RESUMO
Oral mucositis (OM) is one of the main side effects of the head and neck cancer treatment, particularly radiotherapy and/or chemotherapy. OM is characterized by ulcers, erythema, dysphagia, xerostomia, and increased susceptibility to opportunistic infections. In the perspective of finding pharmacological therapies to prevent inflammation and ulceration of OM, the investigation of the pleiotropic effect of commercial drugs is needed, among them gliclazide, an antidiabetic drug. This study aimed to evaluate the effect of gliclazide in an experimental OM model induced by 5-fluorouracil. Male hamsters were pre-treated with oral gliclazide (1, 5, or 10 mg/kg) for 10 days. Cheek pouch samples were subjected to histopathological and immunohistochemical analysis (COX2, iNOS, MMP-2, NFκB P65, GPx) and imunofluorescence (P-selectin). IL-1ß and TNF-α levels, Myeloperoxidase activity (MPO) and malondialdehyde (MDA) levels were investigated by ultraviolet-visible spectroscopy analysis. NFκB NLS P50 protein levels were analyzed by western blotting. The group treated with gliclazide at a dose of 10 mg/kg showed presence of erythema, no evidence of erosion, and absence of mucosal ulceration with a score of 1 (1-2) (p < 0.01). Histopathological data for the group treated with gliclazide 10 mg/kg showed re-epithelialization, discrete mononuclear inflammatory infiltrate and absence of hemorrhage, edema, ulcers and abscesses with a score of 1 (1-1) (p < 0.01). Treatment with gliclazide 10 mg/kg reduced MPO activity (p < 0.001), MDA levels (p < 0.001) and NFκB NLS P50 (p < 0.05) protein levels, resulting in low immunostaining to Cox-2, iNOS (p < 0.05), NFκB P65 (p < 0.05), and negative immunoreaction to MMP-2 (p < 0.001). However, it appeared that for Gpx1, the staining was restored in the GLI 10-FUT group compared with 5FUT/saline (p < 0.05). Immunofluorescence revealed decreased levels of P-selectin (p < 0.001) after treatment with gliclazide 10 mg/kg (p < 0.05). In summary, gliclazide accelerated mucosal recovery and reduced oxidative stress and inflammation in the 5-FU-induced OM in hamsters.
RESUMO
A mucosite oral (MO) é uma inflamação aguda da mucosa oral, sequela mais importante dos tratamentos de radioterapia ou/e quimioterapia. As lesões na cavidade oral são graves, dolorosas e podem levar a sepse e morte. Não existe um protocolo único de prevenção e cura para MO. Na perspectiva de encontrar terapias farmacológicas para prevenir MO, propomos a investigação do efeito pleiotrópico do medicamento comercial gliclazida, um anti-diabético de ação secundária anti-inflamatória e antioxidante nunca estudada na MO. Este estudo teve como objetivo avaliar o efeito da gliclazida em um modelo MO experimental induzido por 5-fluorouracil. Hamsters machos foram pré-tratados com gliclazida oral (1, 5 ou 10mg/kg) por 10 dias. As amostras das mucosas dos animais foram submetidas à análise macroscópica, histopatológica e imuno-histoquímica (COX2, iNOS, MMP-2, NFκB P65, GPx) e imunofluorescência (P-selectina). Os níveis de IL-1ß e TNF-α, a atividade de mieloperoxidase (MPO) e os níveis de malondialdeído (MDA) foram investigados por análise espectroscópica ultravioleta-visível. A expressão protéica de NFκB NLS P50 foram analisados por western blotting. O grupo tratado com gliclazida na dose de 10 mg / kg apresentou melhores resultados como ; presença de eritema, ausência de erosão e de ulceração da mucosa com escore de 1 (1-2) (p <0,01) nos achados clínicos. Os dados histopatológicos do grupo tratado com gliclazida 10 mg / kg mostraram reepitelização, discreto infiltrado inflamatório mononuclear, úlceras com escore de 1 (1-1) (p <0,01). O tratamento com gliclazida 10 mg/kg reduziram os níveis de atividade de MPO (p <0,001), MDA (p <0,001) e NFκB NLS P50 (p <0,05), resultando em baixa imunocoloração para Cox-2, iNOS (p <0,05) , NFκB P65 (p <0,05) e imunorreacção negativa para MMP-2 (p <0,001).Para Gpx, a coloração foi menos intensa no grupo GLI 10-FUT em comparação com 5FUT/solução salina (p <0,05). A Imunofluorescência revelou diminuição dos níveis de P-selectina (p <0,001) após o tratamento com gliclazida 10 mg/kg (p <0,05). A gliclazida na dose de 10mg/kg atenuou a severidade da MO e reduziu o estresse oxidativo e a inflamação na MO induzida pelo 5-FU em hamsters (AU).
