Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.563
Filtrar
1.
J Mycol Med ; 30(3): 101003, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32586733

RESUMO

OBJECTIVE: In order to improve the effect of ketoconazole, poly-lactic acid (PLA) nanoparticles containing ketoconazole were prepared, characterized and tested against dermatophytes and Candida spp planktonic and biofilm cells. METHODS: The ketoconazole-PLA nanoparticles obtained by nanoprecipitation were characterized using dynamic light scattering, scanning electron microscopy, transmission electron microscopy, and differential scanning calorimetry. In addition, quantification of encapsulated ketoconazole and the in vitro release profile were determined. Antifungal susceptibility tests against dermatophytes Trichophyton rubrum, Trichophyton mentagrophytes, and Microsporum gypseum and yeasts Candida albicans, C. dubliniensis, C. krusei, C. parapsilosis, and C. tropicalis were performed. RESULTS: Spherical nanoparticles, with a mean diameter of 188.5nm and an encapsulation efficiency of 45% ketoconazole, were obtained. The nanoparticles containing ketoconazole had superior antifungal activity against all tested fungi strains than free ketoconazole. Inhibition of yeast biofilm formation was also achieved. CONCLUSION: Ketoconazole-PLA nanoparticles resulted in better antifungal activity of ketoconazole nanoparticles than free drug against dermatophytes and Candida species, indicating a promising tool for the development of therapeutic strategies.


Assuntos
Antifúngicos/administração & dosagem , Arthrodermataceae/efeitos dos fármacos , Candida/efeitos dos fármacos , Portadores de Fármacos , Cetoconazol/administração & dosagem , Nanopartículas/química , Poliésteres/química , Antifúngicos/farmacocinética , Arthrodermataceae/fisiologia , Biofilmes/efeitos dos fármacos , Candida/fisiologia , Portadores de Fármacos/síntese química , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Humanos , Cetoconazol/farmacocinética , Teste de Materiais , Testes de Sensibilidade Microbiana , Resultado do Tratamento
2.
AAPS PharmSciTech ; 21(5): 140, 2020 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-32419032

RESUMO

The present study is aimed at enhancing the skin penetration of ketoconazole by formulating it as transethosome. Ketoconazole-loaded transethosome formulations were prepared by conventional thin film evaporation and hydration method and were optimized using concentration of edge activator (span 80), ethanol and sonication time as factors and particle size, polydispersity index and entrapment efficiency as responses. The optimized formulation was further evaluated for in vitro diffusion, anti-fungal activity, ex vivo penetration and in vivo pharmacodynamic activity. The results of in vitro drug diffusion and ex vivo skin penetration studies demonstrated that the amount of drug diffused and penetrated through the skin was increased. Optimized transethosomes showed enhanced in vitro antifungal and in vivo pharmacodynamic activities against Candida albicans in Wistar albino rats when compared to conventional liposomes. Therefore, the developed ketoconazole encapsulated transethosome formulation is capable of enhancing the skin penetration of the drug by overcoming the stratum corneum barrier function and acting as an effective drug delivery system for ketoconazole through the skin for its anti-fungal activity.


Assuntos
Antifúngicos/administração & dosagem , Antifúngicos/química , Administração Cutânea , Animais , Antifúngicos/farmacocinética , Candidíase/tratamento farmacológico , Candidíase/microbiologia , Composição de Medicamentos , Sistemas de Liberação de Medicamentos , Excipientes , Cetoconazol/administração & dosagem , Cetoconazol/química , Lipossomos , Tamanho da Partícula , Ratos , Ratos Wistar , Absorção Cutânea
3.
J Mycol Med ; 30(2): 100949, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32234349

RESUMO

Onychomycosis is one of the most prevalent and severe nail fungal infections, which is affecting a wide population across the globe. It leads to variations like nail thickening, disintegration and hardening. Oral and topical drug delivery systems are the most desirable in treating onychomycosis, but the efficacy of the results is low, resulting in a relapse rate of 25-30%. Due to systemic toxicity and various other disadvantages associated with oral therapy like gastrointestinal, hepatotoxicity, topical therapy is commonly used. Topical therapy improves patient compliance and reduces the cost of treatment. However, due to poor penetration of topical therapy across the nail plate, research is focused on different chemical, mechanical and physical methods to improve drug delivery. Penetration enhancers like Thioglycolic acid, Hydroxypropyl-ß-cyclodextrin (HP-ß-CD), Sodium lauryl sulfate (SLS), carbocysteine, N-acetylcysteine etc. have shown results enhancing the drug penetration across the nail plate. Results with physical techniques such as iontophoresis, laser and Photodynamic therapy are quite promising, but the long-term suitability of these devices is in need to be determined. In this article, a brief analysis of the treatment procedures, factors affecting drug permeation across nail plate, chemical, mechanical and physical devices used to increase the drug delivery through nails for the onychomycosis management has been achieved.


