicas de interesse em clínica médica. MÉTODOS: Foram utilizadas 12 amostras de isolados clínicos de humanos, sendo nove de T. mentagrophytes e três de T. tonsurans. Foram realizados testes de susceptibilidade segundo os métodos de difusão em ágar (DA) e microdiluição em caldo (MC). RESULTADOS: No método de DA, a espécie T. tonsurans apresentou percentual de sensibilidade de 33% em relação à anfotericina B e de 66% ao itraconazol, com 100% de resistência frente ao cetoconazol e ao fluconazol. A espécie T. mentagrophytes também apresentou 100% de resistência frente ao cetoconazol nesta técnica, com 11% de sensibilidade ao cetoconazol, 22% ao itraconazol e 22% das amostras classificadas como sensível dose dependente. No método de MC, a espécie T. tonsurans apresentou percentual de sensibilidade de 66%, 55% e 33% em relação ao cetoconazol, fluconazol e itraconazol, respectivamente. A espécie T. mentagrophytes apresentou percentuais de sensibilidade de 11%, 11%, 33% e 55% para anfotericina B, itraconazol, cetoconazol e fluconazol, respectivamente. CONCLUSÃO: Houve resistência in vitro das espécies do T. mentagrophytes e T. tonsurans frente ao antifúngico fluconazol e resistência relativa frente ao cetoconazol no método de DA. Na MC, no entanto, foram observados importantes percentuais de sensibilidade das duas espécies analisadas frente aos antifúngicos fluconazol e cetoconazol quando comparadas ao itraconazol e à anfotericina B.


Assuntos
Trichophyton/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Farmacorresistência Fúngica , Suscetibilidade a Doenças/microbiologia , Antifúngicos/farmacologia , Tinha/microbiologia , Tinha/tratamento farmacológico , Contagem de Colônia Microbiana , Fluconazol/farmacologia , Anfotericina B/farmacologia , Itraconazol/farmacologia , Cetoconazol/farmacologia
16.
ChemMedChem ; 16(1): 134-144, 2021 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-33428335

RESUMO

The significant antifungal activity of a series of novel 1,2,4-triazole derivatives against different strains of Candida albicans, Candida krusei and Aspergillus fumigatus, compared to the commercial fungicides ketoconazole and itraconazole, is reported. Systemic mycosis and invasive fungal infections, whether from immunodeficiency or hospital-acquired infection, have been on an upward trend for several years. The 1,2,4-triazole ring substituted with other aromatic and heteroaromatic systems plays an important role in the field of antifungal drug discovery and development. Thus, an extensive series of 29 triazoles, substituted in different positions with a variety of aromatic rings, has been designed, synthesized, and evaluated for their fungicidal activity. Almost all the agents tested in vitro showed high activity against all examined fungal strains. It is noteworthy that, in the case of A. fumigatus, all the examined compounds achieved equal or higher antifungal activity than ketoconazole, but less activity than itraconazole. Among all the derivatives studied, the dichlorourea analogue and bromo-substituted triazole stand out as the most promising compounds. Quantitative structure-activity relationship (QSAR) models were built for a systematic structure-activity relationship (SAR) profile to explain and potentially explore the potency characteristics of 1,2,4-triazole analogues.


Assuntos
Antifúngicos/síntese química , Triazóis/química , Antifúngicos/química , Antifúngicos/farmacologia , Aspergillus fumigatus/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Itraconazol/farmacologia , Testes de Sensibilidade Microbiana , Relação Quantitativa Estrutura-Atividade , Triazóis/síntese química , Triazóis/farmacologia
17.
J Biol Chem ; 296: 100223, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33449875

