Rabeprazole reduces the recurrence risk of peptic ulcers associated with low-dose aspirin in patients with cardiovascular or cerebrovascular disease: a prospective randomized active-controlled trial.

BACKGROUND: Patients using low-dose aspirin (LDA) have an increased risk of gastroduodenal mucosal lesions and upper gastrointestinal symptoms. We aimed to clarify the efficacy of rabeprazole for preventing peptic ulcer, esophagitis, and gastrointestinal symptoms associated with LDA. METHODS: Patients with a history of peptic ulcers who were receiving LDA for cardiovascular or cerebrovascular disease were randomly assigned to receive rabeprazole at 10 mg daily, rabeprazole at 20 mg daily, or gefarnate (a cytoprotective anti-ulcer agent) at 50 mg twice daily. The primary endpoint was the development of gastric and/or duodenal ulcer at 12 weeks. The modified Lanza score (MLS) and gastrointestinal symptoms were evaluated at baseline and at 12 weeks. RESULTS: The full analysis set comprised 261 patients (rabeprazole 10 mg: n = 87, rabeprazole 20 mg: n = 89, gefarnate 100 mg: n = 85). The cumulative incidences of gastroduodenal ulcers at 12 weeks in the 10 mg rabeprazole group, 20 mg rabeprazole group, and gefarnate group were 7.4, 3.7, and 26.7 %, respectively (rabeprazole group 5.5 % vs. gefarnate group 26.7 %, hazard ratio [HR] 0.179; 95 % confidence interval [CI] 0.082-0.394; p < 0.0001). The proportions of patients with an MLS of ≥1 and erosive esophagitis were significantly lower in the rabeprazole group than in the gefarnate group at 12 weeks (gastric lesions 33.5 vs. 62.4 %, p < 0.0001; duodenal lesions 5.7 vs. 24.7 %, p < 0.0001; erosive esophagitis 5.8 vs. 19.4 %, p < 0.0001). Rabeprazole was significantly more effective than gefarnate for the resolution and prevention of gastrointestinal symptoms (resolution 53.6 vs. 25.0 %, p = 0.017; occurrence 9.2 vs. 28.3 %, p = 0.0026). CONCLUSIONS: Rabeprazole is more effective than gefarnate for reducing the risk of recurrence of peptic ulcer, esophagitis, and gastrointestinal symptoms in LDA users.

Helicobacter pylori causes runx3 gene methylation and its loss of expression in gastric epithelial cells, which is mediated by nitric oxide produced by macrophages.

Previous reports have indicated that Helicobacter pylori (H. pylori) causes epigenetic changes of certain genes such as cancer suppression genes, which may be associated with carcinogenesis. However, the mechanism by which it causes epigenetic changes in certain genes and not in others is unclear. Presently, we focused on a cancer suppression gene, runx3, and demonstrated the following: (1) H. pylori induces nitric oxide (NO) production in macrophages. (2) NO causes methylation of runx3 in epithelial cells. (3) H. pylori induces the methylation of epithelial cells in the presence of macrophages, which is reversed by an NO-specific inhibitor. These results indicate that H. pylori-induced methylation is mediated by NO, and suggest that NO may be a key to the mechanism of how H. pylori causes epigenetic changes in certain genes. Additionally, we demonstrated that lipopolysaccharide, as well as H. pylori, induces NO-mediated methylation, indicating that other inflammation inducers beside H. pylori might induce aberrant methylation of runx3.

Proton pump inhibitors and recurrent bleeding in peptic ulcer disease.

Peptic ulcer disease (PUD) is one of the main lesions responsible for upper gastrointestinal (GI) bleeding, as well as esophageal varices and Mallory-Weiss tear. Helicobacter pylori and non-steroidal anti-inflammatory drugs (NSAIDs)/aspirin are the major responsible causes. In cases of upper GI bleeding, urgent endoscopy is performed after stabilization of vital signs. There are several modalities for controlling bleeding in PUD, such as ethanol injection or hypertonic saline with epinephrine. Recurrent bleeding occurs in 20% of patients after endoscopic therapy. The combination of endoscopic intervention and a proton pump inhibitor (PPI) is necessary to achieve hemostasis of active bleeding. It has been reported that high-dose omeprazole (80 mg bolus injection, then 8 mg/h continuous infusion for 72 h, then 40 mg/day orally for 1 week) can reduce recurrent bleeding, the need for surgery and mortality from hemorrhagic shock in patients with high-risk peptic ulcer bleeding, as compared with standard-dose omeprazole. The metabolism of PPIs is dependent upon P450 2C19 genotypes and the clinical usefulness of genotypic analysis remains to be determined.

