Metformin versus glyburide in treatment and control of gestational diabetes mellitus: a systematic review with meta-analysis

ABSTRACT Objective To compare the major outcomes of use of metformin and glyburide in treatment of gestational diabetes mellitus. Methods Studies published in English, in the last 10 years, in the databases MEDLINE®, SciELO, LILACS and Cochrane Library were analyzed, and randomized controlled trials were selected. Health Sciences Descriptors were used to compose the search phrase, and the keywords "Gestational diabetes", "Glyburide", "Metformin" and their variations were searched in the Medical Subject Headings. PRISMA systematization was used to prepare this review, and a meta-analysis was conducted aiming to mathematically show the results of fasting blood glucose, postprandial blood glucose, birth weight and weight gain during pregnancy after using metformin and glyburide. Results The studies evaluated birth weight, neonatal hypoglycemia, mode of delivery, need for intensive care, Apgar score, macrosomia, fasting glucose, postprandial glucose and weight gain during pregnancy. In 60% of studies, there were no statistically significant differences regarding safety and efficacy of administration of metformin and glyburide. Meta-analysis demonstrated the absence of statistical differences between these drugs in fasting blood glucose (p=0.821), postprandial blood glucose (p=0.217) and birth weight (p=0.194). However, significant differences were shown in weight gain during pregnancy (p=0.036). Conclusion The methods are effective, but the adverse effects of glyburide are more common; therefore, the use of metformin should be recommended, if in monotherapy.

Transplacental Transfer of Glyburide in the ex vivo Human Placenta Perfusion Model / 中国药学杂志

OBJECTIVEP: To determine the ex vivo human placental transfer of glyburide from maternal circulation to the fetal circulation in Chinese Hans population. METHODS: Perfusion studies were performed on thirty-six placentas from healthy term pregnancies. The circulation of mother-placenta-fetus was set up ex vivo within minutes and accessed by studying spectrometry. Integrity and viability of the placenta were determined by measuring fetal volume loss, pH, pO2, ΔhCG, glucose consumption and lactate production during the perfusion experiments. RESULTS: Following 3 h of perfusion, the fetal transfer rate of glyburide was (1.64±0.85)%. The clearance index of glyburide was (0.05±0.03). CONCLUSION: These data suggest that tiny amount of glyburide can cross the human placenta. Glyburide could be used as a clinically effective alternative to insulin therapy.

Modulatory effect of baicalein on gene expression and activity of antioxidant enzymes in streptozotocin-nicotinamide induced diabetic rats

Oxidative stress plays the central role in the pathogenesis and progression of diabetic complications. The present study aims to investigate the beneficial effect of oral administration of flavone baicalein in streptozotocin-nicotinamide (STZ-NA) induced diabetic rats by measuring oxidative stress markers, antioxidant enzyme activities and expression analysis of antioxidant genes. Experimental diabetes was induced by a single intraperitoneal (i.p.) injection of STZ (55 mg /kg b.wt), 15 min after the i.p. administration of NA. At the end of the experimental period, thiobarbituric acid reactive substances (TBARS), activities of antioxidant enzymes and expression levels of superoxide dismutase (SOD), catalase (CAT), glutathione (GSH) and glutathione peroxidase (GPx) were measured in diabetic rats along with serum biochemical parameters namely total cholesterol (TC), total triglyceride (TG), aspartate transaminase (AST) alanine transaminase (ALT) and glycosylated hemoglobin (HbA1c). Oral administration of baicalein (40 mg/kg b.wt/day) demonstrated a significant ameliorative effect on all studied biochemical and oxidative stress parameters. Biochemical findings were corroborated by qPCR expression analysis which showed significant upregulation of antioxidant genes in diabetic rats. These results suggest that baicalein supplementation may reduce diabetes and its complications by suppressing oxidative stress and enhancing gene expression and antioxidant enzyme activities in diabetic rats.

Caracterización de eventos de hipoglicemia en pacientes diabéticos y no diabéticos atendidos en un servicio de urgencia / Hypoglycemia in an emergency room: review of 251 cases

