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1.
Biomed Pharmacother ; 118: 109299, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31387001

RESUMO

We have recently demonstrated that the neurosteroid-metabolizing enzyme, cytochrome P450c17 is increased in spinal astrocytes contributing to the development of mechanical allodynia in chronic constriction injury (CCI)-induced neuropathic mice. However, the mechanisms by which spinal P450c17 modulates pathological changes in astrocytes remain unclear. In this study we investigated whether P450c17 modulates astrocyte activation and whether this process is mediated by spinal p38 mitogen-activated protein kinase phosphorylation ultimately leading to the development of mechanical allodynia in CCI mice. Sciatic nerve injury induced a significant increase in glial fibrillary acidic protein (GFAP) expression in the superficial dorsal horn (SDH, laminae I-II) and nucleus proprius (NP, laminae III-IV) regions of the spinal cord dorsal horn. Repeated daily (from days 0-3 post-surgery) intrathecal administration of the P450c17 inhibitor, ketoconazole (10 nmol) significantly inhibited the CCI-induced increase in GFAP-immunoreactivity, but had no effect on the CCI-induced increase in Iba-1-immunoreactivity. In addition, intrathecal administration of ketoconazole significantly inhibited the CCI-induced increase in p38 phosphorylation, while the levels of ERK and JNK phosphorylation remained unchanged. The CCI-induced development of mechanical allodynia was attenuated by administration of either ketoconazole (10 nmol) or the p38 MAPK inhibitor, SB203580 (5 nmol). Administration of a sub-effective dose of SB203580 (0.5 nmol) potentiated the pharmacological effect of ketoconazole (1 nmol) on spinal GFAP-immunostaining, as well as, the development of mechanical allodynia following CCI. Collectively these data suggest that spinal P450c17 activates astrocytes via p38 phosphorylation, ultimately leading to the development of mechanical allodynia in a model of peripheral neuropathy.


Assuntos
Astrócitos/enzimologia , Neuralgia/enzimologia , Neuralgia/patologia , Medula Espinal/patologia , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Constrição Patológica , Modelos Animais de Doenças , Hiperalgesia/complicações , Hiperalgesia/patologia , Imidazóis/farmacologia , Cetoconazol/administração & dosagem , Cetoconazol/farmacologia , Vértebras Lombares/enzimologia , Vértebras Lombares/patologia , Masculino , Camundongos , Microglia/efeitos dos fármacos , Microglia/patologia , Fosforilação/efeitos dos fármacos , Piridinas/farmacologia , Corno Dorsal da Medula Espinal/enzimologia , Corno Dorsal da Medula Espinal/patologia , Esteroide 17-alfa-Hidroxilase/metabolismo
2.
J Vet Intern Med ; 33(5): 2235-2238, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31448839

RESUMO

A 11-year-old male neutered Shih Tzu was referred to a tertiary facility with a history of weight loss, decreased appetite, polydipsia, and lethargy. The dog had a 10-year history of nonspecific allergic dermatitis and was being treated with 16 mg/kg of ketoconazole q12h for Malassezia dermatitis. Vague gastrointestinal signs, hypocholesterolemia, and lack of a stress leukogram increased suspicion for hypoadrenocorticism (HA). An adrenocorticotropic hormone (ACTH) stimulation test identified hypocortisolemia on pre- and post-ACTH samples and ketoconazole was discontinued. After a short course of corticosteroid treatment, an ACTH stimulation test was repeated and pre-ACTH cortisol concentration was within the reference range, and the post-ACTH cortisol concentration was mildly increased. The temporal association between return of adequate adrenocortical cortisol production and discontinuation of ketoconazole led to the conclusion that the dog had developed iatrogenic HA secondary to ketoconazole treatment.


Assuntos
Insuficiência Adrenal/veterinária , Doenças do Cão/induzido quimicamente , Doença Iatrogênica/veterinária , Cetoconazol/efeitos adversos , Insuficiência Adrenal/induzido quimicamente , Insuficiência Adrenal/diagnóstico , Hormônio Adrenocorticotrópico/administração & dosagem , Hormônio Adrenocorticotrópico/farmacologia , Animais , Antifúngicos/administração & dosagem , Antifúngicos/efeitos adversos , Antifúngicos/uso terapêutico , Dermatomicoses/tratamento farmacológico , Dermatomicoses/veterinária , Doenças do Cão/diagnóstico , Cães , Hidrocortisona/sangue , Cetoconazol/administração & dosagem , Cetoconazol/uso terapêutico , Malassezia , Masculino
3.
J Biochem Mol Toxicol ; 33(9): e22366, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31332882

RESUMO

Colchicine (COL) is an alkaloid existing in plants of Liliaceous colchicum. It has widely been used in the treatments of many diseases, such as gout, Familial Mediterranean Fever, and tumor. However, the adverse effects of COL are an obstacle to its safe use. The present studies explored the role of metabolic demethylation in the development of COL-induced hepatotoxicity. We found that inhibition of CYP3A increased the susceptibility of mice to COL hepatotoxicity, and induction of CYP3A decreased the susceptibility of animals to the hepatotoxicity. The toxicokinetic study demonstrated that pretreatment with ketoconazole caused elevated area under the concentration-time curve of COL. Three demethylation metabolites of COL were found to be less hepatotoxic than the parent compound. It appears that the formation of electrophilic demethylation metabolites was not involved in the development of COL-induced liver injury.


