High-dose dual therapy is superior to standard first-line or rescue therapy for Helicobacter pylori infection.

BACKGROUND & AIMS: The efficacy of treatment of Helicobacter pylori infection has decreased steadily because of increasing resistance to clarithromycin, metronidazole, and levofloxacin. Resistance to amoxicillin is generally low, and high intragastric pH increases the efficacy of amoxicillin, so we investigated whether a combination of a high-dose proton pump inhibitor and amoxicillin (dual therapy) was more effective than standard first-line or rescue therapies in eradicating H pylori. METHODS: We performed a large-scale multihospital trial to compare the efficacy of a high-dose dual therapy (HDDT) with that of standard therapies in treatment-naive (n = 450) or treatment-experienced (n = 168) patients with H pylori infection. Treatment-naive patients were randomly assigned to groups given HDDT (rabeprazole 20 mg and amoxicillin 750 mg, 4 times/day for 14 days, group A1), sequential therapy for 10 days (group B1), or clarithromycin-containing triple therapy for 7 days (group C1). Treatment-experienced patients were randomly assigned to groups given HDDT for 14 days (group A2), sequential therapy for 10 days (B2), or levofloxacin-containing triple therapy for 7 days (C2). H pylori infection was detected by using the (13)C-urea breath test. We evaluated factors associated with treatment outcomes. RESULTS: In the intention-to-treat analysis, H pylori was eradicated in 95.3% of patients in group A1 (95% confidence interval [CI], 91.9%-98.8%), 85.3% in B1 (95% CI, 79.6%-91.1%), and 80.7% in group C1 (95% CI, 74.3%-87.1%). Infection was eradicated in 89.3% of patients in group A2 (95% CI, 80.9%-97.6%), 51.8% in group B2 (95% CI, 38.3%-65.3%), and 78.6% (95% CI, 67.5%-89.7%) in group C2. The efficacy of HDDT was significantly higher than that of currently recommended regimens, irrespective of CYP2C19 genotype. Bacterial resistance to drugs was associated with treatment failure. There were no significant differences between groups in adverse events or patient adherence. CONCLUSIONS: HDDT is superior to standard regimens as empirical first-line or rescue therapy for H pylori infection, with similar safety profiles and tolerability. ClinicalTrials.gov number: NCT01163435.

Pharmacokinetic- pharmacodynamic analysis of the role of CYP2C19 genotypes in short-term rabeprazole-based triple therapy against Helicobacter pylori.

AIMS: The aim was to explore the role of CYP2C19 polymorphism in short-term rabeprazole-based triple therapy against Helicobacter pylori infection. METHODS: Patients with H. pylori infection were tested for CYP2C19 genotype as poor metabolizers (PMs) or extensive metabolizers (EMs, homozygous EM or heterozygous EM) and given rabeprazole for 7 days. Antibiotics (clarithromycin and amoxicillin) were given on days 1-4, days 4-7, or days 1-7. A direct link model with an effect compartment was used in the population pharmacokinetic-pharmacodynamic analysis. The status of H. pylori infection was evaluated. RESULTS: Rabeprazole clearance was lower in CYP2C19 PMs than in EMs (with average values of 10.7 vs. 16.8 l h(-1) in PMs and EMs, respectively), resulting in higher plasma levels in the former group. The values of EC(50) and k(eo) of gastrin response increased with multiple doses of rabeprazole. The k(eo) values were lower in CYP2C19 PMs than in EMs on day 1 (0.012 vs. 0.017 x 10(-4) l min(-1)), and higher than in EMs on day 4 (0.804 vs. 0.169 x 10(-4) l min(-1)) of rabeprazole treatment. The predicted gastrin-time profile showed a higher response in CYP2C19 PMs than in EMs on days 4 and 7. Helicobacter pylori was eradicated in all CYP2C19 PMs except in one patient infected by a resistant strain. In contrast, in CYP2C19 EMs the eradication rates ranged from 58 to 85%. CONCLUSIONS: CYP2C19 genotypes play a role in H. pylori eradication therapy. Rabeprazole-based short-term triple therapy may be applicable in CYP2C19 PMs for H. pylori eradication.

Effective prevention and treatment of Helicobacter pylori infection using a combination of catechins and sialic acid in AGS cells and BALB/c mice.