Background Hypoglycemia is the main limitation for the achievement of glycemic goals in the treatment of diabetes. Aim To assess the incidence of hypoglycemia in an emergency department. To characterize and identify which patients are at higher risk of having it. Material and Methods We reviewed the electronic records of patients discharged from an adult emergency room with the diagnosis of hypoglycemia between May 2011 and December 2014. Age, sex, diagnosis of diabetes (DM), antidiabetic therapy, glycosylated hemoglobin, creatinine, destination at time of discharge, blood glucose, impairment of conscience, treatment of the event and predictions were recorded. Results Of 175,244 attentions analyzed, 251 in patients aged 69 ± 17 years (54% women) consulted for hypoglycemia (0.14%). Eighty one percent had a type 2 diabetes, 6% a type 1 diabetes and 12% were non-diabetic. Mean blood glucose was 44.1 mg/dl. In diabetic patients, mean glycosylated hemoglobin was 6.5%. Ninety seven percent had impairment of conscience and 77% were admitted to the hospital. Among patients without diabetes, the main comorbidity was the history of a gastric bypass surgery. In type 2 diabetes, glibenclamide used alone or with other medications was involved in 59% of the events, 87% of patients were older than 65 years with a mean glycosylated hemoglobin of 6.3% and 32% had renal failure. Conclusions The incidence of hypoglycemia was low. There were a significant number of events in older patients with type 2 diabetes mellitus and renal failure, who were treated with glibenclamide. Most of these patients had a glycosylated hemoglobin below accepted recommendations.

Evaluación de la prescripción de glibenclamida en diabéticos tipo 2 / Evaluation of glibenclamide prescription in type 2 diabetic patients

RESUMEN Introducción: Las sulfonilureas permanecen junto con la metformina como el tratamiento farmacológico más usado para los pacientes diabéticos tipo 2, y continúan siendo los antidiabéticos más prescritos en algunas regiones del mundo. Objetivo: Evaluar la prescripción de glibenclamida en aspectos relacionados a contraindicaciones, dosificación, y prevención de efectos adversos, en el tratamiento de los pacientes diabéticos tipo 2 que acuden a una institución de salud de baja complejidad en Cartagena de Indias, Colombia. Metodología: Estudio descriptivo con enfoque desde la fármaco-epidemiología dirigido específicamente al campo de los estudios de utilización de medicamentos, basado en los datos recogidos mediante revisión de historias clínicas de 331 pacientes diabéticos tipo 2, mayores de 18 años en un centro de atención primaria en salud de la ciudad de Cartagena de Indias entre los años 2013 y 2014. Se estudiaron variables demográficas, clínicas y paraclínicas, el esquema terapéutico y la calidad de la prescripción. La información se analizó usando estadística descriptiva. Resultados: 57 % (189) de los pacientes utilizaron glibenclamida siendo un 59.3 % (153) prescrito de manera inadecuada, 45.5% (86) tenían alguna contraindicación para el empleo del medicamento. En 1 % de los pacientes de la muestra se prescribió sobrepasando el rango de dosis terapéutica Conclusiones: La calidad de la prescripción de la glibenclamida fue inadecuada en una proporción importante de pacientes, se hace necesario implementar estrategias educacionales que capaciten al personal médico para una correcta utilización de los fármacos antidiabéticos. La glibenclamida comparada con otras sulfonilureas de segunda generación nos brinda más desventajas que ventajas.

ABSTRACT Introduction: Sulfonylureas remain with metformin as the most used drug treatment for type 2 diabetic patients and remain the most prescribed anti-diabetic in some regions of the world. Target: Evaluate prescribing glyburide in aspects related to contraindications, dosage, and prevention of adverse effects, in the treatment of type 2 diabetic patients attending a health institution low complexity in Cartagena de Indias, Colombia. Methodology: Descriptive study with approach from the pharmaco-epidemiology specifically directed to the field of studies of drug use, based on the data collected through review of medical records of 331 type 2 diabetic patients over 18 years in a primary health care in the city of Cartagena de Indias between 2013 and 2014. demographic, clinical and paraclinical variables, the therapeutic plan and prescription quality were studied. Data was analyzed using descriptive statistics. Results: 57 % (189) patients using glyburide. In 59.3% (153) inappropriately prescribed glibenclamide. 45.5% (86) of the patients had a contraindication to the use of the drug. In 1% of patients were prescribed the sample exceeding the therapeutic dose range Conclusions: The quality of prescribing glyburide was inadequate in a substantial proportion of patients, it is necessary to implement educational strategies that enable medical personnel to ensure proper use of antidiabetic drugs. Glyburide compared with other second-generation sulfonylureas gives us more disadvantages than advantages.

Serum concentrations and renal expressions of IL-1 and TNF-a early after hemorrhage in rats under the effect of glibenclamide

ABSTRACT PURPOSE: To investigate changes in the serum concentration and renal expression of IL-1 and TNF-α cytokines in rats that received sevoflurane and glibenclamide prior to hemorrhage. METHODS: Two groups of sevoflurane-anesthetized Wistar rats (n=10): G1 (control) and G2 (glibenclamide, 1 µg/g i.v.); hemorrhage of 30% blood volume (10% every 10 min), with replacement using Ringer solution, 5 ml/kg/h. Serum concentrations of IL-1 and TNF-α were studied in the first hemorrhage (T1) and 50 min later (T2), renal expression, at T2. RESULTS: In serum, G1 TNF-α (pg/mL) was T1=178.6±33.5, T2=509.2±118.8 (p<0.05); IL-1 (pg/mL) was T1=148.8±31.3, T2=322.6±115.4 (p<0.05); in G2, TNF-α was T1=486.2±83.6, T2=261.8±79.5 (p<0.05); IL-1 was T1=347.0±72.0, T2= 327.3±90.9 (p>0.05). The expression of TNF-α and IL-1 in the glomerular and tubular cells was significantly higher in the G2 group. CONCLUSIONS: Hemorrhage and glibenclamide elevated TNF-α and IL-1 concentrations in serum and kidneys. High levels of TNF-α already present before the hemorrhage in the glibenclamide group may have attenuated the damages found in the kidneys after the ischemia event.

