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1.
Microbiol Spectr ; 10(5): e0243722, 2022 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-36098531

RESUMO

Pseudomonas aeruginosa is an opportunistic pathogen that has been declared by the World Health Organization as a "priority 1 critical pathogen" needing immediate new strategies for chemotherapy. During infection, P. aeruginosa uses redundant mechanisms to acquire ferric, heme (Hm), or ferrous iron from the host to survive and colonize. Significant efforts have been undertaken to develop siderophore blockers to inhibit ferric iron acquisition by P. aeruginosa, but there is a lack of inhibitors that can block Hm or ferrous iron acquisition by P. aeruginosa. We developed and employed a targeted high-throughput screen (HTS) and identified a molecule(s) that can specifically inhibit the Hm and ferrous iron acquisition systems of P. aeruginosa. Our targeted approach relies on screening a small-molecule library against P. aeruginosa under three growth conditions, where the only variable was the iron source (ferric, Hm, or ferrous iron). Each condition served as a counterscreen for the other, and we identified molecules that inhibit the growth of P. aeruginosa in the presence of only Hm or ferrous iron. Our data indicate that econazole, bithionate, and raloxifene inhibit the growth of P. aeruginosa in the presence of Hm and that oxyquinoline inhibits the growth of P. aeruginosa in the presence of ferrous iron. These iron-specific inhibitors do not interfere with the activity of meropenem, a commercial antipseudomonal, and can also increase meropenem activity. In conclusion, we present a proof of concept of a successful targeted conditional screening method by which we can identify specific iron acquisition inhibitors. This approach is highly adaptable and can easily be extended to any other pathogen. IMPORTANCE Since acquiring iron is paramount to P. aeruginosa's survival and colonization in the human host, developing novel strategies to block the access of P. aeruginosa to host iron will allow us to starve it of an essential nutrient. P. aeruginosa uses siderophore, heme, or ferrous iron uptake systems to acquire iron in the human host. We have developed a novel approach through which we can directly identify molecules that can prevent P. aeruginosa from utilizing heme or ferrous iron. This approach overcomes the need for the in silico design of molecules and identifies structurally diverse biologically active inhibitor molecules. This screening approach is adaptable and can be extended to any pathogen. Since Gram-negative pathogens share many similarities in iron acquisition at both the mechanistic and molecular levels, our screening approach presents a significant opportunity to develop novel broad-spectrum iron acquisition inhibitors of Gram-negative pathogens.


Assuntos
Pseudomonas aeruginosa , Sideróforos , Proteínas de Bactérias , Econazol , Heme , Ferro , Meropeném , Oxiquinolina , Cloridrato de Raloxifeno
2.
J Biol Chem ; 298(9): 102344, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35944583

RESUMO

Human cytochrome P450 8B1 (CYP8B1) is involved in conversion of cholesterol to bile acids. It hydroxylates the steroid ring at C12 to ultimately produce the bile acid cholic acid. Studies implicated this enzyme as a good drug target for nonalcoholic fatty liver disease and type 2 diabetes, but there are no selective inhibitors known for this enzyme and no structures to guide inhibitor development. Herein, the human CYP8B1 protein was generated and used to identify and characterize interactions with a series of azole inhibitors, which tend to be poorly selective P450 inhibitors. Structurally related miconazole, econazole, and tioconazole bound with submicromolar dissociation constants and were effective inhibitors of the native reaction. CYP8B was cocrystallized with S-tioconazole to yield the first X-ray structure. This inhibitor bound in the active site with its azole nitrogen coordinating the heme iron, consistent with inhibitor binding and inhibition assay data. Additionally, the CYP8B1 active site was compared with similar P450 enzymes to identify features that may facilitate the design of more selective inhibitors. Selective inhibitors should promote a better understanding of the role of CYP8B1 inhibition in normal physiology and disease states and provide a possible treatment for nonalcoholic fatty liver disease and type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2 , Hepatopatia Gordurosa não Alcoólica , Azóis/química , Azóis/farmacologia , Azóis/uso terapêutico , Ácidos e Sais Biliares , Colesterol , Ácidos Cólicos , Sistema Enzimático do Citocromo P-450/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Desenho de Fármacos , Econazol/metabolismo , Heme/metabolismo , Humanos , Ferro , Miconazol , Nitrogênio , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Esteroide 12-alfa-Hidroxilase/metabolismo
3.
Mycologia ; 114(5): 825-840, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35904483