Assuntos
Colchicina/farmacocinética , Colchicina/toxicidade , Fígado/efeitos dos fármacos , Animais , Citocromo P-450 CYP3A/metabolismo , Cetoconazol/administração & dosagem , Fígado/metabolismo , Masculino , Metilação , Camundongos
4.
Int J Pharm ; 567: 118472, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31252146

RESUMO

Candida albicans, as the main causative fungus of vaginal candidiasis, is currently a global issue of concern due to its high prevalence, biofilm formation and emergence of resistance. Ketoconazole (KTZ), an antifungal drug, which has poor water-solubility and penetration capacity, is ineffective against deep-seated Candida infection. Considering these issues, this work aimed to develop a novel multifunctional carrier for KTZ via encapsulation of KTZ/ß-cyclodextrin (ß-CD) co-ground mixture into chitosan/gellan gum gel-flakes (threadlike and polygonal structures). Analytical studies revealed existence of electrostatic-derived complexes between negatively charged gellan gum and positively charged chitosan. Gel-flakes were then loaded in in situ gel of pluronic F-127 (PF-127). Based on gelation temperature (Tgel), viscosity and release studies; selected formulation was further evaluated, showing significant in vitro anti-candida activity. Despite reduced dosage regimen (50 mg/daily/three days), KTZ flakes in situ gel was as effective as Gynoconazol vaginal cream® (80 mg terconazole/daily/three days) in improving patient complaints and Candida eradication. Multifunctionality of KTZ carrier was based on efficient spreading and coating of the vagina due to free-flowing properties during application, flakes entanglement within folded vaginal epithelia, sustained release and increased penetration capacity of KTZ to reach deep-seated infections. In conclusion, flakes in situ gel could be considered as a highly promising KTZ delivery option for treatment of vaginal candidiasis.


Assuntos
Antifúngicos/administração & dosagem , Candida albicans/efeitos dos fármacos , Candidíase Vulvovaginal/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Cetoconazol/administração & dosagem , Adulto , Antifúngicos/química , Candida albicans/crescimento & desenvolvimento , Quitosana/administração & dosagem , Quitosana/química , Composição de Medicamentos , Liberação Controlada de Fármacos , Feminino , Géis , Humanos , Cetoconazol/química , Pessoa de Meia-Idade , Polissacarídeos Bacterianos/administração & dosagem , Polissacarídeos Bacterianos/química , Reologia , Adulto Jovem
5.
Drug Metab Pharmacokinet ; 34(4): 247-252, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31088714

RESUMO

Accurate prediction of cytochrome P450 (CYP) 3A activity in the early stage of drug development and in clinical practice is important. This study aimed to evaluate the previously constructed CYP3A activity prediction model after administration of CYP3A inhibitors and inducers and to modify the model for better prediction of CYP3A activity. Healthy male subjects received the following study drugs during three study periods: midazolam alone (control phase); midazolam with 200 mg of itraconazole (CYP3A inhibition phase); and midazolam with 150 mg of rifampicin (CYP3A induction phase). We quantified the concentrations of several endogenous CYP3A markers in both urine and plasma using gas chromatography-mass spectrometry. The urinary markers, including 6ß-hydroxy (OH)-cortisol/cortisol, 6ß-OH-cortisone/cortisone, 16α-OH-dehydroepiandrosterone (DHEA)/DHEA, 16α-OH-androstenedione (A-dione)/A-dione and 7ß-OH-DHEA/DHEA, were significantly correlated with midazolam clearance in both the CYP3A inhibition and induction phases. We constructed a statistical prediction model after integrating data from a previous study to predict midazolam clearance as follows: Ln(midazolam clearance) = 2.5545 + 0.3988 × ln(7ß-OH-DHEA/DHEA) + 0.1984 × ln(16α-OH-DHEA/DHEA) + 0.5031 × ln(6ß-OH-cortisol/cortisol) - 0.1261 [ln(7ß-OH-DHEA/DHEA) × ln(6ß-OH-cortisol/cortisol)] (r2 = 0.75). We suggest that quantitating endogenous markers in vivo coupled with the statistical prediction model may be useful for predicting CYP3A parameters.