Oral mucositis (OM) is acute inflammation of the oral mucosa, the most important sequelae from radiotherapy and/or chemotherapy treatments. The lesions in the oral cavity are severe and painful, and can lead to sepsis and death. There is no single protocol for preventing or curing OM. From the perspective of finding pharmacological therapies to prevent OM, we propose an investigation of the pleiotropic effect of commercial drugs, among them gliclazide, an anti-diabetic with anti-inflammatory and anti-oxidant side action which has never studied regarding OM. This study aimed to evaluate the effect of gliclazide on an experimental OM model induced by 5-fluorouracil. Male hamsters were pretreated with oral gliclazide (1, 5 or 10 mg/kg) for 10 days. The mucosal samples of the animals were submitted to histopathological and immunohistochemical analysis (COX2, iNOS, MMP-2, NFκB P65, GPx) and immunofluorescence (P-selectin). Levels of IL-1ß and TNF-α, myeloperoxidase activity (MPO) and malondialdehyde levels (MDA) were investigated by ultraviolet-visible spectroscopic analysis. Protein expression of NFkB NLS P50 was analyzed by western blotting. The group treated with gliclazide at a dose of 10 mg/kg presented erythema, absence of erosion and mucosal ulceration with a score of 1 (1-2) (p <0.01) in the clinical findings. The histopathological data of the gliclazide 10 mg/kg group showed reepithelialization, a discrete mononuclear inflammatory infiltrate, and ulcers with a score of 1 (1-1) (p <0.01). Treatment with 10 mg/kg gliclazide reduced the activity levels of MPO (p <0.001), MDA (p <0.001) and NFκB NLS P50 (p <0.05), resulting in low immunostaining for Cox-2, iNOS (p <0.05), NFκB P65 (p <0.05) and negative immunoreaction for MMP-2. For Gpx, staining was restored in the GLI 10-FUT group compared to 5FUT/saline (p <0.05). Immunofluorescence showed a decrease in P-selectin levels (p <0.001) after treatment with 10 mg/kg gliclazide (p <0.05). Furthermore, 10 mg/kg gliclazide attenuated OM severity and reduced oxidative stress, and 5-FU induced OM in hamsters (AU).
Assuntos
Animais , Ratos , Estomatite/patologia , Imuno-Histoquímica , Anti-Inflamatórios/farmacologia , Western Blotting , Análise de Variância , Imunofluorescência , Estatísticas não ParamétricasRESUMO
AIMS: This study aims to evaluate whether there is a difference between the effects of vildagliptin and gliclazide MR (modified release) on glycemic variability (GV) in women with type 2 diabetes (T2DM) as evaluated by continuous glucose monitoring (CGM). METHODS: An open-label, randomized study was conducted in T2DM women on steady-dose metformin monotherapy which were treated with 50â¯mg vildagliptin twice daily or 60-120â¯mg of gliclazide MR once daily. CGM and GV indices calculation were performed at baseline and after 24â¯weeks. RESULTS: In total, 42 patients (age: 61.9⯱â¯5.9â¯years, baseline glycated hemoglobin (HbA1c): 7.3⯱â¯0.56) were selected and 37 completed the 24-week protocol. Vildagliptin and gliclazide MR reduced GV, as measured by the mean amplitude of glycemic excursions (MAGE, pâ¯=â¯0.007 and 0.034, respectively). The difference between the groups did not reach statistical significance. Vildagliptin also significantly decreased the standard deviation of the mean glucose (SD) and the mean of the daily differences (MODD) (pâ¯=â¯0.007 and 0.030). CONCLUSIONS: Vildagliptin and gliclazide MR similarly reduced the MAGE in women with T2DM after 24â¯weeks of treatment. Further studies are required to attest differences between vildagliptin and gliclazide MR regarding glycemic variability.
