Seguridad e interacciones de los Inhibidores de la Bomba de Protones (IBP)

Los IBP han demostrado ser fármacos relativamente seguros después de muchos años de una amplia utilización. Las reacciones adversas con las que más frecuentemente se han asociado son leves y con escasa repercusión clínica. Inducen hipergastrinemia pero esta no se ha relacionado con una capacidad para inducir lesiones malignas Parece que pueden facilitar determinadas infecciones bacterianas a nivel digestivo y del aparato respiratorio, aunque este hecho no limita su prescripción dada la facilidad de su tratamiento. Desde el punto de vista farmacocinético se han descrito la posibilidad de interacciones con otros fármacos a nivel del citocromo P450, pero ello no parece tener mayor trascendencia clínica y terapéutica en general. Sin embargo, recientemente se está incidiendo por las agencias reguladoras en la hipotética interacción de los IBP (sobre todo omeprazol) con el clopidogrel generando una reducción en su efecto antiagregante. Aunque se debe seguir esta recomendación, necesitaria ser evaluado de forma específica para poder determinar su realidad clínica y las posibles alternativas existentes en los pacientes con riesgo de sangrado gastrointestinal. En último lugar se revisa su administración en situaciones especiales, objeto de discusión, como en la mujer embarazada o durante la lactancia materna

New perspectives in the pharmacological treatment of Hepatitis C

Introduction: The infection by the Hepatitis C virus (HCV) is one of the most common causes of liver's disease worldwide. Approximately between 60-80% of infected people, infection becomes chronic, and can lead in the long-term to the development of other liver's diseases such as cirrhosis and the hepatocellular carcinoma. Treatment of HCV has progressed enormously in the last decade, concluding with the development of Direct-acting Antiviral Agents (DAA), which has achieved cure rates over 90%. Objective: To know the different available treatments options as well as which will be available in a near future. Materials and methods: Several systematic searches were made in the PubMed database; in the articles from the "liver meeting" congress of AASLD (American Association for the Study of Liver Diseases) in November 2014 and in the EASL (European Association for the Study of Liver) guide. Development: The arrivals of new drugs with new therapeutic strategies have made this therapy more complex, and for that reason it is necessary to have knowledge of these drugs and their possible combinations. Conclusions: The excellent results of the therapy with AAD have made a huge change in therapeutic recommendations, making possible shorter therapies, better tolerated by patients and safer for health.Keywords: Hepatitis C virus, genotypes, direct acting antivirals, pharmacotherapy, mechanism of action, sofosbuvir, sustained virological response.</p

Coinfección virus de inmunodeficiencia humana-virus de la Hepatitis C: hacia un nuevo escenario terapéutico

Introducción: Las terapias contra el virus de la Hepatitis C han evolucionado vertiginosamente con el desarrollo de los antivirales de acción directa (AADs). Los nuevos regímenes han conseguido igualar las tasas de respuesta al tratamiento en los monoinfectados y los coinfectados con VIH, una población tradicionalmente difícil de tratar debido a la elevada morbimortalidad hepática y sistémica, reacciones adversas e interacciones medicamentosas. Objetivo: Analizar las opciones farmacoterapéuticas más modernas disponibles para los pacientes coinfectados con VIH y VHC, con énfasis en los nuevos antivirales de acción directa, a fin de ofrecer una herramienta útil en el abordaje terapéutico en estos pacientes. Material y métodos: Se revisaron artículos originales, ensayos clínicos y revisiones sistemáticas hasta septiembre de 2016, bases de datos internacionales de interacciones medicamentosas y Guías de Práctica Clínica actualizadas. Desarrollo: Las terapias contra el virus de la Hepatitis C (VHC) han evolucionado vertiginosamente con el desarrollo de los antivirales de acción directa (AADs). Los nuevos regímenes han conseguido igualar las tasas de respuesta al tratamiento en los monoinfectados y los coinfectados con VIH, una población tradicionalmente difícil de tratar que, además, asociaba una elevada morbimortalidad hepática y sistémica, más reacciones adversas y complejas interacciones medicamentosas. Conclusiones: En este nuevo escenario es fundamental dedicar esfuerzos a identificar el elevado porcentaje de infectados no diagnosticados, potenciales interacciones, especialmente con fármacos para patologías asociadas al envejecimiento de los pacientes, reacciones adversas a medio-largo plazos y desarrollo de resistencias, además de garantizar la cobertura universal en todos los contextos clínicos.Palabras claves: Coinfección VIH/VHC, Tratamiento VIH/VHC, Hepatitis C, VIH, Antivirales de acción directa, AAD.</p