Assuntos
Inibidores do Citocromo P-450 CYP3A/farmacologia , Citocromo P-450 CYP3A/metabolismo , Adulto , Biomarcadores/sangue , Biomarcadores/metabolismo , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Relação Dose-Resposta a Droga , Voluntários Saudáveis , Humanos , Itraconazol/administração & dosagem , Itraconazol/farmacologia , Cetoconazol/administração & dosagem , Cetoconazol/farmacologia , Masculino , Midazolam/administração & dosagem , Midazolam/farmacologia , Rifampina/administração & dosagem , Rifampina/farmacologia , Adulto Jovem
6.
Eur J Clin Pharmacol ; 75(8): 1077-1087, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31089768

RESUMO

AIM: The study sought to determine the effect of ketoconazole (KTZ) on the pharmacokinetics of praziquantel (PZQ) and on the formation of its major hydroxylated metabolites, cis- and trans-4-OH-PZQ, and X-OH-PZQ in healthy subjects. METHODS: Two treatments were evaluated by single-dose PK studies; the reference treatment was a 20 mg/kg dose of praziquantel given alone. The test treatment was a 20 mg/kg dose of praziquantel given in combination with 200 mg of ketoconazole. The study had a balanced and randomised cross-over design. Serial blood samples were collected between 0 and 12 h after each drug administration. PZQ, and cis- and trans-4-OH-PZQ and X-OH-PZQ concentrations in plasma were determined by LC-MS. A non-compartmental approach was used for pharmacokinetic analysis. Data were analysed using ANOVA and assessment of the 90% confidence interval of the geometric means of the log-transformed PK parameters obtained for each treatment. RESULTS: The pharmacokinetics of PZQ following the two treatments, PZQ alone and PZQ + KTZ, were not equivalent based on the assessment of the 90% CI of the geometric mean ratios of the AUC and Cmax (α = 0.05). The geometric mean ratios of the AUC and Cmax were found to be 176.8% and 227% respectively. The 90% CI of the AUC and Cmax were found to be 129.8%-239.8% and 151.4%-341.4% respectively. The AUC of PZQ was increased by 75% with KTZ co-administration (3516 vs 6172 ng h/ml) (p < 0.01). Meanwhile, the mean AUC of trans-4-OH-PZQ increased by 67% (61,749 ng h/ml vs 103,105 ng h/ml) (p < 0.01). X-OH-PZQ levels were reduced by about 57% (semi-quantified as 7311 ng h/ml vs 3109 ng h/ml by using trans-4-OH as standards) (p < 0.01) with KTZ co-administration. CONCLUSIONS: The relative bioavailability of praziquantel was increased by concomitant KTZ administration. KTZ preferentially inhibited the formation of X-OH-PZQ rather than 4-OH-PZQ, confirming in vitro data which implicates CYP3A4 in the formation of X-OH-PZQ rather than 4-OH-PZQ. The 4-hydroxylation of PZQ was shown to be the major metabolic pathway of PZQ, as evidenced by larger quantities of 4-OH-PZQ produced, thus explaining the modest albeit significant effect of ketoconazole on PZQ pharmacokinetics.


Assuntos
Anti-Helmínticos/farmacocinética , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Citocromo P-450 CYP3A/metabolismo , Cetoconazol/farmacocinética , Praziquantel/farmacocinética , Adulto , Anti-Helmínticos/administração & dosagem , Anti-Helmínticos/metabolismo , Disponibilidade Biológica , Estudos Cross-Over , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Interações Medicamentosas , Estudos de Viabilidade , Voluntários Saudáveis , Humanos , Cetoconazol/administração & dosagem , Masculino , Praziquantel/administração & dosagem , Praziquantel/metabolismo , Adulto Jovem
7.
Drug Metab Pers Ther ; 34(2)2019 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-31145690

RESUMO

Ruxolitinib is mainly metabolized by cytochrome P450 (CYP) enzymes CYP3A4 and CYP2C9 followed by minor contributions of other hepatic CYP enzymes in vitro. A physiologically based pharmacokinetic (PBPK) model was established to evaluate the changes in the ruxolitinib systemic exposures with co-administration of CYP3A4 and CYP2C9 perpetrators. The fractions metabolized in the liver via oxidation by CYP enzymes (fm,CYP3A4 = 0.75, fm,CYP2C9 = 0.19, and fm,CYPothers = 0.06) for an initial ruxolitinib model based on in vitro data were optimized (0.43, 0.56, and 0.01, respectively) using the observed exposure changes of ruxolitinib (10 mg) with co-administered ketoconazole (200 mg). The reduced amount of fm,CYP3A4 was distributed to fm,CYP2C9. For the initial ruxolitinib model with co-administration of ketoconazole, the area under the curve (AUC) increase of 2.60-fold was over-estimated compared with the respective observation (1.91-fold). With the optimized fm values, the predicted AUC ratio was 1.82. The estimated AUC ratios of ruxolitinib by co-administration of the moderate CYP3A4 inhibitor erythromycin (500 mg) and the strong CYP3A4 inducer rifampicin (600 mg) were within a 20% error compared with the clinically observed values. The PBPK modeling results may provide information on the labeling, i.e. supporting a dose reduction by half for co-administration of strong CYP3A4 inhibitors. Furthermore, an AUC increase of ruxolitinib in the absence or presence of the dual CYP3A4 and CYP2C9 inhibitor fluconazole (100-400 mg) was prospectively estimated to be 1.94- to 4.31-fold. Fluconazole simulation results were used as a basis for ruxolitinib dose adjustment when co-administering perpetrator drugs. A ruxolitinib PBPK model with optimized fm,CYP3A4 and fm,CYP2C9 was established to evaluate victim DDI risks. The previous minimal PBPK model was supported by the FDA for the dose reduction strategy, halving the dose with the concomitant use of strong CYP3A4 inhibitors and dual inhibitors on CYP2C9 and CYP3A4, such as fluconazole at ≤200 mg. Fluconazole simulation results were used as supportive evidence in discussions with the FDA and EMA about ruxolitinib dose adjustment when co-administering perpetrator drugs. Thus, this study demonstrated that PBPK modeling can support characterizing DDI liabilities to inform the drug label and might help reduce the number of clinical DDI studies by simulations of untested scenarios, when a robust PBPK model is established.


