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1.
Arch Biochem Biophys ; 712: 109048, 2021 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-34600893

RESUMO

Like human, fungi too are known to share lot of structural similarities amongst their CYPs (Cytochrome P450 super family of enzymes) which allows antifungal 'azole' compounds to interact with CYPs of human. Clotrimazole, an 'azole' antifungal drug, is a known inhibitor of fungal CYP named CYP51B. Curcumin, a phytochemical obtained from Curcuma longa has the ability to interact with several different human CYPs to induce inhibition. The sequence and the structural similarities amongst both human and fungal CYPs suggest a strong possibility for curcumin to interact with fungal CYP51B to behave like an antifungal agent. To test this hypothesis a study was designed involving mucormycosis agent, Rhizopus oryzae. The ability of curcumin to interact with fungal CYP51B was analysed computationally through molecular docking, MM-GBSA and Molecular Dynamics (MD) simulation assessment. Further, interaction profile for fungal CYP51B-curcumin was compared with human CYP3A4-curcumin, as there are published evidence describing curcumin as an inhibitor of human CYPs. Additionally, to validate in silico findings, an in vitro assay was performed to examine the antifungal potentials of curcumin on the R. oryzae. Conclusive results allow us to determine a plausible mode of action of curcumin to act as an antifungal against a mucormycosis agent.


Assuntos
Antifúngicos/farmacologia , Curcumina/farmacologia , Inibidores das Enzimas do Citocromo P-450/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Proteínas Fúngicas/antagonistas & inibidores , Rhizopus oryzae/efeitos dos fármacos , Sequência de Aminoácidos , Antifúngicos/metabolismo , Clotrimazol/metabolismo , Clotrimazol/farmacologia , Curcumina/metabolismo , Inibidores das Enzimas do Citocromo P-450/metabolismo , Ergosterol/metabolismo , Proteínas Fúngicas/metabolismo , Humanos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Filogenia , Ligação Proteica
2.
Molecules ; 26(18)2021 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-34577009

RESUMO

A fully automated sequential injection system was tested in terms of its application in liberation testing, and capabilities and limitations were discussed for clotrimazole liberation from three semisolid formulations. An evaluation based on kinetic profiles obtained in short and longer sampling intervals and steady-state flux values were applied as traditional methods. The obtained clotrimazole liberation profile was faster in the case of Delcore and slower for Clotrimazol AL and Canesten cream commercial formulations. The steady-state flux values for the tested formulations were 52 µg cm-2 h-1 for Canesten, 35 µg cm-2 h-1 for Clotrimazol AL, and 7.2 µg cm-2 h-1 for Delcore measured in 4 min sampling intervals. A simplified approach for the evaluation of the initial rate based on the gradient between the second and third sampling points was used for the first time and was found to correspond well with the results of the conventional methods. A comparison based on the ratio of the steady-state flux and the initial rate values for Canesten and Clotrimazol AL proved the similarity of the obtained results. The proposed alternative was successfully implemented for the comparison of short-term kinetic profiles. Consequently, a faster and simpler approach for dissolution/liberation testing can be used.


Assuntos
Antifúngicos/análise , Automação Laboratorial/métodos , Clotrimazol/análise , Análise de Injeção de Fluxo/métodos , Composição de Medicamentos , Liberação Controlada de Fármacos , Cinética , Creme para a Pele
3.
Int J Nanomedicine ; 16: 6249-6261, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34531656

RESUMO

Purpose: The aim of this study was to encapsulate clotrimazole (CLT), an antifungal drug with poor water solubility characteristics, into spanlastics (SPs) to provide a controlled ocular delivery of the drug. Methods: Span 60 was used in the formulation of SPs with Tween 80, Pluronic F127, or Kolliphor RH40 as an edge activator (EA). The presence of EA offers more elasticity to the membrane of the vesicles which is expected to increase the corneal permeation of CLT. SPs were prepared using ethanol injection method applying 32 complete factorial design to study the effect of formulation variables (ratio of Span 60: EA (w/w) and type of EA) on SPs characteristics (encapsulation efficiency percent (EE%), average vesicle size (VS), polydispersity index (PDI) and zeta potential (ZP)). Design-Expert software was used to determine the optimum formulation for further investigations. Results: The optimum formulation determined was S1, which contains 20 mg of Tween 80 used as an EA and 80 mg of Span 60. S1 exhibited EE% = 66.54 ± 7.57%, VS = 206.20 ± 4.95 nm, PDI = 0.39 ± 0.00 and ZP = -29.60 ± 0.99 mV. S1 showed highly elastic sphere-shaped vesicles. Furthermore, S1 displayed a sustained release profile and a higher ex vivo permeation across rabbit cornea relative to CLT suspension. Also, S1 revealed superior inhibition of Candida albicans development compared to CLT suspension applying 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) reduction technique. Moreover, in vivo histopathological examination assured the safety of S1 after ophthalmic application in mature male albino rabbits. Conclusion: Overall, the outcomes revealed the marked efficacy of SPs for ocular delivery of CLT.


