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1.
Int J Food Microbiol ; 328: 108687, 2020 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-32474227

RESUMO

Penicilium griseofulvum, the causal agent of apple blue mold, is able to produce in vitro and on apple a broad spectrum of secondary metabolites (SM), including patulin, roquefortine C and griseofulvin. Among them, griseofulvin is known for its antifungal and antiproliferative activity, and has received interest in many sectors, from medicine to agriculture. The biosynthesis of SM is finely regulated by filamentous fungi and can involve global regulators and pathway specific regulators, which are usually encoded by genes present in the same gene cluster as the backbone gene and tailoring enzymes. In the griseofulvin gene cluster, two putative transcription factors were previously identified, encoded by genes gsfR1 and gsfR2, and their role has been investigated in the present work. Analysis of P. griseofulvum knockout mutants lacking either gene suggest that gsfR2 forms part of a different pathway and gsfR1 exhibits many spectra of action, acting as regulator of griseofulvin and patulin biosynthesis and influencing conidia production and virulence on apple. The analysis of gsfR1 promoter revealed that the regulation of griseofulvin biosynthesis is also controlled by global regulators in response to many environmental stimuli, such as carbon and nitrogen. The influence of carbon and nitrogen on griseofulvin production was further investigated and verified, revealing a complex network of response and confirming the central role of gsfR1 in many processes in P. griseofulvum.


Assuntos
Griseofulvina/biossíntese , Patulina/biossíntese , Penicillium/metabolismo , Penicillium/patogenicidade , Esporos Fúngicos/crescimento & desenvolvimento , Carbono/metabolismo , Microbiologia de Alimentos , Griseofulvina/metabolismo , Malus/microbiologia , Família Multigênica , Nitrogênio/metabolismo , Patulina/metabolismo , Esporos Fúngicos/metabolismo , Fatores de Transcrição/genética , Virulência
2.
J Zoo Wildl Med ; 50(4): 1008-1011, 2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31926538

RESUMO

Curvularia spp. are globally distributed saprophytic fungi, classified in the literature as dematiaceous, or darkly pigmented fungi. These fungi have been increasingly recognized as causing cutaneous, ocular, respiratory, and central nervous system infections in humans, but have been infrequently documented as pathogens in the veterinary literature. A 5-yr-old male Chinese goral (Naemorhedus griseus) presented with bilateral fungal dermatitis of the pinnae, and subsequent pyogranulomatous rhinosinusitis. Clinical signs included epistaxis, mucosanguineous nasal discharge, and dyspnea. Sequential histologic examinations of cutaneous and nasal lesions revealed pyogranulomatous inflammation with extracellular and phagocytized nonpigmented yeasts. Fungal culture and polymerase chain reaction identified Curvularia sp. The absence of pigmentation in tissue in this case suggests that pigmentation may not be a consistent histologic finding for this fungus, emphasizing the importance of molecular identification to prevent misidentification. Despite intensive interventions in this goral, the disease progressed, and was ultimately fatal.


Assuntos
Dermatomiosite/veterinária , Rinite/veterinária , Sinusite/veterinária , Animais , Animais de Zoológico , Antifúngicos/uso terapêutico , Clotrimazol/uso terapêutico , Dermatomiosite/tratamento farmacológico , Dermatomiosite/microbiologia , Griseofulvina/uso terapêutico , Masculino , Rinite/tratamento farmacológico , Rinite/microbiologia , Ruminantes , Sinusite/tratamento farmacológico , Sinusite/microbiologia
3.
Int J Antimicrob Agents ; 55(3): 105884, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31931149