RESUMO

Parengyodontium album is a fungal species that frequently occurs in the cultural heritage environment. Although three subclades were initially described in the species, no study has sought to determine the occurrence of each subclade in the cultural heritage context. These subclades are easily distinguishable phylogenetically, but their morphological identification is more difficult. Eighteen strains isolated from different cultural sites and initially identified as P. album were studied phylogenetically, morphologically, and in terms of their susceptibility to econazole nitrate 0.2%, an antifungal product used as preservation treatment in cultural heritage domain. The phylogenetic study revealed that all studied strains belonged to P. album subclade 1 or P. torokii (P. album subclade 3) and none belonged to P. album subclade 2. The morphological study revealed the best characteristics to differentiate the three subclades/species, namely, the ability of the strains to grow at 32 C and 35 C on potato dextrose agar (PDA) medium and the shape of conidia. Finally, the strains displayed variable susceptibilities to econazole nitrate, with no apparent link to any particular subclade/species.


Assuntos
Antifúngicos , Econazol , Antifúngicos/farmacologia , Filogenia , Esporos Fúngicos
4.
Mycoses ; 65(11): 981-988, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35689417

RESUMO

The treatment of invasive aspergillosis caused by cryptic species remains a challenge due to the lack of randomised clinical trials and investigation of the efficacy and safety of different therapeutic strategies. We aimed to evaluate the in vitro activity of 23 conventional and new antifungal drugs against 54 clinical and environmental Aspergillus oryzae isolates by using the Clinical and Laboratory Standards Institute (CLSI) standard M38-A3. The lowest geometric mean MIC values were found for luliconazole and lanoconazole (0.001 µg/ml), followed by anidulafungin (0.104 µg/ml), posaconazole (0.15 µg/ml), itraconazole (0.37 µg/ml), efinaconazole (0.5 µg/ml), voriconazole (0.51 µg/ml), tavaborole (0.72 µg/ml), and amphotericin B (0.79 µg/ml). In contrast, ketoconazole, terbinafine, econazole, tioconazole, ravuconazole, miconazole, nystatin, clotrimazole, griseofulvin, sertaconazole, natamycin, tolnaftate, and fluconazole had no or low activity. Further studies are required to determine how well this in vitro activity translates into in vivo efficacy.


Assuntos
Antifúngicos , Aspergillus oryzae , Anfotericina B , Anidulafungina , Antifúngicos/farmacologia , Clotrimazol , Econazol , Fluconazol , Griseofulvina , Humanos , Itraconazol , Cetoconazol , Miconazol/farmacologia , Testes de Sensibilidade Microbiana , Natamicina , Nistatina , Terbinafina , Tolnaftato , Voriconazol/farmacologia
5.
Microbiol Spectr ; 10(3): e0093722, 2022 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-35467374

RESUMO

Colistin is a last-line antibiotic which acts by causing membrane permeabilization in Gram-negative bacteria. However, its clinical value has been limited by its toxicity and the emergence of resistant organisms. In this study, we showed that econazole and colistin can act synergistically to produce a strong antimicrobial effect sufficient for eradication of starvation-induced tolerant and multidrug-resistant populations of Acinetobacter baumannii, a notorious pathogen causing recalcitrant infections, both in vitro and in mouse infection models. Investigation of the underlying mechanism showed that, while colistin disrupts the membrane structure, econazole causes the dissipation of proton motive force, eliciting a vicious cycle of membrane structural damages and disruption of membrane protein functions, and eventually cell death. This drug combination therefore achieves our goal of using a much smaller dosage of colistin to produce a much stronger antimicrobial effect to tackle the problems of toxicity and resistance associated with colistin usage. IMPORTANCE Findings described in this study constitute concrete evidence that it is possible to significantly enhance the antimicrobial activity of colistin by using an antifungal drug, econazole, as a colistin adjuvant. We showed that this drug combination can kill not only multidrug-resistant A. baumannii but also the tolerant subpopulation of such strains known as persisters, which may cause chronic and recurrent infections in clinical settings. The synergistic killing effect of the econazole and colistin combination was also observable in mouse infection models at a very low concentration, suggesting that such a drug combination has high potential to be used clinically. Findings in this study therefore have important implications for enhancing its clinical application potential as well as developing new approaches to enhance treatment effectiveness and reduce suffering in patients.


