RESUMO
BACKGROUND: Gliclazide is a potential anti-cancer drug candidate for preventing carcinogenesis. However, the effect of gliclazide on colitis-associated colorectal cancer remains unknown. AIMS: We aimed to evaluate whether gliclazide plays a protective role in colitis-associated colorectal cancer and the underlying molecular mechanism. METHODS: The administration of azoxymethane (AOM) followed by dextran sulfate sodium (DSS) aimed to induce colitis-associated colorectal cancer in mice. C57BL mice were gavaged with gliclazide (6 mg/kg by gavage 5 days a week) for 12 weeks immediately following AOM administration. After sacrificing the mice, colon tissues were measured for tumor number and tumor burden. The proliferation- and inflammation-related molecular mechanisms were explored. RESULTS: The administration of gliclazide significantly reduced the tumor number and tumor burden in mice. Cell proliferation decreased in the gliclazide group compared with the control group, as indicated by reduced Ki-67 expression. Furthermore, gliclazide alleviated colonic inflammation, significantly decreased pro-inflammatory factor TNF-α levels and increased anti-inflammatory factor IL-10 levels in vivo. In vivo and vitro, it was shown that gliclazide increased the level of phospho-AMPK (p-AMPK) and inhibited NF-κB activity. Further studies demonstrated that the inhibition of NF-κB activity induced by gliclazide was mediated by p-AMPK in vitro. CONCLUSIONS: Gliclazide effectively alleviated colonic inflammation and prevented colonic carcinogenesis in an AOM-DSS mouse model by modulating the AMPK-NF-κB signaling pathway. Thus, gliclazide holds potential as a chemopreventive agent for colitis-associated colorectal cancer.
Assuntos
Neoplasias Associadas a Colite , Colite , Neoplasias Colorretais , Gliclazida , Animais , Camundongos , NF-kappa B/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Gliclazida/efeitos adversos , Colite/induzido quimicamente , Colite/complicações , Colite/metabolismo , Camundongos Endogâmicos C57BL , Inflamação/metabolismo , Transdução de Sinais , Carcinogênese , Azoximetano/toxicidade , Sulfato de Dextrana/toxicidade , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/prevenção & controle , Neoplasias Colorretais/metabolismoRESUMO
BACKGROUND: Gliclazide has been suspected to be associated with a lower obesity-related cancer risk; however, current evidence is limited by important methodologic shortcomings. This study aimed to evaluate whether gliclazide is preferred over other sulfonylureas regarding obesity-related cancer risk. METHODS: In this prospective cohort study, an annual benchmarking database in Dutch primary care (Zwolle Outpatient Diabetes project Integrating Available CareZODIAC, 1998-2014) was linked to the Netherlands Cancer Registry and the Dutch Personal Record Database. Of the 71,648 patients with type 2 diabetes, we included 26,207 who used sulfonylureas and had no history of cancer or insulin use at baseline. Obesity-related cancer was defined using the latest definition of the World Cancer Research Fund. Cox regression analyses were used to estimate HRs, with both baseline sulfonylurea and cumulative exposure modeled and corrected for baseline covariates. RESULTS: During follow-up for 167,692 person-years, there were 1,111 obesity-related cancer events. For males, the adjusted HRs [95% confidence interval (CI)] for baseline sulfonylurea compared with gliclazide were as follows: glibenclamide, 1.10 (0.92-2.69); glimepiride, 1.13 (0.68-1.84); and tolbutamide, 0.93 (0.59-1.48). For females, these were as follows: glibenclamide, 1.49 (0.72-3.13); glimepiride, 0.96 (0.59-1.54); and tolbutamide, 0.84 (0.54-1.28). The adjusted HRs (95% CI) for one more year of cumulative exposure compared with gliclazide were as follows: glibenclamide, 0.90 (0.71-1.14); glimepiride, 0.96 (0.87-1.06); and tolbutamide, 1.00 (0.92-1.09). For females, these were as follows: glibenclamide, 0.93 (0.77-1.13); glimepiride, 0.99 (0.90-1.10); and tolbutamide, 1.04 (0.96-1.13). CONCLUSIONS: Obesity-related cancer risk was comparable between gliclazide and other sulfonylureas. IMPACT: Gliclazide is not preferred over other sulfonylureas regarding obesity-related cancer risk.
