The Purinergic System as a Pharmacological Target for the Treatment of Immune-Mediated Inflammatory Diseases

Immune-mediated inflammatory diseases (IMIDs) encompass a wide range of seemingly unrelated conditions, such as multiple sclerosis, rheumatoid arthritis, psoriasis, inflammatory bowel diseases, asthma, chronic obstructive pulmonary disease, and systemic lupus erythematosus. Despite differing etiologies, these diseases share common inflammatory pathways, which lead to damage in primary target organs and frequently to a plethora of systemic effects as well. The purinergic signaling complex comprising extracellular nucleotides and nucleosides and their receptors, the P2 and P1 purinergic receptors, respectively, as well as catabolic enzymes and nucleoside transporters is a major regulatory system in the body. The purinergic signaling complex can regulate the development and course of IMIDs. Here we provide a comprehensive review on the role of purinergic signaling in controlling immunity, inflammation, and organ function in IMIDs. In addition, we discuss the possible therapeutic applications of drugs acting on purinergic pathways, which have been entering clinical development, to manage patients suffering from IMIDs

High Levels of β-Amyloid, Tau, and Phospho-Tau in Red Blood Cells as Biomarkers of Neuropathology in Senescence-Accelerated Mouse

Alzheimer’s Disease (AD) is the most common Neurodegenerative Disease (ND), primarily characterised by neuroinflammation, neuronal plaques of β-amyloid (Aβ), and neurofibrillary tangles of hyperphosphorylated tau. α-Synuclein (α-syn) and its heteroaggregates with Aβ and tau have been recently included among the neuropathological elements of NDs. These pathological traits are not restricted to the brain, but they reach peripheral fluids as well. In this sense, Red Blood Cells (RBCs) are emerging as a good model to investigate the biochemical alterations of aging and NDs. Herein, the levels of homo- and heteroaggregates of ND-related proteins were analysed at different stages of disease progression. In particular, a validated animal model of AD, the SAMP8 (Senescence-Accelerated Mouse-Prone) and its control strain SAMR1 (Senescence-Accelerated Mouse-Resistant) were used in parallel experiments. The levels of the aforementioned proteins and of the inflammatory marker interleukin-1β (IL-1β) were examined in both brain and RBCs of SAMP8 and SAMR1 at 6 and 8 months. Brain Aβ, tau, and phospho-tau (p-tau) were higher in SAMP8 mice than in control mice and increased with AD progression. Similar accumulation kinetics were found in RBCs, even if slower. By contrast, α-syn and its heterocomplexes (α-syn-Aβ and α-syn-tau) displayed different accumulation kinetics between brain tissue and RBCs. Both brain and peripheral IL-1β levels were higher in SAMP8 mice, but increased sooner in RBCs, suggesting that inflammation might initiate at a peripheral level before affecting the brain. In conclusion, these results confirm RBCs as a valuable model for monitoring neurodegeneration, suggesting peripheral Aβ, tau, and p-tau as potential early biomarkers of AD

Adverse reactions to oncologic drugs: spontaneous reporting and signal detection

Oncology is one of the areas of medicine with the most active research being conducted on new drugs. New pharmacological entities frequently enter the clinical arena, and therefore, the safety profile of anticancer products deserves continuous monitoring. However, only very severe and (unusual) suspected adverse drug reactions (ADRs) are usually reported, since cancer patients develop ADRs very frequently and some practical selectivity must be used. Notably, a recent study was able to identify 76 serious ADRs reported in updated drug labels of oncologic drugs and 50% of them (n = 38) were potentially fatal. Of these, 49 and 58%, respectively, were not described in initial drug labels. The aims of this article are to provide an overview about spontaneous reporting of ADRs of oncologic drugs and to discuss the available methods to analyze the safety of anticancer drugs using databases of spontaneous ADR reporting

AMPK Activators as Novel Drug Candidates for the Treatment of Inflammatory Bowel Diseases