Assuntos
Infecções por Acinetobacter , Acinetobacter baumannii , Infecções por Acinetobacter/tratamento farmacológico , Infecções por Acinetobacter/microbiologia , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Colistina/farmacologia , Colistina/uso terapêutico , Combinação de Medicamentos , Farmacorresistência Bacteriana Múltipla , Sinergismo Farmacológico , Econazol/farmacologia , Econazol/uso terapêutico , Camundongos , Testes de Sensibilidade Microbiana
6.
Expert Rev Anti Infect Ther ; 20(6): 955-961, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-34913825

RESUMO

INTRODUCTION: Econazole has been found efficacious as antitubercular in in vitro and in vivo animal studies. However, limited information is available for its safety and pharmacokinetics in humans. In our present study we have conducted single ascending dose, safety, and pharmacokinetic evaluation in healthy human volunteers with the purpose of enabling translation for tuberculosis. METHODS: This study was conducted as a single-center, ascending-dose, placebo-controlled, double blind design. Three ascending dose were chosen (250 , 500 , and 1000 mg) to be administered as a single oral dose. The volunteers were screened for potential eligibility. Participants were randomized to receive either Econazole or Placebo in a 6:2 design. Safety assessments and pharmacokinetic evaluations were carried out for each cohort. RESULTS: Econazole was found to be safe at all dose levels. No serious or severe adverse events occurred during the study. The AUC (0-∞) showed a response relationship with a value of 49 ± 3.47 h* µg/ml, 17. 86 ± 8.40 hr* µg/ml, 35.54 ± 13.94 hr* µg/ml for 250 mg, 500 mg, and 1000 mg, respectively. CONCLUSION: Based on the findings of our study, a dose of 500 mg Econazole, once a day orally was considered as appropriate for further evaluation.


Assuntos
Econazol , Área Sob a Curva , Relação Dose-Resposta a Droga , Método Duplo-Cego , Econazol/efeitos adversos , Voluntários Saudáveis , Humanos
7.
J Antimicrob Chemother ; 77(2): 425-432, 2022 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-34747463

RESUMO

OBJECTIVES: Bacterial antibiotic tolerance is responsible for the recalcitrance of chronic infections. This study aims to investigate a potential drug that can effectively kill antibiotic-tolerant bacteria and evaluate the ability of this drug on the eradication of tolerant cells both in vitro and in vivo. METHODS: The in vitro effect of econazole on eradicating starvation-induced tolerant bacterial populations was studied by testing the amount of survival bacteria in the presence of econazole combining conventional antibiotics. Proton motive force (PMF) was determined after econazole treatment by DiOC2(3). Finally, mouse infection models were used to detect the ability of econazole on killing the tolerant populations in vivo. RESULTS: Econazole eradicated starvation-induced tolerant cells of various bacterial species within 24 or 96 h when used in combination with conventional antibiotics. Moreover, mouse survival rate drastically increased along with the decrease of in vivo bacterial count after treatment of infected mice with the econazole and ceftazidime combination for 72 h. PMF was found to have dissipated almost completely in econazole-treated cells. CONCLUSIONS: Econazole could act in combination with conventional antibiotics to effectively eradicate bacterial tolerant cells. The combined use of econazole and ceftazidime was shown to be effective for eradicating tolerant cells in a mouse infection model. The ability of econazole to eradicate tolerant cells was due to its ability to cause dissipation of bacterial transmembrane PMF. Econazole-mediated PMF disruption is a feasible strategy for the treatment of chronic and recurrent bacterial infections.


Assuntos
Antibacterianos , Força Próton-Motriz , Adjuvantes Farmacêuticos , Animais , Antibacterianos/farmacologia , Bactérias , Econazol/farmacologia , Camundongos
8.
Artigo em Inglês | MEDLINE | ID: mdl-34961436

RESUMO

The authors wish to add words "Research Scholar" and "Research Supervisor" to their affiliations [1]. The original article can be found online at https://doi.org/10.2174/1574891X15999201110212725 The corrected affiliation is: 1Department of Pharmaceutics, Rayat-Bahra College of Pharmacy, Hoshiarpur, Punjab 146001, India; 2Faculty of Pharma-ceutical Sciences, Department of Pharmaceutics, PCTE Group of Institutes, Ludhiana, Punjab 142021, India; 3Research Scholar, I.K. Gujral Punjab Technical University, Jalandhar-Punjab 144601, India; 4Research Supervisor, I.K. Gujral Punjab Technical University, Jalandhar-Punjab 144601, India.