Assuntos
Antifúngicos , Clotrimazol , Animais , Candida albicans , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Masculino , Tamanho da Partícula , Permeabilidade , Coelhos
4.
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
5.
Vestn Otorinolaringol ; 86(3): 90-96, 2021.
Artigo em Russo | MEDLINE | ID: mdl-34269031

RESUMO

The article deals with the problem of inflammatory diseases of the external ear. A review of pruritic dermatoses of the external auditory canal was carried out. It has been shown that in chronic dermatoses, the contamination of the skin with bacterial and fungal pathogens significantly increases, which leads to a high risk of developing secondary infectious pathological processes. Treatment of dermatological inflammatory ear diseases includes careful daily hygiene of the external auditory canal and pharmacotherapy, a key aspect of which is the use of topical etiotropic, anti-inflammatory, and symptomatic drugs. The advantage of the combined drug candiderm is described, which, thanks to the unique combination of beclomethasone, gentamicin and clotrimazole in the composition, effectively relieves the symptoms of external ear dermatoses.


Assuntos
Otopatias , Otite Externa , Anti-Inflamatórios , Clotrimazol , Meato Acústico Externo , Otopatias/diagnóstico , Otopatias/tratamento farmacológico , Otopatias/etiologia , Gentamicinas , Humanos , Otite Externa/diagnóstico , Otite Externa/tratamento farmacológico
6.
J Med Life ; 14(2): 250-256, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34104249

RESUMO

This was a clinical trial study that aimed to investigate the efficacy of vaginal chlorhexidine gel in the treatment of vulvovaginal candidiasis, bacterial vaginosis, and nonspecific vaginitis. The study population included patients who complained of vaginal discharge and presented to our University Gynecology Clinic. The data were analyzed using the Statistical Package for the Social Sciences (SPSS) software. The student t-test and Mann-Whitney U test were used to analyze the quantitative and ordinal data, respectively. In order to analyze the qualitative data, the Chi-square or Fischer's exact tests were used. The mean satisfaction score in the vulvovaginal candidiasis patients who received chlorhexiine vaginal gel was 9.06 and 8.29 in the patients who received clotrimazole vaginal cream. The Mann-Whitney test did not show a statistically significant difference between mean scores of VAS in these two groups with vulvovaginal candidiasis (P=0.027). Among the patients with bacterial vaginosis, the mean satisfaction score was 8.91 in the chlorhexidine vaginal gel group and 8.72 in the metronidazole tablet group (P=0.607). In the nonspecific vaginitis group, the mean satisfaction score was 8.83 in the chlorhexidine vaginal gel group and 9.17 in the combination group (metronidazole + clotrimazole vaginal cream)(P=0.401). The highest mean visual analog scale score (VAS) score was documented in the combination therapy group. We found that chlorhexidine vaginal gel is a more effective method for the treatment and improvement of vaginal infections. The benefits of chlorhexidine gel have a positive therapeutic effect as a single drug in nonspecific vaginitis, rather than simultaneous administration of two agents.


Assuntos
Candidíase Vulvovaginal/tratamento farmacológico , Clorexidina/uso terapêutico , Clotrimazol/uso terapêutico , Metronidazol/uso terapêutico , Vaginose Bacteriana/tratamento farmacológico , Vulvovaginite/tratamento farmacológico , Adulto , Clotrimazol/administração & dosagem , Quimioterapia Combinada , Feminino , Humanos , Metronidazol/administração & dosagem , Satisfação do Paciente , Escala Visual Analógica
7.
Transplant Proc ; 53(5): 1583-1588, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33962777

RESUMO

Tacrolimus, an immunosuppressant prescribed to reduce the risk of organ rejection, is metabolized by cytochrome P450 and is a substrate for P-glycoprotein. Many medications affect tacrolimus concentrations, making it difficult to maintain exposure within its narrow therapeutic index. Clotrimazole troches, prescribed to posttransplant recipients immediately for the first 30 days for oral candidiasis prevention, are considered nonsystemic. However, data suggest a potential drug interaction, affecting tacrolimus exposure. To assess the magnitude of the effect of clotrimazole on tacrolimus trough levels, 97 kidney transplant recipients, on a stable dose of tacrolimus, were retrospectively evaluated. Tacrolimus trough concentrations were analyzed 7 and 14 days before and after discontinuation of clotrimazole. The median change in tacrolimus trough level was -1.3 ng/mL (confidence interval, -2.5, -1.0; P < .001) at day 7 and -2.8 ng/mL (confidence interval, -3.3, -1.6; P < .001) at day 14 after clotrimazole discontinuation, from a median baseline of 8.9 ng/mL. Overall, a reduction in tacrolimus level was observed in 60% of patients after discontinuation of clotrimazole. When assessing the effect of race and sex, no influence was found on the degree of change in tacrolimus level after clotrimazole discontinuation. In conclusion, clotrimazole exerts a significant interaction on tacrolimus where close monitoring of tacrolimus trough levels after discontinuation of clotrimazole is warranted.