Assuntos
Onicomicose/terapia , Administração Oral , Administração Tópica , Antifúngicos/administração & dosagem , Antifúngicos/farmacocinética , Química Farmacêutica/métodos , Terapia Combinada , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Sistemas de Liberação de Medicamentos , Humanos , Iontoforese/métodos , Iontoforese/tendências , Terapia a Laser/métodos , Terapia a Laser/tendências , Unhas/efeitos dos fármacos , Unhas/metabolismo , Unhas/efeitos da radiação , Onicomicose/tratamento farmacológico , Onicomicose/epidemiologia , Onicomicose/microbiologia , Permeabilidade/efeitos dos fármacos , Permeabilidade/efeitos da radiação , Fotoquimioterapia/métodos , Fotoquimioterapia/tendências
4.
Int J Infect Dis ; 93: 345-352, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32109625

RESUMO

OBJECTIVES: To characterize the pharmacokinetics (PK) of intravenous voriconazole (VRC) in critically ill patients with liver dysfunction. METHODS: Patients with liver dysfunction in the intensive care unit (ICU) were included prospectively. The Child-Pugh score was used to categorize the degree of liver dysfunction. The initial intravenous VRC dosing regimen comprised a loading dose of 300 mg every 12 h for the first 24 h, followed by 200 mg every 12 h. The first PK curves (PK curve 1) were drawn within one dosing interval of the first dose for 17 patients; the second PK curves (PK curve 2) were drawn within one dosing interval after a minimum of seven doses for 12 patients. PK parameters were estimated by non-compartmental analysis. RESULTS: There were good correlations between the area under the curve (AUC0-12) of PK curve 2 and the corresponding trough concentration (C0) and peak concentration (Cmax) (r2 = 0.951 and 0.963, respectively; both p < 0.001). The median half-life (t1/2) and clearance (CL) of patients in Child-Pugh class A (n = 3), B (n = 5), and C (n = 4) of PK curve 2 were 24.4 h and 3.31 l/h, 29.1 h and 2.54 l/h, and 60.7 h and 2.04 l/h, respectively. In the different Child-Pugh classes, the CL (median) of PK curve 2 were all lower than those of PK curve 1. The apparent steady-state volume of distribution (Vss) of PK curve 1 was positively correlated with actual body weight (r2 = 0.450, p = 0.004). The median first C0 of 17 patients determined on day 5 was 5.27 (2.61) µg/ml, and 29.4% of C0 exceeded the upper limit of the therapeutic window (2-6 µg/ml). CONCLUSIONS: The CL of VRC decreased with increasing severity of liver dysfunction according to the Child-Pugh classification, along with an increased t1/2, which resulted in high plasma exposure of VRC. Adjusted dosing regimens of intravenous VRC should be established based on Child-Pugh classes for these ICU patients, and plasma concentrations should be monitored closely to avoid serious adverse events.


Assuntos
Antifúngicos/farmacocinética , Unidades de Terapia Intensiva , Hepatopatias/metabolismo , Voriconazol/farmacocinética , Administração Intravenosa , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Estado Terminal , Feminino , Meia-Vida , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Voriconazol/administração & dosagem
5.
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
6.
PLoS One ; 15(2): e0229414, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32107486

RESUMO

Onychomycosis, or fungal nail infection, is a common fungal infection largely caused by dermatophyte fungi, such as Trichophyton rubrum or Trichophyton mentagrophytes, which affects a significant number of people. Treatment is either through oral antifungal medicines, which are efficacious but have significant safety concerns, or with topical antifungal treatments that require long treatment regimens and have only limited efficacy. Thus, an efficacious topical therapy remains an unmet medical need. Among the barriers to topical delivery through the nail are the physico-chemical properties of the antifungal drugs. Here, we explore the ability of a range of antifungal compounds with different hydrophilicities to penetrate the nail. Human nail discs were clamped within static diffusion (Franz) cells and dosed with equimolar concentrations of antifungal drugs. Using LC-MS/MS we quantified the amount of drug that passed through the nail disc and that which remained associated with the nail. Our data identified increased drug flux through the nail for the more hydrophilic compounds (caffeine as a hydrophilic control and fluconazole, with LogP -0.07 and 0.5, respectively), while less hydrophilic efinaconazole, amorolfine and terbinafine (LogP 2.7, 5.6 and 5.9 respectively) had much lower flux through the nail. On the other hand, hydrophilicity alone did not account for the amount of drug associated with/bound to the nail itself. While there are other factors that are likely to combine to dictate nail penetration, this work supports earlier studies that implicate compound hydrophilicity as a critical factor for nail penetration.