Assuntos
Citocromo P-450 CYP2C9/metabolismo , Citocromo P-450 CYP3A/metabolismo , Modelos Biológicos , Pirazóis/metabolismo , Pirazóis/farmacocinética , Administração Oral , Células CACO-2 , Interações Medicamentosas , Eritromicina/administração & dosagem , Eritromicina/metabolismo , Eritromicina/farmacocinética , Humanos , Cetoconazol/administração & dosagem , Cetoconazol/metabolismo , Cetoconazol/farmacocinética , Pirazóis/administração & dosagem , Rifampina/administração & dosagem , Rifampina/metabolismo , Rifampina/farmacocinética
8.
Vet Dermatol ; 30(3): 183-e57, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30887651

RESUMO

BACKGROUND: Topical therapy alone can be effective in the treatment of canine pyoderma. Topical products are commercially available as shampoos, sprays, wipes and mousses. To date, no studies have evaluated the efficacy of commercially available mousse products in the treatment of canine pyoderma. OBJECTIVE: To determine the residual antibacterial activity of canine hairs treated with mousse products containing different active ingredients. ANIMALS: Fifteen client-owned dogs with no history of dermatological disease. METHODS AND MATERIALS: Dogs were treated once with five mousse products [(i) 2% chlorhexidine and 1% ketoconazole, (ii) 2% chlorhexidine and 2% miconazole, (iii) 3% chlorhexidine and 0.5% climbazole, (iv) 2% salicylic acid 10% ethyl lactate and (v) phytosphingosine HCl 0.05%; control]. Hair samples were collected from each treatment area before application, one hour after application and on days 2, 4, 7, 10 and 14 post-treatment. Collected hairs were weighed and plated on Mueller-Hinton agar plates streaked with a Staphylococcus pseudintermedius isolate showing no antimicrobial resistance. Plates were incubated for 24 h and bacterial growth inhibition zones around the hairs were measured. RESULTS: Mousses 1, 2 and 3 created significant inhibition zones up to Day 10 when compared to pre-treatment samples. On Day 14, only mousse 3 produced a significant zone of inhibition when compared to the pre-treatment sample. Mousses 4 and 5 showed no statistical difference between any of the samples. CONCLUSIONS AND CLINICAL IMPORTANCE: These results suggest that three of the mousse products had residual activity in inhibiting S. pseudintermedius growth in vitro for at least 10 days.


Assuntos
Antibacterianos/análise , Resíduos de Drogas/análise , Preparações para Cabelo/química , Pioderma/veterinária , Infecções Cutâneas Estafilocócicas/veterinária , Staphylococcus/efeitos dos fármacos , Administração Tópica , Animais , Antibacterianos/administração & dosagem , Clorexidina/administração & dosagem , Doenças do Cão/tratamento farmacológico , Cães , Cabelo , Cetoconazol/administração & dosagem , Miconazol/administração & dosagem , Testes de Sensibilidade Microbiana , Animais de Estimação , Pioderma/tratamento farmacológico , Infecções Cutâneas Estafilocócicas/tratamento farmacológico
9.
J Prosthet Dent ; 121(1): 135-142, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30646999

RESUMO

STATEMENT OF PROBLEM: Antifungal agents incorporated into interim denture resilient liners have been suggested as an adjunct treatment for denture stomatitis (DS). However, before applying this protocol to humans, biocompatibility analysis of such drugs in animal models is required. PURPOSE: The purpose of this animal study was to evaluate the in vivo biocompatibility of an interim resilient liner modified with minimum inhibitory concentrations (MICs) of antifungal drugs for Candida albicans biofilm. MATERIAL AND METHODS: Sixty Wistar rats were divided into 6 groups (n=5): PC=positive control/no protocol; IOD (intraoral device)=rats using an acrylic resin palatal device (PD); Tru=rats using a PD relined with Trusoft; and Ny (nystatin), Chx (chlorhexidine diacetate), and Ke (ketoconazole) groups=rats using a PD relined with Trusoft + drug MICs. The rats were sacrificed at 7 or 14 days of trial. Histopathological qualitative analysis was performed by comparing photomicrographs of histological sections of the intermolar region. Morphological changes in the epithelium and keratin were quantitatively analyzed by computerized planimetry, and data were analyzed by using 2-way ANOVA and the Tukey HSD test (α=.05). RESULTS: Quantitative analysis showed that only PD containing Ke significantly decreased the thickness and area of the keratin compared with the other groups (P<.001), which showed no differences between each other (P>.05). These results agreed with those of qualitative analysis. CONCLUSIONS: Incorporation of MICs of Ny and Chx in Trusoft did not induce histopathological changes in the rat palatal mucosa, suggesting the in vivo biocompatibility of this DS treatment.


