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World Journal of Gastroenterology 2014年第28期20卷 9439-9450页

作者： Carlos Sostres Carla Jerusalen Gargallo Angel Lanas service Department of Digestive Diseases University Hospital Lozano Blesa Digestive Diseases Department Aragon Health Sciences Institute CIBERehd University of Zaragoza (Zaragoza)

Previous reports clearly demonstrated that Helicobacter pylori(***)infection,nonsteroidal anti-inflammatory drugs(NSAID)or low dose aspirin(ASA)use significantly and independently increased the risk for the development of peptic ulcer ***,the presence of *** infection associated with low dose ASA and/or NSAID use in the same patient is becoming more frequent and therefore the potential interaction between these factors and the consequences of it has important *** NSAID intake in the presence of *** infection may further increase the risk of peptic ulcer carried by the presence of only one risk factor is still a matter of *** on the interaction between the two risk factors yielded conflicting data and no consensus has been reached in the last *** addition,the interaction between *** infection and low-dose ASA remains even more *** real clinical practice,we can find different clinical scenarios involving these three factors associated with the presence of different gastrointestinal and cardiovascular risk *** huge variety of possible combinations greatly hinder the decision making process of physicians.

关键词： Nonsteroidal anti-inflammatory drugs Low dose aspirin Helicobacter pylori infection Helicobacter pylori eradication Peptic ulcer disease

Indomethacin but not a selective cyclooxygenase-2 inhibitor inhibits esophageal adenocarcinogenesis in rats

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World Journal of Gastroenterology 2012年第35期18卷 4866-4874页

作者： Paula Esquivias Antonio Morandeira Alfredo Escartín Carmelo Cebrián Sonia Santander Francisco Esteva María Asunción García-González Javier Ortego Angel Lanas Elena Piazuelo CIBER Digestive and Hepatic Deseases service of Surgery University Hospital "Lozano Blesa" service of Pathology University Hospital "Lozano Blesa" Department of Medicine University of Zaragoza service of Clinical Biochemistry University Hospital "Lozano Blesa" aragon health Science Institute service of Gastroenterology University Hospital "Lozano Blesa"

AIM： To evaluate the effects of indomethacin [dual cyclooxygenase （COX）-I/COX-2 inhibitor] and 3-（3,4-difluorophenyl）-4-（4-（methylsulfonyl） phenyl）- 2-（5H）-furanone （MF-tricyclic）（COX-2 selective inhibi- tor） in a rat experimental model of Barrett＇s esophagus and esophageal ***： A total of 112 surviving post-surgery rats were randomly divided into three groups： the control group （n = 48）, which did not receive any treatment; the indomethacin group （n = 32）, which were given 2 mg/kg per day of the COX-I/COX-2 inhibitor; and the MF-tricyclic group （n = 32）, which received 10 mg/kg per day of the selective COX-2 inhibitor. Randomly se- lected rats were killed either 8 wk or 16 wk after sur- gery. The timing of the deaths was in accordance with a previous study performed in our group. Only rats that were killed at the times designated by the protocol were included in the study. We then assessed the histology and prostaglandin E2 （PGE2） expression levels in the rat esophagi. An additional group of eight animals that did not undergo esophagojejunostomy were included in order to obtain normal esophageal tissue as a control. RESULTS： Compared to a control group with no treat- ment （vehicle-treated rats）, indomethacin treatment was associated with decreases in ulcerated esophageal mucosa （16% vs 35% and 14% vs 17%, 2 mo and 4 mo after surgery, respectively; P = 0.021）, length of intestinal metaplasia in continuity with anastomosis （2 4- 1.17 mm vs 2.29 ＋ 0.75 mm and 1.25 4- 0.42 mm vs 3.5 4- 1.54 mm, 2 mo and 4 mo after surgery, respec- tively; P = 0.007）, presence of intestinal metaplasia beyond anastomosis （20% vs 71.4% and 0% vs 60%, 2 mo and 4 mo after surgery, respectively; P = 0.009）, severity of dysplasia （0% vs 71.4% and 20% vs 85.7% high-grade dysplasia, 2 mo and 4 mo after surgery, re- spectively; P = 0.002）, and adenocarcinoma incidence （0% vs 57.1% and 0% vs 60%, 2 mo and 4 mo after surgery, respectively; P 〈 0.0001）. Treatment with the select