Assuntos
Antifúngicos/administração & dosagem , Clotrimazol/administração & dosagem , Imunossupressores/sangue , Transplante de Rim/efeitos adversos , Tacrolimo/sangue , Adulto , Idoso , Interações Medicamentosas , Monitoramento de Medicamentos , Quimioterapia Combinada , Feminino , Humanos , Imunossupressores/administração & dosagem , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Micoses/prevenção & controle , Complicações Pós-Operatórias/microbiologia , Complicações Pós-Operatórias/prevenção & controle , Estudos Retrospectivos , Tacrolimo/administração & dosagem , Adulto Jovem
8.
Cochrane Database Syst Rev ; 5: CD009289, 2021 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-34033120

RESUMO

BACKGROUND: Otomycosis is a fungal infection of the outer ear, which may be treated with topical antifungal medications. There are many types, with compounds belonging to the azole group ('azoles') being among the most widely used. OBJECTIVES: To evaluate the benefits and harms of topical azole treatments for otomycosis. SEARCH METHODS: The Cochrane ENT Information Specialist searched the Cochrane ENT Register; Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE; Ovid Embase; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The search date was 11 November 2020. SELECTION CRITERIA: We included randomised controlled trials (RCTs) in adults and children with otomycosis comparing any topical azole antifungal with: placebo, no treatment, another type of topical azole or the same type of azole but applied in different forms. A minimum follow-up of two weeks was required. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were: 1) clinical resolution as measured by the proportion of participants with complete resolution at between two and four weeks after treatment (however defined by the authors of the studies) and 2) significant adverse events. Secondary outcomes were 3) mycological resolution and 4) other less serious adverse effects. We used GRADE to assess the certainty of evidence for each outcome. MAIN RESULTS: We included four studies with 559 participants from Spain, Mexico and India. Three studies included children and adults; one included only adults. The duration of symptoms was not always explicitly stated. Mycological resolution results were only reported in one study. The studies assessed two comparisons: one type of topical azole versus another and the same azole but administered in different forms (cream versus solution). A. Topical azoles versus placebo None of the studies assessed this comparison. B. Topical azoles versus no treatment None of the studies assessed this comparison. C. One type of topical azole versus another type of topical azole i) Clotrimazole versus other types of azoles (eberconazole, fluconazole, miconazole) Three studies examined clotrimazole versus other types of azoles. The evidence is very uncertain about the difference between clotrimazole and other types of azole in achieving complete clinical resolution at four weeks (risk ratio (RR) 0.80, 95% confidence interval (CI) 0.59 to 1.07; 3 studies; 439 participants; very low-certainty evidence). The anticipated absolute effects are 668 per 1000 for clotrimazole versus 835 per 1000 for other azoles. One study planned a safety analysis and reported no significant adverse events in either group. The evidence is therefore very uncertain about any differences between clotrimazole and other types of azole (no events in either group; 1 study; 174 participants; very low-certainty evidence). Clotrimazole may result in little or no difference in mycological resolution at two weeks follow-up (RR 1.01, 95% CI 0.96 to 1.06; 1 study; 174 participants; low-certainty evidence) or in other (less serious) adverse events at two weeks follow-up (36 per 1000, compared to 45 per 1000, RR 0.79, 95% CI 0.18 to 3.41; 1 study; 174 participants; very low-certainty evidence). ii) Bifonazole cream versus bifonazole solution One study compared bifonazole 1% cream with solution. Bifonazole cream may have little or no effect on clinical resolution at two weeks follow-up when compared to solution, but the evidence is very uncertain (RR 1.07, 95% CI 0.73 to 1.57; 1 study; 40 ears; very low-certainty evidence). Bifonazole cream may achieve less mycological resolution compared to solution at two weeks after the end of therapy, but the evidence for this is also very uncertain (RR 0.53, 95% CI 0.29 to 0.96; 1 study; 40 ears; very low-certainty evidence). Five out of 35 patients sustained severe itching and burning from the bifonazole solution but none with the bifonazole cream (very low-certainty evidence). AUTHORS' CONCLUSIONS: We found no studies that evaluated topical azoles compared to placebo or no treatment. The evidence is very uncertain about the effect of clotrimazole on clinical resolution of otomycosis, on significant adverse events or other (non-serious) adverse events when compared with other topical azoles (eberconazole, fluconazole, miconazole). There may be little or no difference between clotrimazole and other azoles in terms of mycological resolution. It may be difficult to generalise these results because the range of ethnic backgrounds of the participants in the studies is limited.


