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Common misconceptions about 5-aminosalicylates and thiopurines in inflammatory bowel disease

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World Journal of Gastroenterology 2011年第30期17卷 3467-3478页

作者： javier p gisbert María Chaparro Fernando Gomollón Gastroenterology Unit Hospital Universitario de La PrincesaInstituto de Investigación SanitariaPrincesa(IP)and Centro de Investigación Biomédica en Red de Enfermedades Hepáticasy Digestivas28006 MadridSpain Gastroenterology Unit Hospital Clínico Universitario and Centro de Investigación Biomédica en Redde Enfermedades Hepáticasy DigestivasIACS50009 ZaragozaSpain

Misconceptions are common in the care of patients with inflammatory bowel disease(IBD).In this paper,we state the most commonly found misconceptions in clinical practice and deal with the use of 5-aminosalicylates and thiopurines,to review the related scientificevidence,and make appropriate recommendations.prevention of errors needs knowledge to avoid making such errors through ignorance.However,the amount of knowledge is increasing so quickly that one new danger is an overabundance of information.IBD is a model of a very complex disease and our goal with this review is to summarize the key evidence for the most common daily clinical problems.With regard to the use of 5-aminosalicylates,the best practice may to be consider abandoning the use of these drugs in patients withsmall bowel Crohn's disease.The combined approach with oral plus topical 5-aminosalicylates should be the first-line therapy in patients with active ulcerative colitis;once-daily treatment should be offered as a first choice regimen due to its better compliance and higher efficacy.With regard to thiopurines,they seem to be as effective in ulcerative colitis as in Crohn's disease.Underdosing of thiopurines is a form of undertreatment.Thiopurines should probably be continued indefinitely because their withdrawal is associated with a high risk of relapse.Mercaptopurine is a safe alternative in patients with digestive intolerance or hepatotoxicity due to azathioprine.Finally,thiopurine methyltransferase(TpMT)screening cannot substitute for regular monitoring because the majority of cases of myelotoxicity are not TpMT-related.

关键词：氨基水杨酸小肠炎症鸡传染性法氏囊病溃疡性结肠炎硫唑嘌呤临床实践科学证据

Anemia and digestive diseases: An update for the clinician

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World Journal of Gastroenterology 2009年第37期15卷 4615-4616页

作者： Fernando Gomollón javier p gisbert Digestive Diseases Service Clinical University Hospital CIBEREHD IACS Avenida San Juan Bosco 15 Zaragoza 50009 Spain Digestive Diseases Service University Hospital "La Princesa" CIBEREHD C/ Diego León 62 Madrid 28006 Spain

Anemia and iron deficiency are so common in digestive diseases that often are underestimated and undertreated. Our goal is to review from classif ication to treatment of the diverse types of anemias in different digestive diseases to update our knowledge on diagnosis and treatment. With the goal of improving the prognosis and quality of life of digestive diseases patients, we will review current transfusion, intravenous iron, and erythropoietin roles in the treatment of anemia.

关键词：消化道疾病贫血临床医生消化系统疾病红细胞生成素生活质量静脉注射治疗

“Rescue” regimens after Helicobacter pylori treatment failure

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World Journal of Gastroenterology 2008年第35期14卷 5385-5402页

作者： javier p gisbert Gastroenterology Unit Hospital Universitario de la Princesa and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y DigestivasMadridSpain

Helicobacter pylori (H pylori) infection is the main cause of gastritis, gastroduodenal ulcer disease, and gastric cancer. After more than 20 years of experience in H pylori treatment, in my opinion, the ideal regimen to treat this infection is still to be found. Currently, apart from having to know first-line eradication regimens well, we must also be prepared to face treatment failures. Therefore, in designing a treatment strategy we should not focus on the results of primary therapy alone, but also on the final (overall) eradication rate. The choice of a "rescue" treatment depends on which treatment is used initially. If a clarithromycin- based regimen was used initially, a subsequent metronidazole-based treatment (quadruple therapy) may be used afterwards, and then a levofloxacin- based combination would be a third "rescue" option. Alternatively, it has recently been suggested that levofloxacin-based rescue therapy constitutes an encouraging second-line strategy, representing an alternative to quadruple therapy in patients with previous ppI-clarithromycin-amoxicillin failure, with the advantage of efficacy, simplicity and safety. In this case, a quadruple regimen may be reserved as a third-line rescue option. Finally, rifabutin-based rescue therapy constitutes an encouraging empirical fourth- line strategy after multiple previous eradication failures with key antibiotics such as amoxicillin, clarithromycin, metronidazole, tetracycline, and levofloxacin. Even after two consecutive failures, several studies have demonstrated that H pylori eradication can finally be achieved in almost all patients if several rescue therapies are consecutively given. Therefore, the attitude in H pylori eradication therapy failure, evenafter two or more unsuccessful attempts, should be to fight and not to surrender.