关键词： Intestinal metaplasia Esophageal adeno-carcinoma Indomethacin MF-tricyclic

Role of gastrin-peptides in Barrett's and colorectal carcinogenesis

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World Journal of Gastroenterology 2012年第45期18卷 6560-6570页

作者： Eduardo Chueca Angel Lanas Elena Piazuelo IIS aragon Aragon Institute of Health Sciences50009 ZaragozaSpain Networked Biomedical Research Center Hepatic and Digestive Diseases(CIBERehd) C/Corcega 180 bajos dcha08036 BarcelonaSpain Department of Medicine Psychiatry and DermatologyMedical University of ZaragozaC/Domingo Miral50009 ZaragozaSpain service of Gastroenterology Hospital Clinico UniversitarioAvda.San Juan Bosco 1550009 ZaragozaSpain

Gastrin is the main hormone responsible for the stimulation of gastric acid secretion;in addition,gastrin and its derivatives exert proliferative and antiapoptotic effects on several cell *** synthesis and secretion are increased in certain situations,for example,when proton pump inhibitors are *** impact of sustained hypergastrinemia is currently being *** vitro experiments and animal models have shown that prolonged hypergastrinemia may be related with higher cancer rates;although,this relationship is less clear in human *** gastrin levels have been shown to cause hyperplasia of several cell types;yet,the risk for developing cancer seems to be the same in normo-and hypergastrinemic *** tumors also produce their own gastrin,which can act in an autocrine manner promoting tumor *** cancers are extremely dependent on gastrin to *** research focused only on the effects of amidated gastrins,but there has been an interest in intermediates of gastrin in the last few *** intermediates aren't biologically inactive;in fact,they may exert greater effects on proliferation and apoptosis than the completely processed *** certain gastrin overproduction states,they are the most abundant gastrin peptides *** purpose of this review is to examine the gastrin biosynthesis process and to summarize the results from different studies evaluating the production,levels,and effects of the main forms of gastrin in different overexpression states and their possible relationship with Barrett's and colorectal carcinogenesis.

关键词： Gastrin Progastrin Glycine-extended gas-trins C-terminal flanking peptide Hypergastrinemia,Proton pump inhibitors Colorectal cancer Esophagealadenocarcinoma Barrett's esophagus

Sulodexide and Alzheimer’s Disease: A Preliminary Prospective Study

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World Journal of Cardiovascular Diseases 2016年第2期6卷 54-71页

作者： Joaquín Lasierra-Cirujeda María José Aza Pascual-Salcedo María Mercedes Aza Pascual-Salcedo C. Medicine Hematology Logrono Spain The Rioja and Pharmaceutical Act Ministry of Health The Rioja Regional Government Logrono Spain aragon health service Zaragoza Spain

The purpose of this prospective study is to determine the relative incidence of Alzheimer’s disease in patients treated for at least three years, with sulodexide (n = 46, 76.48 ± 7.02 years old) or acenocoumarol (n = 47, 78.21 ± 6.66 years old) in order to prevent primary and secondary venous thromboembolism and atherothrombotic disease. In the sulodexide group, there was an apparent prevention of cognitive and behavioural impairment (relative incidence: 2.02) compared with acenocoumarol group (relative incidence: 4.86). The favourable results in sulodexide group may be related to their pharmacodynamic actions of inhibition of PAI-1, which may interfere with the pathogenesis of Alzheimer’s disease, and to the role of glutathione and PAI-1 in the β-amyloid system in the brain.

关键词： Sulodexide Alzheimer’s Disease Glutathione t-PA PAI-1 Plasminogen Plasmin

Aging: Thromboembolic Disease, Metabolic Syndrome, Type 2 Diabetes Mellitus, and Alzheimer’s Disease

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Journal of Biosciences and Medicines 2016年第5期4卷 1-20页

作者： Joaquín Lasierra-Cirujeda María José Aza Pascual-Salcedo Alicia Lasierra-Ibañez Carmen Lasala Aza María Mercedes Aza Pascual-Salcedo Centro Médico Hematológico Logrono Spain Pharmaceutical Act Ministry of health La Rioja Regional Government Logrono Spain aragon health service Zaragoza Spain