RESUMO

Griseofulvin is a well-known antifungal drug that was launched in 1962 by Merck & Co. for the treatment of dermatophyte infections. However, according to predictions using the Way2Drug computational drug repurposing platform, it may also have antibacterial activity. As no confirmation of this prediction was found in the published literature, this study estimated in-silico antibacterial activity for 42 griseofulvin derivatives. Antibacterial activity was predicted for 33 of the 42 compounds, which led to the conclusion that this activity might be considered as typical for this chemical series. Therefore, experimental testing of antibacterial activity was performed on a panel of Gram-positive and Gram-negative micro-organisms. Antibacterial activity was evaluated using the microdilution method detecting the minimal inhibitory concentration (MIC) and the minimal bactericidal concentration (MBC). The tested compounds exhibited potent antibacterial activity against all the studied bacteria, with MIC and MBC values ranging from 0.0037 to 0.04 mg/mL and from 0.01 to 0.16 mg/mL, respectively. Activity was 2.5-12 times greater than that of ampicillin and 2-8 times greater than that of streptomycin, which were used as the reference drugs. Similarity analysis for all 42 compounds with the (approximately) 470,000 drug-like compounds indexed in the Clarivate Analytics Integrity database confirmed the significant novelty of the antibacterial activity for the compounds from this chemical class. Therefore, this study demonstrated that by using computer-aided prediction of biological activity spectra for a particular chemical series, it is possible to identify typical biological activities which may be used for discovery of new applications (e.g. drug repurposing).


Assuntos
Antibacterianos/farmacologia , Reposicionamento de Medicamentos , Griseofulvina/farmacologia , Antibacterianos/química , Antifúngicos/química , Antifúngicos/farmacologia , Bactérias/efeitos dos fármacos , Griseofulvina/análogos & derivados , Humanos , Testes de Sensibilidade Microbiana
4.
BMJ Case Rep ; 12(12)2019 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-31848138

RESUMO

Elastolytic giant cell granuloma (EGCG), also known as actinic granuloma, is an uncommon granulomatous dermatosis usually characterised by asymptomatic annular plaques on sun-exposed skin. Its aetiology is not fully elucidated, but actinic damage has been considered the main causal factor. Atypical variants with lesions in a non-photodistributed pattern are rare and often related to a systemic disorder, suggesting a more complex pathogenesis and demanding for a screening work-up. Herein, we report a case of an adult obese, diabetic woman presenting with a generalised pruritic papular eruption, histologically revealing an elastolytic giant cell granuloma, with a good response to treatment. In this case, the dermatosis was probably associated with her metabolic comorbidities.


Assuntos
Granuloma Anular/diagnóstico , Granuloma de Células Gigantes/diagnóstico , Griseofulvina/administração & dosagem , Hidroxicloroquina/administração & dosagem , Idoso , Complicações do Diabetes/diagnóstico , Complicações do Diabetes/tratamento farmacológico , Complicações do Diabetes/patologia , Granuloma Anular/tratamento farmacológico , Granuloma Anular/patologia , Granuloma de Células Gigantes/tratamento farmacológico , Granuloma de Células Gigantes/patologia , Griseofulvina/uso terapêutico , Humanos , Hidroxicloroquina/uso terapêutico , Obesidade/complicações , Resultado do Tratamento
5.
Artigo em Inglês | MEDLINE | ID: mdl-31878121

RESUMO

Griseofulvin (GSF) is clinically employed to treat fungal infections in humans and animals. GSF was detected in surface waters as a pharmaceutical pollutant. GSF detection as an anthropogenic pollutant is considered as a possible source of drug resistance and risk factor in ecosystem. To address this concern, a new extraction and enrichment method was developed. GSF-surface molecularly imprinted polymers (GSF-SMIPs) were prepared and applied as solid phase extraction (SPE) sorbent. A dispersive solid phase extraction (DSPE) method was designed and combined with HPLC for the analysis of GSF in surface water samples. The performance of GSF-SMIPs was assessed for its potential to remove GSF from water samples. The factors affecting the removal efficiency such as sample pH and ionic strength were investigated and optimized. The DSPE conditions such as the amount of GSF-SMIPs, the extraction time, the type and volume of desorption solvents were also optimized. The established method is linear over the range of 0.1-100 µg/mL. The limits of detection and quantification were 0.01 and 0.03 µg/mL respectively. Good recoveries (91.6-98.8%) were achieved after DSPE. The intra-day and inter-day relative standard deviations were 0.8 and 4.3% respectively. The SMIPs demonstrated good removal efficiency (91.6%) as compared to powder activated carbon (67.7%). Moreover, the SMIPs can be reused 10 times for water samples. This is an additional advantage over single-use activated carbon and other commercial sorbents. This study provides a specific and sensitive method for the selective extraction and detection of GSF in surface water samples.


