Avaliação das atividades anti-inflamatórias e antioxidantes da gliclazida em modelo experimental de mucosite oral induzida por 5-fluorouracil / Evaluation of the anti-inflammatory and antioxidant activities of gliclazide in an experimental model of oral mucositis induced by 5-fluorouracil

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).

Ensayo clínico cruzado y randomizado de biodisponibilidad relativa de dos formulaciones de gliclazida comprimidos de 30 mg de liberación sostenida, administrados en dosis única a voluntarios sanos / Clinical trial randomized crossover relative bioavailability of two formulations of gliclazide of 30 mg tablets administered sustained release single dose to healthy volunteers

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 product’s 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)

Experiencia clínica sobre la eficacia y la seguridad de GLICLAZIDA MR en el tratamiento de Diabetes Mellitus Tipo 2 / Clinical Experience of effectiveness and security of GLICLAZID MR’S in the treatment of Diabetes Mellitus Type 2

Estudio realizado en los hospitales Teodoro Maldonado Carbo (IESS-Regional 2) y Seguro Social de Milagro; desde marzo a noviembre del 2001. Fueron reclutados 27 pacientes divididos en dos grupos: Grupo I (de reciente diagnóstico) y Grupo II (pacientes ya manejados) para tratamiento farmacológico único de diabetes tipo II con Gliclazida MR.Objetivo: Verificar la eficacia y la seguridad de Gliclazida MR en pacientes diabéticos Tipo 2 recién pesquizados y ya conocidos, estos últimos controlados con antidiabéticos orales.Resultados: La Gliclazida MR redujo la glucosa plasmática en los dos grupos: (Grupo I: 292mg/dl como glicemia media inicial y 10.7 de HbA1c media inicial vs. 122mg/dl glicemia media final y 7.1% de HbA1c media final. Grupo II: 181mg/dl de glicemia media inicial y 9.6% de HbA1c media inicial vs. 116mg7dl glicemia media final y 7.4% de HbA1c final). No hubo diferencias significativas en los parámetros hepáticos de control, ni en los perfiles de peso durante el estudio; ningún paciente presentó datos clínicos compatibles con Hipoglicemia.Conclusión: La eficiencia y la seguridad de Gliclazida MR como una nueva opción farmacológica, fue comprobada.

A prospective study done at the Teodoro Maldonado Carbo’s Hospital (IESS-Regional 2) and the Milagro’s Social Security Hospital during the period between the months of March through November of 2001. We studied 27 patients divided in two groups Group I (recently diagnosed) and Group II (which have received pharmacological treatment) that were to be treated with Gliclazid MR a unique pharmacological treatment for their diabetes type II.Objectives: Evaluate the effectiveness and security of the Gliclazid MR on the cases of diabetics type II, recently discovered and on other patients that have been controlled with oral antidiabetic agents.Results: Gliclazid MR reduced the plasmatic glucose level in the two studied groups. (Group I: from 292 mg/dl of average initial plasmatic glucose level and 10.7 of HbA1c initial average vs 122mg/dl of final average plasmatic glucose and 7.1% of HbA1c final average. Group II: from 181mg/dl of initial average of the plasmatic glucose level and 9.6% of HbA1c initial average to 116mg/dl and 7.4% of HbA1c final average). We didn’t fine differences in the control of hepatic parameters of control during the study and none of the patient’s clinical reports signs or symptoms of Hypoglycemia.Conclusion: The effectiveness and the security of the Gliclazid MR were proved.

Bioequivalencia entre dos formulaciones comerciales de gliclazida en Colombia / Bioequivalence between two commercial formulations of gliclazide in Colombia

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