Assuntos
Antifúngicos/administração & dosagem , Otomicose/tratamento farmacológico , Administração Tópica , Adulto , Antifúngicos/efeitos adversos , Viés , Criança , Clotrimazol/administração & dosagem , Clotrimazol/efeitos adversos , Cicloeptanos/administração & dosagem , Cicloeptanos/efeitos adversos , Fluconazol/administração & dosagem , Fluconazol/efeitos adversos , Humanos , Imidazóis/administração & dosagem , Imidazóis/efeitos adversos , Miconazol/administração & dosagem , Miconazol/efeitos adversos , Placebos/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
9.
Int J Mol Sci ; 22(6)2021 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-33805656

RESUMO

17ß-estradiol (E2) exerts its physiological effects through the estrogen receptor α (i.e., ERα). The E2:ERα signaling allows the regulation of cell proliferation. Indeed, E2 sustains the progression of ERα positive (ERα+) breast cancers (BCs). The presence of ERα at the BC diagnosis drives their therapeutic treatment with the endocrine therapy (ET), which restrains BC progression. Nonetheless, many patients develop metastatic BCs (MBC) for which a treatment is not available. Consequently, the actual challenge is to complement the drugs available to fight ERα+ primary and MBC. Here we exploited a novel anti-estrogen discovery platform to identify new Food and Drug Administration (FDA)-approved drugs inhibiting E2:ERα signaling to cell proliferation in cellular models of primary and MBC cells. We report that the anti-fungal drugs clotrimazole (Clo) and fenticonazole (Fenti) induce ERα degradation and prevent ERα transcriptional signaling and proliferation in cells modeling primary and metastatic BC. The anti-proliferative effects of Clo and Fenti occur also in 3D cancer models (i.e., tumor spheroids) and in a synergic manner with the CDK4/CDK6 inhibitors palbociclib and abemaciclib. Therefore, Clo and Fenti behave as "anti-estrogens"-like drugs. Remarkably, the present "anti-estrogen" discovery platform represents a valuable method to rapidly identify bioactive compounds with anti-estrogenic activity.


Assuntos
Aminopiridinas/farmacologia , Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Clotrimazol/farmacologia , Receptor alfa de Estrogênio/antagonistas & inibidores , Imidazóis/farmacologia , Piperazinas/farmacologia , Piridinas/farmacologia , Antifúngicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/genética , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/genética , Quinase 6 Dependente de Ciclina/metabolismo , Aprovação de Drogas , Descoberta de Drogas , Reposicionamento de Medicamentos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Sinergismo Farmacológico , Estradiol/metabolismo , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Células MCF-7 , Proteólise , Transdução de Sinais , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/metabolismo , Esferoides Celulares/patologia
10.
Toxicol Appl Pharmacol ; 422: 115554, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33910022

RESUMO

Clotrimazole is a non-prescription and broad-spectrum antifungal drug sold under brand names such as Canesten® and Lotrimin®. It is used to treat different types of fungal infections, from oral thrush to athlete's foot and vaginal mycosis. The level of exposure to clotrimazole is uncertain, as the exact usage amongst self-medicating patients is unclear. Recent studies have raised potential concern about the unsupervised use of clotrimazole during pregnancy, especially since it is a potent inhibitor of CYP enzymes of the steroidogenesis pathway. To address some of these concerns, we have assessed the effects of intrauterine exposure to clotrimazole on developing rat fetuses. By exposing pregnant rats to clotrimazole 25 or 75 mg/kg bw/day during gestation days 7-21, we obtained internal fetal concentrations close to those observed in humans. These in vivo data are in strong agreement with our physiologically-based pharmacokinetic (PBK)-modelled levels. At these doses, we observed no obvious morphological changes to the reproductive system, nor shorter male anogenital distance; a well-established morphometric marker for anti-androgenic effects in male offspring. However, steroid hormone profiles were significantly affected in both maternal and fetal plasma, in particular pronounced suppression of estrogens was seen. In fetal testes, marked up-concentration of hydroxyprogesterone was observed, which indicates a specific action on steroidogenesis. Since systemic clotrimazole is rapidly metabolized in humans, relevant exposure levels may not in itself cause adverse changes to the reproductive systems. Its capacity to significantly alter steroid hormone concentrations, however, suggests that clotrimazole should be used with caution during pregnancy.