Assuntos
Econazol , Ácido Oleico , Administração Cutânea , Animais , Ratos , Ratos Wistar , Universidades
9.
Nat Commun ; 12(1): 6284, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34725357

RESUMO

TRPV6 is a calcium-selective ion channel implicated in epithelial Ca2+ uptake. TRPV6 inhibitors are needed for the treatment of a broad range of diseases associated with disturbed calcium homeostasis, including cancers. Here we combine cryo-EM, calcium imaging, and mutagenesis to explore molecular bases of human TRPV6 inhibition by the antifungal drug econazole and the universal ion channel blocker ruthenium red (RR). Econazole binds to an allosteric site at the channel's periphery, where it replaces a lipid. In contrast, RR inhibits TRPV6 by binding in the middle of the ion channel's selectivity filter and plugging its pore like a bottle cork. Despite different binding site locations, both inhibitors induce similar conformational changes in the channel resulting in closure of the gate formed by S6 helices bundle crossing. The uncovered molecular mechanisms of TRPV6 inhibition can guide the design of a new generation of clinically useful inhibitors.


Assuntos
Antifúngicos/química , Bloqueadores dos Canais de Cálcio/química , Canais de Cálcio/química , Econazol/química , Rutênio Vermelho/química , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/química , Sítios de Ligação , Cálcio/metabolismo , Canais de Cálcio/genética , Canais de Cálcio/metabolismo , Humanos , Modelos Moleculares , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismo
10.
Mymensingh Med J ; 30(3): 638-643, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34226449

RESUMO

Fungal infection of the ear canal is called Otomycosis. It is more common in hot and humid condition. There are many modalities of treatment or therapeutic agent for treatment of otomycosis. Econazole Nitrate 1% + Triamcinolone Acetonide 0.1% cream is a topical antifungal agent described to be effective in the treatment of otomycosis. This study was performed to compare the efficacy of topical application clotrimazole 1% solution and Econazole Nitrate 1% + Triamcinolone Acetonide 0.1% cream in the treatment of otomycosis. A controlled, randomized and open clinical trial was carried out in ENT department of Mymensingh Medical College Hospital, Mymensingh, Bangladesh from January 2020 to July 2020. Patients diagnosed with fungal otitis externa who were treated with topical antifungals were included in this study. They were randomized into two treatment groups: i) Clotrimazole 1% solution, 2) Econazole Nitrate 1% + Triamcinolone Acetonide 0.1% cream. Patients were microscopically evaluated at two weeks of treatment to determine resolution of disease. Recurrence and complications were recorded. Demographic and clinical variables were collected and analyzed, follow up and final outcomes (absence of infection) were compared between two groups. One hundred & two (102) patients were included, 51 in the clotrimazole 1% solution group and 51 in the Econazole Nitrate 1% + Triamcinolone Acetonide 0.1% cream group. Predominant symptoms are pain, pruritus, aural fullness and hearing loss. Aspergillus organism was isolated most frequently (63.73%). Treatment with clotrimazole 1% solution groups resulted in 88.23% resolution vs. 80.39% resolution with Econazole Nitrate 1% + Triamcinolone Acetonide 0.1% cream at 2 weeks of treatment. Econazole Nitrate 1% + Triamcinolone Acetonide 0.1% cream group demonstrated higher treatment failure 11.76 and 19.60 respectively. Clotrimazole 1% solution is more effective than Econazole Nitrate 1% + Triamcinolone Acetonide 0.1% cream for uncomplicated otomycosis. More study is needed to corroborate our results.