Assuntos
Antifúngicos/química , Cromatografia Líquida de Alta Pressão/métodos , Recuperação e Remediação Ambiental/métodos , Griseofulvina/química , Polímeros/química , Extração em Fase Sólida/métodos , Poluentes Químicos da Água/química
7.
Colloids Surf B Biointerfaces ; 184: 110540, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31610418

RESUMO

Fungal biofilms are invariably recalcitrant to antifungal drugs and thus can cause recurrent serious infections. The aim of this work was to prepare highly effective form of the antifungal drug griseofulvin using the chloroform solvate embedded into different polymeric matrices. Based on their solid solubility, solvated (chloroform) and non-solvated (methanol and acetone) solid dispersions were prepared using different materials: silica, microcrystalline cellulose, polyvinylpyrrolidone and hydroxypropyl methylcellulose acetate succinate (HPMCAS) by which HPMCAS dispersions showed the highest solubility of about 200 µg/mL compared with ∼30 µg/mL for pure griseofulvin. The anti fungal potential of griseofulvin was assessed against the dermatophytes T. rubrum. Metabolic and protease activity of T. rubrum NCPF 935 with and without the presence of GF:HPMCAS chloroform solvates showed significant reduction compared to the untreated control after 24 h period. Confocal laser scanning microscopy showed thin hyphae compared to Control and GF:HPMCAS (non solvated). Dynamic vapour sorption data showed that HPMCAS formed most stable solvate structure preventing recrystallization and solvate expulsion, which could explain the disruptive effect of the biofilms. This could be explained by the formed hydrogen bonds as revealed by the solid and liquid state NMR data, which was further confirmed via thermal and FTIR analyses.


Assuntos
Antifúngicos/farmacologia , Biofilmes/efeitos dos fármacos , Griseofulvina/farmacologia , Trichophyton/efeitos dos fármacos , Antifúngicos/química , Griseofulvina/química , Metilcelulose/análogos & derivados , Testes de Sensibilidade Microbiana , Tamanho da Partícula , Solubilidade , Propriedades de Superfície , Trichophyton/metabolismo
8.
Eur J Pharm Biopharm ; 145: 12-26, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31622652

RESUMO

A major shortcoming of drug nanocomposites as compared with amorphous solid dispersions (ASDs) is their limited supersaturation capability in dissolution media. Here, we prepared drug hybrid nanocrystal-amorphous solid dispersions (HyNASDs) and compare their performance to ASDs. A wet-milled griseofulvin (GF, BCS II drug) nanosuspension and a GF solution, both containing the same dissolved polymer-surfactant (SDS: sodium dodecyl sulfate) with 1:1 and 1:3 GF:polymer mass ratios, were spray-dried. Hydroxypropyl cellulose (HPC) and Soluplus (Sol) were used as matrix-forming polymers. XRPD, DSC, and Raman spectroscopy reveal that ASDs were formed upon spray-drying the solution-based feed, whereas nanocomposites and nanocomposites with >10% amorphous content, HyNASDs, were formed with the nanosuspension-based feed. Sol provided higher GF relative supersaturation, up to 180% and 360% for HyNASDs and ASDs, respectively, in the dissolution tests than HPC (up to 50% for both) owing to Sol's stronger intermolecular interactions and miscibility with GF and its recrystallization inhibition. Besides the higher kinetic solubility of GF in Sol, presence of GF nanoparticles vs. micron-sized particles in the nanocomposites enabled fast supersaturation. This study demonstrates successful preparation of fast supersaturating (190% within 20 min) HyNASDs, which renders nanoparticle formulations competitive to ASDs in bioavailability enhancement of poorly soluble drugs.


