RESUMEN
Vonoprazan (VPZ) has been available in Japan since 2015. Endoscopic features of proton-pump inhibitor (PPI)-related gastric mucosal changes, including fundic gland and hyperplastic polyps, have been observed. However, the relationship between gastric polyps and VPZ remains unclear. A 65-year-old man with reflux esophagitis-associated symptoms refractory to PPI was referred to our hospital. VPZ (20 mg) was administered for 3 weeks, which proved effective. Afterward, VPZ dose was reduced to 10 mg; the reflux symptoms worsened, and 20 mg VPZ was restarted. Afterward, esophagogastroduodenoscopy (EGD) revealed a gradually enlarging gastric polyp in the cardia. After 5 years of VPZ administration, the patient developed a reddish polyp (approximately 10 mm) with a whitish substance in the cardia. Based on the clinical course, the polyp was considered to have enlarged because of the long-term VPZ administration. After being informed of the endoscopic findings, the patient decided to discontinue VPZ. One year after VPZ discontinuation, EGD revealed a shrunken polyp (5 mm). Long-term acid suppression causes hypergastrinemia, which may lead to gastric mucosal changes, including gastric polyps. There are few case reports of a decrease in the number and size of gastric polyps after VPZ discontinuation. Hence, some VPZ-induced endoscopic changes may be reversible.
Asunto(s)
Endoscopía del Sistema Digestivo , Inhibidores de la Bomba de Protones , Pirroles , Sulfonamidas , Humanos , Masculino , Sulfonamidas/efectos adversos , Sulfonamidas/administración & dosificación , Anciano , Pirroles/efectos adversos , Pirroles/administración & dosificación , Inhibidores de la Bomba de Protones/administración & dosificación , Inhibidores de la Bomba de Protones/efectos adversos , Esofagitis Péptica/tratamiento farmacológico , Esofagitis Péptica/inducido químicamente , Neoplasias Gástricas/patología , Mucosa Gástrica/patología , Mucosa Gástrica/efectos de los fármacos , Pólipos AdenomatososRESUMEN
Aim: 20 mg of vonoprazan (VPZ20) is recommended in most countries to treat erosive esophagitis (EE). Whether other doses of vonoprazan, such as 5 mg (VPZ5), 10 mg (VPZ10), 20 mg (VPZ20), and 40 mg (VPZ40) are more effective is unknown. Materials & methods: Three databases were electronically searched to identify studies published before November 2021. Network meta-analysis was performed using STATA 14.0. Results: VPZ20 and VPZ40 were comparable to PPI, VPZ5 and VPZ10 in 4- and 8-week healing rates, and this was also detected in patients with refractory EE. All regimens resulted in similar treatment-emergent adverse events (TEAEs). However, VPZ40 ranked first for healing rate and TEAEs; however, VPZ20 ranked worst for TEAEs. Conclusion: Different doses of VPZ are comparable in efficacy and safety, but VPZ40 may be best in both effectiveness and safety.
Asunto(s)
Esofagitis Péptica , Úlcera Péptica , Humanos , Inhibidores de la Bomba de Protones/uso terapéutico , Esofagitis Péptica/inducido químicamente , Esofagitis Péptica/tratamiento farmacológico , Metaanálisis en Red , Pirroles/uso terapéutico , Resultado del TratamientoRESUMEN
OBJECTIVE: To provide a basis for the clinical identification of true and false reflux, integrated traditional Chinese and Western medicine, and psychosomatic treatment, we conducted a retrospective study of the etiology and epidemiological and Traditional Chinese Medicine (TCM) syndrome characteristics of patients with reflux/heartburn symptoms. METHODS: The 210 10 patients with reflux/heartburn treated at Tianjin Nankai Hospital from January 1, 2016, to December 31, 2019, were divided into four groups according to their pathogenesis. Sex, age, course of disease, incidence rate, gastroscopy, 24-h pH-impedance, esophageal manometry, Hamilton Anxiety Scale (HAMA) / Hamilton Depression Scale (HAMD) score, 8-week proton pump inhibitor (PPI) treatment effect, and TCM syndrome characteristics were statistically analyzed. RESULTS: A total of 21010 patients (8864 men and 12146 women), with reflux/heartburn symptoms were screened, including 6284 (29.9%) patients with reflux esophagitis (RE), 10427 (49.6%) patients with non-erosive reflux esophagitis (NERD), 2430 (11.6%) patients with reflux hypersensitivity (RH), and 1870 (8.9%) patients with functional heartburn (FH). The incidence of the disease was higher in women than in men (0.0001). The ranking of the incidence of anxiety and depression in these four groups was FH>RH>NERD>RE ( 0.0001). There were more women than men in the groups with anxiety and more men than women in the groups with depression ( 0.0001), and there was no significant difference in the distribution of anxiety and depression between men and women ( 0.5689). There were significant differences in TCM syndrome characteristics between NERD, RE, and functional esophageal diseases ( 0.01). The highest proportion of functional esophageal disease TCM symptoms was stagnation and phlegm obstruction syndrome (36.16%), and there was no significant difference between RH and FH. The effective rates of PPI treatment at 8 weeks in patients in the RE, NERD, RH, and FH groups were 89%, 72%, 54%, and 0%, respectively. RE was classified into grades A, B, C, and D according to the Los Angeles grading system. The ranking of the incidence of these four grades was A>B>C>D ( 0.0001). The effective rates of PPI treatment at 8 weeks were 91%, 81%, 69%, and 63% in patients with grade A, B, C, and D RE, respectively ( 0.0001). The highest proportion of TCM syndrome types of NERD and RE was the stagnated heat syndrome in the liver and stomach syndrome, 38.99% and 33.90%, respectively. CONCLUSION: Reflux/heartburn symptoms are relatively common in middle-aged women, and NERD is the most common etiology, followed by RE, RH, and FH. The most common TCM syndrome characteristics in NERD and RE were stagnated heat syndrome in the liver and stomach syndrome, and stagnation and phlegm obstruction syndrome in functional esophageal diseases. Most patients with reflux/heartburn symptoms also experienced anxiety and depression.