Assuntos
Econazol , Otomicose , Administração Tópica , Antifúngicos/uso terapêutico , Bangladesh , Clotrimazol/uso terapêutico , Econazol/uso terapêutico , Humanos , Otomicose/tratamento farmacológico , Triancinolona Acetonida/uso terapêutico
11.
J Pharm Sci ; 110(11): 3702-3714, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34293406

RESUMO

Econazole nitrate, an antifungal drug used in the handling of skin ailments, is commercially not efficient as these ailments typically require a more elevated concentration of the drug to offer an effective pharmacological retort. Like so, it is proposed to assess the effectiveness of the topical hydrogel of econazole-loaded nanosponge in the management of skin ailment(s). Econazole nitrate-laden ß-cyclodextrin nanosponges were developed by employing the melt method using ß-cyclodextrin as the organic polymer and N,N-carbonyldiimidazole as the crosslinker. The critical factors disturbing the quality of the formulation were uniquely identified by the Ishikawa diagram, and they were optimized by the statistical experiment design concept. ß-cyclodextrin loaded nanosponges were uniquely designed using the Placket-Burman approach and optimized utilizing the Box-Behnken method. The optimized nanosponges (EN-CDN) were  421.37 ± 6.19 nm in size with an entrapment efficiency of 70.13% ± 5.73%. The topical hydrogel of nanosponges (EN-TG) was prepared using carbopol 934 and pyrrolidone as permeation enhancers. In vitro skin permeation studies affirmed the improved transport crosswise the goatskin for topical hydrogel in comparison to the marketed product. EN-TG was able to control the fungal infection in the selected animal model in comparison to the marketed preparation. Stability studies reported favorably that nanogel remained stable under normal and accelerated settings.


Assuntos
Econazol , beta-Ciclodextrinas , Animais , Antifúngicos , Portadores de Fármacos , Hidrogéis , Pele
12.
Naunyn Schmiedebergs Arch Pharmacol ; 394(6): 1231-1249, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33620548

RESUMO

Econazole, miconazole, and sertaconazole, the structurally related azoles with imidazole moiety, were evaluated for their cytotoxicity and their ability to bind to mammalian tubulin. Our results indicated that sertaconazole and econazole bound to goat brain tubulin with a dissociation constant of 9 and 19 µM respectively, while miconazole did not bind to goat brain tubulin. Econazole, miconazole, and sertaconazole inhibited the proliferation of HeLa cells with an IC50 of 28, 98, and 38 µM respectively with sertaconazole alone inducing a mitotic block in the treated cells. Since sertaconazole bound to goat brain tubulin with higher affinity and blocked the cells at mitosis, we hypothesized that its cytotoxic mechanism might involve inhibition of tubulin and econazole which did not block the cells at mitosis may have additional targets than tubulin. Sertaconazole inhibited the polymerization of tubulin in HeLa cells and the in vitro assembled goat brain tubulin. Competitive tubulin-binding assay using colchicine and computational simulation studies showed that sertaconazole bound closer to the colchicine site and induced the tubulin dimer to adopt a "bent" conformation which is incompetent for the polymerization. Results from RT-PCR analysis of the A549 cells treated with sertaconazole indicated activation of apoptosis. Sertaconazole significantly inhibited the migration of HeLa cells and showed synergistic antiproliferative potential with vinblastine. Collectively, the results suggest that sertaconazole which is already in clinical practice could be useful as a topical chemotherapy agent for the treatment of skin cancers in combination with other systemic anticancer agents.


Assuntos
Antineoplásicos/farmacologia , Imidazóis/farmacologia , Microtúbulos/efeitos dos fármacos , Mitose/efeitos dos fármacos , Tiofenos/farmacologia , Células A549 , Animais , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Econazol/farmacologia , Cabras , Células HEK293 , Células HeLa , Humanos , Concentração Inibidora 50 , Miconazol/farmacologia , Tubulina (Proteína)/efeitos dos fármacos , Tubulina (Proteína)/metabolismo , Vimblastina/administração & dosagem
13.
Laryngoscope ; 131(5): E1640-E1646, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33141477

RESUMO

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


Assuntos
Antifúngicos/administração & dosagem , Aspergilose/tratamento farmacológico , Econazol/administração & dosagem , Nistatina/administração & dosagem , Otomicose/tratamento farmacológico , Triancinolona Acetonida/administração & dosagem , Administração Tópica , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antifúngicos/efeitos adversos , Aspergilose/diagnóstico , Aspergilose/microbiologia , Aspergillus niger/isolamento & purificação , Criança , Pré-Escolar , Dermatite Irritante/epidemiologia , Dermatite Irritante/etiologia , Combinação de Medicamentos , Meato Acústico Externo/efeitos dos fármacos , Meato Acústico Externo/microbiologia , Dor de Orelha/induzido quimicamente , Dor de Orelha/epidemiologia , Econazol/efeitos adversos , Feminino , Cefaleia/induzido quimicamente , Cefaleia/epidemiologia , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Nistatina/efeitos adversos , Otomicose/microbiologia , Estudos Prospectivos , Suspensões , Resultado do Tratamento , Triancinolona Acetonida/efeitos adversos , Adulto Jovem
14.
Int J Pharm ; 591: 119979, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33068694