Assuntos
Gliclazida/efeitos adversos , Hipoglicemiantes/efeitos adversos , Neoplasias/induzido quimicamente , Obesidade/induzido quimicamente , Estudos de Coortes , Feminino , Gliclazida/farmacologia , Humanos , Hipoglicemiantes/farmacologia , Incidência , Masculino , Estudos Prospectivos , Fatores de RiscoRESUMO
Several studies have shown that the use of sulfonylureas in patients with type 2 diabetes mellitus (T2DM) is associated with a higher risk of hepatocellular carcinoma (HCC). In this study, we investigated the effects of individual sulfonylureas on HCC development using the National Health Insurance Service-National Sample Cohort in South Korea. Among 47,738 subjects aged 40 years or older who had newly diagnosed with diabetes, 241 incident HCC cases and 1205 matched controls were identified. Adjusted odds ratios (ORs) as estimates of the relative risk of HCC were calculated using logistic regression analysis. Compared to patients never treated with a sulfonylurea, those treated with a sulfonylurea had a 1.7-fold increased risk of HCC development. Of the different types of sulfonylureas, the exclusive use of glimepiride was associated with a significantly elevated risk of HCC (OR = 1.89, 95% CI = 1.02-3.47) compared to those who were never treated with sulfonylureas. No significant associations were observed between exclusive gliclazide use and incident HCC (OR = 2.04, 95% CI = 0.75-5.52). In conclusion, the association between the use of sulfonylureas and risk of HCC was different according to the type of sulfonylurea, in patients with new-onset T2DM. Further prospective studies are warranted to confirm these results and translate them into clinical practice.
Assuntos
Carcinoma Hepatocelular , Diabetes Mellitus Tipo 2 , Gliclazida , Neoplasias Hepáticas , Compostos de Sulfonilureia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/epidemiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Gliclazida/administração & dosagem , Gliclazida/efeitos adversos , Humanos , Incidência , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/epidemiologia , Masculino , Pessoa de Meia-Idade , República da Coreia/epidemiologia , Fatores de Risco , Compostos de Sulfonilureia/administração & dosagem , Compostos de Sulfonilureia/efeitos adversosAssuntos
Carcinoma Hepatocelular/etiologia , Gliclazida/efeitos adversos , Hipoglicemiantes/efeitos adversos , Neoplasias Hepáticas/etiologia , Compostos de Sulfonilureia/efeitos adversos , Idoso , Carcinoma Hepatocelular/epidemiologia , Feminino , Humanos , Incidência , Neoplasias Hepáticas/epidemiologia , Masculino , Pessoa de Meia-Idade , RiscoAssuntos
Desprescrições , Complicações do Diabetes , Diabetes Mellitus/tratamento farmacológico , Gliclazida , Hipertensão/tratamento farmacológico , Hipoglicemia , Falência Renal Crônica , Metformina , Idoso de 80 Anos ou mais , Complicações do Diabetes/diagnóstico , Complicações do Diabetes/fisiopatologia , Complicações do Diabetes/terapia , Diabetes Mellitus/epidemiologia , Quimioterapia Combinada/efeitos adversos , Gliclazida/administração & dosagem , Gliclazida/efeitos adversos , Humanos , Hipertensão/diagnóstico , Hipoglicemia/diagnóstico , Hipoglicemia/etiologia , Hipoglicemia/fisiopatologia , Hipoglicemia/terapia , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/etiologia , Falência Renal Crônica/terapia , Masculino , Metformina/administração & dosagem , Metformina/efeitos adversos , Multimorbidade , Polimedicação , Resultado do TratamentoRESUMO
Erythroderma is generalized exfoliative dermatitis, which involves more than 90% of the patient's skin. The most common cause of erythroderma is exacerbation of an underlying skin disease, malignancies or drug reaction. There is a long list of drugs responsible for erythroderma such as antiepileptics, sulfonamides, antibiotics, and angiotensin converting enzyme (ACE) inhibitors. We herein report a case of erythroderma due to gliclazide usage which is also proved by histopathologic examination and patch test. We could not find any case report of gliclazide, an oral antidiabetic, as a cause erythroderma in the literature.