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Esofagitis Péptica , Reflujo Gastroesofágico , Masculino , Persona de Mediana Edad , Humanos , Femenino , Lactante , Pirosis/tratamiento farmacológico , Pirosis/epidemiología , Pirosis/etiología , Esofagitis Péptica/inducido químicamente , Estudios Retrospectivos , Medicina Tradicional China , Reflujo Gastroesofágico/complicaciones , Reflujo Gastroesofágico/tratamiento farmacológico , Reflujo Gastroesofágico/epidemiología , Inhibidores de la Bomba de Protones/efectos adversosRESUMEN
ABSTRACT: The relationship between chronic obstructive pulmonary disease (COPD) and reflux esophagitis (RE) was controversial. We investigated the factors influencing RE development in patients with COPD and evaluated the association between RE and AECOPD.Patients with COPD who underwent esophagogastroduodenoscopy from January 2003 to December 2013 in St. Paul's Hospital, the Catholic University of Korea (Seoul, Korea) were enrolled retrospectively. The grade of RE was based on the Los Angeles classification and minimal change esophagitis. Body mass index, smoking history, medical history, AECOPD, pulmonary function test data, endoscopic findings, and comorbidities were reviewed.Of a total of 218 patients with COPD, 111 (50.9%) were diagnosed with RE. None of age, sex, smoking history, or the severity of airflow limitation was associated with RE. AECOPD was not related to either the presence or severity of RE. There was no significant correlation between RE grade by Los Angeles classification and severity of airflow limitation (Pâ=â.625). Those who had RE used theophylline (Pâ=â.003) and long-acting muscarinic antagonists (Pâ=â.026) significantly more often than did controls. The use of theophylline (OR 2.05; 95% CI, 1.16-3.65, Pâ=â.014) was associated with an increased incidence of RE.The use of theophylline might increase the risk of RE in COPD patients. RE may not be associated with airflow limitation or AECOPD.
Asunto(s)
Esofagitis Péptica/epidemiología , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Factores de Edad , Anciano , Anciano de 80 o más Años , Índice de Masa Corporal , Broncodilatadores/efectos adversos , Comorbilidad , Endoscopía del Sistema Digestivo , Esofagitis Péptica/inducido químicamente , Femenino , Humanos , Masculino , Persona de Mediana Edad , Antagonistas Muscarínicos/efectos adversos , República de Corea , Pruebas de Función Respiratoria , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Factores Sexuales , Fumar/epidemiología , Teofilina/efectos adversosRESUMEN
BACKGROUND/AIMS: The aim of this study is to examine the protective effect of the cholinergic anti-inflammatory pathway (CAP) in experimental esophagitis in rats. METHODS: A total of 40 male Sprague-Dawley (SD) rats were randomly divided into five groups as follows: control group, sham + saline group, sham + acid group, operation + saline group, and operation + acid group. Two weeks after the dorsal motor nucleus of the vagus (DMV) destruction, hydrochloric acid with pepsin was perfused into the lower part of the esophagus for 90 min. The rats were sacrificed 60 min after perfusion. The esophagus was prepared for hematoxylin and eosin (HE) staining, and the degree of inflammation and NF-κB activation in the esophagus was measured. Inflammatory cytokines (TNF-α, IL-6, IL-1ß, and PGE2) in the esophagus were measured by ELISA. The brain was removed and processed for c-fos immunohistochemistry staining. The c-fos-positive neurons were counted and analyzed. RESULTS: The TNF-α, IL-1ß, IL-6, and PGE2 concentrations in the esophageal tissue increased after acid perfusion. The microscopic esophagitis scores and the activation of NF-κB p65 in the esophagus were significantly higher in the operation + acid group than in the operation + saline group. c-fos-positive neurons significantly increased in rats receiving acid perfusion in the amygdala (AM), the paraventricular nucleus of the hypothalamus (PVN), the parabrachial nucleus (PBN), the nucleus of the solitary tract (NTS)/DMV, the nucleus ambiguous (NA), the reticular nucleus of the medulla (RNM), and the area postrema (AP). After DMV destruction, c-fos expression was reduced in the AM, PVN, PBN, NTS/DMV, NA, RNM, and AP, especially in the AM, PVN, NTS/DMV, RNM, and AP. CONCLUSIONS: The DMV is an important nucleus of the CAP. The DMV lesion can aggravate esophageal inflammation and injury from acid-induced acute esophagitis in a rat model. The CAP has a protective effect on the acute esophagitis rat model and could be a new therapy for reflux esophagitis (RE).