Aging can be interpreted as an unavoidable process whose end point is the death. Aging entails, in the hemostasis field, some changes that favour blood hypercoagulability. Both the plasminogen activator inhibitor (PAI-1), specific inhibitor of the tissue plasminogen activator (t-PA), accompanied by the oxidative stress and the marked decrease of the main antioxidant—glutathione are fundamental in the bases of elderly pathologies which can cause death. There is some scientific evidence of the relationship between aging, neuro-degenerative diseases, an excessive production of reactive oxygen species and the decrease of proteolysis in brain. The cerebral plasminogen/plasmin system represents the essential proteolytic mechanism that degrades amyloid peptides (β-amyloidosis) for action of plasmin with effectiveness. This physiologic process is being considered as a preventive neurodegenerative mechanism. At the same time, the decrease of glutathione levels in aging entails a decrease of cerebral plasmin activity and a progressive descent of t-PA activity due to a descent in t-PA expression and an increase in PAI production. All of them entail an increment of amyloid beta peptides (Aβ) production and a lower level of their clearance. Both mechanisms, oxidative stress, direct consequence of the oxygenate metabolism of aerobics cells, and changes in the systemic fibrinolysis and cerebral b-amyloidolytic activity, play a very important role in thromboembolic disease, metabolic syndrome—obesity, insulin resistance, hyperglycemia—, type 2 Diabetes Mellitus and Alzheimer’s disease, clinical processes that accompany the aging. In this revision we show the importance of the interaction between glutathione, proteolytic t-PA/plasminogen/plasmin system, and the inhibitor PAI-1 in aging physiopathology, whose results suggest the hypothesis of the importance of a therapeutic strategy using the inhibition of PAI-1 as a goal, because it is increased in the different aging pathologic pro

关键词： Aging Alzheimer’s Disease T2DM PAI-1 Glutathione

Protons pump inhibitor treatment and lower gastrointestinal bleeding: Balancing risks and benefits

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World Journal of Gastroenterology 2016年第48期22卷 10477-10481页

作者： Alberto Lué Angel Lanas Digestive Diseases service University Clinic Hospital Lozano Blesa Avenida San Juan Bosco IIS aragon Avenida San Juan Bosco University of Zaragoza Calle de Pedro Cerbuna CIBERehd Av. Monforte de Lemos

Proton pump inhibitors(PPIs) represent a milestone in the treatment of acid-related diseases, and are the mainstay in preventing upper gastrointestinal bleeding in high-risk patients treated with nonsteroidal antiinflammatory drugs(NSAIDs) or low-dose aspirin. However, this beneficial effect does not extend to the lower gastrointestinal tract. PPIs do not prevent NSAID or aspirin-associated lower gastrointestinal bleeding(LGB). PPIs may increase both small bowel injury related to NSAIDs and low-dose aspirin treatment and the risk of LGB. Recent studies suggested that altering intestinal microbiota by PPIs may be involved in the pathogenesis of NSAID-enteropathy. An increase in LGB hospitalization rates may occur more frequently in older patients with more comorbidities and are associated with high hospital resource utilization, longer hospitalization, and increased mortality. Preventive strategies for NSAID and aspirin-associated gastrointestinal bleeding should be directed toward preventing both upper and lower gastrointestinal damage. Future research should be directed toward identifying patients at low-risk for gastrointestinal events associated with the use of NSAIDs or aspirin to avoid inappropriate PPI prescribing. Alternatively, the efficacy of new pharmacologic strategies should be evaluated in high-risk groups, with the aim of reducing the risk of both upper and lower gastrointestinal bleeding in these patients.

关键词： Proton pump inhibitor Small bowel Small bowel Lower gastrointestinal bleeding Nonsteroidal anti-inflammatory drugs

The Physiopathological Crossroads of Aging

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Journal of Biosciences and Medicines 2019年第6期7卷 102-128页

作者： J.Lasierra-Cirujeda P.Coronel M.J.aza pascual-salcedo M.Gimeno M.M.Aza Pascual Salcedo A.Lasierra-Ibanez C.Lasala-Aza logrono(la rioja) spain tedec-meji farma saalcala de henaresmadridspain pharmacy service la rioja health departmentla riojaspain pharmacy service aragon health servicezaragozaspain sciences faculty grade biochemistryuniversity of navarranavarraspain pharmacy faculty university of valenciavalenciaspain