RESUMO

Cytochrome P450 (P450) 3A4 is the enzyme most involved in the metabolism of drugs and can also oxidize numerous steroids. This enzyme is also involved in one-half of pharmacokinetic drug-drug interactions, but details of the exact mechanisms of P450 3A4 inhibition are still unclear in many cases. Ketoconazole, clotrimazole, ritonavir, indinavir, and itraconazole are strong inhibitors; analysis of the kinetics of reversal of inhibition with the model substrate 7-benzoyl quinoline showed lag phases in several cases, consistent with multiple structures of P450 3A4 inhibitor complexes. Lags in the onset of inhibition were observed when inhibitors were added to P450 3A4 in 7-benzoyl quinoline O-debenzylation reactions, and similar patterns were observed for inhibition of testosterone 6ß-hydroxylation by ritonavir and indinavir. Upon mixing with inhibitors, P450 3A4 showed rapid binding as judged by a spectral shift with at least partial high-spin iron character, followed by a slower conversion to a low-spin iron-nitrogen complex. The changes were best described by two intermediate complexes, one being a partial high-spin form and the second another intermediate, with half-lives of seconds. The kinetics could be modeled in a system involving initial loose binding of inhibitor, followed by a slow step leading to a tighter complex on a multisecond time scale. Although some more complex possibilities cannot be dismissed, these results describe a system in which conformationally distinct forms of P450 3A4 bind inhibitors rapidly and two distinct P450-inhibitor complexes exist en route to the final enzyme-inhibitor complex with full inhibitory activity.


Assuntos
Clotrimazol/farmacologia , Inibidores do Citocromo P-450 CYP3A/farmacologia , Citocromo P-450 CYP3A/química , Indinavir/farmacologia , Itraconazol/farmacologia , Cetoconazol/farmacologia , Ritonavir/farmacologia , Esteroide Hidroxilases/antagonistas & inibidores , Animais , Biocatálise , Clonagem Molecular , Clotrimazol/química , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A/química , Ensaios Enzimáticos , Escherichia coli/genética , Escherichia coli/metabolismo , Expressão Gênica , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Humanos , Hidroxiquinolinas/síntese química , Hidroxiquinolinas/metabolismo , Indinavir/química , Itraconazol/química , Cetoconazol/química , Cinética , Ratos , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Ritonavir/química , Esteroide Hidroxilases/química , Esteroide Hidroxilases/genética , Esteroide Hidroxilases/metabolismo
18.
Eur J Pharmacol ; 895: 173892, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33497608

RESUMO

P-glycoprotein (P-gp), is an important efflux pump involved in chemotherapy resistance in human colon cancer. We investigated the efficacy of itraconazole as a P-gp inhibitor and its therapeutic synergistic relationship to paclitaxel through 99mTc-MIBI accumulation in HT-29 tumor-bearing nude mice. Histopathological screening along with in vitro experiments was done for further assessment. Itraconazole successfully inhibited P-gp mediated 99mTc-MIBI efflux, increasing its in vitro accumulation in itraconazole-receiving dishes. Notably, the co-administration of itraconazole with paclitaxel significantly enhanced the in vitro cytotoxicity effect of paclitaxel in itraconazole + paclitaxel wells containing HT-29 cells. Compared to the control, tumor volume in mice treated with itraconazole, paclitaxel and itraconazole +paclitaxel showed growth suppression approximately by 36.21, 60.02, and 73.3% respectively. And compared to paclitaxel group, the nude mice co-treated with paclitaxel and itraconazole showed suppression of tumor growth by about 33.31 % at the end of the treatment period. Also the biodistribution result showed that the co-administration of itraconazole with paclitaxel raised the mean tumor radioactivity accumulation compared to control and paclitaxel group. When given paclitaxel alone, the ID% of hepatic and cardiac tissue was reduced while co-administration of itraconazole with paclitaxel increased 99mTc-MIBI accumulation in these organs. Furthermore, the histopathological findings confirmed the biodistribution results. These results demonstrate that although monotherapy with itraconazole or paclitaxel has anti-tumor activity against HT-29 human colorectal cancer, a synergistic anti-tumor activity can be achieved when itraconazole is co-administered with paclitaxel. Also, 99mTc-MIBI is an effective radiotracer for monitoring response to treatment in MDR tumors.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias do Colo/tratamento farmacológico , Itraconazol/farmacologia , Paclitaxel/farmacologia , Compostos Radiofarmacêuticos/metabolismo , Tecnécio Tc 99m Sestamibi/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Animais , Antineoplásicos Fitogênicos/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/metabolismo , Neoplasias do Colo/diagnóstico por imagem , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Sinergismo Farmacológico , Feminino , Células HT29 , Humanos , Camundongos Nus , Paclitaxel/metabolismo , Distribuição Tecidual , Imagem Corporal Total , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Molecules ; 26(2)2021 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-33477259