Regulation of Oxygen Distribution in Tissues by Endothelial Nitric Oxide

Nitric oxide (NO) decreases cellular oxygen (O2) consumption by competitively inhibiting cytochrome c oxidase. Here, we show that endogenously released endothelial NO, either basal or stimulated, can modulate O2 consumption both throughout the thickness of conductance vessels and in the microcirculation. Furthermore, we have shown that such modulation regulates O2 distribution to the surrounding tissues. We have demonstrated these effects by measuring O2 consumption in blood vessels in a hypoxic chamber and O2 distribution in the microcirculation using the fluorescent oxygen-probe Ru(phen)3^2+. Removal of NO by physical or pharmacological means, or in eNOS^¯/¯ mice, abolishes this regulatory mechanism. Our results indicate that, in addition to its well-known effect on the regulation of vascular tone, endothelial NO plays a major role in facilitating the distribution of O2, an action which is crucial for the adaptation of tissues, including the vessel wall itself, to hypoxia. It is possible that changes in the distribution of O2 throughout the vessel wall may be implicated in the origin of vascular pathologies such as atherosclerosis.Victor Gonzalez, Victor Manuel, [email protected] ; d'Ocon Navaza, Maria Pilar, [email protected] ; Esplugues Mota, Juan Vicente, [email protected]

Discrepancies Between Nitroglycerin and NO-Releasing Drugs on Mitochondrial Oxygen Consumption, Vasoactivity, and the Release of NO

It has been generally acknowledged that the actions of glyceryl trinitrate (GTN) are a result of its bioconversion into NO. However, recent observations have thrown this idea into doubt, with many studies demonstrating that NO is present only when there are high concentrations of GTN. We have explored this discrepancy by developing a new approach that uses confocal microscopy to directly detect NO. Intracellular levels of NO in the rat aortic vascular wall have been compared with those present after incubation with 3 different NO donors (DETA-NO, 3 morpholinosydnonimine, and S-nitroso-N-acetylpenicillamine), endothelial activation with acetylcholine, or administration of GTN. We have also evaluated the relaxant effects of these treatments on isolated rings of aorta following activation of the enzyme soluble guanylyl cyclase and their inhibitory action on mitochondrial respiration, which is an index of the interaction of NO with the enzyme of the electron transport chain cytochrome C oxidase. In the case of the various NO donors and acetylcholine, we detected a concentration-dependent relationship in the intensity of vascular relaxation and degree of NO fluorescence and an increase in the Michaelis constant (Km) for O2. GTN did not produce similar effects, and although clinically relevant concentrations of this compound caused clear, concentration-related relaxations, there was neither any increase in NO-related fluorescence nor an augmented Km for O2. The nature of these differences suggests that these concentrations of GTN do not release free NO but probably a different species that, although it interacts with soluble guanylyl cyclase in vascular smooth muscle, does not inhibit O2 consumption by vascular mitochondria.Victor Gonzalez, Victor Manuel, [email protected] ; Esplugues Mota, Juan Vicente, [email protected] ; d'Ocon Navaza, Maria Pilar, [email protected]

Induction of CD36 and Thrombospondin-1 in Macrophages by Hypoxia-Inducible Factor 1 and Its Relevance in the Inflammatory Process

Inflammation is part of a complex biological response of vascular tissue to pathogens or damaged cells. First inflammatory cells attempt to remove the injurious stimuli and this is followed by a healing process mediated principally by phagocytosis of senescent cells. Hypoxia and p38-MAPK are associated with inflammation, and hypoxia inducible factor 1 (HIF-1) has been detected in inflamed tissues. We aimed to analyse the role of p38-MAPK and HIF-1 in the transcriptional regulation of CD36, a class B scavenger receptor, and its ligand thrombospondin (TSP-1) in macrophages and to evaluate the involvement of this pathway in phagocytosis of apoptotic neutrophils. We have also assessed HIF-1α, p38-MAPK and CD36 immunostaining in the mucosa of patients with inflammatory bowel disease. Results show that hypoxia increases neutrophil phagocytosis by macrophages and induces the expression of CD36 and TSP-1. Addition of a p38-MAPK inhibitor significantly reduced the increase in CD36 and TSP-1 expression provoked by hypoxia and decreased HIF-1α stabilization in macrophages. Transient transfection of macrophages with a miHIF-1α-targeting vector blocked the increase in mRNA expression of CD36 and TSP-1 during hypoxia and reduced phagocytosis, thus highlighting a role for the transcriptional activity of HIF-1. CD36 and TSP-1 were necessary for the phagocytosis of neutrophils induced by hypoxic macrophages, since functional blockade of these proteins undermined this process. Immunohistochemical studies revealed CD36, HIF-1α and p38-MAPK expression in the mucosa of patients with inflammatory bowel disease. A positive and significant correlation between HIF-1α and CD36 expression and CD36 and p38-MAPK expression was observed in cells of the lamina propria of the damaged mucosa. Our results demonstrate a HIF-1-dependent up-regulation of CD36 and TSP-1 that mediates the increased phagocytosis of neutrophils by macrophages during hypoxia. Moreover, they suggest that CD36 expression in the damaged mucosa of patients with inflammatory bowel disease depends on p38-MAPK and HIF-1 activity

Angiotensin II Induces Leukocyte–Endothelial Cell Interactions In Vivo Via AT1 and AT2 Receptor–Mediated P-Selectin Upregulation