Assuntos
Antifúngicos/administração & dosagem , Candida albicans/efeitos dos fármacos , Reembasadores de Dentadura , Mucosa Bucal/efeitos dos fármacos , Resinas Acrílicas , Análise de Variância , Animais , Biofilmes/efeitos dos fármacos , Clorexidina/administração & dosagem , Queratinas/efeitos dos fármacos , Cetoconazol/administração & dosagem , Teste de Materiais , Testes de Sensibilidade Microbiana , Mucosa Bucal/citologia , Nistatina/administração & dosagem , Ratos , Ratos Wistar
10.
Drug Dev Ind Pharm ; 45(1): 168-176, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30231655

RESUMO

OBJECTIVE: The main purpose of this article is to show the valuable characteristics that liotropic liquid crystal systems possess to be employed as new drug delivery systems. SIGNIFICANCE: Colloidal aqueous dispersions of lyotropic liquid crystal mesophases such as the identified as cubosomes and hexosomes, and so on, have received considerable attention due to their unique nanostructures and their thermodynamic properties, which provide the potential as a sustained drug release matrix. Additionally, their large surface area and similarity with the liquid crystal structures of intercellular lipids of stratum corneum enhances the interaction with the skin and mucous, increasing the potential for topical drug delivery efficiency of biopharmaceutical class II drugs as the antifungal ketoconazole. METHODS: This article presents the results in morphological characteristics, particle size, ζ potential, flow, thermal behavior and drug release studies of hexosomes containing ketoconazole (LHLC-K) obtained with glycerol monooleate, propylene glycol monolaurate, poloxamer, and water mixtures. RESULTS: This colloidal system exhibits a Newtonian-type flow and a hexagonal nanostructure with a median particle size of 107 ± 20 nm and ζ potential of +4.45 ± 0.50 mV. Through differential scanning calorimetry studies, the LHLC-K demonstrated physical and chemical stability for more than six months and mesophasic thermal reversibility between 10 and 50 °C. Finally, LHLC-K releases ketoconazole following a kinetics described by the first order model. CONCLUSIONS: Physicochemical properties of the hexosomes containing ketoconazole are important for topical mycosis treatment administration, conditions of storage, and for its incorporation into the formulation of semi-solid dosage forms.


Assuntos
Antifúngicos/química , Sistemas de Liberação de Medicamentos/métodos , Cetoconazol/química , Cristais Líquidos/química , Administração Tópica , Antifúngicos/administração & dosagem , Antifúngicos/análise , Fenômenos Químicos , Cetoconazol/administração & dosagem , Cetoconazol/análise , Cristais Líquidos/análise
11.
Cornea ; 38(2): 141-145, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30334872

RESUMO

PURPOSE: To evaluate the efficacy of the topical, systemic and targeted therapy (TST) protocol in management of fungal keratitis. METHOD: All cases of treatment-naive smear- or culture-proven fungal keratitis presenting between June 2013 and May 2017 were recruited. The TST protocol included initial treatment with topical natamycin 5% with addition of oral ketoconazole or voriconazole in ulcers with size >5 mm, depth >50%, or impending perforation. Topical voriconazole 1% was included in case of poor response at 7 to 10 days. Intrastromal or intracameral antifungal injections were administered in case of poor response to combination therapy. Penetrating keratoplasty was performed in case of poor response to any of the regimen. RESULTS: The study included 223 cases of fungal keratitis with a mean age of 43.6 ± 15.3 years and a male-to-female ratio of 1.8:1. The mean area of the ulcer and infiltrate at presentation was 25.52 ± 19 and 25.7 ± 14.4 mm, respectively. Corrected distance visual acuity at presentation was 2.05 ± 0.43 logMAR that improved to 1.6 ± 0.4 logMAR at 3 months. Fusarium (42.2%) was the most common microorganism isolated, followed by Aspergillus (32.8%). The mean healing time was 41.5 ± 22.2 days, with a final scar size of 14.6 ± 8.2 mm. The treatment success rate with the TST protocol was 79.8%. Corneal perforation developed in 7% of cases (n = 15), and keratoplasty was performed for 20.2% of cases (n = 45). CONCLUSIONS: The TST protocol provides a stepwise treatment algorithm for management of cases of fungal keratitis with varying severity.