RESUMO

Several strategies have been explored to obtain effective econazole nitrate (ECN) concentrations at the site of application for a prolonged time. In this paper, different gelatin-based film formulations for vaginal application were investigated, containing ECN (10% w/w with respect to gelatin) as pure drug or as drug-solid dispersions (SD). For the production of SD, different polymers were evaluated: polyvinylpyrrolidone (PVP), Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer) and Gelucire® 50/13 (mixture of mono-, di- and triglycerides of fatty acids, esters of PEG 1500 and free PEG). Gelucire®-SD showed the best solubility enhancement, increasing 9.2 times the ECN solubility in pH 4.5 solution respect to pure drug; DSC and XRD analysis confirmed the crystalline form of the drug. XRD results evidenced that all gelatin-based films, containing either the drug or the SD, underwent the topotactic transformation of ECN into crystalline econazole (EC), owing to a strong interaction between the drug and the gelatin. Films containing Gelucire®-based SD displayed lower brittleness and rigidity with respect to the other samples; moreover they demonstrated good structural integrity after 24 h of incubation in the acidic solution (swelling degree of about 350%). Then, Gelucire®-SD based films were compared with the corresponding formulations cross-linked by genipin (2% w/w). The addition of genipin did not interfere with the drug-gelatin interaction. Gelucire®-SD based films showed similar release profiles to neat gelatin films, enhancing the drug release in the first 5 h and controlling the EC release over time, avoiding the use of a crosslinking additive. Finally, gelatin films containing Gelucire® solid dispersion displayed good adhesiveness and anti-Candida activity. Overall, results support the potential use of this film formulation as noncytotoxic EC delivery system for the treatment of vaginal candidiasis.


Assuntos
Econazol , Gelatina , Parto Obstétrico , Feminino , Humanos , Polietilenoglicóis , Gravidez , Solubilidade
15.
Am J Trop Med Hyg ; 103(5): 2127-2128, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32901593

RESUMO

Trichophyton tonsurans is an anthropophilic dermatophyte with a worldwide distribution and is responsible for superficial mycosis with a wide range of clinical manifestations. We report two atypical cases of tinea due to T. tonsurans in two children: a case of extensive tinea corporis and a case of inflammatory tinea capitis.


Assuntos
Antifúngicos/administração & dosagem , Econazol/administração & dosagem , Griseofulvina/administração & dosagem , Inflamação/diagnóstico , Tinha do Couro Cabeludo/diagnóstico , Trichophyton/isolamento & purificação , Adolescente , Criança , Humanos , Inflamação/tratamento farmacológico , Inflamação/microbiologia , Inflamação/patologia , Masculino , Tinha do Couro Cabeludo/tratamento farmacológico , Tinha do Couro Cabeludo/microbiologia , Tinha do Couro Cabeludo/patologia
16.
J Chromatogr A ; 1621: 461085, 2020 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-32376018

RESUMO

Two analytical methodologies based on the combined use of hydroxypropyl-ß-cyclodextrin and two different amino acid-based chiral ionic liquids (tetrabutylammonium-L-lysine or tetrabutylammonium-L-glutamic acid) in electrokinetic chromatography were developed in this work to perform the enantioselective determination of econazole and sulconazole in pharmaceutical formulations. The influence of different experimental variables such as buffer concentration, applied voltage, nature and concentration of the ionic liquid, temperature and injection time, on the enantiomeric separation was investigated. The combination of hydroxypropyl-ß-cyclodextrin and tetrabutylammonium-L-lysine under the optimized conditions enabled to achieve the enantiomeric determination of both drugs with high enantiomeric resolution (3.5 for econazole and 2.4 for sulconazole). The analytical characteristics of the developed methodologies were evaluated in terms of linearity, precision, LOD, LOQ and recovery showing good performance for the determination of both drugs which were successfully quantitated in pharmaceutical formulations. This work reports the first analytical methodology enabling the enantiomeric determination of sulconazole in pharmaceutical formulations.