Measurement of serum branched-chain amino acids to tyrosine ratio level is useful in a prediction of a change of serum albumin level in chronic liver disease.

AIM: In patients with hepatitis C virus (HCV)-associated chronic liver diseases, especially in those with liver cirrhosis, accurate evaluation of their protein nutrition status is very important to improve their quality of life. Whereas the serum albumin level is commonly used to evaluate patients' protein nutrition status, in the present study, the serum amino acid levels were measured, as they also provide valuable information. METHODS: Serum albumin levels and branched-chain amino acids (BCAA) to tyrosine ratio (BTR) were determined in 447 patients with HCV-associated chronic liver diseases (313 with chronic hepatitis and 134 with liver cirrhosis). RESULTS: Chronic hepatitis progressed to liver cirrhosis, serum albumin and serum BTR levels decreased significantlyas chronic hepatitis progressed to liver cirrhosis. Hypoalbuminemia was significantly more common in patients with liver cirrhosis than in those with chronic hepatitis; however, the incidence of an amino acid imbalance was significantly higher than that of hypoalbuminemia in patients with liver cirrhosis. The presence of an amino acid imbalance was associated with a reduction in the serum albumin level 1 year later. CONCLUSIONS: It is important to evaluate serum albumin levels and the BTR in patients with HCV-associated chronic liver diseases.

Effect of symptomatic gastroesophageal reflux disease on quality of life of patients with chronic liver disease.

AIM: Reflux esophagitis is becoming increasingly more prevalent in Japan. It has been noted that symptomatic gastroesophageal reflux disease (GERD) and chronic liver disease may adversely affect patients' quality of life. METHODS: In the present study, 238 chronic liver disease patients (151 patients with chronic hepatitis and 87 patients with liver cirrhosis) were enrolled. The diagnosis of GERD was made based on the Quality-of-Life and Utility Evaluation Survey Technology questionnaire. Health-related quality of life was evaluated using the Short Forum 36 questionnaire. RESULTS: Symptomatic GERD was present in 31.8% (48/151) of patients with chronic hepatitis and 36.8% (32/87) of patients with liver cirrhosis. Among the chronic hepatitis group, compared to the GERD-negative group, the GERD-positive group had significantly lower scores in six domains, including "rolelimitation due to physical problem", "bodily pain", "general health perception", "vitality", "role limitation due to emotional problem", and "mental health". Among the cirrhotic group, compared to the GERD-negative group, the GERD-positive group had significantly lower scores in the "role limitation due to emotional problem" domain. Significant improvement in the "physical functioning", "bodily pain", and "general health perception" domain scores was noted in chronic hepatitis patients treated with rabeprazole. CONCLUSION: The QOL of chronic liver disease patients with symptomatic GERD was impaired.

Protective effect of n-3 polyunsaturated fatty acid on primary culture of rat hepatocytes.

BACKGROUND AND AIM: Recently, we reported on the beneficial clinical effects of eicosapentaenoic acid (EPA) in patients with primary biliary cirrhosis (PBC) who were unresponsive to ursodeoxycholic acid (UDCA). In this study we examined the effect of EPA on rat hepatocytes in primary culture. METHODS: Hepatocytes were isolated from rat liver by perfusion of collagenase and cultured with or without EPA. Cell damage induced by chenodeoxycholic acid (CDCA) was assessed by WST-8 assay and lactate dehydrogenase (LDH) release. PGE(2) and LTB(4) concentrations in the culture medium were measured by enzyme-linked immunosorbent assay (ELISA). cDNA was made from total RNA that was extracted from hepatocytes, and TaqMan polymerase chain reaction (PCR) was performed to assess the expression of CuZn and Mn superoxide dismutase (SOD) mRNA. RESULTS: When rat hepatocytes were cultured in the presence of EPA, the damage caused by CDCA was significantly decreased compared with cells cultured without EPA. Cytotoxicity significantly decreased in the presence of EPA. Furthermore, SOD mRNA expression was increased by adding EPA. These findings indicated that EPA protects cells by scavenging superoxide radicals ((*)O(2-)) mediated by SOD production. CONCLUSION: EPA has a direct protective effect on rat hepatocytes, which is in agreement with the clinical efficacy of EPA in PBC patients.