Effects of metformin on expression of renal tissue AGEs in type 2 diabetic rats / 中国药理学通报

Aims To observe the influences of met-formin ( MET ) on the expression of renal tissue ad-vanced glyclation end-products( AGEs) protein and its receptor mRNA ( RAGE mRNA ) in type 2 diabetes mellitus (T2DM) model rats, and to discuss the mech-anism of the MET in the treatment of diabetic nephrop-athy ( DN ) . Methods The rat model of T2 DM was established by fed with high-fat diet and intraperitoneal injection of low-dose of streptozotocin ( STZ ) . All rats were randomly divided into metformin group( MET,300 mg·kg-1 ·d-1 ) , glyburide group( GLY,5 mg·kg-1 ·d-1),T2DM model group(T2DM) and normal con-trol group ( NC ) . After 8 weeks ’ observation, blood glucose ( BG ) , glycated hemoglobin ( HbA1 c ) , blood urea nitrogen(BUN), urinary albumin,urinary AGEs and urine creatinine were detected. The expression of renal tissue AGEs was detected by immunohistochemis-try assay, and the expression of RAGE mRNA was measured by real-time PCR. Results The levels of BG, HbA1c , urinary albumin/urine creatinine ( UACR ) , glomerular basement membrane thickness ( GBMT ) in MET group and GLY group were signifi-cantly lower than those of T2DM group, while higher than those of NC group(P0. 05 ) . The urinary AGEs/urine creatinine( UGCR) , the expressions of re-nal tissue AGEs and RAGE mRNA in MET group and GLY group were significantly decreased compared with those of T2 DM group ( P < 0. 05 ) , but higher than those of NC group ( P <0. 05 ) . The UGCR, the ex-pressions of AGEs and RAGE mRNA in MET group were lower than those of GLY group(P<0. 05). Con-clusion MET can reduce the accumulation of AGEs in the renal tissue,and down-regulate the over-expres-sion of RAGE mRNA in T2DM rats.

Effect of C-peptide Alone or in Combination with Nicotinamide on Insulin Levels from Pancreatic Islets in Mouse

Background: Both c-peptide and nicotinamide are known to increase blood insulin in diabetes. In the present study, we examined the effect of c-peptide alone or in combination with nicotinamide on insulin levels in pancreatic islets in mice. Methods: This study was conducted with 60 adult male Naval Medical Research Institute (NMARI) mice weighing 25 to 30 g. Pancreatic islets from normal mice were isolated by the collagenase digestion method. Mice were divided into ten groups of six (n = 6): control, glyburide (1 and 10 μM), C-peptide (50 and 100 nM), nicotinamide (10, 25, and 100 mM), nicotinamide + C-peptide (100 mM and 100 nM), and buffer in different glucose concentrations (2.8, 5.6, and 16.7 mM). Insulin secretion was measured using insulin radioimmunoassay method. Results: Insulin secretion significantly increased at 16.7 mM glucose concentration compared with 2.8 and 5.6 mM glucose concentrations. Incubation of islets at 2.8 and 5.6 mM glucose concentrations and nicotinamide + C-peptide, nicotinamide 25 and 100 mM, and C-peptide 100 nM significantly increased insulin secretion compared with the control group. In addition, incubation of islets at 16.7 mM glucose with nicotinamide + C-peptide significantly increased insulin secretion. Glyburide at 10 μM concentration was more effective than nicotinamide at 10 and 100 mM, C-peptide 50 and 100 nM in the presence of 16.7 mM glucose concentration. However, the combination of nicotinamide + C-peptide was more effective than glyburide at a concentration of 10 μM in the presence of a 16.7 mM glucose concentration. Conclusions: This paper suggests that c-peptide, nicotinamide, and the combination of c-peptide and nicotinamide in-creases insulin secretion from pancreatic islets.