关键词：幽门杆菌胃炎胃十二指肠溃疡胃癌治疗

Severe ulcerative colitis: At what point should we define resistance to steroids?

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World Journal of Gastroenterology 2008年第36期14卷 5504-5507页

作者： Maria Esteve javier p gisbert Department of Gastroenterology Hospital Universitari Mútua de Terrassa Fundació per la Recerca Mútua de Terrassa University of Barcelona Terrassa Catalonia Spain Department of Gastroenterology Hospital Universitario de la Princesa Madrid and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas Spain

Corticoesteroids are still the first-line treatment for active ulcerative colitis more than 50 years after the publication of trials assessing their beneficial effect, with about a 50% remission rate in cases of severe disease. The mortality related to severe attacks of ulcerative colitis has decreased dramatically, to less than 1%, in experienced centers, due to the appropriate use of intensive therapeutic measures (intravenous steroids, fluids and electrolytes, artificial nutritional support, antibiotics, etc), along with timely decision-making about second-line medical therapy and early identification of patients requiring colectomy. One of the most difficult decisions in the management of severe ulcerative colitis is knowing for how long corticosteroids should be administered before deciding that a patient is a non-responder. Studies assessing the outcome of acute attacks after steroid initiation have demonstrated that, in steroid-sensitive patients, the response generally occurs early on, in the first days of treatment. Different indexes to predict treatment failure, when applied on the third day of treatment, have demonstrated a high positive predictive value for colectomy. In contrast to this resolute approach, which is the most widely accepted, other authors have suggested that in some patients a completeand prolonged response to steroids may take longer. Either way, physicians taking care of these patients need to recognize that severe ulcerative colitis may be life-threatening, and they need to be careful with excessively prolonged medical treatment and delayed surgery.

关键词：溃疡性结肠炎胃肠疾病类固醇抗病性

Optimizing clarithromycin-containing therapy for Helicobacter pylori in the era of antibiotic resistance

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World Journal of Gastroenterology 2014年第30期20卷 10338-10347页

作者： javier Molina-Infante javier p gisbert Department of Gastroenterology Hospital San Pedro de Alcantara10003 CaceresSpain Department of Gastroenterology Hospital Universitario de la PrincesaInstituto de Investigación Sanitaria Princesa and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas28006 MadridSpain

The efficacy of triple therapy for Helicobacter pylori infection has dramatically declined over the last decade,largely related to increasing clarithromycin resistance rates.From a microbiological standpoint,bismuth quadruple therapy is the ideal replacement since it combines drugs for which resistance does not impair its efficacy.Nonetheless,several obstacles such as availability,complexity or tolerance prevent a general implementation of bismuth quadruple therapy,so nonbismuth quadruple regimens remain the best firstline treatment in clinical practice in many geographical areas.We review the rationale and efficacy of several optimization tools(increasing the length of duration,high-dose acid suppression,probiotics),which have been largely evaluated over the last 5 years to increase the effectiveness of standard triple therapy.Then,we update available evidence on the effectiveness of several non-bismuth quadruple therapies(sequential,concomitant,hybrid,miscellaneous therapy),which have gained interest lately.We also revise evidence on the efficacy of the aforementioned optimization tools for non-bismuth quadruples schemes and,finally we provide a novel regionalized therapeutic algorithm,based on novel formulas recently developed for predicting the outcome of non-bismuth quadruple regimens,upon local antibiotic resistance rates.

