Uso de la técnica de perifusión de células hepáticas de rata en la investigación de las acciones metabólicas y mitocondriales directas de dos tiazolindionas, pioglitazona y rosiglitazona

[ES] La Pioglitazona (PIO) y Rosiglitazona( ROSI) son antidiabéticos orales de la clase tiazolidinadiona que ejercen sus acciones antidiabéticas hipoglucemiantes, a medio y largo plazo, de forma indirecta por activación selectiva de los receptores PPARg que son muy abundantes en el tejido adiposo pero no tanto en el hígado y en el músculo. Se sabe que las TZDs son capaces de actuar sobre el hígado donde dichos receptores son bastante escasos por lo que se plantea la posibilidad de que las TZDs puedan ejercer efectos DIRECTOS no mediados por dichos receptores sobre el metabolismo hepático y su función mitocondrial. Nosotros demostramos que en hepatocitos de rata perifundidos con dihidroxiacetona, fructosa, glicerol y lactato más piruvato como sustratos, pioglitazona y rosiglitazona ejercen acciones antidiabéticas directas e independientes de la activación de los receptores PPARg, inhibiendo la gluconeogénesis y activando la glucólisis. En las mismas condiciones experimentales, PIO y ROSI antagonizan los efectos pro-diabéticos del glucagón disminuyendo la activación de la hidrólisis de la glucosa 6-fosfato. Todos los efectos inhibidores de PIO y ROSI sobre la gluconeogénesis y su activación estimulada por el glucagón, son mediados por una acción inhibidora directa sobre la enzima gluconeogénica más importante: la glucosa 6-fosfatasa. En hepatocitos de rata perifundidos con dihidroxiacetona, PIO y ROSI activan la degradación de la glucosa liberada desde el glucógeno por glucógenolisis hasta la formación de lactato más piruvato. Todos los efectos activadores de pioglitazona y rosiglitazona sobre la glucólisis y sobre la degradación de la glucosa liberada en la glucógenolisis, son mediados por una acción directa sobre la enzima glucolítica más importante: piruvato quinasa. Además, en hepatocitos intactos y mitocondrias aisladas, pioglitazona y rosiglitazona inhiben la respiración de forma dosis-dependiente al actuar sobre los complejos I y III de la cadena respiratoria. Las dos glitazonas muestran efectos antioxidantes muy claros en mitocondrias aisladas de hígado, inhibiendo la producción de especias reactivas de oxígeno a nivel mitocondrial.[EN] The Pioglitazone (PIO) and rosiglitazone (ROSI) are oral antidiabetic thiazolidinedione class that exert their hypoglycemic antidiabetic actions in the medium and long term, indirectly by selective activation of PPAR receptors which are abundant in adipose tissue but not both liver and muscle. It is known that TZDs are able to act on the liver, where these receptors are very rare so it raises the possibility that TZDs may exert direct effects not mediated by these receptors on liver metabolism and mitochondrial function. We showed that in rat hepatocytes perifundidos with dihydroxyacetone, fructose, glycerol and lactate over pyruvate as substrates, pioglitazone and rosiglitazone exert direct anti-diabetic actions independent of PPAR receptor activation by inhibiting gluconeogenesis and activating glycolysis. In the same experimental conditions, PIO and ROSI antagonize the pro-diabetic effects of glucagon decreased activation of the hydrolysis of glucose 6-phosphate. All the inhibitory effects of PIO and ROSI on gluconeogenesis and glucagon-stimulated activation are mediated by a direct inhibitory action on the most important gluconeogenic enzyme, glucose 6-phosphatase. Perifundidos rat hepatocytes with dihydroxyacetone, PIO and ROSI activate the degradation of glucose released from glycogen by glycogenolysis to the formation of lactate pyruvate. All activating effects of pioglitazone and rosiglitazone on glycolysis and the degradation of glucose released in glycogenolysis are mediated by a direct action on the most important glycolytic enzyme, pyruvate kinase. Furthermore, in intact hepatocytes and isolated mitochondria, pioglitazone and rosiglitazone inhibit breathing dose-dependent manner by acting on complex I and III of the respiratory chain. The two glitazones show very clear antioxidant effects in isolated mitochondria of liver, inhibiting the production of reactive oxygen species in mitochondria

Effectiveness of an intervention for improving drug prescription in primary care patients with multimorbidity and polypharmacy:Study protocol of a cluster randomized clinical trial (Multi-PAP project)

This study was funded by the Fondo de Investigaciones Sanitarias ISCIII (Grant Numbers PI15/00276, PI15/00572, PI15/00996), REDISSEC (Project Numbers RD12/0001/0012, RD16/0001/0005), and the European Regional Development Fund ("A way to build Europe").Background: Multimorbidity is associated with negative effects both on people's health and on healthcare systems. A key problem linked to multimorbidity is polypharmacy, which in turn is associated with increased risk of partly preventable adverse effects, including mortality. The Ariadne principles describe a model of care based on a thorough assessment of diseases, treatments (and potential interactions), clinical status, context and preferences of patients with multimorbidity, with the aim of prioritizing and sharing realistic treatment goals that guide an individualized management. The aim of this study is to evaluate the effectiveness of a complex intervention that implements the Ariadne principles in a population of young-old patients with multimorbidity and polypharmacy. The intervention seeks to improve the appropriateness of prescribing in primary care (PC), as measured by the medication appropriateness index (MAI) score at 6 and 12months, as compared with usual care. Methods/Design: Design:pragmatic cluster randomized clinical trial. Unit of randomization: family physician (FP). Unit of analysis: patient. Scope: PC health centres in three autonomous communities: Aragon, Madrid, and Andalusia (Spain). Population: patients aged 65-74years with multimorbidity (≥3 chronic diseases) and polypharmacy (≥5 drugs prescribed in ≥3months). Sample size: n=400 (200 per study arm). Intervention: complex intervention based on the implementation of the Ariadne principles with two components: (1) FP training and (2) FP-patient interview. Outcomes: MAI score, health services use, quality of life (Euroqol 5D-5L), pharmacotherapy and adherence to treatment (Morisky-Green, Haynes-Sackett), and clinical and socio-demographic variables. Statistical analysis: primary outcome is the difference in MAI score between T0 and T1 and corresponding 95% confidence interval. Adjustment for confounding factors will be performed by multilevel analysis. All analyses will be carried out in accordance with the intention-to-treat principle. Discussion: It is essential to provide evidence concerning interventions on PC patients with polypharmacy and multimorbidity, conducted in the context of routine clinical practice, and involving young-old patients with significant potential for preventing negative health outcomes. Trial registration: Clinicaltrials.gov, NCT02866799Publisher PDFPeer reviewe