Assuntos
Dermatite Esfoliativa/induzido quimicamente , Gliclazida/efeitos adversos , Hipoglicemiantes/efeitos adversos , Idoso , Dermatite Esfoliativa/diagnóstico , Dermatite Esfoliativa/patologia , Toxidermias/patologia , Feminino , Gliclazida/uso terapêutico , Humanos , Hiperglicemia/complicações , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Pele/patologia , Testes CutâneosRESUMO
AIMS/HYPOTHESIS: Type 2 diabetes has been associated with an increased risk of cancer. This study examines the effect of more vs less intensive glucose control on the risk of cancer in patients with type 2 diabetes. METHODS: All 11,140 participants from the Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation (ADVANCE) trial (ClinicalTrials.gov NCT00145925) were studied. Cancer incidence and cancer mortality was compared in groups randomised to intensive or standard glucose control. Information on events during follow-up was obtained from serious adverse event reports and death certificates. HRs (95% CI) were calculated for all cancers, all solid cancers, cancer deaths and site-specific cancers. RESULTS: After a median follow-up of 5 years, 363 and 337 cancer events were reported in the intensive and standard control groups, respectively (incidence 1.39/100 person-years [PY] and 1.28/100 PY; HR 1.08 [95% CI 0.93-1.26]). The incidences of all solid cancers and cancer deaths were 1.25/100 PY and 0.55/100 PY in the intensive group and 1.15/100 PY and 0.63/100 PY in the standard group (HR 1.09[95% CI 0.931.27] for solid cancers, and 0.88 [0.711.10] for cancer death) [corrected].Across all the major organ systems studied, no significant differences in the cancer incidences were observed in the intensive and standard control groups. CONCLUSIONS/INTERPRETATIONS: More intensive glucose control achieved with a regimen that included greater use of gliclazide, insulin, metformin and other agents, did not affect the risk of cancer events or death in patients with type 2 diabetes.
Assuntos
Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/efeitos adversos , Neoplasias/epidemiologia , Idoso , Diabetes Mellitus Tipo 2/mortalidade , Feminino , Gliclazida/efeitos adversos , Gliclazida/uso terapêutico , Humanos , Hipoglicemiantes/uso terapêutico , Insulina/efeitos adversos , Insulina/uso terapêutico , Masculino , Metformina/efeitos adversos , Metformina/uso terapêutico , Pessoa de Meia-Idade , Neoplasias/etiologiaRESUMO
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
OBJECTIVE: To compare the efficacy and tolerability of metformin, rosiglitazone and gliclazide MR as monotherapy and in combination in the treatment of type 2 diabetes. SUBJECTS AND METHODS: 250 patients treated with oral antidiabetic agents for at least 24 weeks in monotherapy or in combination therapy were included in this retrospective study. RESULTS: As monotherapy the reduction of fasting plasma glucose (FPG), postprandial glycemia (PPG) and HbA1c was similar with the three drugs after 24 weeks. Among patients on combination therapy, the reduction in HbA1c, FPG and PPG was significantly lower with rosiglitazone plus metformin, as compared to metformin plus gliclazide MR or gliclazide MR plus rosiglitazone. Patients treated with rosiglitazone achieved less favorable changes in lipid profile. CONCLUSION: In monotherapy all drugs were equally effective in improving glycemic control, whereas the combination of metformin plus gliclazide MR provided the best results concerning the improvement of both, glycemic control and lipid profile.
OBJETIVO: Comparar a eficácia e a tolerabilidade da metformina, rosiglitazona e gliclazida MR em monoterapia ou em combinação no tratamento do diabetes tipo 2. SUJEITOS E MÉTODOS: 250 pacientes tratados com antidiabéticos orais por pelo menos 24 semanas, em monoterapia ou em terapia combinada, foram incluídos neste estudo retrospectivo. RESULTADOS: Como monoterapia, a redução da glicemia de jejum (GJ), glicemia pós-prandial (GPP) e HbA1c foi similar com as três drogas, após 24 semanas. Entre os pacientes em terapia combinada, a redução da HbA1c, GJ e GPP foi significativamente menor com rosiglitazona e metformina, em comparação com metformina e gliclazida MR ou gliclazida MR mais rosiglitazona. Os pacientes tratados com rosiglitazona obtiveram mudanças menos favoráveis no perfil lipídico. CONCLUSÃO: Em monoterapia todos os medicamentos foram igualmente eficazes na melhora do controle glicêmico, enquanto a combinação de metformina e gliclazida MR proporcionou os melhores resultados relativos à melhoria de ambos, controle glicêmico e perfil lipídico.