关键词： Helicobacter pylori Eradication Clarithromycin Seq

Effectiveness of infliximab after adalimumab failure in Crohn's disease

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World Journal of Gastroenterology 2012年第37期18卷 5219-5224页

作者： María Chaparro Montserrat Andreu Manuel Barreiro-de Acosta Esther García-planella Elena Ricart Eugeni Domènech María Esteve Olga Merino pilar Nos Mireia pealva javier p gisbert Department of Gastroenterology Hospital Universitario de La PrincesaInstituto de Investigación Princesa(IP)and Centro de Investigación Biomédica en Red de Enfermedades Hepáticasy Digestivas(CIBEREHD)28006 MadridSpain Americio 17 portal E 2℃28021 Madrid Department of Gastroenterology Hospital del Mar Department of Gastroenterology Hospital Clínico Universitario de Santiago Department of Gastroenterology Hospital Santa Creui Sant Pau Department of Gastroenterology Hospital ClínicBarcelonaand Centro de Investigación Biomédica en Red de Enfermedades Hepáticasy Digestivas Department of Gastroenterology Hospital Germans Triasi Pujol and Centro de Investigación Biomédica en Red de Enfermedades Hepáticasy Digestivas(CIBEREHD) Department of Gastroenterology Hospital Mutua de Terrassa Department of Gastroenterology Hospital de Cruces Department of Gastroenterology Hospital Universitario La Fe and Centro de Investigación Biomédica en Red de Enfermedades Hepáticasy Digestivas(CIBEREHD) Department of Gastroenterology Hospital de Bellvitge Department of Gastroenterology Hospital Universitario de La PrincesaInstituto de Investigación Princesa(IP)and Centro de Investigación Biomédica en Red de Enfermedades Hepáticasy Digestivas(CIBEREHD)

AIM:To evaluate the effectiveness of infliximab as a second-line therapy in Crohn's disease patients after adalimumab failure. METHODS:A historical cohort study in a community-based gastroenterology practice evaluated Crohn's disease patients treated with infliximab (induction plus maintenance) after adalimumab failure. patients were identified using a large Spanish database (ENEIDA). RESULTS:We included 15 Crohn's disease patients who received infliximab after adalimumab failure. Five patients discontinued adalimumab due to loss of response, 3 due to adverse events and 7 due to partial response. After infliximab therapy was started, all patients who had interrupted adalimumab due to loss of efficacy regained response. All patients who discontinued adalimumab due to adverse events responded to infliximab and maintained this response; one of these patients had an uneventful course on infliximab, but 2 developed adverse events. None of the 7 patients who interrupted adalimumab due to partial response reached remission with infliximab. CONCLUSION:Switching from adalimumab to infliximab may be useful in patients who develop adverse effects or loss of response, however, the benefit of infliximab in primary nonresponders was not established.

关键词：单抗胃肠病学队列研究开关频率患者治疗数据库西班牙

Crohnology: A tale of time and times and inflammatory bowel diseases

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World Journal of Gastroenterology 2008年第36期14卷 5489-5490页

作者： Fernando Gomollón javier p gisbert Miquel ngel Gassull Hospital Clínico Universitario Zaragoza Spain Centro de Investigación Biomédica en Enfermedades Hepáticas y Digestivas CIBEREHD IACS Spain Hospital Universitario de la princesa CIBEREHD Madrid Spain Instituto de Investigación en Ciéncias de la Salud Fundación Germans Trias i Pujol CIBEREHD Badalona Spain

Time, times and timing are key words in inflammatory bowel diseases (IBD). The leifmotif of this issue o World Journal of Gastroenterology is time. We have asked experts to review on the epidemiology of these diseases over time, the changes in innate immunity that could be present in the first time, and then the timing of key treatments. The correct time of using azathioprine, mercaptopurine, infliximab, cyclosporine and surgery are reviewed. We have chosen experts with not only great clinical expertise but also persona interest in clinical and basic investigation. Our goa in this monograph is to get an idea not only of the present but of the immediate future in some of the key management issues in IBD. To this end, we think tha the authors are the most adequate.