Assuntos
Antifúngicos/toxicidade , Clotrimazol/toxicidade , Disruptores Endócrinos/toxicidade , Feto/efeitos dos fármacos , Hormônios Esteroides Gonadais/sangue , Animais , Antifúngicos/sangue , Antifúngicos/farmacocinética , Biomarcadores/sangue , Clotrimazol/sangue , Clotrimazol/farmacocinética , Disruptores Endócrinos/sangue , Disruptores Endócrinos/farmacocinética , Estrogênios/sangue , Feminino , Sangue Fetal/metabolismo , Feto/metabolismo , Idade Gestacional , Humanos , Hidroxiprogesteronas/sangue , Masculino , Exposição Materna , Gravidez , Ratos Sprague-Dawley , Medição de Risco , Especificidade da Espécie , Toxicocinética
11.
Int J Pharm ; 601: 120578, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33839222

RESUMO

Biomimetic adhesive surfaces have a number of potential applications in the pharmaceutical and biomedical fields. Fabrication techniques must be adapted to biocompatible and biodegradable materials required for controlled drug release applications. In this study biomimetic adhesive poly(lactic-co-glycolic acid) (PLGA) films loaded with different concentrations of clotrimazole (CTZ) were prepared without combining other adhesive excipients as a controlled release system for potential local oral drug delivery. The films were fully characterized from morphological point of view, and CTZ-loaded biomimetic films exhibited adequate surface pH values, high drug encapsulation efficiency, and loading content. The adhesion strength of the obtained films was significantly higher compared to a flat film reference under different contact conditions. Thermal analysis indicated a decrease of drug crystallinity upon incorporation into PLGA films. The in vitro release of CTZ from PLGA biomimetic films was tested in simulated saliva, and it exhibited an initial burst release, accompanied by a sustained release phase over 10 days. Finally, the mucoadhesive properties of the obtained films was studied using agar/mucin plate as a representative mucosal substrate, and the results demonstrated superior mucoadhesion potential of CTZ-loaded biomimetic film in comparison to its flat counterpart. Having demonstrated the ability to load CTZ into PLGA biomimetic films with enhanced adhesion capacity, the potential use in local oral drug delivery applications warrants further in vitro and in vivo investigations.


Assuntos
Clotrimazol , Ácido Poliglicólico , Adesividade , Biomimética , Portadores de Fármacos , Liberação Controlada de Fármacos , Ácido Láctico , Copolímero de Ácido Poliláctico e Ácido Poliglicólico
12.
J Pharm Pharmacol ; 73(2): 212-220, 2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33793810

RESUMO

OBJECTIVES: Microcomputed tomography (µCT) is a powerful analytical tool for non-invasive structural analysis. The stability of drug substances and formulations subjected to X-ray radiation may be a concern in the industry. This study examines the effect of X-ray radiation on the stability of freeze-dried pharmaceuticals. The investigation is a proof of concept study for the safety of µCT X-ray radiation doses during the non-destructive investigation of freeze-dried products. METHODS: Different formulations of clotrimazole, insulin and l-lactate dehydrogenase were freeze-dried and the products exposed to a defined dose of radiation by µCT. Conservative freeze-drying conditions were used. Irradiated and normal samples were analysed for their stability directly after freeze-drying and after stability testing. KEY FINDINGS: The stability of model compounds was well maintained during freeze-drying. Some degradation of all compounds occurred during accelerated stability testing. The results showed no differences between the irradiated and normal state directly after freeze-drying and accelerated stability testing. CONCLUSIONS: No evidence of a detrimental effect of 100 Gy X-ray exposure on a model small molecule, peptide and protein compound was found while useful structural information could be obtained. Consequently, the technology may be useful as a non-destructive tool for product inspections if the formulation proves stable.


Assuntos
Clotrimazol/química , Insulina/química , L-Lactato Desidrogenase/química , Microtomografia por Raio-X/métodos , Química Farmacêutica/métodos , Clotrimazol/administração & dosagem , Estabilidade de Medicamentos , Liofilização , Insulina/administração & dosagem , L-Lactato Desidrogenase/administração & dosagem , Doses de Radiação , Tecnologia Farmacêutica/métodos
13.
J Med Life ; 14(1): 111-117, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33767795

RESUMO

Candidal vaginitis has a relatively high prevalence, and its resistance to treatment is on the rise. Considering the complications of chemical drugs, the use of herbal medicines has now been favored due to the lack of changes in the normal vaginal flora. The aim of this study was to compare the effectiveness of Satureja khuzestanica and clotrimazole vaginal creams for the treatment of candidal vulvovaginitis. A randomized clinical trial was conducted on 84 reproductive-aged women in the city of Ahvaz, Iran. Individuals were randomly divided into two treatment groups: 1% Satureja khuzestanica vaginal creams (n=42) and 1% clotrimazole vaginal cream (n=42) who used a one-full applicator daily for one week. About 4-7 days after the end of treatment, a clinical examination and laboratory re-tests were performed to determine the level of treatment. The data were analyzed using the Mann-Whitney U, t-test and Chi-square tests, with SPSS version 22. After the treatment, no significant difference was observed between the two groups in terms of vaginal discharge (p = 0.32), vaginal itching (p = 0.26), dysuria (p = 0.99) and dyspareunia (p = 0.60). Moreover, the results of culture (p = 0.62) and smear (p = 0.58) were not statistically significant in the two groups. Also, there was no significant difference between the two groups in terms of complete recovery after the treatment (p = 0.35). Satureja khuzestanica seems to have the same effect as clotrimazole in improving the symptoms of vaginal candidiasis, the negative results of culture and smear, as well as complete treatment.