Assuntos
Liberação Controlada de Fármacos/efeitos dos fármacos , Griseofulvina/química , Nanopartículas/química , Celulose/análogos & derivados , Celulose/química , Cristalização/métodos , Composição de Medicamentos/métodos , Nanocompostos/química , Tamanho da Partícula , Polietilenoglicóis/química , Polímeros/química , Polivinil/química , Dodecilsulfato de Sódio/química , Solubilidade , Tensoativos/química , Suspensões/química
9.
Pharm Res ; 36(11): 162, 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31529336

RESUMO

PURPOSE: Mucins are the principal glycoproteins in mucus and have been implicated in the limitation of intestinal drug absorption; however, the contribution of these molecules to intestinal drug absorption remains unclear. In this study, the relationship between the effect of the mucus layer on intestinal drug permeation and mucin distribution in different parts of the rat gastrointestinal tract was evaluated. METHODS: The intestinal permeability of various lipophilic drugs in rat small intestine was evaluated using the in vitro sac method. The expression profiles of mucin mRNA and proteins were evaluated by quantitative real-time RT-PCR and western blotting, respectively. RESULTS: The intestinal permeability of griseofulvin and antipyrine was enhanced by dithiothreitol (DTT) treatment in the proximal small intestine, such as duodenum and jejunum, but not in the distal regions. The mRNA expression analysis of rat mucin genes revealed that the intestinal expression of Muc5ac was considerably higher in the duodenum, whereas that of Muc1, Muc2, and Muc3A was gradually increased toward the lower intestine. In addition, Muc5ac protein was detected only in the luminal fluids from the proximal small intestine after DTT treatment. CONCLUSIONS: Mucus limits the intestinal permeation of lipophilic drugs in the rat proximal small intestine, in which Muc5ac may be involved.


Assuntos
Antipirina/farmacologia , Griseofulvina/farmacologia , Intestino Delgado/metabolismo , Lipossomos , Glicoproteínas de Membrana/metabolismo , Mucinas/metabolismo , Animais , Antipirina/metabolismo , Composição de Medicamentos , Griseofulvina/metabolismo , Absorção Intestinal , Mucinas/genética , Ratos
10.
AAPS PharmSciTech ; 20(7): 304, 2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31502233

RESUMO

The objective of this study is to elucidate the combined effects of a novel type of material being investigated as a new excipient, an octenylsuccinate-modified dendrimer-like biopolymer (OS-DLB) and poloxamer (PLX), on the solubility of poorly water-soluble compounds. Phenytoin (PHT), griseofulvin (GSF), ibuprofen (IBU), and loratadine (LOR) were used as model compounds. Phase solubility measurements were conducted to determine the relative proportions of API, OS-DLB, and PLX that result in the most stable dendrimeric complexes. The solubilizing power of OS-DLB increases with increasing hydrophobicity of the solute. In the presence of PLX, the solubilization effect of OS-DLB is modestly accentuated for the most hydrophobic drugs (IBU and LOR) but has no effect on the least hydrophobic one (PHT). The maximum potentiation effect of PLX on the solubilizing properties of OS-DLB was observed for GSF, the drug of intermediate hydrophobicity. Three different types of solubilization profiles were obtained in the study. All three different profiles can be appropriately described by a single solubilization model, depending on the specific parameter values. The defining parameters of the model reflect the hydrophobicity of the drug on the one hand and, on the other hand, the inherent tendency of the drug (crystal lattice energy) toward crystallization.


Assuntos
Biopolímeros/química , Dendrímeros/química , Liberação Controlada de Fármacos , Griseofulvina/química , Interações Hidrofóbicas e Hidrofílicas , Nanoestruturas , Poloxâmero/química
11.
Int J Nanomedicine ; 14: 5623-5636, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31440045