Assuntos
2-Hidroxipropil-beta-Ciclodextrina/química , Cromatografia Capilar Eletrocinética Micelar/métodos , Econazol/análise , Ácido Glutâmico/química , Imidazóis/análise , Líquidos Iônicos/química , Lisina/química , Compostos de Amônio Quaternário , Estereoisomerismo , Temperatura , Fatores de Tempo
17.
Anal Biochem ; 602: 113791, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32473119

RESUMO

Econazole is a widely used chiral antifungal drug. In this paper, an enantioselective liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has been developed and validated for determination of econazole enantiomers in rat plasma for the first time. After addition of the internal standard (IS) clotrimazole, plasma samples were extracted by liquid-liquid extraction with n-hexane:2-propanol (98.5:1.5, v/v). Baseline separation of the enantiomers was achieved on a Chiralpak® IC column (250 mm × 4.6 mm, 5 µm) using acetonitrile-ammonium acetate buffer (5 mM) (85:15, v/v) as mobile phase. The detection of the analytes was performed in multiple reaction monitoring (MRM) mode with positive electrospray ionization. Transitions of m/z 381.07 â†’ 124.92 and 276.78 â†’ 164.92 were monitored for econazole enantiomers and clotrimazole, respectively. The linear range was 0.20-50.00 ng/mL with the lower limit of quantification of 0.20 ng/mL for both econazole enantiomers in plasma. The intra-day and inter-day precisions were not exceeding 10.2% and the accuracies were within ±15.0%. The validated method was successfully applied to the stereoselective pharmacokinetic study of econazole enantiomers in rat plasma after transdermal administration of racemic econazole nitrate cream. Significant differences were observed in Cmax, AUC and CL/F of econazole enantiomers, indicating the enantioselective pharmacokinetic behavior of econazole in rats.


Assuntos
Econazol/sangue , Econazol/farmacocinética , Administração Cutânea , Animais , Econazol/química , Masculino , Estrutura Molecular , Ratos , Ratos Wistar , Estereoisomerismo , Distribuição Tecidual
18.
Int J Pharm ; 580: 119229, 2020 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-32184178

RESUMO

The study aims to assess the ultrasound-assisted econazole nitrate (EN) permeation from topically applied formulations with potential for treating Raynaud's phenomenon. Optimization of ultrasound parameters such as the distance of the horn, application time and amplitude were performed. In vitro percutaneous absorption studies were performed using econazole formulations (F2_HPMC dispersion, F4_Lipoderm® Activemax™ Cream) across the ultrasound-treated porcine skin and were compared with the control group (skin samples without ultrasound). Histology and ATR-FTIR studies were performed on treated skin samples. A constant frequency (20 kHz) ultrasound application with 40% amplitude, 0.5 cm distance between ultrasound horn and the skin surface for 2 min was optimized. The permeation of EN was found to be higher from ultrasound-treated skin samples than the control group. Drug permeation from F2_HPMC dispersion was found to be higher as compared to the other formulations and the marketed EN cream. Histological evaluation confirmed that F2_HPMC dispersion showed no signs of toxicity. ATR-FTIR studies revealed a slight increase in the CH2 stretching vibrations (~2920 cm-1 and 2850 cm-1) in ultrasound-treated skin samples as compared with the control. In conclusion, the ultrasound-assisted transdermal delivery of F2_HPMC dispersion could be further studied as a new therapy for Raynaud's phenomenon.


Assuntos
Econazol/administração & dosagem , Doença de Raynaud/tratamento farmacológico , Administração Cutânea , Animais , Antifúngicos/administração & dosagem , Química Farmacêutica/métodos , Permeabilidade , Pele/metabolismo , Absorção Cutânea/fisiologia , Suínos
19.
Int J Pharm ; 574: 118896, 2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31765779