[PPI-test].

GERD (gastro esophageal reflux disease) is defined as a condition that develops when the reflux of stomach contents causes troublesome symptoms and/or complications. Endoscopic-positive GERD can be easily diagnosed with endoscopy, while endoscopic-negative GERD cannot be. PPI test, which reveals the disorders by judging symptom-relief after PPI administration, is an effective tool for diagnosis of NERD, and extraesophageal GERD such as LPRD and bronchial asthma. Diagnostic power of PPI test is limited owing to the low PPI's cure rate against NERD, about 40%. PPI test-negative NERD is considered as non-acid associated NERD. Most of the NERD patients have the symptoms of functional dyspepsia(FD) for which the most effective medication is PPI administration, leading to the notion that subgroup of GERD and FD is considered as an acid associated disorder. This diagnostic entity is practical in a sense that anti-acid treatment is very effective for this disease. Besides, PPI test is a very useful tool to differentiate acid associated disorder from GERD and/or FD.

The pharmacodynamic effect of omeprazole 10 mg and 20 mg once daily in patients with nonerosive reflux disease in Japan.

BACKGROUND: To evaluate the pharmacodynamic effect, efficacy, and safety of omeprazole 10 mg and 20 mg once daily in patients with nonerosive reflux disease (NERD) in Japan. METHODS: A total of 37 patients were randomized to omeprazole 10 mg or omeprazole 20 mg once daily for 4 weeks. Eligible patients had a history of moderate-to-severe heartburn for 2 days or more per week during the last 1 month or longer prior to the study screening, grade M or grade N on Hoshihara's modification of the Los Angeles classification (i.e., no sign of mucosal break on esophagogastroduodenoscopy), and heartburn episodes for 2 days or more per week during the last week of the observation period while taking antacids. Ambulatory 24-h intraesophageal pH was monitored on the day before treatment and on the last day of treatment. The occurrence of a heartburn episode was recorded during pH monitoring. The primary endpoint was the change in the percentage of time with intraesophageal pH < 4 during the 24-h period before and after omeprazole treatment. RESULTS: Both omeprazole 10 mg and omeprazole 20 mg once daily reduced the percentage of time with intraesophageal pH < 4. The percentage reduction in time with intraesophageal pH < 4 after treatment with omeprazole was associated with a reduced number of heartburn episodes. Patients with grade M or grade N esophagus had similar pH profiles and NERD characteristics (e.g., pH holding time, symptom index) and comparable responses to omeprazole. No serious, drug-related adverse events were reported. CONCLUSIONS: Omeprazole 10 mg or 20 mg reduces the percentage of time with intraesophageal pH < 4, is efficacious, and is well tolerated in patients with NERD in Japan, regardless of the patient's endoscopic classification.

Case-control study on the association of upper gastrointestinal bleeding and nonsteroidal anti-inflammatory drugs in Japan.

OBJECTIVE: Studies in Western populations have shown the association of nonsteroidal anti-inflammatory drugs (NSAIDs) and upper gastrointestinal bleeding (UGIB). The role of Helicobacter pylori infection in NSAIDs-related UGIB remains to be studied. We conducted a case-control study in Japan to investigate these related topics. METHODS: Cases of UGIB due to duodenal or gastric ulcer, or gastritis were identified in 14 study hospitals in various areas of Japan. For each case, two controls were identified from population registries in the same district. Information on drugs and other risk factors was obtained from 175 cases and 347 controls by telephone interviews. Anti-H. pylori antibody in the urine was measured in a single laboratory for all the cases and 225 controls. RESULTS: The odds ratio (OR) of UGIB was 5.5 for aspirin and 6.1 for other NSAIDs (NANSAIDs) (p<0.01). The OR for regular use was higher than for occasional use both for aspirin (7.7 vs 2.0) and NANSAIDs (7.3 vs 4.1). Loxoprofen (5.9), frequently used in Japan as a safe 'prodrug', was significantly associated with UGIB. The odds ratio for H. pylori infection was 4.9 and the relative excess risk due to the interaction between H. pylori and the use of NSAID was 1.2 (95% CI: -5.8-8.1). CONCLUSION: NSAIDs including loxoprofen increase the risk of UGIB in Japan as in Western countries, with a similar magnitude of association. There was no evidence of biological interaction between NSAIDs and H. pylori infection.