Assuntos
Antifúngicos/administração & dosagem , Infecções Oculares Fúngicas/tratamento farmacológico , Ceratite/tratamento farmacológico , Administração Oral , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Injeções Intraoculares , Ceratite/microbiologia , Cetoconazol/administração & dosagem , Masculino , Pessoa de Meia-Idade , Natamicina/administração & dosagem , Soluções Oftálmicas/uso terapêutico , Estudos Prospectivos , Acuidade Visual , Voriconazol/administração & dosagem , Adulto Jovem
12.
Mycopathologia ; 184(1): 187-192, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29761326

RESUMO

Superficial mycoses are commonly reported in captive pinnipeds, usually maintained in wet and warm environments, favorable to fungal growth. Most superficial mycoses in pinnipeds have been described as difficult to treat; however, the majority of the reports come from past decades. Cutaneous lesions associated with opportunistic Fusarium sp. infections have been previously recognized in this taxon. We described the clinical signs, associated lesions and diagnosis (thermography, imprint cytology, histopathology, culture, electron microscopy, PCR) of a fusariosis case by Fusarium sp. in the nails and skin of an adult male captive South American sea lion (Otaria flavescens) recently transferred from another zoological institution, and its successful long-term treatment with Ketoconazole PO (60 days) and Miconazole solution spray TO, followed by Itraconazole PO (30 days). Herein we provide a successful approach to the diagnosis and treatment of fusariosis.


Assuntos
Fusariose/veterinária , Fusarium/isolamento & purificação , Leões-Marinhos , Animais , Antifúngicos/administração & dosagem , Cães , Fusariose/diagnóstico , Fusariose/microbiologia , Histocitoquímica , Itraconazol/administração & dosagem , Cetoconazol/administração & dosagem , Masculino , Miconazol/administração & dosagem , Técnicas Microbiológicas , Técnicas de Diagnóstico Molecular , Pele/microbiologia , Pele/patologia , América do Sul , Resultado do Tratamento
13.
Int J Pharm ; 556: 372-382, 2019 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-30553957

RESUMO

Polymers functionally contribute to supersaturation and precipitation inhibition of the active pharmaceutical ingredient (API) in amorphous solid dispersions (ASD). Therefore, it is necessary to monitor physicochemical changes of the polymeric carrier caused by the manufacturing process. This is especially important when the material is exposed to heat and shear stress as in case of hot-melt extrusion (HME). This study evaluated the impact of HME process conditions on physical characteristics of poly(vinylpyrrolidone-co-vinyl-acetate) 60:40 (PVP-VA64) which is a widely used polymer for HME. Focus was set on molecular weight (Mw) and polydispersity index (PDI), by means of absolute molar mass detection via multi-angle light scattering. The generation of a high Mw fraction together with a decrease of the average Mw was detected. In a next step, the influence of these changes on the dissolution behavior of ASD was evaluated. Different stress conditions were applied onto PVP-VA64 in placebo extrusions. The obtained stressed polymer samples were subsequently used to prepare verum ASD with ketoconazole by spray drying (SD). SD dispersions (SDD) of thermally stressed PVP-VA64 were compared to SDD prepared with bulk powder. Although there were only slight changes in Mw and PDI, they significantly impacted supersaturation and precipitation of the formulation.


Assuntos
Química Farmacêutica/métodos , Cetoconazol/administração & dosagem , Polímeros/química , Pirrolidinas/química , Compostos de Vinila/química , Portadores de Fármacos/química , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Temperatura Alta , Cetoconazol/química , Luz , Peso Molecular , Pós , Espalhamento de Radiação , Solubilidade , Tecnologia Farmacêutica/métodos
14.
Rev Peru Med Exp Salud Publica ; 35(3): 476-482, 2018.
Artigo em Espanhol | MEDLINE | ID: mdl-30517509

RESUMO

The effectiveness of various pharmaceutical formulations of ketoconazole was evaluated in experimental models of cutaneous leishmaniasis (LC) in BALB C mice. Topical gel, lipogel, and cream formulations containing permeation enhancers and different concentrations of ketoconazole were prepared. Stability, toxicity and anti-Leishmania activity were determined in vitro. In addition, the effectiveness of topically applied formulations in LC-infected mice infected with Leishmania (Viannia) braziliensis was evaluated in vivo. Cream formulations were additionally evaluated in mice infected with L. (V.) panamensis. The systems evaluated maintained in vitro the activity of ketoconazole against parasites; however, none of the formulations were effective in curing LC lesions in mice. Topical treatment with miltefosine (used as a control) cured the lesions. It is concluded that the ketoconazole-containing formulations designed in this study were not effective against LC in infected mice.