RESUMO

Purpose: The objective of this study was to compare the in vitro Fick's first law, in vitro lipolysis, and in vivo rat assays for oral absorption of Biopharmaceutical Classification Systems Class II (BCS II) drugs in self-nanoemulsifying drug delivery system (SNEDDS), and studied drugs and oils properties effects on the absorption. Methods: The transport abilities of griseofulvin (GRI), phenytoin (PHE), indomethacin (IND), and ketoprofen (KET) in saturated water solutions and SNEDDS were investigated using the in vitro Madin-Darby canine kidney cell model. GRI and cinnarizine (CIN) in medium-chain triglycerides (MCT)-SNEDDS and long-chain triglycerides (LCT)-SNEDDS were administered in the in vivo SD rat and in vitro lipolysis models to compare the oral absorption and the distribution behaviors in GIT and build an in vitro-in vivo correlation (IVIVC). Results: In the cell model, the solubility of GRI, PHE, IND, and KET increased 6-8 fold by SNEDDS, but their permeability were only 18%, 4%, 8%, and 33% of those of their saturated water solutions, respectively. However, in vivo absorption of GRI-SNEDDS was twice that of the GRI suspension and those of CIN-SNEDDS were 15-21 fold those of the CIN suspension. In the lipolysis model, the GRI% in aqueous and pellet phases of MCT were similar to that in LCT. In contrast, the CIN% in the aqueous and pellet phases were decreased but that of the lipid phase increased. In addition, an IVIVC was found between the CIN% in the lipid phase and in vivo relative oral bioavailability (F r). Conclusion: The in vitro cell model was still a suitable tool to study drug properties effects on biofilm transport and SNEDDS absorption mechanisms. The in vitro lipolysis model provided superior oral absorption simulation of SNEDDS and helped to build correlation with in vivo rats. The oral drug absorption was affected by drug and oil properties in SNEDDS.


Assuntos
Absorção Fisiológica , Sistemas de Liberação de Medicamentos , Emulsões/química , Lipólise , Modelos Biológicos , Nanopartículas/química , Administração Oral , Animais , Permeabilidade da Membrana Celular , Cinarizina/administração & dosagem , Cinarizina/química , Cinarizina/farmacologia , Cães , Griseofulvina/administração & dosagem , Griseofulvina/farmacologia , Células Madin Darby de Rim Canino , Masculino , Preparações Farmacêuticas , Ratos Sprague-Dawley , Solubilidade
12.
Drug Dev Ind Pharm ; 45(9): 1477-1486, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31260340

RESUMO

Griseofulvin is a commonly used antifungal agent which is administered per oral (p.o.). The oral administration route, however, shows rather low bioavailability. The aim of this study was to improve the bioavailability and to evaluate and interpret the pharmacokinetic profiles after subcutaneous (s.c.) administration of crystalline griseofulvin nano- and microsuspensions. Both formulations were injected at 5 and 500 µmol/kg to rats. For the lower concentration, the profiles were similar after s.c. injection but extended as compared to p.o. administration. For the higher concentration, injection of microsuspension resulted in a maintained plateau whereas the nanosuspension resulted in an obvious peak exposure followed by extended elimination. Both suspensions showed improved exposure with dose. The differences in peak exposures between nano- and microparticles, at the high dose, were mainly ascribed to differences in dissolution rate, experimentally determined in vitro, using spectroscopic methods. The extended appearance in the circulation may depend on the physicochemical properties of the compound and the physiological conditions at the injection site. The bioavailability was improved for both formulations compared with an orally administered nanosuspension, suggesting the s.c. route to be a preferred administration option for compounds with low oral bioavailability regarding both overall exposure and extended efficacy.


Assuntos
Composição de Medicamentos/métodos , Griseofulvina/farmacocinética , Nanopartículas/administração & dosagem , Administração Oral , Animais , Antifúngicos/administração & dosagem , Disponibilidade Biológica , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Avaliação Pré-Clínica de Medicamentos , Liberação Controlada de Fármacos , Griseofulvina/administração & dosagem , Injeções Subcutâneas , Masculino , Modelos Animais , Tamanho da Partícula , Ratos , Solubilidade , Suspensões
13.
Mycoses ; 62(10): 949-953, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31343780

RESUMO

Outbreaks of tinea capitis (TC) can be a source of medical and economic burden for healthcare systems; Griseofulvin and terbinafine are considered to be effective first-line treatments for TC. In order to compare the efficacy of griseofulvin and terbinafine for the treatment of TC in a paediatric population of African immigrants in the Tel Aviv area, we conducted a retrospective cohort study of all cases of TC diagnosed and treated between March 2016 and February 2018 at a dedicated TC paediatric dermatology clinic at the Tel Aviv Medical Center (which serves as a referral centre for the paediatric refugee population in the Tel Aviv metropolitan area). Epidemiologic, clinical and laboratory data were collected, and 304 patients were included. Trichophyton violaceum (TV), Trichophyton soudanense (TS) and Microsporum audouinii (MA) were the prominent causative organisms. Treatment with griseofulvin suspension for 12 weeks was compared with (a) griseofulvin suspension for 8 weeks and with (b) terbinafine tablets for 4 weeks. There was no statistically significant difference between the groups regarding age, sex, country of birth, ethnicity and the causative organism. Twelve weeks of griseofulvin treatment had a statistically significant better cure rate than 4 weeks of terbinafine. Treatment was significantly more effective when TC was due to infections with MA and TS as compared with TV. No statistically significant difference was observed between 12- and 8-week treatment with griseofulvin.