Background—Angiotensin II (Ang II) plays a critical role in the development of vascular lesions in hypertension, atherosclerosis, and several renal diseases. Because Ang II may contribute to the leukocyte recruitment associated with these pathological states, the aim of the present study was to assess the role of Ang II in leukocyte–endothelial cell interactions in vivo. Methods and Results—Intravital microscopy of the rat mesenteric postcapillary venules was used. Sixty minutes of superfusion with 1 nmol/L Ang II induced a significant increase in leukocyte rolling flux (83.8±20.7 versus 16.4±3.1 cells/min), adhesion (11.4±1.0 versus 0.8±0.5 cells/100 µm), and emigration (4.0±0.7 versus 0.2±0.2 cells/field) without any vasoconstrictor activity. These effects were not mediated by mast cell activation. Intravenous pretreatment with AT1 (losartan) or AT2 (PD123,319) receptor antagonists significantly reduced Ang II–induced responses. A combination of both receptor antagonists inhibited the leukocyte rolling flux, adhesion, and extravasation elicited by Ang II at 60 minutes. Pretreatment of animals with fucoidin or an adhesion-blocking anti–rat P-selectin monoclonal antibody abolished Ang II–induced leukocyte responses. Furthermore, rat platelet P-selectin expression was not affected by Ang II stimulation. Conclusions—Ang II induces significant leukocyte rolling, adhesion, and emigration, which may contribute not only to hypertension but also to the onset and progression of the vascular damage associated with disease states in which plasma levels of this peptide are elevated.Piqueras Ruiz, Laura, [email protected] ; Alvarez Ribelles, Angeles, [email protected] ; Esplugues Mota, Juan Vicente, [email protected] ; Sanz Ferrando, Maria Jesus, [email protected]

M1 Macrophages Activate Notch Signalling in Epithelial Cells: Relevance in Crohn's Disease

Background: The Notch signalling pathway plays an essential role in mucosal regeneration, which constitutes a key goal of Crohn's disease (CD) treatment. Macrophages coordinate tissue repair and several phenotypes have been reported which differ in the expression of surface proteins, cytokines and hypoxia-inducible factors (HIFs). We analysed the role of HIFs in the expression of Notch ligands in macrophages and the relevance of this pathway in mucosal regeneration. Methods: Human monocytes and U937-derived macrophages were polarized towards the M1 and M2 phenotypes and the expression levels of HIF-1α, HIF-2α, Jagged 1 (Jag1) and delta-like 4 (Dll4) were evaluated. The effects of macrophages on the expression of hairy and enhancer of split-1 (HES1, the main target of Notch signalling) and intestinal alkaline phosphatase (IAP, enterocyte marker) in epithelial cells in co-culture were also analysed. Phenotype macrophage markers and Notch signalling were evaluated in the mucosa of CD patients. Results: M1 macrophages were associated with HIF-1-dependent induction of Jag1 and Dll4, which increased HES1 protein levels and IAP activity in co-cultured epithelial cells. In the mucosa of CD patients a high percentage of M1 macrophages expressed both HIF-1α and Jag1 while M2 macrophages mainly expressed HIF-2α and we detected a good correlation between the ratio of M1/M2 macrophages and both HES1 and IAP protein levels. Conclusion: M1, but not M2, macrophages are associated with HIF-1-dependent induction of Notch ligands and activation of epithelial Notch signalling pathway. In the mucosa of chronic CD patients, the prevalence of M2 macrophages is associated with diminution of Notch signalling and impaired enterocyte differentiation. Key Words: MacrophagesCrohn's diseasemucosal healingNotch signallin

Progastrin Represses the Alternative Activation of Human Macrophages and Modulates Their Influence on Colon Cancer Epithelial Cells

Macrophage infiltration is a negative prognostic factor for most cancers but gastrointestinal tumors seem to be an exception. The effect of macrophages on cancer progression depends on their phenotype, which may vary between M1 (pro-inflammatory, defensive) to M2 (tolerogenic, pro-tumoral). Gastrointestinal cancers often become an ectopic source of gastrins and macrophages present receptors for these peptides. The aim of the present study is to analyze whether gastrins can affect the pattern of macrophage infiltration in colorectal tumors. We have evaluated the relationship between gastrin expression and the pattern of macrophage infiltration in samples from colorectal cancer and the influence of these peptides on the phenotype of macrophages differentiated from human peripheral monocytes in vitro. The total number of macrophages (CD68+ cells) was similar in tumoral and normal surrounding tissue, but the number of M2 macrophages (CD206+ cells) was significantly higher in the tumor. However, the number of these tumor-associated M2 macrophages correlated negatively with the immunoreactivity for gastrin peptides in tumor epithelial cells. Macrophages differentiated from human peripheral monocytes in the presence of progastrin showed lower levels of M2-markers (CD206, IL10) with normal amounts of M1-markers (CD86, IL12). Progastrin induced similar effects in mature macrophages treated with IL4 to obtain a M2-phenotype or with LPS plus IFNγ to generate M1-macrophages. Macrophages differentiated in the presence of progastrin presented a reduced expression of Wnt ligands and decreased the number and increased cell death of co-cultured colorectal cancer epithelial cells. Our results suggest that progastrin inhibits the acquisition of a M2-phenotype in human macrophages. This effect exerted on tumor associated macrophages may modulate cancer progression and should be taken into account when analyzing the therapeutic value of gastrin immunoneutralization