Gliclazide may have an antiapoptotic effect related to its antioxidant properties in human normal and cancer cells

Experimental and clinical studies suggest that gliclazide may protect pancreatic β-cells from apoptosis induced by an oxidative stress. However, the precise mechanism(s) of this action are not fully understood and requires further clarification. Therefore, using human normal and cancer cells we examined whether the anti-apoptotic effects of this sulfonylurea is due to its free radical scavenger properties. Hydrogen peroxide (H2O2) as a model trigger of oxidative stress was used to induce cell death. Our experiments were performed on human normal cell line (human umbilical vein endothelial cell line, HUVEC-c) and human cancer cell lines (human mammary gland cell line, Hs578T; human pancreatic duct epithelioid carcinoma cell line, PANC-1). To assess the effect of gliclazide the cells were pre-treated with the drug. The 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay was employed to measure the impact of gliclazide on cell viability. Generation of reactive oxygen species, mitochondrial membrane potential (∆Ψm), and intracellular Ca2+ concentration [Ca2+] were monitored. Furthermore, the morphological changes associated with apoptosis were determined using double staining with Hoechst 33258-propidium iodide (PI). Gliclazide protects the tested cells from H2O2-induced cell death most likely throughout the inhibition of ROS production. Moreover, the drug restored loss of ΔΨm and diminished intracellular [Ca2+] evoked by H2O2. Double staining with Hoechst 33258-PI revealed that pre-treatment with gliclazide diminished the number of apoptotic cells. Our findings indicate that gliclazide may protect both normal and cancer human cells against apoptosis induced by H2O2. It appears that the anti-apoptotic effect of the drug is most likely associated with reduction of oxidative stress

Disgregation time of spheroids (modified drop pills) using different vehicles and solid supports

En el presente trabajo se evalúan los tiempos de disgregación de los esferoides seleccionados entre los obtenidos a partir de seis excipientes y doce polvos receptores diferentes, de acuerdo a las características morfológicas. También se analiza el comportamiento reológico de dos excipientes hidrosolubles utilizados (polietilenglicol 4.000 y 6.000). De la comparación de los resultados surge que los tiempos de disgregación se mantienen menores a los 5 minutos en el caso de los excipientes hidrosolubles ensayados, constituyendo una excepción los obtenidos con cubierta del derivado acrílico (Eudragit L-100). Estos resultados parecen apoyar la utilidad de esta nueva forma farmacéutica (esferoides) cuando se deseen vehiculizar principios muy activos con los excipientes y cubiertas adecuados para modular la velocidad de disolución.In this work disgregation rates of "spheroids" made with six vehicles and twelve receiver powders are evaluated, according to the morphological characteristics. The rheological behavior of two water-soluble vehicles (polyethilene glycol 4000 and 6000) is also analyzed. Results show that watersoluble vehicles provides disgregation time lower than five minutes, except those spheroids made with acrylic (Eudragit L-100) cover. Spheroids could be a really useful pharmaceutical form when very active principles need to be vehiculized, as dissolution rate can be adequately modulated by selecting appropriate vehicles and covers.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Spheroids: effect of the fixation of the solid bed on the erosion time

Se verificó la cantidad de lecho sólido pulverizado que se fija a la gota de polímero que cae sobre el mismo y de qué manera ese polvo adherido influye en el tiempo de erosión de los esferoides formados. Los resultados permiten observar notorias diferencias respecto a la cantidad de polvo fijado, estudiando el comportamiento de once sustancias. Asimismo, los tiempos de erosión de los esferoides son distintos, aunque no guardan relación con la cantidad de polvo usado.The amount of powdered solid bed futed to the drop of a polymer that falls on it was determined, so as the influence than the mode of adherence exerts on the erosion time of the spheroids. The amount of powder adhered to the spheroid is not constant (eleven substances were tested) and the erosion time of different spheroids also varies, but seemingly there is no relation between both facts.Se verificó la cantidad & lecho sólido pulverizado que se fija a la gota de polímero que cae sobre el mismo y de qué manera ese polvo adherido influye en el tiempo de erosión de los esferoides formados. Los resultados permiten observar notorias diferencias respecto a la cantidad de polvo fijado, estudiando el comportamiento de once sustancias. Asimismo, los tiempos de erosión de los esferoides son distintos, aunque no guardan relación con la cantidad de polvo usado.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Disgregation time of spheroids (modified drop pills) using different vehicles and solid supports

En el presente trabajo se evalúan los tiempos de disgregación de los esferoides seleccionados entre los obtenidos a partir de seis excipientes y doce polvos receptores diferentes, de acuerdo a las características morfológicas. También se analiza el comportamiento reológico de dos excipientes hidrosolubles utilizados (polietilenglicol 4.000 y 6.000). De la comparación de los resultados surge que los tiempos de disgregación se mantienen menores a los 5 minutos en el caso de los excipientes hidrosolubles ensayados, constituyendo una excepción los obtenidos con cubierta del derivado acrílico (Eudragit L-100). Estos resultados parecen apoyar la utilidad de esta nueva forma farmacéutica (esferoides) cuando se deseen vehiculizar principios muy activos con los excipientes y cubiertas adecuados para modular la velocidad de disolución.In this work disgregation rates of "spheroids" made with six vehicles and twelve receiver powders are evaluated, according to the morphological characteristics. The rheological behavior of two water-soluble vehicles (polyethilene glycol 4000 and 6000) is also analyzed. Results show that watersoluble vehicles provides disgregation time lower than five minutes, except those spheroids made with acrylic (Eudragit L-100) cover. Spheroids could be a really useful pharmaceutical form when very active principles need to be vehiculized, as dissolution rate can be adequately modulated by selecting appropriate vehicles and covers.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Short-term hyperglycaemia causes non-reversible changes in arterial gene expression in a fully 'switchable' in vivo mouse model of diabetes

Aims/hypothesis Irreversible arterial damage due to early effects of hypo- or hyperglycaemia could account for the limited success of glucose-lowering treatments in preventing cardiovascular disease (CVD) events. We hypothesised that even brief hypo- or hyperglycaemia could adversely affect arterial gene expression and that these changes, moreover, might not be fully reversible. Methods By controlled activation of a 'switchable' c-Myc transgene in beta cells, adult pIns-c-MycER(TAM) mice were rendered transiently hypo- and then hyperglycaemic, after which they were allowed to recover for up to 3 months. Immediate and sequential changes in aortic global gene expression from normal glycaemia through hypo- and hyperglycaemia to recovery were assessed. Results Gene expression was compared with that of normoglycaemic transgenic and tamoxifen-treated wild-type controls. Overall, expression of 95 genes was significantly affected by moderate hypoglycaemia (glucose down to 2.5 mmol/l), whereas over 769 genes were affected by hyperglycaemia. Genes and pathways activated included several involved in atherogenic processes, such as inflammation and arterial calcification. Although expression of many genes recovered to initial pre-exposure levels when hyperglycaemia was corrected (74.9%), in one in four genes this did not occur. Quantitative reverse transcriptase PCR and immunohistochemistry verified the gene expression patterns of key molecules, as shown by global gene arrays. Conclusions/interpretation Short-term exposure to hyperglycaemia can cause deleterious and persistent changes in arterial gene expression in vivo. Brief hypoglycaemia also adversely affects gene expression, although less substantially. Together, these results suggest that early correction of hyperglycaemia and avoidance of hypoglycaemia may both be necessary to avoid excess CVD risk in diabetes