Assuntos
Candidíase Vulvovaginal/tratamento farmacológico , Clotrimazol/uso terapêutico , Satureja/química , Cremes, Espumas e Géis Vaginais/uso terapêutico , Adulto , Antifúngicos/uso terapêutico , Candidíase Vulvovaginal/diagnóstico , Feminino , Humanos , Irã (Geográfico) , Resultado do Tratamento
14.
J Toxicol Sci ; 46(3): 131-142, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33642519

RESUMO

Pluripotent stem cells (PSCs) possess unique characteristics that distinguish them from other cell types. Human embryonic stem (ES) cells are recently gaining attention as a powerful tool for human toxicity assessment without the use of experimental animals, and an embryonic stem cell test (EST) was introduced for this purpose. However, human PSCs have not been thoroughly investigated in terms of drug resistance or compared with other cell types or cell states, such as naïve state, to date. Aiming to close this gap in research knowledge, we assessed and compared several human PSC lines for their resistance to drug exposure. Firstly, we report that RIKEN-2A human induced pluripotent stem (iPS) cells possessed approximately the same sensitivity to selected drugs as KhES-3 human ES cells. Secondly, both ES and iPS cells were several times less resistant to drug exposure than other non-pluripotent cell types. Finally, we showed that iPS cells subjected to naïve-state induction procedures exhibited a sharp increase in drug sensitivity. Upon passage of these naïve-like cells in non-naïve PSC culture medium, their sensitivity to drug exposure decreased. We thus revealed differences in sensitivity to drug exposure among different types or states of PSCs and, importantly, indicated that naïve-state induction could increase this sensitivity.


Assuntos
Diferenciação Celular , Resistência a Medicamentos , Células-Tronco Embrionárias/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Amiodarona/toxicidade , Animais , Aspirina/toxicidade , Atorvastatina/toxicidade , Linhagem Celular , Clotrimazol/toxicidade , Resistência a Múltiplos Medicamentos , Células-Tronco Embrionárias/fisiologia , Humanos , Células-Tronco Pluripotentes Induzidas/fisiologia
15.
Int J Pharm ; 596: 120290, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33524521

RESUMO

Vulvovaginal candidiasis is a vaginal infection caused by the fungal pathogen Candida albicans that, most commonly, affects women of reproductive age. Its first-line treatment consists in topical applications of conventional drug formulations (e.g., creams, gels, tablets) containing imidazole drugs. The treatment involves single or multiple daily applications and, in the case of recurrences, daily administration of oral antifungal drugs for up to one month. Intravaginal rings are flexible, biocompatible medical devices that, compared to conventional drug formulations, offer the possibility of a controlled vaginal drug delivery over a determined period with a single application, thus increasing patient compliance. Among innovative manufacturing techniques, in recent years, fused deposition modeling 3D printing has emerged in the pharmaceutical field to produce different therapeutics combining drugs and polymers. This technique allows to print objects layer by layer with many different thermoplastic materials after a computer-assisted design. Thermoplastic polyurethanes are flexible and biocompatible materials that can be efficiently employed for the manufacturing of drug release systems, already utilized to prepare vaginal devices. In this work, we produced a clotrimazole-loaded intravaginal ring by fused deposition modeling 3D printing combining the drug with thermoplastic polyurethane using hot melt extrusion. The rings were computer-designed and then printed with two different drug concentrations (i.e., 2% and 10% w/w). The intravaginal rings were first tested in an agar-diffusion test to evaluate their effectiveness against C. albicans; and the 10% loaded ring was selected for further studies. Drug release was evaluated in two different media (i.e., 50% ethanol and vaginal fluid simulant) showing a sustained release over a period of seven days. Next, in vitro time-kill analysis against C. albicans in simulated vaginal fluid was performed and displayed a complete growth inhibition after 5 days, compared to the control. These results suggest a potential application of these 3D printed intravaginal rings for the treatment of vulvovaginal candidiasis and for the long-time treatment of recurrences.