Assuntos
Antifúngicos/farmacologia , Antifúngicos/farmacocinética , Micoses/tratamento farmacológico , Doenças da Unha/tratamento farmacológico , Unhas/efeitos dos fármacos , Administração Tópica , Antifúngicos/administração & dosagem , Antifúngicos/química , Humanos , Interações Hidrofóbicas e Hidrofílicas , Micoses/metabolismo , Micoses/microbiologia , Doenças da Unha/metabolismo , Doenças da Unha/microbiologia , Unhas/metabolismo , Unhas/microbiologia , Permeabilidade , Distribuição Tecidual
7.
J Oncol Pharm Pract ; 26(1): 5-12, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30854922

RESUMO

BACKGROUND: Posaconazole reduces the risk of invasive Aspergillus in transplant patients, but significantly inhibits tacrolimus metabolism. One study demonstrated that a three-fold dose reduction of tacrolimus was required to obtain therapeutic concentrations when used with posaconazole. However, with empiric dose reduction, there is a risk of subtherapeutic tacrolimus levels and subsequent graft failure or graft-versus-host disease. Overall, the existing data on the impact of posaconazole on tacrolimus pharmacokinetics is limited. OBJECTIVE: The purpose of this study is to determine whether tacrolimus doses should be decreased upon initiation of posaconazole in patients receiving an allogeneic stem cell transplant. METHODS: This is a retrospective chart review at an academic medical center. All allogeneic stem cell transplant adults who received concomitant posaconazole and tacrolimus from February 2016 through December 2017 were included. RESULTS: Seventy-nine patients identified using an internal electronic database were analyzed. The median time to therapeutic tacrolimus concentration was significantly longer in patients who did not receive an empiric dose reduction (0% DR, 10d; 1-30% DR, 4d; 31-65% DR, 5d; >65% DR, 4d; p = 0.0395). The rate of supratherapeutic levels was highest amongst patients who did not receive an empiric DR, and was noted to be significant compared to the group that had 31-65% DR (p < 0.001). CONCLUSION: This study validates our current practice of instituting an empiric 50% dose reduction of oral tacrolimus to 0.03 mg/kg/day when used concomitantly with posaconazole to achieve therapeutic levels in allogeneic stem cell transplant patients.


Assuntos
Antifúngicos/farmacocinética , Transplante de Células-Tronco Hematopoéticas/tendências , Imunossupressores/farmacocinética , Transplante de Células-Tronco/tendências , Tacrolimo/farmacocinética , Triazóis/farmacocinética , Adulto , Antifúngicos/administração & dosagem , Esquema de Medicação , Interações Medicamentosas/fisiologia , Feminino , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Humanos , Imunossupressores/administração & dosagem , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tacrolimo/administração & dosagem , Triazóis/administração & dosagem
9.
Pharm Dev Technol ; 25(4): 440-453, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31851857

RESUMO

In this study, voriconazole (VCZ) incorporated polyvinyl alcohol/sodium alginate electrospun nanofibers were produced and, then crosslinked with glutaraldehyde for topical antifungal treatment. The nanofibers were characterized in terms of fiber size, surface morphology, and compatibility between drug-polymer and polymer-polymer using scanning electron microscopy, atomic force microscopy, attenuated total reflection-Fourier transform infrared spectroscopy, and high pressure liquid chromatography. After optimization studies, in vitro drug release, skin penetration, and deposition studies were performed using Franz diffusion cells. Antifungal activities of the nanofiber formulations against Candida albicans, Candida tropicalis, and Candida parapysilosis strains were evaluated using susceptibility test and subsequently time-kill study was performed against C. albicans. The cytotoxicity study was performed using 4-succinate dehydrogenase viability assay on mouse fibroblast cell line. The release rate of VCZ from crosslinked nanofibers was slower than that of non-crosslinked nanofibers and Higuchi kinetic model best fitted to the in vitro release data of both of formulations. VCZ deposited in deeper skin layers from nanofiber formulations was higher than that of the control formulation (VCZ solution in propylene glycol (1% (w/v)). According to the susceptibility and time-kill studies, all of the nanofiber formulations showed antifungal activity against C. albicans with confirming no cytotoxicity on mouse fibroblast cells.