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Esofagitis Péptica/inducido químicamente , Bulbo Raquídeo/patología , Nervio Vago/patología , Ácidos/administración & dosificación , Animales , Dinoprostona/metabolismo , Modelos Animales de Enfermedad , Esofagitis Péptica/patología , Esofagitis Péptica/fisiopatología , Inmunohistoquímica , Inflamación/inducido químicamente , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Masculino , Bulbo Raquídeo/metabolismo , Neuroinmunomodulación/efectos de los fármacos , Perfusión , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Ratas Sprague-Dawley , Factor de Transcripción ReIA/metabolismo , Nervio Vago/metabolismoAsunto(s)
Alendronato/efectos adversos , Conservadores de la Densidad Ósea/efectos adversos , Esofagitis Péptica/inducido químicamente , Dolor Abdominal/etiología , Anciano de 80 o más Años , Endoscopía del Sistema Digestivo , Esofagitis Péptica/diagnóstico , Esofagitis Péptica/tratamiento farmacológico , Femenino , Humanos , Lansoprazol/uso terapéutico , Náusea/etiología , Osteoporosis Posmenopáusica/tratamiento farmacológico , Inhibidores de la Bomba de Protones/uso terapéutico , Vómitos/etiologíaRESUMEN
BACKGROUND: Long-term aspirin use in cardiovascular disease prevention may result in gastrointestinal bleeding. Although proton pump inhibitors (PPI) have been shown to reduce the risks of peptic ulcers and dyspeptic symptoms in long-term aspirin users in the randomized controlled trials, there are safety concerns about the long-term use of PPI. STUDY QUESTION: What is the safety and efficacy of PPI in patients using aspirin in long term for prevention of cardiovascular diseases and stroke? METHODS: We searched MEDLINE, EMBASE, CENTRAL, CINAHL, ProQuest, and relevant references from inception through February 2015, and used random-effects model for meta-analysis. RESULTS: A total of 10 publications from 9 studies (n = 6382) were included in the meta-analysis. Compared with control, PPI reduced the risks of peptic ulcers [risk ratio (RR): 0.19; 95% confidence interval: 0.13-0.26; P < 0.00001], gastric ulcers [0.24 (0.16-0.35); P < 0.00001], duodenal ulcers [0.12 (0.05-0.29); P < 0.00001], bleeding ulcers [0.22 (0.10-0.51); P = 0.0004], and erosive esophagitis [0.14 (0.07-0.28); P < 0.00001]. PPI increased the resolution of epigastric pain [1.13 (1.03-1.25); P = 0.01], heartburn [1.24 (1.18-1.31); P < 0.00001], and regurgitation [1.26 (1.13-1.40); P < 0.0001], but did not increase the risks of all-cause mortality [1.72 (0.61-4.87); P = 0.31], cardiovascular mortality [1.80 (0.59-5.44); P = 0.30], nonfatal myocardial infarction/ischemia [0.56 (0.22-1.41); P = 0.22], ischemic stroke/transient ischemic attack [1.09 (0.34-3.53); P = 0.89] and other adverse events. CONCLUSIONS: The PPI seems to be effective in preventing peptic ulcers and erosive esophagitis and in resolution of dyspeptic symptoms without increasing adverse events, cardiac risks or mortality in long-term aspirin users.
Asunto(s)
Aspirina/uso terapéutico , Esofagitis Péptica/epidemiología , Infarto del Miocardio/prevención & control , Úlcera Péptica Hemorrágica/epidemiología , Úlcera Péptica/epidemiología , Inhibidores de la Bomba de Protones/uso terapéutico , Accidente Cerebrovascular/prevención & control , Esofagitis Péptica/inducido químicamente , Esofagitis Péptica/prevención & control , Humanos , Infarto del Miocardio/mortalidad , Oportunidad Relativa , Úlcera Péptica/inducido químicamente , Úlcera Péptica/complicaciones , Úlcera Péptica/prevención & control , Úlcera Péptica Hemorrágica/etiología , Úlcera Péptica Hemorrágica/prevención & control , Ensayos Clínicos Controlados Aleatorios como Asunto , Accidente Cerebrovascular/mortalidad , Factores de Tiempo , Resultado del TratamientoRESUMEN
Non-steroidal anti-inflammatory drugs (NSAIDs) are the most prescribed group of drugs in the world. They are used primarily for pain relief in chronic inflammatory joint disease and act by inhibiting enzymes COX1 and COX2 and ultimately preventing the production of active prostanoids which are required for the innate inflammatory pathway. The use of NSAIDs have been associated with the development of gastrointestinal (GI) symptoms ranging from simple dyspepsia to life threatening GI bleeds and perforations. The definition of dyspepsia has evolved over the years and this has hampered accurate studies on the prevalence of dyspepsia as different studies used varying criteria to define dyspepsia. It is now known that NSAIDs significantly increase the risk of dyspepsia.The risk of developing peptic ulcer disease vary with specific NSAIDs and dosages but there is no correlation between the symptoms of dyspepsia and underlying peptic ulcers. The pathogenesis of dyspepsia with NSAIDs is not completely understood. Peptic ulceration alone is not able to account for the majority of dyspepsia symptoms encountered by NSAIDs users. Erosive oesophagitis secondary to NSAIDs may be contributing factor to the prevalence of dyspepsia in NSAIDs users. Altered gut permeability and changes in gastric mechanosensory function due to NSAIDs may also be a contributory factor. Management of NSAID induced dyspepsia is involves a multipronged approach. Drug avoidance if possible would be ideal. Other options include using the lowest effective dose, changing to an NSAIDs with a safer GI risk profile, avoiding concurrent use with other NSAIDs or if the patient has a previous history of peptic ulcer disease, and co-prescribing with anti-secretory medications such as proton pump inhibitors. Eradication of Helicobacter pylori has a protective role against developing peptic ulcers and may also improve symptoms of NSAIDs induced dyspepsia.