Metformina y gliburida en el tratamiento de la diabetes gestacional / Metformin and glyburide in the treatment of gestational diabetes

INTRODUCCIÓN: La diabetes gestacional es una alteración de la tolerancia a la glucosa de severidad variable reconocida por primera vez en el embarazo en curso. La insulina ha sido el tratamiento farmacológico estándar para la diabetes gestacional, sin embargo la metformina y la gliburida son alternativas terapéuticas para el control de la glicemia. OBJETIVO: Determinar las ventajas de la metformina y la gliburida sobre la insulina en el tratamiento de la diabetes gestacional. MATERIALES Y MÉTODOS: Se realizó una búsqueda sistemática en las bases de datos Medline (PubMed) y Scielo. Los términos DeCS utilizados fueron: "Diabetes Gestacional", "Gliburida", y "Metformina" en diferentes combinaciones; sus homólogos MeSH fueron: "Diabetes, Gestational", "Glyburide" y "Metformin". La búsqueda obtenida incluyó 130 artículos, de los cuáles fueron seleccionados 53. RESULTADOS: La gliburida es un medicamento categoría C en el embarazo. Sus concentraciones en cordón umbilical son insignificantes y es considerado seguro. Su tasa de éxito para lograr el control de la glicemia c varía del 79% al 86%. La metformina es un medicamento categoría B en el embarazo. No ha mostrado efectos teratógenos en el primer trimestre del embarazo y logra un control de la glicemia en 24 horas. CONCLUSIONES: La metformina y la gliburida logran valores de control de glicemia en diabetes gestacional similares a la insulina y no aumentan la teratogénesis en el primer trimestre del embarazo. Las complicaciones perinatales por su uso deben ser más estudiadas

INTRODUCTION: Gestational diabetes is an impaired glucose tolerance of variable severity first recognized in the current pregnancy. Insulin has been the standard drug treatment for gestational diabetes, however metformin and glyburide are therapeutic alternatives to control glycemia. OBJECTIVE: Determine the advantages of metformin and glyburide over insulin in the treatment of gestational diabetes. MATERIALS AND METHODS: A systematic research was performed in the databases Medline (PubMed) and Scielo. The DeCS terms used were: "Diabetes Gestacional", "Gliburida", and "Metformina" in different combinations; MeSH counterparts were: "Diabetes, Gestational", "Glyburide" and "Metformin". The search obtained covered 130 articles, of which 53 were selected. RESULTS: Glyburide is a category C drug in pregnancy. Their concentrations in umbilical cord are insignificant and is considered safe. Its success rate to achieve glycemic control ranges from 79% to 86%. Metformin is a category B drug in pregnancy. It has shown no teratogenic effects in the first trimester of pregnancy. It achieves glycemic control in 24 hours. CONCLUSIONS: Metformin and glyburide achieved glycemic control values in gestational diabetes similar to insulin. They do not increase the teratogenesis in the first trimester of pregnancy. Perinatal complications from its use should be more studied

Interaction of mouse intestinal P-glycoprotein with oral antidiabetic drugs and its inhibitors.

Type 2 diabetes (T2DM) is a progressive insulin secretory defect accompanied by resistance to insulin, and thereby making glycemic control a major concern in the treatment of these patients. Oral drug administration, though a popular option for its non-invasiveness, suffer from poor bioavailability. It could be related to the efflux transport of intestinal P-glycoprotein (Pgp). In the present study, we explored the binding interactions of antidiabetic drugs i.e., sulfonylurea drugs (glimepiride, glipizide, glyburide) and rapid acting insulin secretagogues viz., nateglinide, repaglinide and rosiglitazone; and Pgp inhibitors i.e., Generation I (verapamil and tamoxifen), III (tetradrine and tariquidar), and natural inhibitors (fumagillin and piperine) in mouse Pgp model. Our results revealed that fumagillin piperine and verapamil possess maximum interaction energies with Pgp compared to antidiabetic drugs. These observations elucidate the role of fumagillin and piperine as potential natural compounds which could intervene in the efflux action of Pgp in extruding the antidiabetic drugs and may have implications for increasing efficacy of oral antidiabetic therapy.

Effect of glyburide on the proliferation, differentiation, and apoptosis of MC3T3-E1 osteoblasts under high glucose / 中华内分泌代谢杂志

After MC3T3-E1 cells were treated with 1,10,and 20 μmol/L glibenclamide for 48 h,the proliferation rate of cells was detected by CCK-8 assay.Flow cytometry was used to test cell apoptosis.The mRNA expressions of collagen I (COL-1) and osteopontin (OPN) were tested by realtime fluorescence quantitative PCR.Western blot was used to detect the expression levels of apoptosis-related proteins Bax and Bcl-2.The results showed that compared with the control group,the proliferation rate of MC3T3-E1 cells was gradually increased (P＜0.05),the apoptosis rate decreased (P ＜ 0.05),the expressions of COL-1 mRNA,OPN mRNA,and Bcl-2 protein were progressively raised (P＜0.05),and the expression of Bax protein were gradually decreased (P＜0.05) along with increasing concentration of glyburide.It suggested that glibenclamide could promote the proliferation and differentiation of MC3T3-E1 cells in high glucose and may inhibit apoptosis in a concentration-dependent manner within a certain range.