Assuntos
Antifúngicos/administração & dosagem , Candida/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Nanofibras/química , Voriconazol/administração & dosagem , Administração Tópica , Alginatos/química , Animais , Antifúngicos/farmacocinética , Antifúngicos/farmacologia , Candidíase/tratamento farmacológico , Linhagem Celular , Liberação Controlada de Fármacos , Humanos , Camundongos , Álcool de Polivinil/química , Absorção Cutânea , Suínos , Voriconazol/farmacocinética , Voriconazol/farmacologia
10.
Drug Deliv ; 26(1): 1167-1177, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31738083

RESUMO

Onychomycosis is a progressive fungal infection of the nails that involves the deeper nail layer and nail bed. It is important to maintain sufficient drug concentration in the diseased tissues after topical application. In this study, a stable topical delivery system for efinaconazole (EFN) was designed to enhance absorption potential through the skin and nail plate by incorporating ethanol, diethylene glycol monoethyl ether (Transcutol P) and isopropyl myristate, and cyclomethicone into the topical solution as a delivery vehicle, permeation enhancers, and a wetting agent, respectively. In addition, the stability of EFN in the formulation was significantly improved by adding butylated hydroxytoluene, diethylenetriamine pentaacetic acid, and citric acid as an antioxidant, chelating agent, and pH-adjusting agent, respectively, without discoloration. The optimum EFN formulation (EFN-K) showed 1.46-fold greater human skin permeation than that of the reference control (commercial 10% EFN topical solution). Furthermore, after a 24-hour incubation, the amount of infiltrated EFN from EFN-K in the human nail plate was 4.11-fold greater than that of the reference control, resulting in an 89.7% increase in nail flux at 7 days after treatment. EFN-K significantly accelerated structural recovery of the keratin layer in a Trichophyton mentagrophytes-infected guinea pig onychomycosis model, decreasing the mean viable fungal cell count by 54.3% compared to the vehicle-treated group after once-daily treatment for 4 weeks. Thus, the accelerated skin and nail penetration effect of EFN-K is expected to achieve good patient compliance, and improve the complete cure rate of onychomycosis.


Assuntos
Antifúngicos/uso terapêutico , Unhas/efeitos dos fármacos , Onicomicose/tratamento farmacológico , Pele/efeitos dos fármacos , Tinha/tratamento farmacológico , Triazóis/uso terapêutico , Administração Tópica , Animais , Antifúngicos/administração & dosagem , Antifúngicos/farmacocinética , Modelos Animais de Doenças , Cobaias , Humanos , Técnicas In Vitro , Masculino , Membranas Artificiais , Unhas/metabolismo , Onicomicose/metabolismo , Onicomicose/microbiologia , Permeabilidade , Pele/metabolismo , Absorção Cutânea/efeitos dos fármacos , Tinha/metabolismo , Triazóis/administração & dosagem , Triazóis/farmacocinética , Trichophyton/efeitos dos fármacos
11.
Int J Pharm ; 572: 118719, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31654700

RESUMO

Amphotericin B (AmB), which plays a central role in the treatment of systemic fungal infections, is difficult to formulate because it's sparingly soluble in water and organic solvents. We previously prepared AmB-loaded micelles using styrene-maleic acid copolymer (SMA). Although solubilization was achieved by this formulation, stability in the blood circulation was as insufficient as that of Fungizone®, which is a conventional formulation of AmB. Meanwhile, it is well known that polymer-drug conjugates are more stable in circulation than drug-loaded micelles. Therefore, in this study, we developed covalently conjugated SMA-AmB (SMA-AmB conjugate). The SMA-AmB conjugate was found to be soluble and present as micelles in aqueous solution. Furthermore, it was revealed that this micelle behaves as a larger molecule by forming a complex with albumin. The circulation in the blood increased significantly compared to that of Fungizone®, which was suggested to be due to this complex-forming ability. Although in vitro and in vivo antifungal activity of the SMA-AmB conjugate against Saccharomyces cerevisiae was reduced by 1/3 compared to that of Fungizone®, hemolysis decreased to 1/40 or less, and the LD50 decreased to 1/10. In conclusion, it is expected that the SMA-AmB conjugate can be a polymer-therapeutic agent with high antifungal selectivity.