Asunto(s)
Antiinflamatorios no Esteroideos/efectos adversos , Dispepsia/inducido químicamente , Enfermedades Gastrointestinales/inducido químicamente , Antiinflamatorios no Esteroideos/administración & dosificación , Dispepsia/fisiopatología , Esofagitis Péptica/inducido químicamente , Esofagitis Péptica/patología , Enfermedades Gastrointestinales/fisiopatología , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/tratamiento farmacológico , Helicobacter pylori/aislamiento & purificación , Humanos , Úlcera Péptica/inducido químicamente , Úlcera Péptica/epidemiología , Úlcera Péptica/patología , PrevalenciaRESUMEN
Introducción: La esofagitis supone una complicación poco frecuente del reflujo gastroesofágico, pero hay que tenerla en cuenta y detectar datos clínicos sugestivos de esta afección para solicitar una endoscopia digestiva. Pacientes y métodos: Estudio descriptivo retrospectivo de casos de esofagitis por reflujo (durante el periodo 1995-2010) y análisis estadístico de los datos. Resultados: Se obtuvo una muestra de 41 pacientes, de 4 meses a 16 años de edad, con mayor frecuencia de esofagitis en varones y adolescentes. El 80,5% de los casos eran esofagitis de grado I-II; se observó hernia de hiato en el 58,5% de los casos, sin asociarse a una mayor gravedad de esofagitis (p= 0,7). La patología neurológica, muy frecuente, se asociaba a esofagitis graves (p= 0,03) y peor evolución (p= 0,035). Las manifestaciones clínicas referidas con más frecuencia fueron los vómitos con sangrado digestivo superior, la epigastralgia y la pirosis. La disfagia fue el único síntoma relacionado con un mayor grado de esofagitis (p= 0,05). También se observaron síntomas extradigestivos por reflujo gastroesofágico (25%). Conclusiones: En los pacientes con Helicobacter pylori, la erradicación de la bacteria supuso una mejora de los síntomas de reflujo. Se detectó una escasa correlación entre los hallazgos de la pH-metría y los endoscópicos (p= 0,32) (AU)
Introduction: Esophagitis is a rare complication of gastroesophageal reflux, but we must take this into account to find clinical suggestive data and to apply the endoscopy. Patients and methods: A retrospective study of reflux esophagitis during 1995-2010 and statistical analysis of the data. Results: 41 patients, aged 4 month to 16 years, higher frequency of esophagitis in males and adolescents. Esophagitis grade I-II in 80.5%, hiatal hernia (58.5%) not associated with severity of esophagitis (p= 0.7). Neurological disease, very common, was associated with severe esophagitis (p= 0.03) and poor outcome (p= 0.035). Clinical manifestations were vomiting and upper gastrointestinal bleeding, epigastric pain and heartburn; dysphagia was the only symptom associated with a higher degree of esophagitis (p= 0.05). Extragastrointestinal symptoms was noted in 25%. Conclusion: Helicobacter pylori eradication led to an improvement in reflux symptoms; pH monitoring and endoscopic findings show poor correlation in infants (p= 0.32) (AU)
Asunto(s)
Humanos , Masculino , Niño , Adolescente , Esofagitis Péptica/complicaciones , Esofagitis Péptica/diagnóstico , Endoscopía del Sistema Digestivo/métodos , Endoscopía del Sistema Digestivo/tendencias , Esofagitis Péptica/inducido químicamente , Endoscopía del Sistema Digestivo , Helicobacter pylori/clasificación , Helicobacter pylori/enzimologíaRESUMEN
Nonerosive esophagitis (NEO) - a chronic inflammatory condition with diagnostic and therapy unclear approaches. The aim of study was to develop the new models of NEO using the chemical ulcerogens: carbon tetrachloride (CCl(4)), hydrogen sulfide (H(2)S). We modified the method of NEO with cytoprotective prostaglandins (COX) and H(2)S biosynthesis carried out on rats, divided into groups: 1st - vehicle (1 ml 0.9% NaCl), CCl(4) (twice 0.3 ml/200g/body weight); the next day 2(nd) - vehicle; 3(rd) - nonselective blocker of COX (naproxen; 30 mg/kg); 4(th) - ATB-346 (H(2)S-releasing naproxen; 43.5 mg/kg, «Antibe Therapeutics¼, Canada) with per os administration. After H(2)S-biosythesis modification by intraperitoneal administration of cystathionine g-lyase (CSE) inhibitor, DL-propargylglycine (PAG, 25 mg/kg), cystathionine-b-synthetase (CBS) inhibitor, O-carboxymethyl-hydroxylamine hemihydrochloride (CHH, 50 mg/kg) or H(2)S donor NaHS (100 mlmol/kg), stress was inducted by Takagi, 1964. The lower third of EM and esophagogastric junction were estimated via histological score index, IL-17, IL-10 by ELISA. The obtained data indicated the strong cytotoxic influence of CCl(4) on EM, corneal and epithelial layers thickness increasing, muscle plate and submucosal edema disorganization vs control and ATB-346 treatment. Over-expression of IL-17 was achieved using PAG and BCA vs control. WIRS-associated EM injury with blocking CSE, CBS characterized by submucosal oedema, neutophilic infiltration, destructive lesions, HSI rising up to 6 vs control. Increased IL-17 to 65% and decreased IL-10 in 30% vs control. H(2)S plays key role in the integrity of oesophageal mucosa and modification of H(2)S synthesis and CCl(4)-related injury can be novel approach of animal model production NEO, similar to human NERD and will help in its pathogenesis identification and preventive drugs creation.