Glibenclamide for the prevention of cerebral edema and hemorrhagic transformation in ischemic stroke / 国际脑血管病杂志

Cerebral edema and hemorrhagic transformation(HT) are the common complications of ischemic stroke. Ischemic cerebral edema is the primary cause of death in patients w ith large infarction. The sulfonylurea receptor 1 (Sur1) transient receptor potential M4 (Trpm4) channel plays an important role in focal cerebral ischemia. Both animal experiment and clinical studies have show n that the Sur1 selective inhibitor glibenclamide provides neuroprotection for ischemic stroke, including infarct volume reduction and improvement of neurological function, especial y in attenuating cerebral edema and reducing the incidence of HT. This article review s the advances in research on glibenclamide for the prevention of cerebral edema and HT in patients w ith ischemic stroke.

Estudo das propriedades físico-químicas da glibenclamida e excipientes que influem sobre resultados do ensaio de dissolução para medicamento similar e genérico / Effect of the physicochemical properties of glyburide on the results of dissolution test for generic and similar drugs

Alguns insumos farmacêuticos ativos (IFA) possuem como característica, a possibilidade de apresentarem o polimorfismo, que pode se desenvolver em alguma das etapas do processo de produção na indústria. No caso deste não ser caracterizado e especificado, um diferente polimorfo poderá ser utilizado equivocadamente durante o processo de fabricação. A ocorrência de polimorfismo pode originar importantes variações nas propriedades físico-químicas dos IFAs, principalmente quanto à solubilidade. Alguns medicamentos de glibenclamida (GLIB) apresentaram denúncias de ineficácia terapêutica e a presença de polimorfos pode ser uma das possíveis causas. Neste trabalho foram analisados cinco medicamentos e cinco IFAS de diferentes fornecedores. Para os medicamentos foram feitos testes característicos de verificação de equivalência farmacêutica. Nos IFAS, as diversas técnicas empregadas não evidenciaram presença de polimorfos ou alterações importantes nas propriedades físico-químicas e na velocidade de dissolução intrínseca. Entretanto, os perfis de dissolução dos medicamentos, principalmente, entre os dois similares A e B demonstraram diferenças apontadas pelos valores do fator f2, respectivamente, de 20 e 42, os quais indicaram associação destes valores com a presença de distintos excipientes, como por exemplo o manitol e diferentes processos de produção industrial.

Some active pharmaceutical ingredients (API) might present polymorphism at any stage of the industryproduction process. In caseit is not characterized and specified, a different polymorph might beerroneously used during the manufacturing procedure. Polymorphisms cause some variations in thephysicochemical properties of APIs, especially in solubility. Therapeutic inefficacy was detected in someglyburide drug products, and the occurrence of polymorphs might be one of the possible reasons. Thisstudy analyzed five drug products and five APIs., The characteristic pharmaceutical equivalence testswere used for analyzing the drug products. The techniques employed to evaluate the APIs showed nodifferences in polymorphism, no significant changes in the physicochemical properties or in the intrinsicdissolution rate. However, the dissolution profiles of the drug products, mainly between two similarproducts A and B, showed significant differences in the f2 factor values, being 20 and 42, respectively,indicating that these values were related to the occurrence of different excipients, such as mannitol.

Hipoglicemiantes orales para el tratamiento de la diabetes mellitus gestacional: revisión sistemática de la literatura / Oral hypoglycaemic agents for the treatment of gestational diabetes mellitus: systematic review of the literature

Antecedentes: la diabetes mellitus gestacional (DMG) se asocia a mayor riesgo materno y perinatal. El manejo habitual de ésta patología es la dieta, el ejercicio y la insulina. Los hipoglicemiantes orales (HGO) son una terapia emergente para el tratamiento de la DMG. Objetivos: realizar una revisión sistemática de toda la evidencia tipo I disponible acerca del uso de HGO para tratamiento de DMG y realizar un metaanálisis de los resultados maternos y perinatales significativos. Resultados: diez estudios cumplieron criterios de selección. Tres estudios comparaban metformina vs insulina, cuatro gliburide vs insulina y tres metformina vs gliburide. Los estudios no encontraron diferencias significativas en control glicémico ni en complicaciones perinatales entre metformina vs insulina, gliburide vs insulina y metformina vs gliburide. Nuestro metaanálisis mostró que la glicemia de ayuno es significativamente menor (DM 1,74; IC95 por ciento 0,383,10) y la glicemia postprandial a las 2 horas es significativamente mayor en el grupo insulina vs HGO (DM -2,97; IC95 por ciento -27,24 a -5,36). Nuestro metaanálisis muestra que la incidencia de fetos grandes para edad gestacional fue significativamente menor en el grupo metformina vs gliburide (OR 0,38; IC95 por ciento 0,18-0,78). El fracaso del tratamiento con gliburide fue significativamente menor que con metformina (27,6 por ciento vs 38,5 por ciento, p<0,0001; IC95 por ciento 1,21-1,60). Conclusión: los HGO son un tratamiento seguro y efectivo para DMG. Recomendamos gliburide (glibenclamida) para el tratamiento de las pacientes con DMG que fracasan su control glicémico con dieta y ejercicio, por no cruzar la placenta, tener menor tasa de fallo y ser igualmente efectiva que metformina.