Stress, inflammation and Plasminogen activator inhibitor 1 (PAI-1) are key mechanisms throughout the development of aging, constituting a crossroad in the most frequent pathologies that accompany it. Among metabolic processes, obesity, metabolic syndrome and type 2 diabetes mellitus are included and Alzheimer’s disease among the neurodegenerative processes. Stress is a mechanism of defense of the organism against exogenous and endogenous actions called stressors. In the case of low intensity stimuli, the organism responds with actions aimed at a physiological adaptation (Homeostasis). On the other hand, when a high intensity (experimental level) or chronic stimulus (oxidative stress) is repeated, structural and functional changes are observed in different organs with activation of the hypothalamus-pituitary-adrenal axis, the renin angiotensin system and the sympathetic nervous system, stimulating the production of hormones that release cytokines with proin-flammatory/antiinflammatory properties that play an important role in the previously mentioned pathologies, as well as a marked increase in PAI-1, a gene regulated by stress and by cytokines, with manifest action at the origin of thromboembolic disease, so frequent in aging. The objective of this review is to highlight the importance of the binomial stress and PAI-1 in aging and in the pathologies that accompany it. Because PAI-1 is part of the pathology and complications in aging, some authors suggest the study of PAI-1 inhibitors to achieve its physiological levels, as part of the treatment of these diseases.

关键词： Aging. Oxidative Stress Plasminogen Activator Inhibitor 1 Transforming Growth Factor Beta 1 Glutathione Alzheimer’s Disease

Superoxide dismutase prevents development of adenocarcinoma in a rat model of Barrett's esophagus

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World Journal of Gastroenterology 2005年第47期11卷 7436-7443页

作者： Elena Piazuelo Carmelo Cebrián Alfredo Escartín Pilar Jiménez Fernando Soteras Javier Ortego Angel Lanas Instituto aragonés de Ciencias de la Salud Unidad Mixta de InvestigaciónC/Domingo Miral s/n 50009 ZaragozaSpain service of Pathology Hospital Clínico Universitario "Lozano Blesa"Avenida San Juan Bosco15 50009 ZaragozaSpain Unidad Mixta de Investigatión University of ZaragozaDomingo Miral s/n 50009 ZaragozaSpain Unidad Mixta de Investigación University of ZaragozaDomingo Miral s/n 50009 ZaragozaSpain service of Gastroenterology Hospital Clínico Universitario "Lozano Blesa"Avenida San Juan Bosco15 50009 ZaragozaSpain

AIM： To test whether antioxidant treatment could prevent the progression of Barrett＇s esophagus to adenocarcinoma. METHODS： In a rat model of gastroduodenoesophageal reflux by esophagojejunal anastomosis with gastric preservation, groups of 6-10 rats were randomized to receive treatment with superoxide dismutase （SOD） or vehicle and followed up for 4 too. Rat＇s esophagus was assessed by histological analysis, superoxide anion and peroxinitrite generation, SOD levels and DNA oxidative damage. RESULTS： All rats undergoing esophagojejunostomy developed extensive esophageal mucosal ulceration and inflammation by mo 4. The process was associated with a progressive presence of intestinal metaplasia beyond the anastomotic area （9% 1st mo and 50% 4th too）（94% at the anastomotic level） and adenocarcinoma （11% 1^ST mo and 60% 4th too）. These changes were associated with superoxide anion and peroxinitrite mucosal generation, an early and significant increase of DNA oxidative damage and a significant decrease in SOD levels （P〈0.05）. Exogenous administration of SOD decreased mucosal superoxide levels, increased mucosal SOD levels and reduced the risk of developing intestinal metaplasia beyond the anastomotic area （odds ratio = 0.326; 95%CI： 0.108-0.981; P = 0.046）, and esophageal adenocarcinoma （odds ratio = 0.243; 95%CI： 0.073-0.804; P = 0.021）. CONCLUSION： Superoxide dismutase prevents the progression of esophagitis to Barrett＇s esophagus and adenocarcinoma in this rat model of gastrointestinal reflux, supporting a role of antioxidants in the chemoprevention of esophageal adenocarcinoma.