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Tetracloruro de Carbono , Esofagitis Péptica/inducido químicamente , Esofagitis Péptica/patología , Esófago/patología , Sulfuro de Hidrógeno/metabolismo , Naproxeno/farmacología , Animales , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Esofagitis Péptica/tratamiento farmacológico , Interleucina-10/metabolismo , Interleucina-17/metabolismo , Membrana Mucosa/patología , Óxido Nítrico/metabolismo , Ratas , Ratas WistarRESUMEN
Patients with reflux esophagitis experience an increased incidence of esophageal cancer. In China, this may be the result of contamination of the food supply by Aspergillus fungi, which is known to harbor sterigmatocystin, a carcinogenic mycotoxin. To delineate the potential link between sterigmatocystin and esophageal cancer, an experimental model of reflux esophagitis was developed in rats that had undergone a cardiectomy and partial pylorus ligation. The rats were treated with sterigmatocystin or saline, and esophageal squamous cell hyperplasia was assessed based on the pathological evaluation. The expression of proliferating cell nuclear antigen (PCNA), transporter associated with antigen processing 1 (TAP1) and low molecular weight protein 2 (LMP2) was determined by immunohistochemistry. Intraperitoneal administration of sterigmatocystin promoted the proliferation of squamous epithelium. In addition, it also increased the expression of PCNA in esophageal epithelial cells in rats with reflux esophagitis and was correlated with the increased severity of epithelial hyperplasia. The expression levels of TAP1 and LMP2, which are located in the cytoplasm of esophageal epithelial cells, were reduced in rats with reflux esophagitis, and sterigmatocystin exposure further decreased the expression. Thus, the downregulation of TAP1 and LMP2 proteins by sterigmatocystin may directly affect tumor immunity by allowing transformed cells to escape the host immune surveillance, thereby promoting esophageal cancer.
Asunto(s)
Esterigmatocistina/toxicidad , Transportador de Casetes de Unión a ATP, Subfamilia B, Miembro 2 , Transportadoras de Casetes de Unión a ATP/metabolismo , Animales , Cisteína Endopeptidasas/metabolismo , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Esofagitis Péptica/inducido químicamente , Esofagitis Péptica/patología , Esófago/efectos de los fármacos , Esófago/metabolismo , Esófago/patología , Masculino , Membrana Mucosa/efectos de los fármacos , Membrana Mucosa/metabolismo , Membrana Mucosa/patología , Antígeno Nuclear de Célula en Proliferación/metabolismo , Ratas , Ratas WistarRESUMEN
Nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) has been implicated in both DNA damage induction and aberrant cell signalling in various tissue and cell backgrounds. We investigated here the role of iNOS and NO in DNA damage induction and nuclear factor-kappa B (NF-κB) signalling in esophageal cells in vitro. As esophageal adenocarcinoma develops in a background of Barrett's esophagus secondary to reflux disease, it is possible that inflammatory mediators like NO may be important in esophageal cancer development. We show that reflux components like stomach acid and bile acids [deoxycholic acid (DCA)] can induce iNOS gene and protein expression and produce NO generation in esophageal cells, using real-time PCR, western blotting and NO sensitive fluorescent probes, respectively. This up-regulation of iNOS expression was not dependent on NF-κB activity. DCA-induced DNA damage was independent of NF-κB and only partially dependent on iNOS and NO, as measured by the micronucleus assay. These same reflux constituents also activated the oncogenic transcription factor NF-κB, as measured by transcription factor enzyme-linked immunosorbent assay and gene expression studies with NF-κB linked genes (e.g. interleukin-8). Importantly, we show here for the first time that basal levels of NF-κB activity (and possibly acid and DCA-induced NF-κB) are dependent on iNOS/NO and this may lead to a positive feedback loop whereby induced iNOS is upstream of NF-κB, hence prolonging and potentially amplifying this signalling, presumably through NO activation of NF-κB. Furthermore, we confirm increased protein levels of iNOS in esophageal adenocarcinoma and, therefore, in neoplastic development in the esophagus.