Assuntos
Candidíase Vulvovaginal , Administração Intravaginal , Antifúngicos/uso terapêutico , Candidíase Vulvovaginal/tratamento farmacológico , Clotrimazol , Liberação Controlada de Fármacos , Feminino , Humanos , Impressão Tridimensional , Comprimidos
16.
Acta Biomater ; 125: 312-321, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33639312

RESUMO

Vulvovaginal candidiasis (VVC) represents a considerable health burden for women. Despite the availability of a significant array of antifungal drugs and topical products, the management of the infection is not always effective, and new approaches are needed. Here, we explored cationic N-(2-hydroxy)-propyl-3-trimethylammonium, O-palmitoyl chitosan nanoparticles (NPs) as carriers of clotrimazole (CLT) for the topical treatment of VVC. CLT-NPs with approximately 280 nm in diameter were obtained by self-assembly in water and subsequent stabilization by ionic crosslinking with tripolyphosphate. The nanosystem featured pH-independent sustained drug release up to 24 h, which affected both in vitro anti-Candida activity and cytotoxicity. The CLT-loaded nanostructured platform yielded favorable selectivity index values for a panel of standard strains and clinical isolates of Candida spp. and female genital tract cell lines (HEC-1-A, Ca Ski and HeLa), as compared to the free drug. CLT-NPs also improved in vitro drug permeability across HEC-1-A and Ca Ski cell monolayers, thus suggesting that the nanocarrier may provide higher mucosal tissue levels of the active compound. Overall, data support that CLT-NPs may be a valuable asset for the topical treatment of VVC. STATEMENT OF SIGNIFICANCE: Topical azoles such as clotrimazole (CLT) are first line antifungal drugs for the management of vulvovaginal candidiasis (VVC), but their action may be limited by issues such as toxicity and poor capacity to penetrate the genital mucosa. Herein, we report on the ability of a new cationic N-(2­hydroxy)-propyl-3-trimethylammonium, O-dipalmitoyl chitosan derivative (DPCat35) to yield tripolyphosphate-reinforced micelle-like nanostructures that are suitable carriers for CLT. In particular, these nanosystems were able to improve the in vitro selectivity index of the drug and to provide enhanced epithelial drug permeability when tested in cell monolayer models. These data support that CLT-loaded DPCat35 nanoparticles feature favorable properties for the development of new nanomedicines for the topical management of VVC.


Assuntos
Candidíase Vulvovaginal , Quitosana , Nanopartículas , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Candida , Candidíase Vulvovaginal/tratamento farmacológico , Clotrimazol/farmacologia , Feminino , Humanos
17.
Neurochirurgie ; 67(5): 508-515, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33450263

RESUMO

This paper presents a short review of data supporting a dexamethasone sparing regimen, SEC, to reduce glioblastoma related brain edema. The conclusion of the reviewed data is that the rationale and risk/benefit ratio favors a pilot study to determine if the three drug regimen of SEC can reduce need for corticosteroid use during the course of glioblastoma. Details of how selected pathophysiological aspects of brain edema occurring during the course of glioblastoma and its treatment intersect with the established action of the three old drugs of SEC indicate that they can be repurposed to reduce that edema. Current first-line treatment of this edema is dexamethasone or related corticosteroids. There are multiple negative prognostic implications of both the edema itself and of dexamethasone, prime among them shortened survival, making a dexamethasone sparing regimen highly desirable. SEC uses spironolactone, an antihypertensive potassium-sparing diuretic acting by mineralocorticoid receptor inhibition, ecallantide acting to inhibit kallikrein activation marketed to treat hereditary angioedema, and clotrimazole, an old antifungal drug that inhibits intermediate conductance Ca++ activated K+ channel (KCa3.1). These three old drugs are well known to most clinicians, have a well-tolerated safety history, and have a robust preclinical database showing their potential to reduce the specific edema of glioblastoma. Additionally, these three drugs were chosen by virtue of each having preclinical evidence of glioblastoma growth and/or migration inhibition independent of their edema reduction action. A clinical study of SEC is being planned.


Assuntos
Clotrimazol , Glioblastoma , Clotrimazol/uso terapêutico , Dexametasona , Glioblastoma/tratamento farmacológico , Humanos , Peptídeos , Projetos Piloto , Espironolactona/uso terapêutico
18.
J Biol Chem ; 296: 100223, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33449875

RESUMO

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


Assuntos
Clotrimazol/farmacologia , Inibidores do Citocromo P-450 CYP3A/farmacologia , Citocromo P-450 CYP3A/química , Indinavir/farmacologia , Itraconazol/farmacologia , Cetoconazol/farmacologia , Ritonavir/farmacologia , Esteroide Hidroxilases/antagonistas & inibidores , Animais , Biocatálise , Clonagem Molecular , Clotrimazol/química , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A/química , Ensaios Enzimáticos , Escherichia coli/genética , Escherichia coli/metabolismo , Expressão Gênica , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Humanos , Hidroxiquinolinas/síntese química , Hidroxiquinolinas/metabolismo , Indinavir/química , Itraconazol/química , Cetoconazol/química , Cinética , Ratos , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Ritonavir/química , Esteroide Hidroxilases/química , Esteroide Hidroxilases/genética , Esteroide Hidroxilases/metabolismo
19.
Fish Physiol Biochem ; 47(2): 265-279, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33405060

RESUMO

Biological organisms are constantly challenged by xenobiotics and have evolved mechanisms to reduce, neutralize, or repair toxic outcomes. The various chemical defenses all utilize energy, but their specific costs and impacts on energy budgets are currently unknown. In this study, the energetic costs associated with the induction and substrate transport of the efflux transporter P-glycoprotein (P-gp [ABCB1, MDR1]) were examined in rainbow trout. An intraperitoneal injection of the P-gp inducer clotrimazole (0, 0.1, 1.0, and 10 mg/kg) increased P-gp activity (as measured by a competitive rhodamine 123 transport assay in hepatocytes) in a dose-dependent manner reaching a maximum induction of 2.8-fold. Maximum P-gp induction occurred at 50 h post-administration with the highest dose; significant induction of P-gp activity remained elevated over constitutive values until the last sampling time point (168 h). In vitro measurements of hepatocyte respiration indicated that basal P-gp activity transporting R123 as a substrate did not significantly increase respiration rates (range 18.0 to 23.2 ng O2/min/106 cells); however, following the induction of P-gp by clotrimazole and exposure to the P-gp substrate R123, respiration rates increased significantly (3.52-fold) over baseline values. Using whole animal respirometry, it was shown that respiration rates in fish exposed to R123 only or induced with clotrimazole were not different from controls (range 1.2 to 2.1 mg O2/kg/min); however, respiration rates were significantly increased in fish with induced P-gp levels and also exposed to R123. This work indicates that basal and induced levels of P-gp activity do not incur significant energetic costs to fish; however, upon induction of P-gp and concomitant substrate exposures, energetic costs can increase and could pose challenges to organisms facing limited energy resources.


Assuntos
Inibidores de 14-alfa Desmetilase/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Clotrimazol/farmacologia , Metabolismo Energético/fisiologia , Oncorhynchus mykiss/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Animais , Sobrevivência Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/fisiologia , Consumo de Oxigênio
20.
Arch Gynecol Obstet ; 303(1): 151-160, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32940765

RESUMO

PURPOSE: To compare the clinical response, microscopic examination and fungal culture between dequalinium chloride (DQC) and clotrimazole (CT) for treating vaginal candidiasis (VC). METHODS: The double-blind, randomized study was conducted from September 2014 to September 2016 at Siriraj Hospital, Thailand. Eligible participants were Thai women diagnosed with VC by microscopic examination. The exclusion criteria included immunocompromised conditions, consumption of antifungal drugs, and having recurrent VC. Each participant was randomized with a 1:1 allocation to receive six vaginal tablets of 100 mg CT or 10 mg DQC. Two visits included 10 ± 2 days (C1) and 38 ± 4 days (C2). Outcome measures were improvement of VC symptoms, microscopic examination, culture, satisfaction and tolerability. RESULTS: Of 155 eligible participants, 150 were randomized and allocated into CT (N = 76) and DQC (N = 74). The average age was 31.1 ± 7.2 years. Comparable improvement of clinical response was demonstrated (OR at C1 0.79, 95% CI 0.56-1.10, p = 0.197; and OR at C2 0.99, 95% CI 0.69-1.43, p = 0.985). Of CT and DQC groups, the microscopic examination was positive at 11/75 (14.9%) vs 18/72 (25.3%) at C1 and 18/74 (24.3%) vs 28/66 (42.4%) at C2. And the culture was positive at 25/75 (33.8%) vs 46/72 (65.7%) at C1 and at 26/74 (36.6%) vs 46/66 (69.7%) at C2. Most participants had high satisfaction and tolerability and none reported any side effects. CONCLUSION: DQC and CT show comparable clinical response but CT results in greater improvement of microscopic examination and fungal culture. CLINICAL TRIAL REGISTRATION: The Clinical Trial Registry number was NCT02242695. (September 17, 2014).


Assuntos
Anti-Infecciosos Locais/uso terapêutico , Antifúngicos/uso terapêutico , Candidíase Vulvovaginal/tratamento farmacológico , Clotrimazol/uso terapêutico , Dequalínio/uso terapêutico , Adulto , Candidíase Vulvovaginal/diagnóstico , Método Duplo-Cego , Feminino , Humanos , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Comprimidos/administração & dosagem , Tailândia , Cremes, Espumas e Géis Vaginais
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