RESUMO

Over the past 20-30 years, Trichophyton rubrum represented the most widespread dermatophyte with a prevalence accounting for 70% of dermatophytosis. The treatment for cutaneous infections caused by Trichophyton spp. are imidazoles (ketoconazole (KTZ)) and triazoles (itraconazole (ITZ)). T. rubrum can develop resistance to azoles after prolonged exposure to subinhibitory concentrations resulting in therapeutic failures and chronic infections. These problems have stimulated the search for therapeutic alternatives, including essential oils, and their potential use in combination with conventional antifungals. The purpose of this study was to evaluate the antifungal activity of tea tree oil (TTO) (Melaleuca alternifolia essential oil) and the main components against T. rubrum and to assess whether TTO in association with KTZ/ITZ as reference drugs improves the antifungal activity of these drugs. We used a terpinen-4-ol chemotype (35.88%) TTO, and its antifungal properties were evaluated by minimum inhibitory and minimum fungicidal concentrations in accordance with the CLSI guidelines. The interaction between TTO and azoles was evaluated through the checkerboard and isobologram methods. The results demonstrated both the fungicide activity of TTO on T. rubrum and the synergism when it was used in combination with azoles. Therefore, this mixture may reduce the minimum effective dose of azole required and minimize the side effects of the therapy. Synergy activity offered a promise for combination topical treatment for superficial mycoses.


Assuntos
Antifúngicos , Arthrodermataceae/crescimento & desenvolvimento , Itraconazol , Cetoconazol , Melaleuca/química , Óleo de Melaleuca , Antifúngicos/química , Antifúngicos/farmacologia , Sinergismo Farmacológico , Itraconazol/agonistas , Itraconazol/química , Itraconazol/farmacologia , Cetoconazol/agonistas , Cetoconazol/química , Cetoconazol/farmacologia , Óleo de Melaleuca/química , Óleo de Melaleuca/farmacologia
20.
Life Sci ; 265: 118803, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33238167

RESUMO

AIMS: According to the WHO, 20-25% of people worldwide are affected by skin infections caused by dermatophytes, such as those of the Trichophyton genus. Additionally, several dermatophytes have developed resistance to drugs such as griseofulvin and itraconazole. This study tested 2S albumins-derived antimicrobial peptides (AMPs) as alternative antidermatophytic molecules. MAIN METHODS: Membrane pore formation assays, tests to detect overproduction of ROS, scanning electron microscopy (SEM) and fluorescence microscopy (FM) were carried out to provide insight into the mechanisms of antidermatophytic action. KEY FINDINGS: All AMPs (at 50 µg mL-1) tested reduced the mycelial growth of T. mentagrophytes and T. rubrum by up to 95%. In contrast, using a concentration 20-fold higher, griseofulvin only inhibited T. mentagrophytes by 35%, while itraconazole was not active against both dermatophytes. Scanning electron and fluorescence microscopies revealed that the six AMPs caused severe damage to hyphal morphology by inducing cell wall rupture, hyphal content leakage, and death. Peptides also induced membrane pore formation and oxidative stress by overproduction of ROS. Based on the stronger activity of peptides than the commercial drugs and the mechanism of action, all six peptides have the potential to be either employed as models to develop new antidermatophytic drugs or as adjuvants to existing ones. SIGNIFICANCE: The synthetic peptides are more efficient than conventional drug to treat infection caused by dermatophytes being potential molecules to develop new drugs.


Assuntos
Antifúngicos/farmacologia , Arthrodermataceae/efeitos dos fármacos , Griseofulvina/farmacologia , Itraconazol/farmacologia , Fragmentos de Peptídeos/farmacologia , Antifúngicos/síntese química , Arthrodermataceae/fisiologia , Técnicas de Química Sintética , Griseofulvina/síntese química , Humanos , Itraconazol/síntese química , Fragmentos de Peptídeos/síntese química
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