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Ácido Desoxicólico/farmacología , Esofagitis Péptica/metabolismo , Esófago/metabolismo , FN-kappa B/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Óxido Nítrico/metabolismo , Transducción de Señal/efectos de los fármacos , Western Blotting , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Daño del ADN , Esofagitis Péptica/inducido químicamente , Esofagitis Péptica/patología , Esófago/citología , Esófago/efectos de los fármacos , Humanos , Concentración de Iones de Hidrógeno , Técnicas para Inmunoenzimas , Pruebas de Micronúcleos , FN-kappa B/genética , Óxido Nítrico Sintasa de Tipo II/genética , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
The purpose of this study was to develop an acute animal model of reflux esophagitis, which would be suitable to induce the esophageal damage caused by gastric acid reflux, thus mimicking the esophageal injury of human gastroesophageal reflux disease (GERD). Global research indicates that GERD is rapidly increasing among the world's population. NSAIDs are known to induce gastrointestinal damage and low doses of aspirin (ASA) have been shown to increase the incidences of GERD in humans. Gastric acid and pepsin secretion and enhanced COX-2 expression were implicated in the pathogenesis of reflux esophagitis, but the effect of selective COX-2 inhibitors against lesions induced by the reflux of gastric acid content into esophagus has not been thoroughly studied. Here, we compared the effect of aspirin (ASA) and so called "safe" nitric oxide (NO) derivative of ASA with those of non-selective and selective cyclooxygenase (COX)-1 and COX-2 in rat model of reflux esophagitis. Reflux esophagitis was induced in anesthetized rats by ligating the pylorus and limiting ridge transitional region between the forestomach and the corpus of stomach. Subsequently, the total gastric reservoir to store gastric juice was greatly diminished, resulting in the reflux of this juice into the esophagus. Rats with esophagitis received intragastric (i.g.) pretreatment either with: 1) vehicle (saline), 2) ASA or NO-ASA (100 mg/kg); 3) the non-selective COX inhibitor, indomethacin (5 mg/kg); 4) the selective COX-1 inhibitor, SC-560 (10 mg/kg), and 5) the selective COX-2 inhibitor, celecoxib (5 mg/kg). In a separate series of rats with reflux oesophagitis, the efficacy of ASA combined with a donor of NO, glyceryl trinitrate (GTN; 10 mg/kg i.g.) to prevent esophageal mucosal injury was investigated. Four hours after induction of esophagitis the gross mucosal damage was graded with a macroscopic lesion index (LI) from 0-6. The esophageal blood flow (EBF) was determined by H2-gas clearance technique, the oesophageal mucosal and blood samples were collected for histology and analysis of the RT-PCR expression and release of proinflammatory cytokines IL-1ß, TNF-α and IL-6 using specific ELISA. The exposure of the esophagus to reflux of gastric acid time-dependently increased the esophageal LI and morphologic damage, and decreased EBF with the most significant changes observed at 4 hrs after the ligation procedure. The pretreatment with native ASA in the dose that suppressed the generation of mucosal PGE2, enhanced gross and histologic esophageal damage and produced a significant fall in EBF. NO-ASA or ASA coupled with GTN counteracted the aggravation of the damage and accompanying fall in EBF when compared with native ASA applied alone to rats with esophagitis. The proinflammatory cytokines IL-1ß and TNF-α were overexpressed in rats with esophagitis and those pretreated with ASA but this effect was significantly attenuated by NO-ASA. Plasma IL-1ß, TNF-α and IL-6 were negligible in the intact rats but significantly increased in those with esophagitis, with this effect being further enhanced by non-selective (indomethacin) and selective (SC-560, celecoxib) COX-1 and COX-2 inhibitors. We conclude that conventional NSAID such as aspirin augments esophagitis, while NO-ASA exerts the beneficial protective effect against reflux esophagitis via the enhancement of esophageal microcirculation due to NO release and an inhibitory effect on expression and release of pro-inflammatory cytokines.
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Aspirina/análogos & derivados , Citocinas/biosíntesis , Esofagitis Péptica/tratamiento farmacológico , Esofagitis Péptica/metabolismo , Esófago/efectos de los fármacos , Esófago/patología , Donantes de Óxido Nítrico/farmacología , Animales , Antiinflamatorios no Esteroideos/farmacología , Aspirina/farmacología , Celecoxib , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa/farmacología , Citocinas/sangre , Citocinas/genética , Dinoprostona/metabolismo , Esofagitis Péptica/inducido químicamente , Esofagitis Péptica/patología , Esófago/irrigación sanguínea , Esófago/metabolismo , Ácido Gástrico/metabolismo , Humanos , Indometacina/farmacología , Masculino , Óxido Nítrico/farmacología , Nitroglicerina/farmacología , Pirazoles/farmacología , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Ratas , Ratas Wistar , Sulfonamidas/farmacologíaRESUMEN
BACKGROUND AND AIMS: We investigated the incidence of upper gastrointestinal lesions in the esophagus, stomach and duodenum in patients on low-dose aspirin (LDA) therapy. METHODS: The subjects were 101 consecutive outpatients who had been on LDA therapy (average age 67.2 +/- 8.3 years; male : female ratio 3.8:1). All subjects underwent endoscopy without ceasing their antiplatelet or anticoagulant therapy. We investigated the rates of endoscopic peptic ulcer, reflux esophagitis (RE) and malignant lesion. RESULTS: RE was detected in eight subjects and esophageal ulcer in one subject. The severity of RE, according to the Los Angeles classification, was grade A in one subject, B in four, C in two and D in one. All nine subjects (8.9%) with RE and esophageal ulcer were negative for Helicobacter pylori infection. Gastric ulcer was detected in 12 subjects (six H. pylori positive, six negative) and duodenal ulcer in four (one H. pylori positive, three negative). The incidence of gastroduodenal ulcer was 15.8% (16/101). The incidence of esophageal and gastric cancers was high at 5.9% (6/101). Subjects were surveyed using the gastrointestinal symptom rating scale, with no differences in scores for acid reflux, abdominal pain or indigestion according to the presence or absence of RE, gastric ulceration or duodenal ulceration. CONCLUSION: Upper gastrointestinal mucosal injuries and neoplasm were found in not only the stomach, but also the esophagus and duodenum in LDA taking subjects. These results emphasize the importance of endoscopic surveillance in patients on LDA therapy.