Assuntos
Anfotericina B , Antifúngicos , Maleatos , Estireno , Anfotericina B/administração & dosagem , Anfotericina B/sangue , Anfotericina B/química , Anfotericina B/farmacocinética , Animais , Antifúngicos/administração & dosagem , Antifúngicos/sangue , Antifúngicos/química , Antifúngicos/farmacocinética , Liberação Controlada de Fármacos , Eritrócitos/efeitos dos fármacos , Hemólise/efeitos dos fármacos , Dose Letal Mediana , Masculino , Maleatos/administração & dosagem , Maleatos/sangue , Maleatos/química , Maleatos/farmacocinética , Camundongos , Micelas , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/crescimento & desenvolvimento , Solubilidade , Estireno/administração & dosagem , Estireno/sangue , Estireno/química , Estireno/farmacocinética
12.
Pak J Pharm Sci ; 32(4): 1671-1677, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31608889

RESUMO

The current research aims at development and assessment of o/w nystatin microemulsion. The pseudoternary phase diagrams were developed to determine microemulsion existence regions by water titration method. Nystatin was liquefied in the blend of oil phase, surfactant and cosurfactant. Microemulsion was made by deliberate mixing of water and stirring in this blend. The S-mix (surfactant-cosurfactant mixtures) of the ratio 1:2 was found better than 1:1 and 2:1 S-mix ratios. In vitro permeation studies by Franz diffusion cell revealed faster rate of nystatin release from such microemulsion (5.37µg/cm2/h) as compared to nystrin (4.79µg/cm2/h), a commercially available aqueous suspension. Kinetic modeling demonstrated zero order drug release and release mechanism found to be anomalous i.e. superposition of dispersion and swelling controlled drug release. Antifungal activity was performed using well diffusion method in vitro against Candida albicans cultures grown on Sabouraud's dextrose agar. The results also confirmed the high diffusion rate of drug from microemulsion as compared to aqueous suspension. The outcomes of this study propose that topical microemulsion of nystatin provides better antifungal activity as compared to emulsion gels or aqueous suspensions.


Assuntos
Antifúngicos/farmacologia , Emulsões/química , Emulsões/farmacologia , Nistatina/farmacologia , Administração Tópica , Antifúngicos/administração & dosagem , Antifúngicos/química , Antifúngicos/farmacocinética , Candida albicans/efeitos dos fármacos , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Avaliação Pré-Clínica de Medicamentos , Liberação Controlada de Fármacos , Emulsões/administração & dosagem , Emulsões/farmacocinética , Excipientes/química , Concentração de Íons de Hidrogênio , Nistatina/administração & dosagem , Nistatina/química , Nistatina/farmacocinética , Solubilidade , Tensoativos , Viscosidade
13.
Expert Opin Drug Metab Toxicol ; 15(11): 881-895, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31550939

RESUMO

Introduction: Therapeutic drug monitoring (TDM) has been shown to optimize the management of invasive fungal infections (IFIs), particularly for select antifungal agents with a well-defined exposure-response relationship and an unpredictable pharmacokinetic profile or a narrow therapeutic index. Select triazoles (itraconazole, voriconazole, and posaconazole) and flucytosine fulfill these criteria, while the echinocandins, fluconazole, isavuconazole, and amphotericin B generally do not do so. Given the morbidity and mortality associated with IFIs and the challenges surrounding the use of currently available antifungal agents, TDM plays an important role in therapy.Areas covered: This review seeks to describe the rationale for TDM of antifungal agents, summarize their pharmacokinetic and pharmacodynamic properties, identify treatment goals for efficacy and safety, and provide recommendations for optimal dosing and therapeutic monitoring strategies.Expert opinion: Several new antifungal agents are currently in development, including compounds from existing antifungal classes with enhanced pharmacokinetic or safety profiles as well as agents with novel targets for the treatment of IFIs. Given the predictable pharmacokinetics of these newly developed agents, use of routine TDM is not anticipated. However, expanded knowledge of exposure-response relationships of these compounds may yield a role for TDM to improve outcomes for adult and pediatric patients.


Assuntos
Antifúngicos/administração & dosagem , Monitoramento de Medicamentos/métodos , Infecções Fúngicas Invasivas/tratamento farmacológico , Adulto , Antifúngicos/farmacocinética , Antifúngicos/farmacologia , Criança , Desenvolvimento de Medicamentos , Humanos , Infecções Fúngicas Invasivas/microbiologia
14.
Rev. iberoam. micol ; 36(3): 115-119, jul.-sept. 2019. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-191399