Efficacy of a Low-Dose Omeprazole-Based Triple-Therapy Regimen for Helicobacter pylori Eradication Independent of Cytochrome P450 Genotype : The Japanese MACH Study.

OBJECTIVES: To investigate the efficacies of two different triple-therapy regimens (standard versus low doses), and the influence of cytochrome P450 enzyme (CYP) genetic polymorphism on these efficacies, in Japanese patients undergoing Helicobacter pylori eradication treatment. METHODS: All patients received 1 week of triple therapy. Patients in group A (low-dose regimen) received omeprazole 40 mg/day + amoxicillin 1500 mg/day + clarithromycin 800 mg/day; patients in group B (standard-dose regimen) received omeprazole 40 mg/day + amoxicillin 2000 mg/day + clarithromycin 1000 mg/day. RESULTS: A total of 225 patients (113 in group A and 112 in group B) were randomised to one of the two triple-therapy regimens. The eradication rates were 78.8% (89/113 patients; 95% CI 70.1, 85.9) in group A and 83.0% (93/112 patients; 95% CI 74.8, 89.5) in group B. Genetic polymorphism of CYP2C19, a major metabolic enzyme of omeprazole, did not affect eradication rates, while susceptibility to clarithromycin greatly affected the success of eradication. The cumulative ulcer relapse rate at 24 weeks after endoscopically documented ulcer healing (30 weeks after completion of the drug regimen) was 8.3% for group A and 12.5% for group B (log rank test: p = 0.6248). However, comparison of the cumulative relapse rate of 6.7% in patients after successful H. pylori eradication with the relapse rate of 27.3% in those who failed H. pylori eradication revealed a significant difference in the remission-time curve (log rank test: p = 0.0047). This finding suggested the existence of a relationship between H. pylori eradication failure and ulcer relapse. Both drug regimens were well tolerated. Endoscopically proven reflux esophagitis developed in about 10% of patients after eradication, but was not clinically significant. CONCLUSIONS: One week of triple therapy with a low-dose regimen provides adequate H. pylori eradication in Japanese patients. CYP genetic polymorphism is of minimal clinical significance with both triple-therapy regimens.

[Significance of PPI-test in the diagnosis of GERD].

Gastroesophageal reflux disease (GERD) is defined as 'Chronic symptoms or mucosal damage produced by the abnormal reflux of gastric contents into the esophagus'. Reflux esophagitis refers to a subgroup of GERD patients with histopathologically demonstrated characteristic changes in the esophageal mucosa. Besides, GERD includes symptoms without endoscopic findings (endoscopic negative GERD) and extra-esophageal symptoms. Therefore, GERD cannot be diagnosed only by endoscopy. Three methods are indispensable in the diagnosis of GERD; endoscopy, evaluation of patient symptoms and acid reflux. Since 'Symptom relief is well correlated with the degree or suppression of gastric acid secretion in GERD', symptom in relation to acid reflux can be evaluated by PPI-test. Characteristics of PPI-test including extra-esophageal GERD diagnosis are discussed in this review.

Clinical significance of KL-6, a marker of interstitial pneumonia, in cases of HCV-associated chronic liver disease.