Background: gestational diabetes mellitus (GDM) is associated to a higher maternal and perinatal risk. Usually GDM is controlled with diet, exercise and insulin. Oral hypoglycaemic agents (OHA) are an emergent therapy for the treatment of GDM. Objectives: conduct a systematic review of all class I evidence available regarding the use of OHA for GDM treatment, and perform a metaanalysis of significant maternal and perinatal outcomes. Results: ten studies accomplished inclusion criteria. Three studies compared metformin to insulin, four compared glyburide to insulin and three compared metformin to glyburide. Studies showed no significant differences in glycaemic control or perinatal complications, between metformin and insulin, between glyburide and insulin, or between metformin and glyburide. Our metaanalysis comparing OHA to insulin shows significantly lower fasting blood glucose (MD 1.74; 95 percent IC 0.38-3.10) and larger 2-hr postprandial glucose in the insulin group compared to OHA groups (MD -2.97; 95 percent IC -27.24-5.36). Our metaanalysis comparing shows a significantly lower incidence of large for gestational age in the metformin vs. gliburide group (OR 0.38; 95 percent IC 0.18-0.78). Failure of treatment was significantly lower using gliburide than metformin (27.6 percent vs. 38.5 percent, p<0.0001; 95 percent IC 1.21-1.60). Conclusion: OHA are a safe and effective treatment for GDM. We recommend the use of glyburide (glibenclamide) in GDM patients that fail to obtain glycemic control with diet and exercise, since glyburide does not crosses the placental barrier, has a lower rate of treatment failure and is equally affective as metformin.

Low glibenclamide concentrations affect endoplasmic reticulum stress in INS-1 cells under glucotoxic or glucolipotoxic conditions

BACKGROUND/AIMS: beta-Cell apoptosis caused by increased endoplasmic reticulum (ER) stress is an important pathogenic component of type 2 diabetes mellitus. In theory, sulfonylureas, used for the treatment of diabetes, can contribute to ER stress. We assessed changes in ER stress in pancreatic beta-cells under glucotoxic or glucolipotoxic conditions using low concentrations of the sulfonylurea, glibenclamide (GB). METHODS: Low concentrations of GB (10 or 100 nM) were added to INS-1 cells cultured under glucotoxic or glucolipotoxic conditions. The degree of viability, level of apoptosis and levels of markers associated with ER stress were measured. RESULTS: Apoptosis decreased in response to low concentrations of GB under glucolipotoxic but not glucotoxic conditions. Most ER stress markers decreased upon the addition of GB. Under glucotoxic conditions, changes in the levels of ER stress markers were not consistent. However, all decreased significantly under glucolipotoxic conditions. CONCLUSIONS: Low concentrations of GB exerted antiapoptotic effects through the attenuation of ER stress under glucolipotoxic conditions.

Cuantificación de glibenclamida en muestras de limpieza de equipos farmacéuticos mediante cromatografía líquida de alta resolución / Quantification of glibenclamide in cleaning samples of pharmaceutical equipment through high performance liquid chromatography

Objetivo: proponer un procedimiento analítico selectivo para la cuantificación de glibenclamida en muestras de limpieza de equipos farmacéuticos mediante cromatografía líquida de alta resolución. Métodos: la fase móvil consistió en una mezcla equivalente de volúmenes de acetonitrilo y solución amortiguadora KH2PO4 de concentración 0,037 mol/L a pH 5,25 y flujo 1,5 mL/min, en una columna Nucleosil 100 C8. La glibenclamida se inyectó con progesterona como estándar interno y empleando detector UV a una l= 230 nm. Resultados: el método resultó lineal en el intervalo de concentraciones de 0,4-150 mg/mL, teniendo como límites de detección y cuantificación 10 y 40 ng/mL respectivamente y siendo específico al analito en presencia del placebo, sus productos de degradación y a otros ingredientes farmacéuticamente activos. Se consideraron potenciales de interferencias para el método propuesto: captopril, clortalidona, dexametasona, digoxina, 8-cloroteofilina, difenhidramina HCl, fenobarbital, haloperidol, hidroclorotiazida, ácido fumárico, ketotifeno, metoclopramida HCl, piridoxina HCl, piroxicam, prednisona y nifedipino. Se identificaron: ibuprofeno, indometacina, trifluoperazina HCl, tioridazina HCl e imipramina HCl, como interferentes del procedimiento en concentraciones cercanas a 10 mg/mL. Conclusiones: el método desarrollado es sensible, rápido y especialmente selectivo para la evaluación de residuales del principio activo glibenclamida en equipos de producción de tabletas, empleando un muestreo por hisopado, y pudiera utilizarse potencialmente cuando exista sospecha de contaminación cruzada de glibenclamida con otros fármacos de los aquí descritos.