Assuntos
Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , /tratamento farmacológico , Gliclazida/efeitos adversos , Hipoglicemiantes/efeitos adversos , Metformina/efeitos adversos , Tiazolidinedionas/efeitos adversos , Análise de Variância , /metabolismo , Quimioterapia Combinada/efeitos adversos , Estudos RetrospectivosRESUMO
OBJECTIVE: To identify the demographic and clinical characteristics of sulfonylurea users. To assess the risk of hypoglycemia in patients treated with sulfonylureas in clinical practice, and to characterize the risk in relation to the different drugs used. RESEARCH DESIGN AND METHODS: A cohort of 33,243 sulfonylurea users chosen from 719 clinical practices in the United Kingdom were identified through the VAMP-Research database. Information on demographic characteristics, medical diagnoses and use of medical services was obtained through the computerized records. For a stratified sample of 500 patients, general practioners completed a structured questionnaire on the duration, treatment, and complications of diabetes mellitus, obesity, alcohol use, and smoking history. Patients with a diagnosis of hypoglycemia, as recorded in the database within a time-window of a sulfonylurea prescription, were identified. Incidence rates per person-year of sulfonylurea therapy were estimated. RESULTS: Other than a longer duration of diabetes in users of chlorpropamide, no differences were observed among users of different sulfonylurea agents with respect to diabetic complications, adequacy of diabetic control, obesity, smoking, and excessive alcohol consumption. A diagnosis of hypoglycemia during sulfonylurea therapy was recorded in 605 people over 34,052 person-years of sulfonylurea therapy, which converted into an annual risk of 1.8%. The risk in glibenclamide users was higher than in users of other types of sulfonylureas uses. Duration of therapy, concomitant use of insulin, sulfonylurea-potentiating or antagonizing and concomitant use of beta-blockers were predictive of the risk of developing hypoglycemia. DISCUSSION: Drug use patterns showed comparability among users of different sulfonylurea agents. Our findings suggest that the rate of diagnosis of hypoglycemia made by physicians is higher for glibenclamide than for other sulfonylureas. An epidemiological study with objectively diagnosed hypoglycemia should be undertaken to confirm these results.
Assuntos
Hipoglicemia/induzido quimicamente , Hipoglicemiantes/efeitos adversos , Compostos de Sulfonilureia/efeitos adversos , Adulto , Idoso , Clorpropamida/efeitos adversos , Feminino , Gliclazida/efeitos adversos , Glipizida/efeitos adversos , Glibureto/efeitos adversos , Humanos , Hipoglicemia/etiologia , Incidência , Masculino , Pessoa de Meia-Idade , Distribuição de Poisson , Risco , Fatores de Risco , Inquéritos e Questionários , Fatores de Tempo , Tolbutamida/efeitos adversosRESUMO
In the present open clinical pilot study of 12 months duration we tested the metabolic and hemato-biological efficacy as well as the clinical tolerance of the oral antidiabetic agent gliclazide, a second-generation sulfonylurea derivate, on a group of 20 hospitalized geriatric patients (mean age 80.5 +/- 10.2 years). Gliclazide was proven to be a reliable blood-sugar lowering agent with a generally good subjective tolerance. There were no undesired side-effects on the renal, hepatic and hematopoietic systems.
Assuntos
Diabetes Mellitus Tipo 2/terapia , Gliclazida/uso terapêutico , Compostos de Sulfonilureia/uso terapêutico , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Glicemia/metabolismo , Feminino , Gliclazida/efeitos adversos , Humanos , Masculino , Projetos PilotoRESUMO
Numerous drugs and chemicals affect the function of human blood platelets. The mechanism of action of some medications is partly understood. Aspirin is the most frequently involved drug. It appears to interfere with the platelet release reaction by acetylation of a platelet membrane protein which may be involved in the synthesis of prostaglandins. Other anti-inflammatory drugs, including indomethacin, phenylbutazone, ibuprophen (Motrin) and clonixin, also interfere with the release reaction but have a shorter acting course than aspirin. Some drugs stimulate adenylcyclase (gliclazide) or block phosphodiesterase, (dipyridamole, caffeine) both of which actions lead to an increase in adenosine cyclic 3':5' monophosphate (cAMP) and decrease aggregation by adenosine diphosphate (ADP). These interactions should be known to clinical scientists since patients using these medicaments may manifest abnormal platelet function tests in the laboratory and mild hemorrhagic syndromes in the clinic.