OBJECTIVE: Various antiviral therapies, including interferon therapy, are being conducted to treat chronic hepatitis C and suppress the onset of hepatocellular carcinoma. However, interstitial pneumonia is beginning to be recognized as one of the adverse reactions of this therapy, and is one of the complications associated with chronic hepatitis. Therefore, we measured the level of KL-6, an interstitial pneumonia marker, in patients with HCV-associated chronic disease, and then determined the possibility of utilizing serum KL-6 as a predictive factor for interstitial pneumonia and the clinical significance of KL-6 in HCV-associated chronic disease. SUBJECTS AND METHODS: The subjects were 308 patients who were diagnosed with chronic liver disease through biochemical blood tests and abdominal diagnostic imaging. All patients tested positive for either the HCV antibody or HCV-RNA, and those who were suspected of having autoimmune hepatitis were excluded. One hundred eighty-five patients had chronic hepatitis (average age: 56 +/- 14 years), while 123 patients had liver cirrhosis (average age: 64 +/- 9 years). The purpose of the present study was explained to every subject, and informed consent was obtained. RESULTS: The mean KL-6 level for chronic hepatitis patients without interstitial pneumonia was 283.5 +/- 131.4 U/ml, while that for cirrhotic patients without interstitial pneumonia was significantly higher, at 377.6 +/- 212.1 U/ml (p<0.0001). In addition, with a cut-off value of 500 U/ml, the ratio of high KL-6 for the chronic hepatitis patients was 5.41% (10/185), while that for the cirrhotic patients was significantly higher, at 20.33% (25/123) (p<0.0001). Furthermore, the mean KL-6 level for patients with a serum hyaluronic acid level of less than 100 ng/ml was 258.4 +/- 124.6 U/ml, while that for patients with a serum hyaluronic acid level of 100 ng/ml or above was significantly higher, at 381.0 +/- 197.3 U/ml (p<0.0001). CONCLUSION: Although KL-6 is a marker of interstitial pneumonia, the results of the present study suggest that, in HCV-associated chronic disease, this marker reflects hepatic fibrosis better than pulmonary fibrosis.

Follow-up survey of a large-scale multicenter, double-blind study of triple therapy with lansoprazole, amoxicillin, and clarithromycin for eradication of Helicobacter pylori in Japanese peptic ulcer patients.

BACKGROUND: To evaluate histopathological changes and effects on inhibition of ulcer recurrence, a follow-up survey was performed in Japanese patients with Helicobacter pylori-positive active peptic ulcers. These patients had previously participated in a large-scale multicenter trial of triple therapy with lansoprazole (LPZ)/amoxicillin (AMPC)/clarithromycin (CAM) for eradication of H. pylori. METHODS: Patients who had been treated with LPZ only or a combination of LPZ, AMPC, and CAM for a period of 7 days and in whom ulcer healing had been confirmed after treatment were grouped according to successful or failed eradication of H. pylori. They were examined endoscopically to determine whether ulcers had recurred. The updated Sydney system was applied to study histological changes after H. pylori eradication therapy, compared with baseline. RESULTS: Twelve months after treatment for H. pylorieradication, gastric ulcers had recurred in 11.4% of those with successful H. pylorieradication and in 64.5% of those with unsuccessful H. pylori eradication. Duodenal ulcers had recurred in 6.8% of patients for whom H. pylori eradication was successful and in 85.3% of patients in whom eradication failed. These findings proved that H. pylori eradication significantly reduced ulcer recurrence ( P < 0.0001 for both types of ulcers). Histopathological findings of inflammation and activity grade in both gastric and duodenal ulcers were more favorable in patients with successful eradication than in those with unsuccessful eradication. CONCLUSIONS: H. pylori eradication significantly inhibited ulcer recurrence in Japanese peptic ulcer patients. Histopathological findings were also improved with regard to inflammation and activity (neutrophils) in patients in whom H. pylori eradication was successful.

Virtual endoscopy: current perspectives.

Virtual endoscopy is a new method for evaluating the gastrointestinal tract using either thin-section computed tomography (CT) or magnetic resonance imaging (MRI). The acquired data are then subjected to computer manipulation to render images simulating the conventional endoscopic view. CT and MR imaging data can provide information that is not accessible endoscopically. These important features include information on tissue extending through and beyond organ walls and the anatomic context of the entire gastrointestinal tract, which permits correct anatomic localization of the lesion. Many clinical studies have shown that it is a safe, noninvasive, well-tolerated alternative to conventional endoscopy. Virtual endoscopy may have potential as a method of screening for colorectal cancer. This review describes the technique, reviews reported results, and discusses the present and future applications of this technique, focusing on CT colography (CTC).