Assuntos
Adamantano/análogos & derivados , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Gliclazida/administração & dosagem , Hipoglicemiantes/administração & dosagem , Nitrilas/administração & dosagem , Pirrolidinas/administração & dosagem , Adamantano/administração & dosagem , Adamantano/efeitos adversos , Adulto , Idoso , Glicemia/efeitos dos fármacos , Automonitorização da Glicemia , Brasil/epidemiologia , Preparações de Ação Retardada/administração & dosagem , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Feminino , Gliclazida/efeitos adversos , Hemoglobinas Glicadas/análise , Humanos , Hipoglicemiantes/efeitos adversos , Metformina/uso terapêutico , Pessoa de Meia-Idade , Nitrilas/efeitos adversos , Pirrolidinas/efeitos adversos , Compostos de Sulfonilureia/administração & dosagem , Compostos de Sulfonilureia/efeitos adversos , Resultado do Tratamento , VildagliptinaRESUMO
In the absence of an official dissolution method for modified-release tablets of gliclazide, dissolution parameters, such as apparatuses (1, 2, and 3), rotation speeds, pH, and composition of the dissolution medium were investigated. The results show that although the drug presents a pH-mediated solubility (pH 7.0 > 6.8 > 6.4 > 6.0 > 5.5 > 4.5), the in vitro release of the studied tablets was not dependent on this parameter, despite of the apparatus tested. On the other hand, the rotation speed demonstrated a greater influence (100 rpm >50 rpm). Using similar hydrodynamic conditions, the three different apparatuses were compared in pH 6.8 and provided the following trend: apparatus 1 at 100 rpm >2 at 50 rpm ≈3 at 10 dpm. As a complete, but slow release is expected from modified-release formulations, apparatus 2, in phosphate buffer pH 6.8 and 100 rpm, were selected as the optimized dissolution method. In comparison to apparatus 1 under the same conditions, the paddle avoids the stickiness of formulation excipients at the mesh of the basket, which could prejudice the release of gliclazide. Results obtained with biorelevant medium through the developed dissolution method were similar to the buffer solution pH 6.8. The application of the optimized method as a quality control test between two different brands of gliclazide modified-release tablets showed that both dissolution profiles were considered similar by the similarity factor (f2 = 51.8). The investigation of these dissolution profiles indicated a dissolution kinetic following first-order model.
Assuntos
Química Farmacêutica/métodos , Gliclazida/análise , Gliclazida/química , Preparações de Ação Retardada/análise , Preparações de Ação Retardada/química , Excipientes/análise , Excipientes/química , Solubilidade , Comprimidos/químicaRESUMO
This study aimed to formulate, characterize and evaluate the Gliclazide (GLZ) microcapsules prepared with sodium alginate, guar gum and pectin in different ratios by ionotropic-gelation method. The microcapsules were evaluated against different parameters such as particle size and shape, Carr's index, Hausner's ratio, rheological studies and drug release kinetics. Fourier Transform Infra Red (FTIR) and Differential Scanning Calorimetric (DSC) studies demonstrated the absence of any drug - polymers interaction. Promising characteristics were observed in rheological behavior and release kinetics. The size of microcapsules and percentage yield was in the range of 676 to 727 µm and 69 to 77%, respectively. Scanning electron micrographs revealed that microcapsules were discrete, spherical and free flowing. Entrapment efficiency and uniform drug release kinetics were some of the probable characteristics depicting the novel formulation design of Gliclazide microcapsules.