Inflammatory bowel diseases (IBDs), mainly represented by ulcerative colitis and Crohn’s disease, are chronic and idiopathic diseases of the digestive tract. They incidence and prevalence is raising significantly in both developed and developing countries, thus representing a major challenge for the worldwide healthcare systems. The pharmacological armamentarium for the treatment of IBDs is far from being satisfactory, as the therapeutic success of the available drugs is still limited. Accordingly, the development of novel and effective compounds is highly requested. In this context, the serine/threonine heterotrimeric kinase AMPK (adenosine monophosphate-activated protein kinase) seems a sound target to strike. Known as the central hub of energy homeostasis in eukaryotic cells, AMPK contributes also to the modulation of immune/inflammatory cell functions. Actually, alterations in AMPK expression and/or activity play a key role in the pathophysiology of immune-mediated inflammatory diseases characterized by abnormal immune cell functions, like IBDs. Moreover, AMPK is able to improve intestinal health by enhancing para-cellular junctions, nutrient transporters, autophagy and apoptosis. Accordingly, AMPK activation represents a promising therapeutic strategy for the treatment of intestinal inflammatory disorders. Here we describe a novel heterocyclic derivative, developed as AMPK activator. Tested in C2C12 myoblast cell lines, our compound significantly increased AMPK activity, in a concentration-dependent manner, turning out to be more effective than the well-known activator acadesine (ACA). Moreover, assayed in a mouse model of acute DNBS-induced colitis, the novel heterocycle displayed a relevant anti-inflammatory efficacy, proving to ameliorate both systemic- and tissue-related inflammatory parameters like body and spleen weight, colon length, macroscopic damage, TNF and MDA levels. Also in this case, our compound turned out to be significantly more active that the known reference ACA, thus imposing itself as a novel and valuable drug candidate for the treatment of IBDs

Mechanisms of gastroprotection by lansoprazole pre-treatment against experimentally induced injury in rats: role of mucosal oxidative damage and sulfhydryl compounds

This study investigated the mechanisms involved in the protective actions exerted by lansoprazole against experimental gastric injury. Following the intraluminal injection of ethanol-HCl, the histomorphometric analysis of rat gastric sections demonstrated a pattern of mucosal lesions associated with a significant increase in the mucosal contents of malondialdehyde and 8-iso-prostaglandin F(2alpha) (indices of lipid peroxidation), as well as a decrease in the levels of mucosal sulfhydryl compounds, assayed as reduced glutathione (GSH). Pretreatment with lansoprazole 90 micromol/kg, given intraduodenally as single dose or once daily by intragastric route for 8 days, significantly prevented ethanol-HCl-induced gastric damage. The concomitant changes in the mucosal levels of malondialdehyde, 8-iso-prostaglandin F(2alpha) and GSH elicited by ethanol-HCl were also counteracted by lansoprazole. In separate experiments, performed on animals undergoing 2-h pylorus ligation, lansoprazole did not enhance the concentration of prostaglandin E(2), bicyclo-prostaglandin E(2), or nitric oxide (NO) metabolites into gastric juice. Western blot analysis revealed the expression of both type 1 and 2 cyclooxygenase (COX) isoforms in the gastric mucosa of pylorus-ligated rats. These expression patterns were not significantly modified by single-dose or repeated treatment with lansoprazole. Lansoprazole also exhibited direct antioxidant properties by reducing 8-iso-prostaglandin F(2alpha) generation in an in vitro system where human native low-density lipoproteins were subjected to oxidation upon exposure to CuSO(4). The present results suggest that the protective effects of lansoprazole can be ascribed to a reduction of gastric oxidative injury, resulting in an increased bioavailability of mucosal sulfhydryl compounds. It is also proposed that lansoprazole does not exert modulator effects on the gastric expression of COX isoforms as well as on the activity of NO pathways

Lansoprazole prevents experimental gastric injury induced by non-steroidal anti-inflammatory drugs through a reduction of mucosal oxidative damage

AIM: This study investigated the mechanisms of protection afforded by the proton pump inhibitor lansoprazole against gastric injury induced by different non-steroidal anti-inflammatory drugs (NSAIDs) in rats. METHODS: Male Sprague-Dawley rats were orally treated with indomethacin (100 micromol/kg), diclofenac (60 micromol/kg), piroxicam (150 micromol/kg) or ketoprofen (150 micromol/kg). Thirty minutes before NSAIDs, animals were orally treated with lansoprazole 18 or 90 micromol/kg. Four hours after the end of treatments, the following parameters were assessed: gastric mucosal PGE2, malondialdehyde (MDA), myeloperoxidase (MPO) or non-proteic sulfhydryl compounds (GSH) levels; reverse transcription-polymerase chain reaction (RT-PCR) of mucosal COX-2 mRNA; gastric acid secretion in pylorus-ligated animals; in vitro effects of lansoprazole (1-300 micromol/L) on the oxidation of low density lipoproteins (LDLs) induced by copper sulphate. RESULTS: All NSAIDs elicited mucosal necrotic lesions which were associated with neutrophil infiltration and reduction of PGE2 levels. Increments of MPO and MDA contents, as well as a decrease in GSH levels were detected in the gastric mucosa of indomethacin- or piroxicam-treated animals. Indomethacin enhanced mucosal cyclooxygenase-2 expression, while not affecting cyclooxygenase-1. At the oral dose of 18 micromol/kg lansoprazole partly counteracted diclofenac-induced mucosal damage, whereas at 90 micromol/kg it markedly prevented injuries evoked by all test NSAIDs. Lansoprazole at 90 micromol/kg reversed also the effects of NSAIDs on MPO, MDA and GSH mucosal contents, without interfering with the decrease in PGE2 levels or indomethacin-induced cyclooxygenase-2 expression. However, both lansoprazole doses markedly inhibited acid secretion in pylorus-ligated rats. Lansoprazole concentration-dependently reduced the oxidation of LDLs in vitro. CONCLUSION: These results suggest that, besides the inhibition of acid secretion, lansoprazole protection against NSAID-induced gastric damage depends on a reduction in mucosal oxidative injury, which is also responsible for an increment of sulfhydryl radical bioavailability. It is also suggested that lansoprazole does not influence the down-regulation of gastric prostaglandin production associated with NSAID treatment