RESUMO

Antecedentes: Candida albicans es uno de los microorganismos más frecuentemente involucrados en diversas infecciones; la cavidad bucal del paciente, los nichos de caries o la enfermedad periodontal pueden actuar en ocasiones como reservorio. El desarrollo de resistencia a los medicamentos disponibles y otros factores justifican la búsqueda de nuevos antimicóticos. Objetivos: Estudiar de forma comparativa los efectos in vitro del medicamento antitumoral dietilestilbestrol (DES) y del fluconazol (FLZ) sobre el crecimiento de cepas clínicas de C. albicans aisladas de pacientes con enfermedades odontológicas y médicas. Métodos: Se emplearon siete cepas de C. albicans: a) la cepa de colección ATCC 90028, sensible a FLZ (ATCC); b) cuatro aislamientos bucales de sendas pacientes oncológicas con enfermedad periodontal (period 8, 9, 10 y 11); y c) dos aislamientos bucales de un paciente con sida y candidiasis orofaríngea: un aislamiento era sensible a FLZ (2-76) y el otro resistente (12-99). Se evaluó el crecimiento celular por técnicas espectrofotométricas estandarizadas (M27-A3, CLSI) y se calculó la concentración inhibitoria 50% (CI50) por análisis de funciones mediante el programa Graph Pad. Resultados: El DES inhibió el crecimiento de C. albicans, tanto sensible como resistente al FLZ. Los datos se ajustan adecuadamente a curvas teóricas saturables de tipo concentración del inhibidor versus respuesta. Las concentraciones inhibitorias mínimas fueron con DES y FLZ, respectivamente, las siguientes: 28,18µg/ml y 4,90µg/ml (ATCC); 17,16µg/ml y 3,14µg/ml (period); 27,64µg/ml y 4,22µg/ml (2-76); 6,16µg/ml y 438,19µg/ml (12-99). Conclusiones: El DES tiene actividad antimicótica sobre aislamientos de C. albicans de pacientes con enfermedades odontológicas y médicas. La mayor potencia antimicótica observada fue sobre el aislamiento resistente al FLZ


Background: Candida albicans is a microorganism frequently involved in several infections; the patient's oral cavity, caries niches or periodontal disease can sometimes be the reservoir.. The fungal resistance to the available treatments, among other reasons, has led to the search for new antifungal alternatives. Aims: To carry out a comparative study of the in vitro effects of diethylstilboestrol (DES) and fluconazole (FLZ) on the growth of clinical strains of C. albicans. Methods: Seven strains of C. albicans were used: a) one FLZ-sensitive culture collection strain, ATCC 90028 (ATCC); b) four oral isolates from four oncological patients with periodontal disease (period 8, 9, 10, and 11); and c) two oral isolates from an AIDS patient with oropharyngeal candidiasis: one FLZ- sensitive (2-76), and another FLZ- resistant (12-99). The MIC was evaluated by standard spectrophotometric techniques using the CLSI (M27-A3) guidelines. The inhibitory concentration 50% (IC50) was calculated using functional analysis with the Graph Pad software. Results: DES inhibited the growth of all C. albicans strains, whether sensitive or resistant to FLZ. Experimental data fitted non-linear functions of inhibitor concentration versus response. Minimum inhibitory concentrations (MIC) for DES and FLZ were as follows: 28.18µg/ml and 4.90µg/ml (ATCC); 17.16µg/ml and 3.14µg/ml (period); 27.64µg/ml and 4.22µg/ml (2-76); 6.16µg/ml and 438.19µg/ml (12-99), respectively. Conclusions: DES showed antifungal activity on all clinical C. albicans strains isolated from patients with dental and medical diseases. It showed the highest potency on the FLZ-resistant isolate


Assuntos
Humanos , Dietilestilbestrol/farmacocinética , Candida albicans/efeitos dos fármacos , Resistência Microbiana a Medicamentos , Azóis/farmacocinética , Candida albicans/patogenicidade , Testes de Sensibilidade Microbiana/métodos , Técnicas In Vitro/métodos , Antifúngicos/farmacocinética
15.
Clin Drug Investig ; 39(11): 1109-1116, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31432392