Objective: to submit a selective analytical method for quantization of glibenclamide in cleaning samples of pharmaceutical equipment using high performance liquid chromatography. Methods: the mobile phase consisted of an equal mixing of acetonitrile/phosphate buffer KH2PO4; with 0.037 mol/L concentration pH 5.25 and flow of 1.5 mL/min, in a Nucleosil 100 C8 column. Glibenclamide was injected with progesterone as internal standard and using an UV detector= 230 nm Results: the method was linear in the 0.4-150 mg/mL concentration interval having a detection and quantization limits of 10 and 40 ng/mL respectively. It was specific to analyte when placebo is present, to degradation products and to other active ingredients. Possible interferences with the proposed method was considered for captopril, chlortalidone, dexametasone, diphenhydramin HCl, digoxine, 8-chlortheophylline, diphenhydramina HCl, phenobarbital, haloperidol, hydrochlorothiazide, fumaric acid, ketotifen, metoclopramide HCl, piridoxine HCl, piroxicam, prednisone and nifedipine, On the other hand, ibuprofen, indometacin, trifluoperazine HCl, thioridazine HCl and imipramine were identified as interferences in the procedure at concentration figures close to 10 mg/mL. Conclusions: the present method is sensitive, quick and selective for the evaluation of residues of active pharmaceutical principle glibenclamide in tablet production equipment after a swap sampling and it could be potentially used in case of cross-contamination of glibenclamide and other drugs already described.

Retrospective Cohort Study Comparing Neonatal Outcomes of Women Treated with Glyburide or Insulin in Gestational Diabetes: A 5-Year Experience in a South Indian Teaching Hospital.

Objective: To assess the effectiveness of glyburide in preventing complications of gestational diabetes in neonates as compared to insulin. Materials and Methods: Information from birth register, maternal and neonatal records were obtained. Five hundred and seventy-seven gestational diabetics with moderate hyperglycemia i.e., with highest fasting plasma glucose value of ≤130 mg/dl and/or highest post-prandial value of ≤250 mg/dl treated with insulin or glyburide were included from a cohort of 769 women needing additional therapy to initial diet therapy during a 5-year period. Thus neonatal outcomes of 303 women treated with insulin and 274 women treated with glyburide were compared. Results: Baseline plasma glucose levels in the group treated with insulin were higher. The mean birth weight (SD) of the neonates in women treated with insulin was 3021.3 g (604.19) as compared to 3104.6 g (499.35, P = 0.07) in the group treated with glyburide. Neonatal outcomes such as hypoglycemia (4.9%, 3.6%, P = 0.44), hypocalcemia (1.3%, 0.7%, P = 0.48), polycythemia (1.7%, 0.7%, P = 0.31), macrosomia (11.6%, 8.7%, P = 0.26), congenital anomalies (2.1%, 2.3%, P = 0.87), birth trauma (1.4%, 1.2%, P = 0.79) were similar in both groups. Neonates of women treated with insulin were more likely to have hyperbilirubinemia (11.5%, 6.5%, P = 0.03). Conclusion: Neonatal outcomes of women treated with glyburide were comparable to those in women treated with insulin. More number of neonates of mothers treated with insulin had hyperbilirubinemia compared to neonates of mothers treated with glyburide (11.5%, 6.5% P = 0.03).

Genetic analysis of neonatal diabetes mellitus and its influence on treatment outcome / 中华内分泌代谢杂志

Fourteen neonatal diabetes mellitus(NDM)patients were recruited. 9 patients were treated with glyburide and the other 5 with insulin. ABCC8, KCNJ11, and INS genes were sequenced in 6 of them. Gene mutations were found in 2, 1, and 1 cases in these genes, respectively. One case with 6q24 hypomethylation and another without known mutation were also found. 8 out of 9 patients treated with glyburide reached euglycemia(88.9%). The other 5 patients with insulin therapy either died or lost contact. The results suggest that glyburide therapy is effective in neonatal diabetes mellitus, while insulin therapy may contribute to poor compliance.