RESUMO
The present study was initiated with the objective of studying the in vitro dissolution behavior of gliclazide from its solid dispersion with polyethylene glycol 6000. In this work, a solid dispersion of gliclazide with polyethylene glycol was prepared by the fusion method. In vitro dissolution study of gliclazide, its physical mixture and solid dispersion were carried out to demonstrate the effect of PEG 6000. Analytical techniques of FT-IR spectroscopy, differential scanning calorimetry and X-ray diffractometry were used to characterize the drug in the physical mixtures and solid dispersions. The dissolution studies of solid dispersion and physical mixture showed greater improvement compared to that of the pure drug. The mechanisms for increased dissolution rate may include reduction of crystallite size, a solubilization effect of the carrier, absence of aggregation of drug crystallites, improved wettability and dispersbility of the drug from the dispersion, dissolution of the drug in the hydrophilic carrier or conversion of drug to an amorphous state. The FT-IR spectra suggested that there was no interaction between gliclazide and PEG 6000 when prepared as a solid dispersion. DSC and XRD study indicated that the drug was converted in the amorphous form.
O presente trabalho foi realizado com o objetivo de estudar o comportamento in vitro da dissolução da gliclazida a partir da sua dispersão sólida com polietileno glicol 6000. Neste trabalho, as dispersões sólidas de gliclazida com polietileno glicol foram preparadas pelo método de fusão. Os estudo de dissolução in vitro da gliclazida, na mistura física e nas dispersões sólidas foram realizados para demonstrar o efeito de PEG 6000. Técnicas analíticas como espectroscopia FT-IR, calorimetria diferencial de varredura e difração de raios-X foram empregadas para caracterizar o fármaco nas misturas físicas e nas dispersoes sólidas. Os estudos de dissolução demonstraram maior melhoria. Os mecanismos para aumentar a velocidade de dissolução podem incluir a redução do tamanho dos cristais, a solubilização do carreador, a ausência de agregação dos cristais do fármaco, a melhoria da molhabilidade e dispersibilidade do fármaco a partir da dispersão, a dissolução do fármaco no carreador hidrofílico ou conversão da forma cristalina do fármaco para estado amorfo. Os espectros de FT-IR sugeriram que não houve interação entre gliclazide PEG 6000 e na sua combinação. Os estudos de DSC e DRX indicaram que o fármaco foi convertido para a forma amorfa.
Assuntos
Avaliação de Medicamentos , Dissolução/estatística & dados numéricos , Gliclazida/análise , Técnicas In Vitro , Propilenoglicol/farmacologia , Composição de MedicamentosRESUMO
El objetivo principal consistió en conocer la biodisponibilidad relativa de una nueva formulación de gliclazida (Gliclazida comprimidos de liberación sostenida Laboratorios Genven) con respecto a la formulación de Laboratorios Servier tomada como referencia, y establecer su bioequivalencia de acuerdo a los criterios recomendados por las autoridades sanitarias. Se hizo asimismo una valoración de la tolerancia de ambos preparados. Se diseñó un estudio abierto, randomizado, cruzado, dos periodos, con siete días de lavado, con 12 voluntarios sanos de ambos sexos, entre 21 y 55 años, quienes ingirieron un comprimido del fármaco en estudio: GLICLAZIDA comprimidos DE LIBERACIÓN SOSTENIDA de 30 mg, fabricados por Laboratorios GENVEN, o del Fármaco control: GLICLAZIDA comprimidos DE LIBERACIÓN SOSTENIDA de 30 mg, fabricados por Laboratorios SERVIER, comercializados en Venezuela con el nombre de DIAMICROM MR®. La bioequivalencia se determinó con los parámetros farmacocinéticos de área bajo la curva AUC (0-t), AUC 0-∞ y concentración máxima (Cmax). Con ambas formulaciones se inicia la aparición en plasma de niveles cuantificables desde los 30 minutos, ambos productos alcanzan su Cmax alrededor de las 12 horas, con una Cmax para Gliclazida de Laboratorios Genven (GL) de 558.57 +/- 191.43 ng/mL y para Gliclazida marca Diamicrón MR® (GD) de 514.56 +/- 140.94 ng/mL sin diferencias significativas (P= 0.66). En cuanto al área debajo de la curva (AUC), encontramos valores de AUC 0-t de 539.68 +/- 210.75 ng/mL/h para GL y de 585.07 +/- 240.66 ng/mL/h para GD sin diferencias significativasentre estas (P= 0.91). Para el AUC0-∞ los valores fueron de 569.14 +/- 216,95 ng/mL/h para GL y de 616.93 +/- 244.37ng/mL/h para GD (P= 0.71)