关键词：肠炎流行病学先天免疫治疗

Immunogenicity and mechanisms impairing the response to vaccines in inflammatory bowel disease

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World Journal of Gastroenterology 2015年第40期21卷 11273-11281页

作者： Alicia C Marín javier p gisbert María Chaparro Gastro- enterology Unit Hospital Universitario de La Princesa and Instituto de Investigación Sanitaria PrincesaCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas28021 MadridSpain

Inflammatory bowel disease(IBD) is an immunological disorder that is usually treated with immunosuppressive therapy,potentially leading to increases in vulnerability to infections. Although many infections can be pre-vented by vaccination,vaccination coverage in these patients in clinical practice is insufficient. Therefore,the seroprotection condition should be verified,even for routine vaccines,such as hepatitis B or pneu-mococcus. Response to vaccines in IBD patients is thought to be impaired due to the immunological alterations generated by the disease and to the immunomodulatory treatments. The immunogenicity of hepatitis B,influenza,and pneumococcal vaccines is impaired in IBD patients,whereas the response to papillomavirus vaccine seems similar to that observed in the healthy population. On the other hand,data on the immunogenicity of tetanus vaccine in IBD patients are conflicting. Studies assessing the response to measles-mumps-rubella,varicella,and herpes zoster vaccines in IBD patients are scarce. The cellular and molecular mechanisms responsible for the impairment of the response to vaccination in IBD patients are poorly understood. Studies aiming to assess the response to vaccines in IBD patients and to identify the mechanisms involved in their immunogenicity are warranted. A better understanding of the immune response,specifically to vaccines,in patients with immune-mediated diseases(such as IBD),is crucial when developing vaccines that trigger more potent immunologic responses.

关键词： Crohn’s disease Inflammatory bowel disease Tumor n

preclinical evaluation of azathioprine plus buthionine sulfoximine in the treatment of human hepatocarcinoma and colon carcinoma

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World Journal of Gastroenterology 2011年第34期17卷 3899-3911页

作者： Borja Hernández-Breijo Jorge Monserrat Sara Ramírez-Rubio Eva p Cuevas Diana Vara Inés Díaz-Laviada M Dolores Fernández-Moreno Irene D Román javier p gisbert Luis G Guijarro Molecular Hepatic Toxicology Unit Biochemistry and Molecular Biology Department University of Alcalá Networked Biomedical Research Center of Hepatic and Digestive Diseases (CIBEREHD) Medicine Department University of Alcalá Neuroendocrinology of Cannabinoid/Vanilloid System Unit Biochemistry and Molecular Biology Department University of Alcalá Gastroenterology Unit Hospital de la Princesa Institute of Health Research Princesa Networked Biomedical Research Center of Hepatic and Digestive Diseases (CIBEREHD)

AIM: To evaluate the efficacy and the safety of azathioprine (AZA) and buthionine sulfoximine (BSO) bylocalized application into HepG2 tumor in vivo.METHODS: Different hepatoma and colon carcinoma cell lines (HepG2, HuH7, Chang liver, LoVo, RKO, SW-48, SW-480) were grown in minimal essencial medium supplemented with 10% fetal bovine serum and 1% antibiotic/antimycotic solution and maintained in a humidified 37 ℃ incubator with 5% CO2. These cells were pretreated with BSO for 24 h and then with AZA for different times. We examined the effects of this combination on some proteins and on cellular death. We also studied the eff icacy and the safety of AZA (6 mg/kg per day) and BSO (90 mg/kg per day) in HepG2 tumor growth in vivo using athymic mice. We measured safety by serological markers such as aminotransferases and creatine kinase.RESULTS: The in vitro studies revealed a new mechanism of action for the AZA plus BSO combination in the cancer cells compared with other thiopurines (6-mercaptopurine, 6-methylmercaptopurine, 6-thioguanine and 6-methylthioguanine) in combination with BSO. The cytotoxic effect of AZA plus BSO in HepG2 cells resulted from necroptosis induction in a mitochondrial-dependent manner. From kinetic studies we suggest that glutathione (GSH) depletion stimulates c-Jun amino-terminal kinase and Bax translocation in HepG2 cells with subsequent deregulation of mitochondria (cytochrome c release, loss of membrane potential), and proteolysis activation leading to loss of membrane integrity, release of lactate dehydrogenase and DNA degradation. Some of this biochemical and cellular changes could be reversed by N-acetylcysteine (a GSH replenisher). In vivo studies showed that HepG2 tumor growth was inhibited when AZA was combined with BSO.CONCLUSION: Our studies suggest that a combination of AZA plus BSO could be useful for localizedtreatment of hepatocellular carcinoma as in the currently used transarterial chemoembolization method.

关键词：硫唑嘌呤结肠癌肝癌 HepG2细胞评价亚砜肿瘤生长临床