Effects of esomeprazole on healing of non-steroidal anti-inflammatory drug (NSAID)-induced gastric ulcers in the presence of a continued NSAID treatment: characterization of molecular mechanisms

Proton pump inhibitors promote ulcer repair in nonsteroidal anti-inflammatory drug (NSAID)-treated patients with ongoing NSAID-induced gastric toxicity, although the underlying mechanisms remain unclear. We examined the healing mechanisms of esomeprazole on NSAID-induced gastric ulcerations in the presence of a continued NSAID treatment. Ulcerations were induced in rats by oral indomethacin (6 mu mol/kg/day) for 14 days. Indomethacin administration was continued, alone or combined with equivalent acid inhibitory doses of esomeprazole (5 mu mol/kg/day), lansoprazole (15 mu mol/kg/day) or famotidine (20 mu mol/kg/day), for additional 7 days. Stomachs were then processed for: histomorphometric analysis of mucosal injury; mucosal levels of prostaglandin E-2 (PGE(2)) and malondialdehyde (MDA); expression of vascular endothelial growth factor (VEGF), proliferating cell nuclear antigen (PCNA), caspase-3, and cyclooxygenase-2 (COX-2) (Western blot); expression of Ki-67 (immunohistochemistry). Indomethacin for 14 days elicited mucosal damage, reduced PGE(2) levels and increased MDA. After additional 7 days, indomethacin induced the following effects: further enhancement of mucosal damage and MDA content; decrease in PGE(2) levels; increase in COX-2 and activated caspase-3 expression; decrease in VEGF. PCNA and Ki-67 expression. In the presence of indomethacin, esomeprazole and lansoprazole were more effective than famotidine in promoting resolution of mucosal damage. Concomitantly, esomeprazole and lansoprazole, but not famotidine, restored PCNA and Ki-67 expression, and normalized MDA levels. Moreover, esomeprazole, lansoprazole and famotidine partly counteracted caspase-3 activation, without affecting VEGF expression. The healing activity of esomeprazole on indomethacin-induced gastric ulcerations can be ascribed to two mechanisms: (1) acid-dependent reduction of pro-apoptotic signalling; (2) acid-independent restoration of proliferating/repairing pathways. (C) 2010 Elsevier Ltd. All rights reserved