RESUMO

BACKGROUND AND OBJECTIVES: New intravenous and solid oral formulations of the antifungal agent posaconazole have been developed. This randomized, open-label, crossover study in 18 healthy adult Chinese male and female subjects evaluated the pharmacokinetics of single-dose posaconazole (oral 300-mg posaconazole tablet fasted, intravenous 300-mg posaconazole solution fasted, and oral 300-mg posaconazole tablet with standard high-fat breakfast). Primary objectives were to determine the single-dose pharmacokinetics of posaconazole in healthy Chinese subjects when administered as an intravenous solution and as an oral tablet under fasted conditions and the effect of food on the absorption of posaconazole. METHODS: The three treatments consisted of the following: a single oral dose of posaconazole 300 mg (fasted), a single oral dose of posaconazole 300 mg (high-fat breakfast), and a single intravenous dose of posaconazole 300 mg (fasted). Blood samples for pharmacokinetic analysis were collected before dosing and at regular intervals after dosing. Adverse events were monitored throughout. The pharmacokinetic population included the per-protocol population. The safety population included all subjects who received one or more doses of the study drug. RESULTS: Time to maximum plasma concentration of intravenous posaconazole coincided with the end of infusion; the half-life (t½) was 25.76 h. Geometric mean (% coefficient of variation) values of area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC0-∞) and maximum plasma concentration (Cmax) were 59,925 (36.2%) h·ng/mL and 3999 (28.5%) ng/mL, respectively. The posaconazole tablet had a time to maximum plasma concentration of 4 h and a t½ of 25.21 h after fasting. Geometric mean (coefficient of variation) values of AUC0-∞ and Cmax were 25,263 (39.9%) h·ng/mL and 674.5 (29.6%) ng/mL, respectively. Standard high-fat breakfast increased the exposure of posaconazole approximately twofold with geometric mean ratios (high-fat breakfast/fasted) for AUC0-∞ and Cmax of 2.06 (90% confidence interval 1.86-2.30) and 1.95 (90% confidence interval 1.65-2.31), respectively. The geometric mean absolute bioavailability of the tablet formulation was 42.2% in the fasted state and 87.1% under high-fat breakfast conditions. The most commonly reported adverse events were nausea, vomiting, dizziness, and first-degree atrioventricular block for intravenous posaconazole 300 mg and nausea for oral posaconazole 300 mg (high-fat breakfast). All adverse events were mild and resolved without sequelae. CONCLUSIONS: Posaconazole was generally well tolerated in healthy Chinese male and female subjects. The safety and the high-fat breakfast and fasted pharmacokinetics of posaconazole in healthy Chinese subjects are within exposures demonstrated to be generally well tolerated and efficacious and compare reasonably well with the overall posaconazole data across Western countries.


Assuntos
Antifúngicos/efeitos adversos , Antifúngicos/farmacocinética , Jejum/fisiologia , Interações Alimento-Droga/fisiologia , Triazóis/efeitos adversos , Triazóis/farmacocinética , Administração Intravenosa , Administração Oral , Adulto , Antifúngicos/administração & dosagem , Estudos Cross-Over , Dieta Hiperlipídica , Feminino , Voluntários Saudáveis , Humanos , Masculino , Náusea/induzido quimicamente , Náusea/diagnóstico , Comprimidos , Triazóis/administração & dosagem , Adulto Jovem
16.
AAPS PharmSciTech ; 20(7): 297, 2019 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-31444661

RESUMO

Miconazole nitrate (MZ) is a BCS class II antifungal poorly water-soluble drug with limited dissolution properties and gastrointestinal side effects. Self-nanoemulsifying delivery system-based gel of MZ can improve both solubility and oral mucosal absorption with enhanced antifungal activity. The study aims to formulate MZ self-nanoemulsion (MZ-NE) and combine it within hyaluronic acid-based gel. MZ solubility in various oils, surfactants, and cosurfactant used in NE formulations were evaluated. Mixture design was implemented to optimize the levels of NE components as a formulation variable to study their effects on the mean globule size and antifungal inhibition zones. Further, the optimized MZ-NE was loaded into a hyaluronic acid gel base. Rheological behavior of the prepared gel was assessed. Ex vivo permeability of optimized formulation across buccal mucous of sheep and inhibition against Candida albicans were examined. Mixture design was used to optimize the composition of MZ-NE formulation as 22, 67, and 10% for clove oil, Labrasol, and propylene glycol, respectively. The optimized formulation indicated globule size of 113 nm with 29 mm inhibition zone. Pseudoplastic flow with thixotropic behavior was observed, which is desirable for oral gels. The optimized formulation exhibited higher ex vivo skin permeability and enhanced antifungal activity by 1.85 and 2.179, respectively, compared to MZ-SNEDDS, and by 1.52 and 1.72 folds, respectively, compared to marketed gel. Optimized MZ-NE hyaluronic acid-based oral gel demonstrated better antifungal activity, indicating its potential in oral thrush pharmacotherapy.


Assuntos
Antifúngicos/administração & dosagem , Candidíase Bucal/tratamento farmacológico , Química Farmacêutica/métodos , Ácido Hialurônico/administração & dosagem , Miconazol/administração & dosagem , Nanocápsulas/administração & dosagem , Administração Oral , Animais , Antifúngicos/síntese química , Antifúngicos/farmacocinética , Candidíase Bucal/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Emulsões/administração & dosagem , Emulsões/síntese química , Emulsões/farmacocinética , Ácido Hialurônico/síntese química , Ácido Hialurônico/farmacocinética , Hidrogéis/administração & dosagem , Hidrogéis/síntese química , Hidrogéis/farmacocinética , Miconazol/síntese química , Miconazol/farmacocinética , Nanocápsulas/química , Ovinos
17.
Future Microbiol ; 14: 957-967, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31373226

RESUMO

Aim: To investigate biopharmaceutical and antifungal properties of pure and complexed ellagic acid. Materials & methods: Caco-2 cells cultured in a Transwell® inserts were infected with Candida albicans to develop an in vitro model. Ellagic acid was complexed with cyclodextrins. Microbial compositions, ellagic acid concentration as function of time and characterization studies of complexes were evaluated. Results: Ellagic acid presented ability to reduce C. albicans invasion, although this was not statistically significant. Its poor water solubility and absorption probably limited this ability. Water solubility was increased after complexation with hydroxypropyl-ß-CD; however, ellagic acid/hydroxypropyl-ß-CD did not improve the antifungal activity. Conclusion: Although ellagic acid presented a promising antifungal activity, its biopharmaceutical properties limit such activity and should be improved.