RESUMO

Econazole nitrate (ECN) is a weakly basic drug with very low aqueous solubility that hampers its permeation through biological membranes and results in low ECN bioavailability. Formation of drug/cyclodextrin (drug/CD) inclusion complexes is a formulation technology that can be applied to enhance drug solubility in aqueous media. The aim of this study was to determine the effect of CD complexation and pH adjustments on the ECN solubility. The ECN pH-solubility and ECN/CD phase-solubility profiles were determined. The solubility of ECN in aqueous acidic solutions containing α-cyclodextrin (αCD) was relatively high and much higher than in aqueous γ-cyclodextrin (γCD) solutions under same conditions. The complexation efficiency of the ECN/CD complex was relatively low for the unionized drug. Formation of ECN/CD inclusion complex was verified by proton nuclear magnetic resonance spectroscopy. Formation of ECN/CD complexes enhanced the drug stability during autoclaving. γCD complexes self-assembled to form nano- and microparticles whereas αCD complexes had negligible tendency to self-assemble. Formation of CD complex nano- and microparticles was investigated by dynamic light scattering and by drug permeation through semipermeable membranes of different molecular weight cut-off. The largest aggregate fraction was observed for the unionized ECN in aqueous pH 7.5 solution containing high CD concentration, that is 10% (w/v) CD. It was shown that in acidic solutions ECN/αCD can enhance the antifungal activity to filamentous fungi. This was associated with the increased ECN solubility and increase of readily available ECN molecules in aqueous αCD solutions.


Assuntos
Antifúngicos/química , Econazol/química , alfa-Ciclodextrinas/química , gama-Ciclodextrinas/química , Química Farmacêutica/métodos , Sistemas de Liberação de Medicamentos/métodos , Estabilidade de Medicamentos , Difusão Dinâmica da Luz/métodos , Concentração de Íons de Hidrogênio , Nanopartículas/química , Solubilidade/efeitos dos fármacos
20.
Acta Biomater ; 101: 507-518, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31629894

RESUMO

Treatment of skin infection by dermatophytes is still limited, and the application of conventional topical formulations (ointments, creams, etc.) cause patient discomfort due to repeated administration and low efficacy. This study describes the film-forming system (FFS) hybridized with econazole (ECO)-loaded nanostructured lipid carriers (NLC) for enhanced antifungal activity against dermatophytes. We assumed that the application of NLC could effectively increase the skin permeability of ECO, thereby suppressing the growth of dermatophytes in stratum corneum as well as in epidermis. Meanwhile, ECO-NLC hybrid FFS (ECO-NLC@FFS) could increase the adhesion of ECO-NLC to the skin and prolong the antifungal activity of ECO. First, we optimized ECO-NLC, which shows nanosized particle (199 nm), high encapsulation efficiency (92.5%), and biocompatibility. ECO-NLC@FFS formed a transparent, homogeneous, and hard-to-remove film after topical application. In vitro skin permeation and deposition studies demonstrated that ECO-NLC@FFS showed 1.5-fold higher skin permeation and 3-fold higher ECO deposition in the epidermis layer than a commercial product, which resulted from the nanosized particle and its occlusion effect. And, ex vivo and in vivo antifungal activity studies confirmed that ECO-NLC@FFS improved the skin adhesion of ECO-NLC, thereby allowing ECO to be continuously exposed to the infection sited and reducing the number of applications with a single dose. These results showed that this hybrid system could be a potential for effectively improving the efficacy of antifungal agents and the patient compliance in the treatment of dermatophytes. STATEMENT OF SIGNIFICANCE: Treatment of skin infection by dermatophytes is difficult due to the inconvenience and low efficacy of conventional topical formulations. Here, we demonstrated the potential of a film-forming system (FFS) hybridized with nanostructured lipid carriers (NLC). First, we confirmed that the enhanced skin permeability of drug was improved by NLC. In addition, the hybridization of NLC with FFS improved the skin adhesion of NLC, allowing the drug to exhibit a sustained release profile and prolong antifungal activity. Given the maximized antifungal activity, this hybrid system can be used as a potential pharmaceutical technique to improve patient convenience and achieve complete treatment of skin infection.


Assuntos
Antifúngicos/farmacologia , Arthrodermataceae/efeitos dos fármacos , Biofilmes/efeitos dos fármacos , Portadores de Fármacos/química , Econazol/farmacologia , Lipídeos/química , Nanoestruturas/química , Animais , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células HaCaT , Humanos , Masculino , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana , Nanoestruturas/ultraestrutura , Permeabilidade , Ratos Sprague-Dawley , Pele/efeitos dos fármacos , Distribuição Tecidual/efeitos dos fármacos
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