Essays in macroeconomics

Esta tesis consta de tres capítulos, cada uno de los cuales analiza temas relevantes en el campo de la Macroeconomía. La investigación realizada en los tres capítulos se basa en la metodología de los modelos dinámicos de equilibrio general. Los fundamentos microeconómicos se encuentran en el núcleo de este tipo de modelos, en los que los agentes forman sus expectativas sobre el futuro de manera racional. Esta metodología ha demostrado ser una herramienta poderosa para abordar un gran conjunto de problemas económicos. El primer capítulo, ``Risk Aversion, Entrepreneurship and Wealth Distribution'', explora el efecto de la heterogeneidad en la aversión al riesgo sobre el emprendimiento, el comportamiento del ahorro y la distribución de la riqueza. La distribución de la riqueza es uno de los temas más debatidos no solo en la política contemporánea, sino también en los medios de comunicación y en ámbitos académicos. En particular, la gran concentración de riqueza en la parte superior de la distribución, que se observa en muchas economías avanzadas, se ha situado en el centro del debate. La relevancia de este problema no se ha visto socavada a pesar de la dificultad que supone estimar los niveles de riqueza acumulada en manos de los hogares más ricos. Apoyado por razones empíricas, el marco teórico para analizar la distribución de la riqueza debe incluir tanto el emprendimiento como la heterogeneidad de las preferencias. Con este objetivo, en el primer capítulo se desarrolla un modelo de elección ocupacional con agentes heterogéneos en el que los hogares varían en su aversión al riesgo, se enfrentan a perturbaciones idiosincrásicas no asegurables, tienen restricciones financieras y deben decidir si convertirse en trabajadores o en emprendedores. Esta decisión se basa en una combinación de la aversión al riesgo individual, las habilidades específicas en cada ocupación y los niveles de riqueza acumulados. Como resultado se obtiene que la aversión al riesgo tiene un efecto directo e indirecto en la decisión de ahorro y en la ocupación de los agentes. Por un lado, una mayor aversión al riesgo disuade a los agentes de convertirse en emprendedores y, por lo tanto, los ahorros destinados a superar las restricciones financieras son menores. Por otro lado, una mayor aversión al riesgo también conduce a un mayor ahorro por motivo de precaución que, indirectamente, atenúa las restricciones financieras y hace que la opción de convertirse en emprendedor sea más atractiva. En el modelo desarrollado, el último efecto domina, y los agentes con mayor aversión al riesgo acumulan mayores niveles de riqueza y también se convierten en emprendedores. La contribución más importante de este modelo es que permite desentrañar los efectos que la aversión al riesgo y las fricciones financieras tienen sobre el emprendimiento, que es un factor clave para explicar la desigualdad en la acumulación de la riqueza. El segundo capítulo se titula ``Long-term business relationships, bargaining and monetary policy'' y es un trabajo conjunto con Mirko Abbritti y Tommaso Trani. Su motivación se deriva de la creciente literatura empírica que documenta la importancia de las relaciones comerciales a largo plazo y los procesos de negociación sobre la rigidez de los precios y las dinámicas empresariales. Este artículo introduce relaciones comerciales entre empresas (B2B) a largo plazo y procesos de negociación de precios en un modelo monetario de equilibrio general dinámico estocástico (DSGE) estándar. El modelo se basa en dos suposiciones. Primero, tanto los productores mayoristas como los minoristas necesitan gastar recursos para formar nuevas relaciones comerciales. Segundo, una vez que se forma una relación comercial, el precio se establece en una negociación bilateral entre las empresas. El modelo proporciona un marco riguroso para estudiar el efecto de las relaciones comerciales a largo plazo y los procesos de negociación sobre la política monetaria y la dinámica del ciclo económico. Además, se demuestra que estas relaciones comerciales reducen tanto el papel de asignación de los precios intermedios como los efectos reales de las perturbaciones de la política monetaria. También encontramos que el modelo hace un gran trabajo al replicar los segundos momentos y las correlaciones cruzadas de los datos, y que mejora con respecto al modelo de referencia Neo Keynesiano en explicar dichos estadísticos. El tercer y último capítulo de esta tesis, ``On Staggered Prices and Optimal Inflation'', es coautoreado con uno de mis directores, Miguel Casares. En este artículo se calcula la tasa de inflación óptima en estado estacionario bajo dos especificaciones de rigidez de precios diferentes, Calvo (1983) y Taylor (1980), en un modelo con competencia monopolística. Encontramos que la tasa óptima de inflación en estado estacionario es siempre positiva. Este resultado es robusto a los cambios en el grado de rigidez de los precios. En ambos casos con rigidez de precios, la tasa de inflación óptima es aproximadamente igual al cociente entre la tasa de descuento y la elasticidad de Dixit-Stiglitz. Para calibraciones estándar, el coste de bienestar de la inflación es cuantitativamente pequeño, pero significativamente más alto si los precios son rígidos a la Calvo que si son rígidos a la Taylor.Fundación Banco Sabadell, Fundación Bancaria Caja Navarra y Universidad Pública de NavarraPrograma de Doctorado en Economía, Empresa y Derecho (RD 99/2011)Ekonomiako, Enpresako eta Zuzenbideko Doktoretza Programa (ED 99/2011

Oral sucrosomial iron is as effective as intravenous ferric carboxy‐maltose in treating anemia in patients with ulcerative colitis

Anemia is a frequent complication of ulcerative colitis, and is frequently caused by iron deficiency. Oral iron supplementation displays high rates of gastrointestinal adverse effects. However, the formulation of sucrosomial iron (SI) has shown higher tolerability. We performed a prospective study to compare the effectiveness and tolerability of oral SI and intravenous ferric carboxy‐maltose (FCM) in patients with ulcerative colitis in remission and mild‐to‐moderate anemia. Patients were randomized 1:1 to receive 60 mg/day for 8 weeks and then 30 mg/day for 4 weeks of oral SI or intravenous 1000 mg of FCM at baseline. Hemoglobin and serum levels of iron and ferritin were assessed after 4, 8, and 12 weeks from baseline. Hemoglobin and serum iron increased in both groups after 4 weeks of therapy, and remained stable during follow up, without significant treatment or treatment‐by‐time interactions (p = 0.25 and p = 0.46 for hemoglobin, respectively; p = 0.25 and p = 0.26 for iron, respectively). Serum ferritin did not increase over time during SI supplementation, while it increased in patients treated with FCM (treatment effect, p = 0.0004; treatment‐bytime interaction effect, p = 0.0002). Overall, this study showed that SI and FCM displayed similar effectiveness and tolerability for treatment of mild‐to‐moderate anemia in patients with ulcerative colitis under remission