Assuntos
Candida albicans/efeitos dos fármacos , Candidíase Invasiva/microbiologia , Ciclodextrinas/farmacologia , Ácido Elágico/farmacologia , Antifúngicos/farmacocinética , Antifúngicos/farmacologia , Células CACO-2 , Ciclodextrinas/farmacocinética , Ácido Elágico/farmacocinética , Células Epiteliais/metabolismo , Humanos , Modelos Biológicos , Solubilidade
18.
Colloids Surf B Biointerfaces ; 183: 110446, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31465938

RESUMO

Cryptococcus neoformans-mediated meningoencephalitis is a critical infectious disorder of the human central nervous system. However, efficient treatment for the disease is limited due to the poor penetration across the blood brain barrier (BBB). Here, we develop a nose-to-brain drug delivery system utilizing nanostructured lipid carriers (NLCs). We demonstrated that fluorescent-dye-loaded NLCs efficiently uptake into the cytoplasm of encapsulated C. neoformans cells. In comparison with current antifungal drugs, the ketoconazole (keto)-NLCs show significantly increased antifungal activity against C. neoformans in vivo under various growth conditions. The NLCs show enhanced tissue colonization properties. Importantly, using animal imaging analyses, NLCs are able to enter brain tissues via the olfactory bulb region by intranasal administration, bypassing the BBB. In addition, NLCs maintain prolonged residence in tissues. In mouse brain tissue, keto-NLCs showed significantly enhanced antifungal activity when administered intranasally, drastically dampening the C. neoformans burden. Taken together, NLCs not only improve the ketoconazole penetration efficiency against capsulated C. neoformans cells, but also boost the efficacy of antifungal drugs. Most importantly, keto-NLCs significantly contribute to the treatment of cryptococcal meningoencephalitis in mice by bypassing the BBB via the olfactory system.


Assuntos
Criptococose/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Cetoconazol/administração & dosagem , Lipídeos/química , Meningoencefalite/tratamento farmacológico , Nanoestruturas/química , Administração Intranasal , Animais , Antifúngicos/administração & dosagem , Antifúngicos/química , Antifúngicos/farmacocinética , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/microbiologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/microbiologia , Criptococose/microbiologia , Cryptococcus neoformans/efeitos dos fármacos , Cryptococcus neoformans/fisiologia , Portadores de Fármacos/química , Cetoconazol/química , Cetoconazol/farmacocinética , Meningoencefalite/microbiologia , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Transmissão , Nanoestruturas/ultraestrutura , Nariz/efeitos dos fármacos , Nariz/microbiologia , Tamanho da Partícula
19.
Int J Antimicrob Agents ; 54(4): 463-470, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31279853

RESUMO

Individualisation of the therapeutic strategy for the oral antifungal agent voriconazole (VCZ) is extremely important for treatment optimisation. To date, regulatory agencies include CYP2C19 as the only major pharmacogenetic (PGx) biomarker in their dosing guidelines; however, the effect of other genes might be important for VCZ dosing prediction. We developed an exploratory PGx study to identify new biomarkers related to VCZ pharmacokinetics. We first designed a 'clinical practice VCZ-AUC prediction model' based on CYP2C19 to be used as a reference model in this study. We then designed a multifactorial polygenic prediction model and found that genetic variability in FMO3, NR1I2, POR, CYP2C9 and CYP3A4 partially contributes to VCZ total area under the concentration-time curve (AUC0-∞) interindividual variability, and its inclusion in VCZ AUC0-∞ prediction algorithms improves model precision. To our knowledge, there are no PGx studies specifically relating POR, FMO3 and NR1I2 polymorphisms to VCZ pharmacokinetic variability. Further research is needed in order to test the model proposed here.


Assuntos
Antifúngicos/administração & dosagem , Antifúngicos/farmacocinética , Estudos de Associação Genética , Voriconazol/administração & dosagem , Voriconazol/farmacocinética , Administração Oral , Adulto , Feminino , Humanos , Masculino , Farmacogenética/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Espanha , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA