RESUMEN

Butterfly pea flower (Clitoria ternatea) may serve as an alternative anti-dandruff treatment; however, its effects on Malassezia spp. remain unexplored. The aim of this study was to explore the effects of C. ternatea as an herbal-based anti-dandruff treatment on Malassezia spp. DNA expression, plakoglobin levels, IL-8 levels, sebum levels, dandruff severity scores, adverse effects, and patient satisfaction. An experimental study with a pretest-posttest control design was conducted at the Outpatient Clinic of Dermatology and Venereology, Arifin Achmad Hospital, Pekanbaru, Indonesia, from November 2023 to January 2024. The flower of C. ternatea was used to formulate the shampoo. The study involved 70 female patients aged 18-25 with dandruff, who were divided into two groups: (a) experimental group using 20% C. ternatea shampoo and (b) control group using 2% ketoconazole shampoo. The present study found that 2% ketoconazole shampoo significantly reduced Malassezia spp. DNA expression compared to 20% C. ternatea shampooo (Clitoria ternatea: ΔCq=1.76±3.18; ketoconazole: ΔCq=3.77±2.90; p=0.008). No significant difference was observed in plakoglobin levels (C. ternatea: ΔCq=1.98±3.63; ketoconazole: ΔCq=2.50±2.36; p=0.427) or IL-8 levels (C. ternatea: ΔCq=3.46±4.00; ketoconazole: ΔCq=4.16 ± 3.62; p=0.459). C. ternatea significantly reduced sebum levels more than ketoconazole (C. ternatea: 1.16±0.98%; ketoconazole: 0.22±0.38%; p<0.001). Dandruff scores and patient satisfaction were similar for both shampoos (p=0.115 and p=0.336, respectively). Adverse effects were more common in the 2% ketoconazole shampoo group, affecting 21.2% of the patients. In conclusion, 2% ketoconazole shampoo is more effective in reducing Malassezia spp. DNA expression, while 20% C. ternatea shampoo offers better sebum control. Both shampoos are similarly effective in ameliorating dandruff severity and are well-tolerated, with fewer adverse effects reported for C. ternatea.

Asunto(s)

Caspa , Malassezia , Humanos , Femenino , Adulto , Caspa/tratamiento farmacológico , Caspa/microbiología , Malassezia/efectos de los fármacos , Preparaciones para el Cabello/farmacología , Adolescente , Adulto Joven , Cetoconazol/farmacología , Indonesia , Flores , Clitoria/química , Antifúngicos/farmacología , Satisfacción del Paciente

RESUMEN

Excessive local accumulation of reactive oxygen species (ROS) in vulvovaginal candidiasis (VVC) leads to oxidative stress and aggravates inflammation. This study aimed to optimize and synthesize four ROS-sensitive polyethylene glycol (PEG)-boride polymers (PB, PCB, BPB, and BCPCB). A nanomicelle (BCPCB-K) was constructed using BCPCB-encapsulated ketoconazole (KTZ). Finally, the depolymerization principle and ROS-sensitive drug release of BCPCB-K as well as its anti-Candida albicans (CA) and therapeutic effects on mice with VVC were explored through in vitro and in vivo experiments. BCPCB-K exhibited low toxicity to mammalian cells in vitro and good biocompatibility in vivo. It also improved the dispersion and solubility of the hydrophobic drug KTZ. Furthermore, BCPCB-K simultaneously scavenged ROS and released the drug, thus facilitating the antifungal and VVC-treating effects of KTZ. Overall, the findings of this study broadened the application of ROS-sensitive materials in the drug-loading and antifungal fields and provided a strategy for VVC treatment.

Asunto(s)

Antifúngicos , Candida albicans , Candidiasis Vulvovaginal , Cetoconazol , Pruebas de Sensibilidad Microbiana , Especies Reactivas de Oxígeno , Candida albicans/efectos de los fármacos , Antifúngicos/farmacología , Antifúngicos/química , Especies Reactivas de Oxígeno/metabolismo , Candidiasis Vulvovaginal/tratamiento farmacológico , Candidiasis Vulvovaginal/microbiología , Cetoconazol/farmacología , Cetoconazol/administración & dosificación , Femenino , Animales , Ratones , Micelas , Nanopartículas/química , Humanos , Liberación de Fármacos , Polietilenglicoles/química , Polietilenglicoles/farmacología , Tamaño de la Partícula

RESUMEN

A 20-year-old man had developed dermatitis on his scalp and facial hair between his lower lip and chin, his 'soul patch', for one month. He initially presented to urgent care, where the dermatitis was attributed to Herpes simplex infection, for which he was treated with both oral valacyclovir and topical acyclovir. When no change was observed, he consulted his pediatrician, who prescribed oral clindamycin and referred him to dermatology. Physical examination revealed a crusted plaque on an erythematous and edematous base at the lower cutaneous border of the lower lip (Figure 1). Examination additionally revealed an erythematous scaling plaque on the left temporal area with associated flaking, tenderness, and hair loss and left-sided cervical lymphadenopathy. A fungal culture grew Trichophyton mentagrophytes, but a bacterial culture did not grow. Further investigation revealed that he had a dog; however, no other animal contact to account for a fungal reservoir was present. He was successfully treated with oral terbinafine for 6 weeks, plus ketoconazole 2% shampoo and ketoconazole 2% cream with complete reso-lution (Figure 2).

Asunto(s)

Antifúngicos , Humanos , Masculino , Antifúngicos/uso terapéutico , Antifúngicos/administración & dosificación , Adulto Joven , Cetoconazol/uso terapéutico , Cetoconazol/administración & dosificación , Terbinafina/uso terapéutico , Terbinafina/administración & dosificación , Tiña/tratamiento farmacológico , Tiña/diagnóstico , Animales , Perros , Naftalenos/uso terapéutico , Naftalenos/administración & dosificación , Preparaciones para el Cabello , Trichophyton/aislamiento & purificación

RESUMEN

INTRODUCTION: Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease with prognoses varying from months to years at time of castration-resistant diagnosis. Optimal first-line therapy for those with different prognoses is unknown. METHODS: We conducted a retrospective cohort study of men in a national healthcare delivery system receiving first-line therapy for mCRPC (abiraterone, enzalutamide, docetaxel, or ketoconazole) from 2010 to 2017, with follow-up through 2019. Using commonly drawn prognostic labs at start of mCRPC therapy (hemoglobin, albumin, and alkaline phosphatase), we categorized men into favorable, intermediate, or poor prognostic groups depending on whether they had none, one to two, or all three laboratory values worse than designated laboratory cutoffs. We used Kaplan-Meier methods to examine prostate specific antigen (PSA) progression-free and overall survival (OS) according to prognostic group and first-line therapy, and multivariable cox regression to determine variables associated with survival outcomes. RESULTS: Among 4135 patients, median PSA progression-free survival (PFS) was 6.9 months (95% confidence interval [CI] 6.6-7.3), and median OS 18.8 months (95% CI 18.0-19.6), ranging from 5.7 months (95% CI 4.8-7.0) in the poor prognosis group to 31.3 months (95% CI 29.7-32.9) in the favorable group. OS was similar regardless of initial treatment received for favorable and intermediate groups, but worse for those in the poor prognostic group who received ketoconazole (adjusted hazard ratio 2.07, 95% CI 1.2-3.6). PSA PFS was worse for those who received ketoconazole compared to abiraterone across all prognostic groups (favorable HR 1.76, 95% CI 1.34-2.31; intermediate HR 1.78, 95% CI 1.41-2.25; poor HR 8.01, 95% CI 2.93-21.9). CONCLUSION: Commonly drawn labs at mCRPC treatment start may aid in predicting survival and response to therapies, potentially informing discussions with care teams. First-line treatment selection impacts disease progression for all men with mCRPC regardless of prognostic group, but impacted OS only for men with poor prognosis at treatment start.

Asunto(s)

Androstenos , Docetaxel , Cetoconazol , Feniltiohidantoína , Neoplasias de la Próstata Resistentes a la Castración , Masculino , Humanos , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/mortalidad , Neoplasias de la Próstata Resistentes a la Castración/patología , Neoplasias de la Próstata Resistentes a la Castración/sangre , Anciano , Estudios Retrospectivos , Cetoconazol/uso terapéutico , Pronóstico , Persona de Mediana Edad , Feniltiohidantoína/uso terapéutico , Feniltiohidantoína/análogos & derivados , Docetaxel/uso terapéutico , Docetaxel/administración & dosificación , Androstenos/uso terapéutico , Antígeno Prostático Específico/sangre , Benzamidas/uso terapéutico , Nitrilos/uso terapéutico , Anciano de 80 o más Años , Supervivencia sin Progresión , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Estimación de Kaplan-Meier

RESUMEN

INTRODUCTION: Tinea capitis, a common scalp infection primarily affecting children, is caused by keratinophilic dermatophytic fungi, notably Microsporum and Trichophyton species. Microsporum canis, primarily transmitted from cats and dogs to humans, is rarely reported in non-endemic regions like India. We report a cases involving three family members from Delhi, India, diagnosed with tinea capitis caused by Microsporum canis. The index case, a five-year-old boy, contracted the infection through contact with a cat, while his younger brother and sister acquired it through human-to-human transmission within the family. METHODS: Clinical examination, microscopic analysis, and molecular identification techniques confirmed the diagnosis. Antifungal susceptibility testing revealed sensitivity to itraconazole and terbinafine but resistance to griseofulvin. RESULTS: Treatment with oral terbinafine and topical ketoconazole cream led to successful outcomes for all three patients. Molecular typing confirmed clonality of the isolates, indicating human-to-human transmission. CONCLUSION: This case study underscores the significance of considering atypical sources of infection and human-to-human transmission in the diagnosis and management of tinea capitis caused by Microsporum canis in non-endemic regions. It emphasizes the necessity of thorough contact history assessment and appropriate antifungal therapy for effective control of the infection.

Asunto(s)

Antifúngicos , Microsporum , Terbinafina , Tiña del Cuero Cabelludo , Humanos , Microsporum/genética , Microsporum/aislamiento & purificación , Microsporum/clasificación , Microsporum/efectos de los fármacos , Tiña del Cuero Cabelludo/microbiología , Tiña del Cuero Cabelludo/tratamiento farmacológico , Tiña del Cuero Cabelludo/diagnóstico , Masculino , India , Antifúngicos/uso terapéutico , Antifúngicos/farmacología , Preescolar , Terbinafina/uso terapéutico , Gatos , Femenino , Animales , Pruebas de Sensibilidad Microbiana , Itraconazol/uso terapéutico , Naftalenos/uso terapéutico , Naftalenos/farmacología , Resultado del Tratamiento , Cetoconazol/uso terapéutico , Tipificación Molecular , Familia , Niño , Griseofulvina/uso terapéutico

Asunto(s)

Antifúngicos , Cetoconazol , Región Lumbosacra , Terbinafina , Antifúngicos/uso terapéutico , Antifúngicos/administración & dosificación , Terbinafina/uso terapéutico , Terbinafina/administración & dosificación , Cetoconazol/uso terapéutico , Cetoconazol/administración & dosificación , Resultado del Tratamiento , Dermatomicosis/tratamiento farmacológico , Dermatomicosis/microbiología , Administración Oral , Animales , Humanos , Cabello/efectos de los fármacos , Masculino , Alilamina/análogos & derivados

RESUMEN

Ketoconazole (KTZ) is widely used as a fungicide, but it is also known to target steroid hormone formation which may affect female reproductive health. Our study aims to investigate the effects of KTZ on in vitro matured bovine cumulus-oocyte complexes (COCs), as a model for female reproductive toxicity. Cumulus cells of in vitro maturing COCs produce progesterone and pregnenolone, but exposure to 10-6 M KTZ effectively blocked the synthesis of these hormones. Exposure to lower concentrations of KTZ (i.e. 10-7 M and 10-8 M) had no such effect on steroidogenesis compared to the 0.1 % v/v DMSO vehicle control. Classical parameters of in vitro COC maturation, such as oocyte nuclear maturation to the metaphase II stage and expansion of the cumulus investment, were not affected by any KTZ concentration tested. Apoptosis and necrosis levels were also not altered in cumulus cells or oocytes exposed to KTZ. Moreover, oocytes exposed to KTZ during maturation showed normal cleavage and early embryo development up to day 8 post fertilization; albeit a statistically significant decrease was observed in day 8 blastocysts produced from oocytes exposed to the lowest concentration of 10-8 M KTZ. When unexposed mature oocytes were fertilized, followed by embryo culture for 8 days under KTZ exposure, no adverse effects in embryo cleavage and blastocyst formation were observed. In conclusion, KTZ has no major impact on in vitro bovine oocyte maturation and blastocyst formation in our study, even at concentrations blocking steroidogenesis.

Asunto(s)

Apoptosis , Células del Cúmulo , Cetoconazol , Oocitos , Progesterona , Animales , Oocitos/efectos de los fármacos , Bovinos , Cetoconazol/toxicidad , Células del Cúmulo/efectos de los fármacos , Femenino , Apoptosis/efectos de los fármacos , Pregnenolona , Técnicas de Maduración In Vitro de los Oocitos/veterinaria , Fertilización In Vitro/efectos de los fármacos , Fertilización In Vitro/veterinaria , Células Cultivadas , Desarrollo Embrionario/efectos de los fármacos

RESUMEN

The effect of internal and external magnetic fields on the separation of antifungal drugs by centrifugal acceleration thin-layer chromatography was reported for the first time. External and internal magnetic fields were applied using neodymium magnets and CoFe2O4@SiO2 ferromagnetic nanoparticles. Separation of ketoconazole and clotrimazole was performed using a mobile phase consisting of n-hexane, ethyl acetate, ethanol, and ammonia (2.0:2.0:0.5:0.2, v/v). The influence of the magnetic field on the entire chromatographic system led to changes in the properties of the stationary and mobile phases and the analytes affecting the retention factor, shape, and width of the separated rings. The extent of this impact depended on the structure of the analyte and the type and intensity of the magnetic field. In the presence of the external magnetic field, there were more significant changes in the chromatographic parameters of the drugs, especially the width of the separated rings, and ketoconazole was more affected than clotrimazole. The changes are conceivably due to the effect of the magnetic field on the analyte distribution between the stationary and mobile phases, which is also caused by the possibility of the magnetic field affecting the viscosity, surface tension, and surface free energy between the stationary and mobile phases.

Asunto(s)

Antifúngicos , Cetoconazol , Campos Magnéticos , Cromatografía en Capa Delgada/métodos , Antifúngicos/análisis , Antifúngicos/química , Antifúngicos/aislamiento & purificación , Cetoconazol/química , Cetoconazol/análisis , Clotrimazol/química , Clotrimazol/análisis , Centrifugación/métodos , Dióxido de Silicio/química

RESUMEN

As a powerful imidazole antifungal drug, ketoconazole's low solubility (0.017 mg/mL), together with its odor and irritation, limited its clinical applications. The inclusion complex of ketoconazole with randomly methylated ß-cyclodextrin was prepared by using an aqueous solution method after cyclodextrin selection through phase solubility studies, complexation methods, and condition selection through single factor and orthogonal strategies. The complex was confirmed by FTIR (Fourier-transform infrared spectroscopy), DSC (differential scanning calorimetry), TGA (thermogravimetric analysis), SEM (scanning electron microscope images), and NMR (Nuclear magnetic resonance) studies. Through complexation, the water solubility of ketoconazole in the complex was increased 17,000 times compared with that of ketoconazole alone, which is the best result so far for the ketoconazole water solubility study. In in vitro pharmacokinetic studies, ketoconazole in the complex can be 100% released in 75 min, and in in vivo pharmacokinetic studies in dogs, through the complexation, the Cmax was increased from 7.56 µg/mL to 13.58 µg/mL, and the AUC0~72 was increased from 22.69 µgh/mL to 50.19 µgh/mL, indicating that this ketoconazole complex can be used as a more efficient potential new anti-fungal drug.

Asunto(s)

Antifúngicos , Cetoconazol , Solubilidad , beta-Ciclodextrinas , Cetoconazol/química , Cetoconazol/farmacocinética , Cetoconazol/farmacología , Cetoconazol/administración & dosificación , beta-Ciclodextrinas/química , Animales , Antifúngicos/farmacología , Antifúngicos/farmacocinética , Antifúngicos/química , Perros , Rastreo Diferencial de Calorimetría , Espectroscopía Infrarroja por Transformada de Fourier , Metilación

RESUMEN

Humantenmine, koumine, and gelsemine are three indole alkaloids found in the highly toxic plant Gelsemium. Humantenmine was the most toxic, followed by gelsemine and koumine. The aim of this study was to investigate and analyze the effects of these three substances on tissue distribution and toxicity in mice pretreated with the Cytochrome P450 3A4 (CYP3A4) inducer ketoconazole and the inhibitor rifampicin. The in vivo test results showed that the three alkaloids were absorbed rapidly and had the ability to penetrate the blood-brain barrier. At 5 min after intraperitoneal injection, the three alkaloids were widely distributed in various tissues and organs, the spleen and pancreas were the most distributed, and the content of all tissues decreased significantly at 20 min. Induction or inhibition of CYP3A4 in vivo can regulate the distribution and elimination effects of the three alkaloids in various tissues and organs. Additionally, induction of CYP3A4 can reduce the toxicity of humantenmine, and vice versa. Changes in CYP3A4 levels may account for the difference in toxicity of humantenmine. These findings provide a reliable and detailed dataset for drug interactions, tissue distribution, and toxicity studies of Gelsemium alkaloids.

Asunto(s)

Citocromo P-450 CYP3A , Gelsemium , Alcaloides Indólicos , Animales , Gelsemium/química , Citocromo P-450 CYP3A/metabolismo , Alcaloides Indólicos/toxicidad , Distribución Tisular , Masculino , Ratones , Cetoconazol/toxicidad , Cetoconazol/farmacología , Inductores del Citocromo P-450 CYP3A/farmacología , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/efectos de los fármacos , Inhibidores del Citocromo P-450 CYP3A/farmacología , Alcaloides

RESUMEN

Antifungal medications are important due to their potential application in cancer treatment either on their own or with traditional treatments. The mechanisms that prevent the effects of these medications and restrict their usage in cancer treatment are not completely understood. The evaluation and discrimination of the possible protective effects of the anti-apoptotic members of the Bcl-2 family of proteins, critical regulators of mitochondrial apoptosis, against antifungal drug-induced cell death has still scientific uncertainties that must be considered. Novel, simple, and reliable strategies are highly demanded to identify the biochemical signature of this phenomenon. However, the complex nature of cells poses challenges for the analysis of cellular biochemical changes or classification. In this study, for the first time, we investigated the probable protective activities of Bcl-2 and Mcl-1 proteins against cell damage induced by ketoconazole (KET) and fluconazole (FLU) antifungal drugs in a yeast model through surface-enhanced Raman spectroscopy (SERS) approach. The proposed SERS platform created robust Raman spectra with a high signal-to-noise ratio. The analysis of SERS spectral data via advanced unsupervised and supervised machine learning methods enabled unquestionable differentiation (100 %) in samples and biomolecular identification. Various SERS bands related to lipids and proteins observed in the analyses suggest that the expression of these anti-apoptotic proteins reduces oxidative biomolecule damage induced by the antifungals. Also, cell viability assay, Annexin V-FITC/PI double staining, and total oxidant and antioxidant status analyses were performed to support Raman measurements. We strongly believe that the proposed approach paves the way for the evaluation of various biochemical structures/changes in various cells.

Asunto(s)

Antifúngicos , Fluconazol , Cetoconazol , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Proteínas Proto-Oncogénicas c-bcl-2 , Saccharomyces cerevisiae , Espectrometría Raman , Cetoconazol/farmacología , Antifúngicos/farmacología , Espectrometría Raman/métodos , Fluconazol/farmacología , Saccharomyces cerevisiae/efectos de los fármacos , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/análisis , Aprendizaje Automático

RESUMEN

BACKGROUND: Perianal fistulas are painful ulcers or sinus tracts that disproportionately affect German shepherd dogs and are proposed as a spontaneous animal model of fistulising Crohn's disease. OBJECTIVES: To characterise the rectal and cutaneous microbiota in German shepherd dogs with perianal fistulas and to investigate longitudinal shifts with lesion resolution during immunomodulatory therapy. ANIMALS: Eleven German shepherd dogs with perianal fistulas and 15 healthy German shepherd dogs. MATERIALS AND METHODS: Affected dogs were evaluated and swabbed at three visits, 30 days apart, while undergoing treatment with ciclosporin and ketoconazole. Healthy German shepherd dogs were contemporaneously sampled. Sites included the rectum, perianal skin and axilla. The microbiome was evaluated following sequencing of the V4 hypervariable region of the 16S ribosomal RNA (rRNA) gene. RESULTS: Alpha diversity was not significantly different between healthy and affected dogs at each of the three body sites (p > 0.5), yet rectal and perianal beta diversities from affected dogs differed significantly from those of healthy dogs at Day 0 (p = 0.004). Rectal and perianal relative abundance of Prevotella spp. increased and perianal Staphylococcus spp. relative abundance decreased in affected dogs over time, coincident with lesion resolution. CONCLUSIONS AND CLINICAL RELEVANCE: Changes in lesional cutaneous and rectal microbiota occur in German shepherd dogs with perianal fistulas and shift over time with lesion resolution during immunomodulatory therapy. Further investigations of the role of cutaneous and enteric microbiota in the pathogenesis of perianal fistulas, and whether manipulation of microbial populations may ameliorate disease, are needed.

Asunto(s)

Ciclosporina , Enfermedades de los Perros , Cetoconazol , Fístula Rectal , Animales , Perros , Ciclosporina/uso terapéutico , Ciclosporina/administración & dosificación , Enfermedades de los Perros/tratamiento farmacológico , Enfermedades de los Perros/microbiología , Masculino , Cetoconazol/uso terapéutico , Cetoconazol/administración & dosificación , Femenino , Fístula Rectal/veterinaria , Fístula Rectal/tratamiento farmacológico , Fístula Rectal/microbiología , Estudios Longitudinales , Recto/microbiología , Piel/microbiología , Piel/patología , Microbiota/efectos de los fármacos

RESUMEN

OBJECTIVES: Malassezia species are common, clinically relevant, and lipid-dependent yeasts of humans. They are also the leading causes of the dandruff problem of humans, and the azoles are used primarily in their topical and systemic treatment. Resistance to azoles is an emerging problem among Malassezia sp., which indicates the need of new drug assessments that will be effective against dandruff and limit the use of azoles and other agents in treatment. Among them, the efficacy of various combinations of piroctone olamine and climbazole against Malassezia sp. is highly important. Here, we assessed the efficacies of various piroctone olamine and climbazole formulations against Malassezia sp. in comparison with ketoconazole. METHODS: A total of nine formulations were included in the study, where each formulation was prepared from different concentrations of piroctone olamine and climbazole and both. All formulations contained the same ingredients as water, surfactants, hair conditioning agents, and preservatives. Malassezia furfur CBS1878, Malassezia globosa CBS7874, and Malassezia sympodialis CBS9570 were tested for antifungal susceptibility of each formulation by agar diffusion method. Sizes of the inhibition zones were compared with standard medical shampoo containing 2% ketoconazole, and the data were analyzed by Dunnett's multiple-comparison test. RESULTS: For all Malassezia sp. strains, climbazole 0.5% and piroctone olamine/climbazole (0.1%/0.1% and 0.1%/0.5%) combinations were found to have the same effect as the medical shampoo containing 2% ketoconazole. Piroctone olamine/climbazole 1.0%/0.1% formulation showed the same efficacy as 2% ketoconazole on M. furfur and M. sympodialis, while 0.1%/0.5% formulation to only M. furfur. For M. globosa, none of the formulations tested were as effective as ketoconazole. CONCLUSION: The species distribution of Malassezia sp. varies depending on the anatomical location on the host. According to the results of this study, climbazole and piroctone olamine combinations seem to be promising options against the dandruff problem with their high antifungal/anti dandruff efficacy.

Asunto(s)

Antifúngicos , Caspa , Preparaciones para el Cabello , Cetoconazol , Malassezia , Malassezia/efectos de los fármacos , Preparaciones para el Cabello/farmacología , Humanos , Antifúngicos/farmacología , Caspa/microbiología , Caspa/tratamiento farmacológico , Cetoconazol/farmacología , Imidazoles/farmacología , Pruebas de Sensibilidad Microbiana , Combinación de Medicamentos , Etanolaminas , Piridonas

RESUMEN

OBJECTIVE: This study aimed to investigate the effects of clarithromycin and ketoconazole on the pharmacokinetic properties of tacrolimus in different CYP3A4 genotype recombinant metabolic enzyme systems, so as to understand the drug interactions and their mechanisms further. METHOD: The experiment was divided into three groups: a blank control group, CYP3A4*1 group and CYP3A4*18 recombinant enzyme group. Each group was added with tacrolimus (FK506) of a series of concentrations. Then 1 umol/L clarithromycin or ketoconazole was added to the recombinant enzyme group and incubated in the NADPH system for 30 minutes to examine the effects of clarithromycin and ketoconazole on the metabolizing enzymes' activity of different genotypes. The remaining concentration of FK506 in the reaction system was determined using UPLC-MS/MS, and the enzyme kinetic parameters were calculated using the software. RESULTS: The metabolism of CYP3A4*18 to FK506 was greater than that of CyP3А4*1B. Compared with the CYP3A4*1 group, the metabolic rate and clearance of FK506 in the CYP3A4*18 group significantly increased, with Km decreasing. Clarithromycin and ketoconazole inhibit the metabolism of FK506 by affecting the enzyme activity of CYP3A4*1B and CYP3A4*18B. After adding clarithromycin or ketoconazole, the metabolic rate of FK506 significantly decreased in CYP3A4*1 and CYP3A4*18, with Km increasing, Vmax and Clint decreasing. CONCLUSION: Compared with CYP3A4*1, CYP3A4*18 has a greater metabolism of FK506, clarithromycin and ketoconazole can inhibit both the enzymatic activities of CYP3A4*1 and CYP3A4*18, consequently affecting the metabolism of FK506 and the inhibitory on CYP3A4*1 is stronger.

Asunto(s)

Claritromicina , Citocromo P-450 CYP3A , Interacciones Farmacológicas , Genotipo , Cetoconazol , Tacrolimus , Cetoconazol/farmacología , Tacrolimus/farmacocinética , Tacrolimus/metabolismo , Tacrolimus/farmacología , Claritromicina/farmacología , Claritromicina/metabolismo , Claritromicina/farmacocinética , Citocromo P-450 CYP3A/metabolismo , Citocromo P-450 CYP3A/genética , Humanos , Proteínas Recombinantes/metabolismo , Inmunosupresores/farmacocinética , Inmunosupresores/farmacología , Inhibidores del Citocromo P-450 CYP3A/farmacología

RESUMEN

The first-generation tyrosine kinase inhibitor imatinib has revolutionized the development of targeted cancer therapy and remains among the frontline treatments, for example, against chronic myeloid leukemia. As a substrate of cytochrome P450 (CYP) 2C8, CYP3A4, and various transporters, imatinib is highly susceptible to drug-drug interactions (DDIs) when co-administered with corresponding perpetrator drugs. Additionally, imatinib and its main metabolite N-desmethyl imatinib (NDMI) act as inhibitors of CYP2C8, CYP2D6, and CYP3A4 affecting their own metabolism as well as the exposure of co-medications. This work presents the development of a parent-metabolite whole-body physiologically based pharmacokinetic (PBPK) model for imatinib and NDMI used for the investigation and prediction of different DDI scenarios centered around imatinib as both a victim and perpetrator drug. Model development was performed in PK-Sim® using a total of 60 plasma concentration-time profiles of imatinib and NDMI in healthy subjects and cancer patients. Metabolism of both compounds was integrated via CYP2C8 and CYP3A4, with imatinib additionally transported via P-glycoprotein. The subsequently developed DDI network demonstrated good predictive performance. DDIs involving imatinib and NDMI were simulated with perpetrator drugs rifampicin, ketoconazole, and gemfibrozil as well as victim drugs simvastatin and metoprolol. Overall, 12/12 predicted DDI area under the curve determined between first and last plasma concentration measurements (AUClast) ratios and 12/12 predicted DDI maximum plasma concentration (Cmax) ratios were within twofold of the respective observed ratios. Potential applications of the final model include model-informed drug development or the support of model-informed precision dosing.

Asunto(s)

Interacciones Farmacológicas , Mesilato de Imatinib , Modelos Biológicos , Humanos , Mesilato de Imatinib/farmacocinética , Mesilato de Imatinib/administración & dosificación , Citocromo P-450 CYP3A/metabolismo , Antineoplásicos/farmacocinética , Antineoplásicos/administración & dosificación , Masculino , Simulación por Computador , Adulto , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/administración & dosificación , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Femenino , Citocromo P-450 CYP2C8/metabolismo , Cetoconazol/farmacocinética , Cetoconazol/farmacología , Persona de Mediana Edad , Rifampin/farmacocinética , Rifampin/administración & dosificación

RESUMEN

Malassezia pachydermatis is often reported as the causative agent of dermatitis in dogs. This study aims to evaluate the in vitro and in vivo antifungal activity of azoles and terbinafine (TRB), alone and in combination with the 8-hydroxyquinoline derivatives (8-HQs) clioquinol (CQL), 8-hydroxyquinoline-5-(n-4-chlorophenyl)sulfonamide (PH151), and 8-hydroxyquinoline-5-(n-4-methoxyphenyl)sulfonamide (PH153), against 16 M. pachydermatis isolates. Susceptibility to the drugs was evaluated by in vitro broth microdilution and time-kill assays. The Toll-deficient Drosophila melanogaster fly model was used to assess the efficacy of drugs in vivo. In vitro tests showed that ketoconazole (KTZ) was the most active drug, followed by TRB and CQL. The combinations itraconazole (ITZ)+CQL and ITZ+PH151 resulted in the highest percentages of synergism and none of the combinations resulted in antagonism. TRB showed the highest survival rates after seven days of treatment of the flies, followed by CQL and ITZ, whereas the evaluation of fungal burden of dead flies showed a greater fungicidal effect of azoles when compared to the other drugs. Here we showed for the first time that CQL is effective against M. pachydermatis and potentially interesting for the treatment of malasseziosis.

Asunto(s)

Antifúngicos , Azoles , Dermatomicosis , Drosophila melanogaster , Malassezia , Pruebas de Sensibilidad Microbiana , Animales , Antifúngicos/farmacología , Malassezia/efectos de los fármacos , Malassezia/crecimiento & desarrollo , Azoles/farmacología , Dermatomicosis/tratamiento farmacológico , Dermatomicosis/microbiología , Drosophila melanogaster/microbiología , Drosophila melanogaster/efectos de los fármacos , Perros , Terbinafina/farmacología , Sinergismo Farmacológico , Quimioterapia Combinada , Enfermedades de los Perros/microbiología , Enfermedades de los Perros/tratamiento farmacológico , Cetoconazol/farmacología , Oxiquinolina/farmacología , Sulfonamidas/farmacología , Itraconazol/farmacología , Clioquinol/farmacología , Modelos Animales de Enfermedad

RESUMEN

A healthy 32-year-old woman presented to clinic with tender pruritic lesions of 2-month duration at the vulva and lesions for weeks on the shins. She was treated with topical corticosteroids and intravenous vancomycin without significant improvement. On examination, dozens of follicular hemorrhagic papulopustules were detected at the suprapubic area and vulva (Figure 1). Similar but less prominent lesions were observed on the shins as well. Biopsies of the vulva and shin revealed a follicular inflammatory infiltrate of neutrophils, histiocytes, and lymphocytes as well as fungal hyphae within the follicular infundibulum and hair shafts, consistent with Majocchi's granuloma (MG). Gram and Fite-Faraco staining, direct immunofluorescence, and bacterial culture were negative. Tissue culture grew Trichophyton mentagrophytes, which was identified using sequence analysis of the D1/D2 region of the 28s rDNA. Minimum inhibitory concentrations for terbinafine, ketoconazole, and itraconazole were determined, with terbinafine having the lowest concentration. Additional history revealed that shortly prior to commencement of her clinical manifestations, the patient had acquired a pet guinea pig with eruptions and hair loss (Figure 2). The patient was prescribed ketoconazole cream and terbinafine, 250 mg daily, with almost immediate improvement. Based on clinical response, the patient remained on terbinafine and ketoconazole cream for 6 months. Her skin remained clear 4 months after discontinuing all antifungals. Based on the results of patient's culture, a veterinarian treated her guinea pig successfully with systemic terbinafine and miconazole lotion.