Assuntos
Cetoconazol/administração & dosagem , Leishmaniose Cutânea/tratamento farmacológico , Administração Tópica , Animais , Modelos Animais de Doenças , Composição de Medicamentos , Humanos , Camundongos Endogâmicos BALB C , Resultado do Tratamento , Adulto Jovem
15.
J Pharm Pharm Sci ; 21(1s): 242s-253s, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30348250

RESUMO

Hypochlorhydria is a condition where the production of hydrochloric acid in the stomach is decreased. As a result, the intragastric pH is elevated. This condition can be due to a series of causes, such as disease (gastric mucosal infection caused by Helicobacter pylori and is prominent in AIDS patients), ethnicity, age and also the use of antisecretory agents. This may significantly impact the absorption of other drugs that have pH-dependent solubility, such as ketoconazole, a weak base. Within this context, the purpose of this study was to demonstrate how GastroPlusTM - a physiological based software program- can be used to predict clinical pharmacokinetics of ketoconazole in a normal physiological state vs. elevated gastric pH. A simple physiologically based pharmacokinetic model was built and validated to explore the impact that different physiologic conditions in the stomach (hypochlorhydria, drug administered with water and Coca Cola®) had on ketoconazole's bioavailability. The developed model was able to accurately predict the impact of increased pH and beverage co-administration on dissolution and absorption of the drug, and confirmed that complete gastric dissolution is essential. Particle size only mattered in hypochlorhydric conditions due to the incomplete gastric dissolution, as its absorption would depend on intestinal dissolution, which corroborates with previous studies. Therefore, in silico approaches are a potential tool to assess a pharmaceutical product's performance and efficacy under different physiological and pathophysiological states supporting the assessment of different dosing strategies in clinical practice.


Assuntos
Simulação por Computador , Cetoconazol/farmacocinética , Modelos Biológicos , Disponibilidade Biológica , Humanos , Concentração de Íons de Hidrogênio , Absorção Intestinal/efeitos dos fármacos , Cetoconazol/administração & dosagem , Cetoconazol/química , Tamanho da Partícula , Solubilidade , Propriedades de Superfície
16.
PLoS One ; 13(10): e0203194, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30286109

RESUMO

The level of the vitamin D in the bloodstream is regulated by cytochrome P450 enzyme 24-hydroxylase A1 (CYP24A1). Over expression of CYP24A1 enzyme is correlated with vitamin D deficiency and resistance to vitamin D therapy. Chronic kidney disease (CKD) patients are commonly reported with the above said expression variations. This deregulation could be solved by ligands that act as a vitamin D receptor (VDR) agonists and CYP24A1 antagonists. Posner et al., (2010) first time reported two new vitamin D analogues namely CTA-091 and CTA-018 to inhibit CYP24A1. The CTA-018 inhibited CYP24A1 with an IC50 27 ± 6 nM (10 times more potent than the ketoconazole (253 ± 20 nM)). CTA-018 induced VDR expression (15-fold lower than 1α,25(OH)2D3) and is under phase II clinical trial, whereas CTA-091 was not able to efficiently induce the VDR expression (>2000 nM). To explore the molecular mechanism, binding specificity of these two vitamin D analogues along with native ligand was extensively studied through in silico approaches. Through molecular dynamics simulations studies, we shown that the sulfonic group (O = S = O) in the side chain of CTA-018 plays an important role in the regulation of VDR agonistic activity. The electron lone pairs of the sulfonic group that interacted with His393 lead to be a factor for agonistic mechanism of VDR activity. Compared to azol-based compounds, CTA-018 binds the different sites in the CYP24A1 binding cavity and thus it could be a potent antagonistic for CYP24A1enzyme.


Assuntos
Receptores de Calcitriol/química , Insuficiência Renal Crônica/tratamento farmacológico , Deficiência de Vitamina D/tratamento farmacológico , Vitamina D3 24-Hidroxilase/química , Vitamina D/química , Humanos , Ligação de Hidrogênio , Cetoconazol/administração & dosagem , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Conformação Proteica , Receptores de Calcitriol/agonistas , Receptores de Calcitriol/genética , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/genética , Vitamina D/análogos & derivados , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/genética , Vitamina D3 24-Hidroxilase/antagonistas & inibidores , Vitamina D3 24-Hidroxilase/genética
18.
BMJ Case Rep ; 20182018 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-30219785

RESUMO

We present two cases of culture-proven fungal keratitis on natamycin treatment which developed periocular erythema, oedema, burning sensation and pruritus within 48 hours of the addition of topical voriconazole. On clinical examination, periocular erythema with induration was noted. A diagnosis of orbital cellulitis was suspected, but the absence of pain and tenderness refuted the diagnosis on clinical grounds. A dermatology consultation was sought, and a diagnosis of periocular contact dermatitis with voriconazole was made. A skin patch test was performed with the same medication; however, it was negative. Topical voriconazole therapy was withdrawn, and the patient was prescribed cold compresses and oral antihistamine medication, to which they responded well.


Assuntos
Antifúngicos/efeitos adversos , Dermatite de Contato/etiologia , Infecções Oculares Fúngicas/tratamento farmacológico , Soluções Oftálmicas/efeitos adversos , Voriconazol/efeitos adversos , Administração Oral , Adulto , Antifúngicos/administração & dosagem , Aspergillus flavus/isolamento & purificação , Úlcera da Córnea , Dermatite de Contato/tratamento farmacológico , Humanos , Cetoconazol/administração & dosagem , Soluções Oftálmicas/administração & dosagem , Voriconazol/administração & dosagem
19.
Invest New Drugs ; 36(6): 1085-1092, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30191523