The main objective was evaluated the relative bioavailability of a new formulation of gliclazide (gliclazide sustained release tablets Genven Laboratories) regarding the formulation of Laboratoires Servier taken as a reference and establish their bioequivalence according to the criteria recommended by health authorities. It was also an assessment of tolerance of both preparations. We performed a study open, randomized, crossover two periods, with seven days of washing, with 12 healthy volunteers of both sexes, between 21 and 55 years who ate a pill in drug study: GLICLAZIDE Liberation sustainable tablets 30 mg, manufactured by Genven Laboratories or drug control: GLICLAZIDE Liberation sustainable tablets 30 mg, manufactured by Servier Laboratories in Venezuela, marketed under the name DIAMICROM MR®. The bioequivalence was determined with the pharmacokinetic parameters of area under the curve AUC (0-t), AUC 0-∞ and maximum concentration (Cmax). With both formulations began appearing on plasma levels quantifiable from the 30 minutes, both products reach their Cmax around 12 hours, with a Cmax for gliclazide Genven Laboratory (GL) from 558.57 +/- 191.43 ng/mL and Gliclazide Diamicron MR® (GD) from 514.56+/-140.94 ng/mL without significant differences (P= 0.66). As for the area under the curve (AUC) values were found AUC 0-t 539.68 +/-210.75 ng/mL/h for GL and 585.07 +/- 240.66 ng/mL/h for GD no significant differences between these (P= 0.91). For AUC 0-∞ values were 569.14 +/- 216.95 ng/mL/h for GL and 616.93 +/- 244.37 ng/mL/h for GD (P= 0.71)
Assuntos
Pessoa de Meia-Idade , Disponibilidade Biológica , Gliclazida/análise , Gliclazida/efeitos adversos , Farmacocinética , Preparações Farmacêuticas/análise , Equivalência Terapêutica , FarmacologiaRESUMO
Dos formulaciones comerciales de Gliclazida de 80 mg - tabletas, los productos Glidiab de Tecnoquímicas y Diamicron® de Euroetika-Elsevier, fueron sometidos a estudio para evaluar la equivalencia farmacéutica y la equivalencia biológica.Después de comprobar la equivalencia farmacéutica se llevó a cabo el estudio de la equivalencia biológica en 14 voluntarios sanos; la cuantificación de Gliclazida en plasma se realizó por la técnica de cromatografía líquida de alta resolución (HPLC). Los parámetros farmacocinéticos evaluados fueron: área bajo la curva (AUC) de 0-60 horas, concentración máxima (Cmáx) y el tiempo máximo (tmáx) los cuales se analizaron estadísticamente con intervalos de confianza del 90.0 por ciento y un rango de aceptación para bioequivalencia del 80.0 por ciento al 125.0 por ciento para AUC y Cmáx y del 80.0 por ciento al 120.0 por cinto para el tmáx.Ambas formulaciones presentaron alta variabilidad inter e intrasujeto y se encontró que son bioequivalentes con respecto a AUC, pero no lo son con respecto a Cmáx y tmáx
Two commercial formulations of Gliclazide 80 mg tablets were studied in order to evaluate both pharmaceutical and biological equivalence, Glidiab® Tecnoquímicas Laboratories and Diamicron® Euroetika-Elsevier Laboratories. After proving the pharmaceutical equivalence, a bioequivalence was tested in 14 healthy volunteers and the determination of gliclazide in plasma was carried out by high-performance liquid chromatography (HPLC). The evaluated pharmacokinetic parameters were: area under the curve (AUC) from 0 to 60 hours, maximum concentration (Cmax) and time to maximum concentration (Tmax). In statistical analysis the 90.0% confidence intervals for AUC, Cmax and Tmax, and acceptance range for bioequivalence of 80.0%-125.0% to AUC and Cmax and acceptance range of 80:0%-120.0% to Tmax, were applied. Both formulations presented inter and intra subject high variability and it was found that they are bioequivalent in relation to AUC but they are not bioequivalent in relation to Cmax and Tmax