Assuntos
Antifúngicos/administração & dosagem , Griseofulvina/administração & dosagem , Terbinafina/administração & dosagem , Tinha do Couro Cabeludo/tratamento farmacológico , Criança , Pré-Escolar , Emigrantes e Imigrantes , Feminino , Humanos , Lactente , Israel , Masculino , Microsporum/isolamento & purificação , Estudos Retrospectivos , Tinha do Couro Cabeludo/microbiologia , Resultado do Tratamento , Trichophyton/isolamento & purificação
14.
Int J Pharm ; 567: 118501, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31288055

RESUMO

Manufacturing poorly water-soluble active pharmaceutical ingredients (API) with sufficient bioavailability is a significant challenge in pharmaceutical research. A higher bioavailability can reduce both the applied dosage and the side effects for the patient. One method of increasing the bioavailability is to reduce the particle size of the drug down to the nanoscale. An innovative procedure for the preparation of particles in the submicron size range is spray drying with aerosol conditioning, followed by subsequent separation of the particles in an electrostatic precipitator (ESP). This process has been tested before in an earlier work with aqueous model substances at high production rates (1 g/h) and narrow particle-size distributions (mannitol: d50,0 = 455 nm, span = 0,8) in the submicron range. Spray drying from an aqueous solution with low drug concentrations (<1 wt-%) leads to particles in the lower nanosize range, but the low concentrations make this process inefficient. A custom-made plant was modified in order to handle the organic spray-drying process. In addition, explosion protection had to be considered. This work focuses on the spray drying of submicron particles from organic solvents for the purpose of increasing the dissolution rate of the API griseofulvin. API particles were successfully produced in the submicron size-range, characterized and the dissolution behavior was investigated. The dissolution time to dissolve 80% of the drug, t80, was reduced from 21.5 min for the micronized grade API to 8.5 min for the submicron product.


Assuntos
Dessecação , Tecnologia Farmacêutica , Acetona/química , Liberação Controlada de Fármacos , Griseofulvina/química , Hidroclorotiazida/química , Ozônio/química , Tamanho da Partícula , Solventes/química
16.
Int J Pharm ; 566: 565-572, 2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-31181305

RESUMO

The objective of the study was to evaluate the pharmacokinetic profile after different subcutaneous (s.c.) administrations of nano- and microparticle suspensions of griseofulvin to mice. The solubility of the compound was determined as approximately 40 µM, at 37 °C, independent of particle size, stabilizer mixtures investigated and solvent used for measurement. The present in vivo studies demonstrated non-linear absorption kinetics (in peak concentration, Cmax) for griseofulvin up to 50 mg/kg after s.c. administration of nanocrystals and microsuspensions but linear increase in area under the curve (AUC) at all occasions investigated. Cmax was higher for smaller particles administered. Both investigated suspensions, at 10 and 50 mg/kg, showed significantly sustained plasma profiles compared to i.v. and p.o. administration. Administering 10 and 50 mg/kg of griseofulvin nanocrystals as 10 mL/kg, instead of 2.5 mL/kg, improved Cmax but AUC was unchanged. The present study showed that the bioavailability of griseofulvin, administered as nano- and microparticles, increased significantly after s.c. administration (60-100%) compared with p.o. dosing (17%). The drug is currently orally administered and clearly exposed to a significant first pass metabolism, i.e. an ideal candidate for an alternative administration route, like s.c. injection.