RESUMO

Introduction Ketoconazole is CYP-17 inhibitor with demonstrated activity in men with castration-resistant prostate cancer (CRPC). Lenalidomide is an antiangiogenic and immunomodulatory agent with broad antitumor activity. We hypothesized that the modulation of the cellular immune response to apoptosis caused by ketoconazole may be increased with the addition of lenalidomide. Methods This is an open-label, non-randomized, single-arm phase II study evaluating the efficacy and safety of the combination of ketoconazole and lenalidomide in patients with CRPC. Treatment schema included standard ketoconazole 400 mg orally three times daily plus hydrocortisone orally (20 mg in the morning and 10 mg at night) in combination with lenalidomide 25 mg orally daily for 21 days in a 28-day cycle and aspirin 75 mg daily. The primary endpoint of this study was response (either by ≥ 50% PSA decline or objective disease assessed by RECIST v1.0). Exploratory endpoints included changes in T cell, dendritic cell (DC) marker counts, and their correlation with PSA response to treatment. Results A total of 34 CRPC patients, median age 69 years, 76% ECOG 0 and 76% with metastases participated in the study. Patients received a median of 2 cycles (range 1-35); nine patients (26%) received >10 cycles of treatment. PSA responses were observed in 17 patients (50%) with 11 patients (32%) achieving a PSA decline of >90%. Among the 9 patients with measurable disease, 2 patients (22%) had PR and 2 other (22%) had SD as best response. Median time to failure (TTF) was 2.7 months (range 0.2-32.8); and 8 patients were treated for ≥ 15 months. Most common adverse events included fatigue (76%), skin reactions (62%), lymphopenia (44%) and anemia (44%). One possible treatment-related death was noted. For 16 patients with available serial correlative data, there was a significant increase in the dendritic cells subsets BDCA-1 (+146.7, -20.1 to +501.1%, p = 0.018) and BDCA-3 (39.8%, -100 to 282.6%, p = 0.001) after 8 weeks of treatment. No association between immune cell counts and PSA response at 8 weeks was observed. Conclusion The combination of ketoconazole and lenalidomide was well tolerated but did not meet the primary endpoint of response, despite durable responses were observed in a selected group of patients. Although ketoconazole has now been replaced with more active novel agents, the combination of novel CYP-17 inhibitors with agents capable of modulating the immune system warrants further prospective investigation. NCT00460031.


Assuntos
Cetoconazol/uso terapêutico , Lenalidomida/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Humanos , Cetoconazol/administração & dosagem , Cetoconazol/efeitos adversos , Lenalidomida/administração & dosagem , Lenalidomida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Antígeno Prostático Específico/metabolismo , Tempo para o Tratamento , Resultado do Tratamento
20.
Vet Dermatol ; 29(6): 476-e160, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30251451

RESUMO

BACKGROUND: Malassezia pachydermatis is an opportunistic yeast involved in skin and ear canal infections of dogs and cats. Reports suggest that strains of M. pachydermatis resistant to commonly used antifungal agents may be emerging. Therefore, new therapeutic strategies should be explored. OBJECTIVES: The synergistic effect of oxythiamine (OT) and ketoconazole (KTC) was analysed using a reference strain and field isolates (n = 66) of M. pachydermatis. Hydrogel formulations containing these components also were evaluated. METHODS AND MATERIALS: The minimum inhibitory concentrations (MICs) and minimum fungicidal concentrations (MFCs) of OT, KTC and their mixtures were determined by a broth macrodilution method. The antifungal effects of hydrogel formulations were determined by a plate diffusion method. RESULTS: The MIC and MFC values of OT were in the range 0.08 × 103 to 10 × 103  mg/L. All M. pachydermatis strains showed higher susceptibility to KTC (MICs and MFCs in the range 0.04-0.32 mg/L). Formulations that combined OT and KTC showed a synergistic effect for all tested isolates (n = 66). Hydrogels that contained OT at a concentration of 10 × 103 or 20 × 103  mg/L and KTC at the concentration of 0.1 × 103  mg/L showed a stronger effect than a commercially available product with KTC alone (20 × 103  mg/L). CONCLUSIONS AND CLINICAL IMPORTANCE: Synergy of these drugs may allow for successful topical treatment which utilizes lower doses of KTC without changing its therapeutic effectiveness. Hydrogel formulations proved to be attractive drug carriers for potential topical use.


Assuntos
Antifúngicos/uso terapêutico , Dermatomicoses/veterinária , Doenças do Cão/microbiologia , Cetoconazol/uso terapêutico , Malassezia , Otite Externa/veterinária , Oxitiamina/uso terapêutico , Animais , Antifúngicos/administração & dosagem , Dermatomicoses/tratamento farmacológico , Doenças do Cão/tratamento farmacológico , Cães , Sinergismo Farmacológico , Quimioterapia Combinada , Hidrogel de Polietilenoglicol-Dimetacrilato/administração & dosagem , Cetoconazol/administração & dosagem , Malassezia/efeitos dos fármacos , Testes de Sensibilidade Microbiana/veterinária , Otite Externa/tratamento farmacológico , Otite Externa/microbiologia , Oxitiamina/administração & dosagem
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