Asunto(s)

Cetoconazol , Tiña , Trichophyton , Femenino , Humanos , Animales , Cobayas , Adulto , Terbinafina/uso terapéutico , Cetoconazol/uso terapéutico , Antifúngicos/uso terapéutico , Vulva

RESUMEN

Ketoconazole (Ke) is an important antifungal drug, and two of its diphenylphosphinemethyl derivatives (KeP: Ph2PCH2-Ke and KeOP: Ph2P(O)CH2-Ke) have shown improved antifungal activity, namely against a yeast strain lacking ergosterol, suggesting alternative modes of action for azole compounds. In this context, the interactions of these compounds with a model of the cell membrane were investigated, using POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) large unilamellar vesicles and taking advantage of the intrinsic fluorescence of Ke, KeP and KeOP. Steady-state fluorescence spectra and anisotropy, including partition and aggregation studies, as well as fluorescence lifetime measurements, were carried out. In addition, the ability of the compounds to increase membrane permeability was assessed through carboxyfluorescein leakage. The membrane/water mole fraction partition coefficients (Kp,x): (3.31 ± 0.36) x105, (8.31 ± 1.60) x105 and (4.66 ± 0.72) x106, for Ke, KeP and KeOP, respectively, show that all three compounds have moderate to high affinity for the lipid bilayer. Moreover, KeP, and particularly KeOP interact more efficiently with POPC bilayers than Ke, which correlates well with their in vitro antifungal activity. Furthermore, although the three compounds disturb the lipid bilayer, KeOP is the quickest and most efficient one. Hence, the higher affinity and ability to permeabilize the membrane of KeOP when compared to that of KeP, despite the higher lipophilicity of the latter, points to an important role of Ph2P(O)CH2- oxygen. Overall, this work suggests that membrane interactions are important for the antifungal activity of these azoles and should be considered in the design of new therapeutic agents.

Asunto(s)

Antifúngicos , Cetoconazol , Antifúngicos/farmacología , Cetoconazol/farmacología , Membrana Dobles de Lípidos , Fosfatidilcolinas

RESUMEN

Hepatocellular carcinoma (HCC) is a form of malignancy with limited curative options available. To improve therapeutic outcomes, it is imperative to develop novel, potent therapeutic modalities. Ketoconazole (KET) has shown excellent therapeutic efficacy against HCC by eliciting apoptosis. However, its limited water solubility hampers its application in clinical treatment. Herein, a mitochondria-targeted chemo-photodynamic nanoplatform, CS@KET/P780 NPs, is designed using a nanoprecipitation strategy by integrating a newly synthesized mitochondria-targeted photosensitizer (P780) and chemotherapeutic agent KET coated with chondroitin sulfate (CS) to amplify HCC therapy. In this nanoplatform, CS confers tumor-targeted and subsequently pH-responsive drug delivery behavior by binding to glycoprotein CD44, leading to the release of P780 and KET. Mechanistically, following laser irradiation, P780 targets and destroys mitochondrial integrity, thus inducing apoptosis through the enhancement of reactive oxygen species (ROS) buildup. Meanwhile, KET-induced apoptosis synergistically enhances the anticancer effect of P780. In addition, tumor cells undergoing apoptosis can trigger immunogenic cell death (ICD) and a longer-term antitumor response by releasing tumor-associated antigens (TAAs) and damage-associated molecular patterns (DAMPs), which together contribute to improved therapeutic outcomes in HCC. Taken together, CS@KET/P780 NPs improve the bioavailability of KET and exhibit excellent therapeutic efficacy against HCC by exerting chemophototherapy and antitumor immunity.

Asunto(s)

Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/terapia , Cetoconazol , Sulfatos de Condroitina , Neoplasias Hepáticas/terapia , Inmunoterapia

RESUMEN

In this work, two different multiple dual-mode (MDM) counter-current chromatography methods, conventional MDM and modified MDM elution modes, were compared for the chiral separation of the ketoconazole enantiomers. The biphasic solvent system which consisted of n-hexane: isobutyl acetate: 0.1 mol/L phosphate buffer (2:4:6, v/v) (pH = 8.5) was employed as stationary phase and mobile phase. And the hydroxypropyl-ß-cyclodextrin (HP-ß-CD) with a concentration of 100 mmol/L was dissolved in the phosphate buffer, as the chiral selector. Under two different methods, dual-mode (DM) elution was performed to determine the time of the transformed phase roles and multiple cycles were performed to isolate ketoconazole, respectively. The result indicated that the modified MDM elution had a significant improvement on the separation, increasing the resolution from 0.51 to 1.19, while the resolution was increased from 0.40 to 0.79 by the conventional MDM elution. Ultimately, baseline separation of ketoconazole enantiomers was essentially achieved by high-speed counter-current chromatography under optimized modified MDM separation conditions. The final recoveries of the two enantiomers, R-(K) and S-(K), were 92.5 % and 83.3 %, respectively, corresponding to enantiomeric excess values of 99.0 % and 97.0 %, as determined by HPLC.

Asunto(s)

beta-Ciclodextrinas , beta-Ciclodextrinas/química , Distribución en Contracorriente/métodos , Cetoconazol , 2-Hidroxipropil-beta-Ciclodextrina , Estereoisomerismo , Fosfatos