Assuntos
Antifúngicos/administração & dosagem , Griseofulvina/administração & dosagem , Nanopartículas/administração & dosagem , Administração Oral , Animais , Antifúngicos/farmacocinética , Disponibilidade Biológica , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Feminino , Griseofulvina/farmacocinética , Injeções Subcutâneas , Camundongos Endogâmicos C57BL , Tamanho da Partícula
17.
Curr Top Med Chem ; 19(13): 1145-1161, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31119999

RESUMO

BACKGROUND: Griseofulvin - a mold metabolite produced by Penisilium griseofulvum is known as an antifungal drug. OBJECTIVE: Thus, the goal of this paper is the design and synthesis of new griseofulvin derivatives and evaluation of their antifungal activity. METHODS: Forty-two new compounds were synthesized using classical methods of organic synthesis and evaluated for their antimicrobial activity by microdilution method. RESULTS: All forty-two new compounds exhibited very good activity against eight tested micromycetes with MIC ranging from 0.0075-0.055 mg/ml and MFC from 0.02-024 mg/ml. All compounds exhibited better activity than reference drugs ketoconazole (7-42 times) and bifonazole (3-16 fold). The most promising was compound 15. The most sensitive fungal was found to be T. viride, while the most resistant, as was expected, was A. fumigatus. It should be mentioned that most of compounds exhibited better activity than griseofulvin. The molecular docking studies revealed that the most active compound have the same hydrophobic and H-bonding interactions with Thr276 residue observed for griseofulvin forming 3 hydrogen bonds while griseofulvin only one. In general, the molecular docking results coincide with experimental. CONCLUSION: Forty-two giseofulvin derivatives were designed, synthesized and evaluated for antimicrobial activity. These derivatives revealed good antifungal activity, better than reference drugs ketoconazole, bifonazole, and griseofulvin as well.


Assuntos
Antifúngicos/farmacologia , Aspergillus fumigatus/efeitos dos fármacos , Griseofulvina/farmacologia , Simulação de Acoplamento Molecular , Trichoderma/efeitos dos fármacos , Antifúngicos/síntese química , Antifúngicos/química , Relação Dose-Resposta a Droga , Griseofulvina/síntese química , Griseofulvina/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade
20.
J Agric Food Chem ; 67(22): 6125-6132, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31083998

RESUMO

With environmental pollution, residual hazards accumulate and severe drug resistance and many other problems appear; some highly toxic drugs have been banned, and antifungal agents are far from satisfactory. Natural products play an important role in the discovery and development of new pesticides. The natural product griseofulvin (1) has been known as an antifungal agent in the treatment of dermatomycoses for decades. In this study, a series of new griseofulvin derivatives were synthesized with good yields. Their structures were characterized by 1H and 13C nuclear magnetic resonance and high-resolution mass spectrometry (electrospray ionization). The antifungal activities of griseofulvin analogues were first evaluated against five phytopathogenic fungi ( Cytospora sp., Colletotrichum gloeosporioides, Botrytis cinerea, Alternaria solani, and Fusarium solani) in vitro. Of significance is that most of them showed excellent antifungal activities against C. gloeosporioides. The antifungal activities of the four best compounds (6a, 6c, 6e, and 6f) against C. gloeosporioides were further investigated in vivo using infected apples. The results suggested that compounds 6c, 6e, and 6f [half-maximal inhibitory concentration (IC50) = 47.25 ± 1.46, 49.44 ± 1.50, and 53.63 ± 1.74 µg/mL, respectively] were better than thiophanate-methyl (IC50 = 69.66 ± 6.07 µg/mL). Furthermore, comparative molecular field analysis was performed on the basis of the antifungal activity results of all 22 of the compounds against C. gloeosporioides in vitro. The three-dimensional coefficient contour plots revealed that the suitable bulky and electronegative acyl-substituted groups seem to be more favorable for increasing activity at the 4' position of griseofulvin. The structure-activity relationships were also discussed. Griseofulvin derivatives can be used for the development of highly effective and safe agricultural fungicides.


Assuntos
Fungos/efeitos dos fármacos , Fungicidas Industriais/química , Fungicidas Industriais/farmacologia , Griseofulvina/análogos & derivados , Griseofulvina/farmacologia , Doenças das Plantas/microbiologia , Fungos/crescimento & desenvolvimento , Estrutura Molecular , Relação Quantitativa Estrutura-Atividade
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