关键词： Barrett's esophagus Esophageal adenocarcinoma Free radicals Oxidative damage Superoxide dismutase

Education-based approach to addressing non-evidence-based practice in preventing NSAID-associated gastrointestinal complications

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World Journal of Gastroenterology 2009年第47期15卷 5953-5959页

作者： Angel Lanas Juan V Esplugues Javier Zapardiel Eduardo Sobreviela service of Digestive Diseases University Hospital University of ZaragozaInstituto Aragonés de Ciencias de la Salud(IACS)Centros de Investigación en Red de Enfermedades Hepáticas y Digestivas(CIBERehd)C/San Juan Bosco 15 50009 ZaragozaSpain Department of Pharmacology University of ValenciaCIBERehdAv.Vicent Andrés Estellés s/n46100 BurjassotValenciaSpain Department of Medical AstraZeneca Farmacéutica SpainParque NorteEdificio RobleC/Serrano Galvache 5628033 MadridSpain MediClin-Quintiles c/Sardenya no 541-54308024 BarcelonaSpain

AIM:To evaluate an evidence-based educational program for improving strategies for prevention of non-steroidal anti-inflammatory drug(NSAID)-associated gastrointestinal(GI)complications. METHODS:Four hundred and fifty-six specialists replied to a questionnaire that covered issues related to NSAID-induced adverse *** also collected data from their last five consecutive patients before and after they had attended an evidence-based seminar on GI prevention strategies. RESULTS:Four hundred and forty-one of 456 specialists(96.7%)participated in the survey,and 382(83.7%)in the education-based study that recorded data from 3728 *** specialists overestimated the risk of GI complications with NSAIDs,underestimated the GI safety profile of coxibs,but were aware of the risk factors and of the current prevention *** pump inhibitors were co-prescribed with NSAIDs in>80% of patients with and without risk *** educational program had little impact on prescribing ***:Specialists are informed of advances in NSAID-associated adverse effects and have high rates of GI-prevention *** educational program did not alter these rates.

关键词： Nonsteroidal anti-inflammatory agents Education Gastrointestinal diseases Adverse effects Cyclooxygenase 2 inhibitors Proton pump inhibitors

Blood transfusion for the treatment of acute anaemia in inflammatory bowel disease and other digestive diseases

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World Journal of Gastroenterology 2009年第37期15卷 4686-4694页

作者： José Antonio García-Erce Fernando Gomollón Manuel Muoz Transfusion Medicine and Apheresis Unit Haematology and Haemotherapy Regional Service "Miguel Servet" University Hospital Zaragoza 50009 Spain Gastroenterology Unit University Clinical Hospital and Biomedical Investigation Center at Digestive and Hepatic Disease Network c/San Juan Bosco 15 Zaragoza 50009 Spain Transfusion Medicine School of Medicine University of Málaga Málaga 29071 Spain

Allogeneic blood transfusion (ABT) is frequently used as the first therapeutic option for the treatment of acute anaemia in patients with inflammatory bowel disease (IBD), especially when it developed due to gastrointestinal or perioperative blood loss, but is not risk-free. Adverse effects of ABT include, but are not limited to, acute hemolytic reaction (wrong blood or wrong patient), febrile non-hemolytic transfusional reaction, bacterial contamination, transfusion-related acute lung injury, transfusion associated circulatory overload, transfusion-related immuno-modulation, and transmission of almost all infectious diseases (bacteria, virus, protozoa and prion), which might result in increased risk of morbidity and mortality. Unfortunately, the main physiological goal of ABT, i.e. to increase oxygen consumption by the hypoxic tissues, has not been well documented. In contrast, the ABT is usually misused only to increase the haemoglobin level within a f ixed protocol [mostly two by two packed red blood cell (PRC) units] independently of the patient' s tolerance to normovolemic anaemia or his clinical response to the transfusion of PRC units according to a "one-by-one" administration schedule. Evidencebased clinical guidelines may promote best transfusion practices by implementing restrictive transfusion protocols, thus reducing variability and minimizing the avoidable risks of transfusion, and the use of autologous blood and pharmacologic alternatives. In this regard, preoperative autologous blood donation (PABD) consistently diminished the frequency of ABT, although its contribution to ABT avoidance is reduced when performed under a transfusion protocol. In addition, interpretation of utility of PABD in surgical IBD patients is hampered by scarcity of published data. However, the role of autologous red blood cells as drug carriers is promising. Finally, it must be stressed that a combination of methods used within wellconstructed protocols will offer better prospe

关键词： Anaemia Blood transfusion Autologous blood transfusion Inflammatory bowel diseases Risk assessment