The Effects of Glyburide on Apoptosis and Endoplasmic Reticulum Stress in INS-1 Cells in a Glucolipotoxic Condition

BACKGROUND: beta-cell death due to endoplasmic reticulum (ER) stress has been regarded as an important pathogenic component of type 2 diabetes. The possibility has been suggested that sulfonylurea, currently being used as one of the main oral hypoglycemic agents of type 2 diabetes, increases ER stress, which could lead to sulfonylurea failure. The authors of the present study examined ER stress of beta-cells in a glucolipotoxic condition using glyburide (GB) in an environment mimicking type 2 diabetes. METHODS: Apoptosis was induced by adding various concentrations of GB (0.001 to 200 microM) to a glucolipotoxic condition using 33 mM glucose, and the effects of varied concentrations of palmitate were evaluated via annexin V staining. The markers of ER stress and pro-apoptotic markers were assessed by Western blotting and semi-quantitative reverse transcription-polymerase chain reaction. Additionally, the anti-apoptotic markers were evaluated. RESULTS: Addition of any concentration of GB in 150 microM palmitate and 33 mM glucose did not increase apoptosis. The expression of phosphorylated eukaryotic initiation factor (eIF-2alpha) was increased and cleaved caspase 3 was decreased by adding GB to a glucolipotoxic condition. However, other ER stress-associated markers such as Bip-1, X-box binding protein-1, ATF-4 and C/EBP-homologous protein transcription factor and anti-apoptotic markers phosphor-p85 phosphatidylinositol 3-kinase and phosphorylation of Akt did not change significantly. CONCLUSION: GB did not show further deleterious effects on the degree of apoptosis or ER stress of INS-1 cells in a glucolipotoxic condition. Increased phosphorylation of eIF-2alpha may attenuate ER stress for adaptation to increased ER protein load.

Hipoglicemiantes orais no tratamento de diabetes gestacional: análise metodológica da literatura / Oral hypoglycemic agents in the treatment of gestational diabetes: methodological analysis of literature

Realizar uma revisão crítica da literatura disponívelsobre o uso de hipoglicemiantes orais para o tratamento daDiabetes Melito Gestacional (DMG). Material e Métodos:Realizou-se a pesquisa bibliográfica pela consulta dodescritor “Diabetes Gestacional AND Tratamento”, duranteo primeiro semestre de 2010 (meses janeiro a junho 2010),nas bases eletrônicas de informação em saúde: Scielo(www.scielo.org) e PubMed (www.ncbi.nlm.nih.gov/pubmed). Foram selecionados ensaios clínicos controlados,publicados nos últimos 10 anos, publicados em qualqueridioma, sobre o uso de hipoglicemiantes orais e/ou insulinano tratamento da DMG. Os dados coletados foram: tamanhoda amostra; hipoglicemiante utilizado; país de realização dapesquisa; prováveis riscos; vantagens e desvantagens douso de hipoglicemiantes orais. Buscou-se reunir informaçõessobre a segurança, riscos e opções do tratamento de DMGcom hipoglicemiantes orais. Os dados foram analisadosdescritivamente. Resultados: Foram incluídos 23 estudos,dos quais 16 comprovaram eficácia e segurança no uso dehipoglicemiantes orais, semelhante à insulina. Os riscosprováveis são controversos e os principais medicamentosindicados são gliburida e metformina. Conclusão: Os hipoglicemiantesorais têm potencial para substituir a terapia cominsulina no tratamento da diabetes gestacional. Entre osmedicamentos disponíveis, destaca-se a gliburida e ametformina como melhores opções de tratamento...

To conduct a critical review of available literatureon the use of oral hypoglycemic agents for the treatment ofGestational Diabetes Mellitus (GDM). Material and Methods:The literature search by consulting the descriptor “GestationalDiabetes AND Treatment”, was conducted during the firsthalf of 2010 (months from January to June, 2010), on theelectronic databases of information in health: Scielo(www.scielo.org) and PubMed (www.ncbi.nlm.nih.gov/pubmed). Were selected Controlled Clinical Trials on the oralhypoglycemic agents and/or insulin treatment of GDM,published over the past ten years in any language. Datacollected were: sample size, hypoglycemic agent; countryof the study, probable risks, advantages and disadvantagesof oral hypoglycemic agents. Information about safety, risksand treatment options of GDM with oral hypoglycemic agentswere also collected. Data were analyzed descriptively.Results: The available literature included 23 studies, fromwhich 16 works have proved efficacy and safety in the useof oral hypoglycemic agents, similar to insulin. The probablerisks are controversial and the main given drugs are glyburideand metformin. Conclusion: The oral hypoglycemic agentshave potential to replace the insulin therapy in the treatmentof Gestational Diabetes. Among the availabledrugs, glyburide and metformin are highlighted as the besttreatment options...