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Aspirina/efectos adversos , Fármacos Cardiovasculares/efectos adversos , Úlcera Duodenal/inducido químicamente , Neoplasias Esofágicas/inducido químicamente , Esofagitis Péptica/inducido químicamente , Neoplasias Gástricas/inducido químicamente , Úlcera Gástrica/inducido químicamente , Anciano , Aspirina/administración & dosificación , Fármacos Cardiovasculares/administración & dosificación , Úlcera Duodenal/diagnóstico , Úlcera Duodenal/epidemiología , Endoscopía del Sistema Digestivo , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/epidemiología , Esofagitis Péptica/diagnóstico , Esofagitis Péptica/epidemiología , Femenino , Infecciones por Helicobacter/epidemiología , Infecciones por Helicobacter/microbiología , Helicobacter pylori/aislamiento & purificación , Humanos , Incidencia , Japón/epidemiología , Masculino , Persona de Mediana Edad , Proyectos Piloto , Índice de Severidad de la Enfermedad , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/epidemiología , Úlcera Gástrica/diagnóstico , Úlcera Gástrica/epidemiologíaRESUMEN
OBJECTIVE: To investigate the relationship between use of asthma medication and nitrates and risk of reflux oesophagitis, Barrett's oesophagus and oesophageal adenocarcinoma. MATERIAL AND METHODS: Data were collected on use of asthma medication and nitrates at least 1 year before interview from patients with reflux oesophagitis, Barrett's oesophagus and oesophageal adenocarcinoma. Associations between use of asthma medications and nitrates and the risk of reflux oesophagitis, Barrett's oesophagus and oesophageal adenocarcinoma were estimated using multiple logistic regression. RESULTS: Nine hundred and forty-one subjects were recruited: 230 reflux oesophagitis, 224 Barrett's oesophagus, 227 oesophageal adenocarcinoma patients and 260 population controls. Barrett's oesophagus patients were more likely than controls to have had a diagnosis of asthma (odds ratio 2.15, 95% confidence interval 1.15-4.03) and to have used asthma medications (odds ratio 2.13, 95% confidence interval 1.09-4.16). No significant associations were observed between use of asthma medication or nitrates and reflux oesophagitis or oesophageal adenocarcinoma. CONCLUSIONS: Gastro-oesophageal reflux symptoms appear to confound the association between asthma medication use and Barrett's oesophagus. However, it is possible that asthma medications may increase the risk of Barrett's oesophagus by other mechanisms.
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Adenocarcinoma/inducido químicamente , Antiasmáticos/efectos adversos , Esófago de Barrett/inducido químicamente , Neoplasias Esofágicas/inducido químicamente , Esofagitis Péptica/inducido químicamente , Nitratos/efectos adversos , Anciano , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
BACKGROUND AND OBJECTIVE: Gastroesophageal reflux disease (GERD) has been linked to a number of extra-esophageal symptoms and disorders, primarily in the respiratory tract. Current animal models of reflux esophagitis are adapted to diseases of the digestive system, rather than to reflux-associated respiratory symptoms. The aim of this study was to evaluate a novel external esophageal perfusion model to induce esophageal, tracheal and pneumonic histological injury similar to that associated with GERD. METHODS: Twenty guinea pigs were randomized to the acid-treated or PBS-treated group. Esophageal catheters were used to perfuse the esophageal lumen of guinea pigs with hydrochloric acid containing 1 g/l pepsin or PBS for 14 days. The total cell number and cell differential counts in bronchoalveolar lavage fluid (BALF) were determined 24 h after the last perfusion. Histological changes in the esophageal, tracheal and pneumonic tissues were observed by hematoxylin-eosin staining. RESULTS: The numbers of lymphocytes, eosinophils and total inflammatory cells in the BALF were significantly higher in acid-perfused than PBS-perfused animals. Histological evidence suggested esophageal and pneumonic inflammations were prominent in acid-treated animals. CONCLUSION: Repetitive, acid-perfused, esophageal events copied the animal models of reflux esophagitis, and elicited inflammatory responses in the airways and lungs of guinea pigs.
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Esofagitis Péptica/complicaciones , Esófago , Reflujo Gastroesofágico/complicaciones , Pulmón , Perfusión , Enfermedades Respiratorias/etiología , Tráquea , Animales , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunología , Modelos Animales de Enfermedad , Esofagitis Péptica/inducido químicamente , Esofagitis Péptica/inmunología , Esofagitis Péptica/patología , Esófago/inmunología , Esófago/patología , Estudios de Factibilidad , Femenino , Reflujo Gastroesofágico/inducido químicamente , Reflujo Gastroesofágico/inmunología , Reflujo Gastroesofágico/patología , Cobayas , Ácido Clorhídrico , Pulmón/inmunología , Pulmón/patología , Masculino , Pepsina A , Enfermedades Respiratorias/inmunología , Enfermedades Respiratorias/patología , Factores de Tiempo , Tráquea/inmunología , Tráquea/patologíaRESUMEN
Aspirin is used widely as an antithrombotic drug for the prevention of cardiovascular and cerebrovascular events. Although aspirin increases the risk for gastrointestinal mucosal injury, the effect on esophageal mucosa is unclear. This study investigates whether aspirin induces esophageal mucosal injury and whether a proton-pump inhibitor can prevent such injury in relation to CYP2C19 genotypes. Fifteen healthy Japanese volunteers are dosed for 7 days in a 5-way randomly crossover trial: placebo, aspirin 100 mg, rabeprazole 10 mg, and aspirin 100 mg plus rabeprazole 10 mg either once daily or 4 times per day. All subjects undergo endoscopy and 24-hour intragastric pH monitoring on day 7. With the aspirin regimen, esophageal mucosal disorders occur in 7 patients (46.7%) (5, grade M; 2, grade A). The median 24-hour pH differs significantly among subjects who develop grade M or A gastroesophageal reflux disease and those who do not develop gastroesophageal reflux disease; the median pH in grade A gastroesophageal reflux disease is significantly lower (1.5 [range, 1.1-1.9]) than that in patients without gastroesophageal reflux disease (5.6 [range, 0.8-8.4], P = .04). Rabeprazole significantly inhibits acid secretion irrespective of CYP2C19 genotypes and decreases the incidence of aspirin-related esophageal injury and symptoms according to increasing pH value. Aspirin induces esophageal mucosal injury in an acid-dependent manner. Concomitant proton-pump inhibitor therapy may prevent advanced effects of low-dose aspirin.
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2-Piridinilmetilsulfinilbencimidazoles/uso terapéutico , Antiinflamatorios no Esteroideos/efectos adversos , Antiulcerosos/uso terapéutico , Aspirina/efectos adversos , Esofagitis Péptica/inducido químicamente , Esofagitis Péptica/prevención & control , Mucosa Gástrica/efectos de los fármacos , Reflujo Gastroesofágico/inducido químicamente , Reflujo Gastroesofágico/prevención & control , Inhibidores de Agregación Plaquetaria/efectos adversos , 2-Piridinilmetilsulfinilbencimidazoles/administración & dosificación , Administración Oral , Antiinflamatorios no Esteroideos/administración & dosificación , Antiulcerosos/administración & dosificación , Hidrocarburo de Aril Hidroxilasas/genética , Pueblo Asiatico , Aspirina/administración & dosificación , Estudios Cruzados , Citocromo P-450 CYP2C19 , ADN , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Quimioterapia Combinada , Monitorización del pH Esofágico , Esofagitis Péptica/fisiopatología , Esofagoscopía , Femenino , Mucosa Gástrica/metabolismo , Reflujo Gastroesofágico/fisiopatología , Genotipo , Pirosis/inducido químicamente , Pirosis/prevención & control , Humanos , Japón , Masculino , Mutación , Inhibidores de Agregación Plaquetaria/administración & dosificación , Rabeprazol , Adulto JovenRESUMEN
OBJECTIVE: Incompetence of the lower esophageal sphincter (LES) is a key factor in the pathogenesis of gastroesophageal reflux disease (GERD). Drugs with anticholinergic properties, such as tricyclic antidepressants (TCAs), may facilitate GERD by a relaxing effect on the LES. AIM: To investigate whether the use of TCAs is associated with an increased risk of reflux esophagitis (RE). METHOD: A population-based case-control study was conducted within a large Dutch primary care database over the period 1996-2005. Cases with endoscopy-confirmed RE were identified and matched with up to 10 controls on gender, age, GP practice, and calendar time. Exposure to TCAs was assessed in the year prior to diagnosis and categorized as current (last prescription covered or ended within one month prior to the index date), past, and no use. The relative risk of RE was estimated by odds ratios (OR) with 95% confidence intervals (95% CI) using multivariate conditional logistic regression analysis. RESULTS: During the study period, 1,462 cases with endoscopy-confirmed RE were identified. The risk of RE was increased in current TCA users (OR(adj) 1.61, 95% CI 1.04-2.50). Drug-specific analyses revealed that only clomipramine was associated with an increased risk of RE (OR(adj) 4.6, 95% CI 2.0-10.6) in a duration- and dose-dependent manner (OR(adj) 7.1, 95% CI 2.7-19.2 for use >180 days and OR(adj) 9.2, 95% CI 1.6-51.5 for >1 DDD equivalent/day). CONCLUSION: No association was observed between the risk of RE and the use of TCAs other than clomipramine. The association between RE and clomipramine might be drug-related or a result of the underlying indication.
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Antidepresivos Tricíclicos/efectos adversos , Esofagitis Péptica/inducido químicamente , Estudios de Casos y Controles , Esfínter Esofágico Inferior/efectos de los fármacos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
Peptic ulcer and gastroesophageal reflux are common acid-peptic related diseases. The pathophysiology of peptic ulcer disease has been centered on an imbalance between aggressive and defensive factors. This study was conducted to examine whether the combined use of omeprazole (CAS 73590-58-6), a proton pump inhibitor, and DA-9601, a novel anti-ulcer formulation of the extract of Artemisia asiatica Nakai, has synergistic effects on various peptic ulcers and gastroesophageal reflux diseases in animal models. An optimal combination ratio of omeprazole and DA-9601 was investigated in an acetic acid-induced ulcer model. In the results, oral pretreatment with omeprazole and DA-9601 (combination ratio, 1:3) significantly reduced alcohol-, indometacin-, acetic acid-, and cysteamine-induced gastrointestinal lesions in a synergistical manner in rats. The combination treatment also significantly attenuated the gross and histopathological lesions in an experimental reflux esophagitis model as compared to the single treatment of omeprazole or DA-9601. In an alcohol-induced gastritis model, the combined treatment resulted in a significant decrease in lipid peroxidation with concomitant increases in glutathione content and prostaglandin E2 level, which was proportional to the inhibitory effect of the combination therapy. These results suggest that the combined therapy with omeprazole and DA-9601, a cytoprotectant, can be beneficial for the treatment of peptic ulcer and reflux esophagitis.