The increasing emergence of Helicobacter pylori strains resistant to antibiotics may cause unsuccessful treatment. An alternative agent or mixture with anti-H. pylori effect is urgently required to reduce H. pylori infection. We explored the preventive and therapeutic potential of a combination of catechins and sialic acid on H. pylori-infected human gastric cells in vitro and in mice in vivo. We evaluated the anti-H. pylori activity of catechins and/or sialic acid using the agar dilution and checkerboard methods. The effect of catechins and/or sialic acid on H. pylori infection-induced oxidative stress and apoptosis/autophagy in cell culture was explored using an ultrasensitive chemiluminescence analyzer, immunocytochemistry, and Western blotting. Specific pathogen-free BALB/c mice were divided into uninfected control, infected control, pretreated, and post-treated groups. The effects of catechins/sialic acid were determined by histology and immunocytochemistry. The combination of catechins and sialic acid showed synergistic or additive anti-H. pylori activity and significantly reduced inducible nitric oxide synthase expression and Bax/Bcl-2-mediated apoptosis but enhanced Beclin-1-mediated autophagy. All mice infected with H. pylori displayed gastritis and accumulation of 3-nitrotyrosine and 4-hydroxynonenal. Pretreatment with catechins/sialic acid completely prevented H. pylori infection and resulted in normal histology. Post-treatment with catechins/sialic acid decreased the bacterial load and gastritis score and eradicated up to 60% of H. pylori infections in a dose-dependent manner. This is the first demonstration to our knowledge of a nonprobiotic, nonantibiotic treatment that is 100% effective in preventing and has promising possibilities for treating H. pylori infection. Further studies are needed to confirm this result in humans.

Acute pancreatitis combined with acute Budd-Chiari syndrome as the initial manifestation of small cell lung cancer.

Tumor metastasis to the pancreas is a rare but recognized cause of acute pancreatitis. Autopsy series have reported a 24-40% of pancreatic involvement in small cell lung cancer. However, only a very few cases of tumor-induced acute pancreatitis have been described. Budd-Chiari syndrome complicating lung cancer is a rarely reported condition. We report a 68-year-old woman with extensive small cell lung cancer with the unusual initial presentation of both acute pancreatitis and acute Budd-Chiari syndrome. This patient suffered from progressive epigastralgia for 3 weeks. Severe epigastralgia with radiation to back and progressive jaundice developed 2 days prior to admission. After admission, the liver enlarged rapidly and the ascites increased markedly. Chest roentgenogram showed a mass lesion over the left lower lung field. Poorly differentiated carcinoma cells were found in ascites and bone marrow. The patient died on the ninth day of hospitalization before chemotherapy was initiated. Prompt diagnosis of extensive-stage small cell lung cancer may allow early chemotherapy treatment which favorably influences recovery when the pancreatitis is mild. Although prolonged survival might have been expected had this patient recovered from pancreatitis and received chemotherapy, diagnosis was delayed due to difficulty in immunohistochemical diagnosis of the tumor and the unusual clinical presentation. The use of stains employing antibodies against neurofilament and neuron-specific enolase cell antigens is important for early diagnosis of poorly differentiated metastatic tumor cells.

Time-dependent amplified pharmacokinetic and pharmacodynamic responses of rabeprazole in cytochrome P450 2C19 poor metabolizers.

STUDY OBJECTIVES: To determine the pharmacokinetic and pharmacodynamic rationale for the optimum regimen of rabeprazole in the treatment of Helicobacter pylori infection in patients who are cytochrome P450 (CYP) 2C19 poor metabolizers or extensive metabolizers. DESIGN: Prospective, multiple-dose pharmacokinetic and pharmacodynamic study. SETTING: University-affiliated medical center in Taiwan. SUBJECTS: Twelve healthy volunteers (aged 20-30 yrs) who were identified as CYP2C19 poor metabolizers (six subjects) or extensive metabolizers (six). INTERVENTION: Each subject received rabeprazole 20 mg twice/day for 3 consecutive days and once/day on the fourth day. MEASUREMENTS AND MAIN RESULTS: Pharmacokinetic and pharmacodynamic parameters were compared between CYP2C19 poor and extensive metabolizers on day 1 and day 4 of dosing. The mean +/- SD values of area under the concentration-time curve of rabeprazole and rabeprazole thioether were significantly higher in poor metabolizers than in extensive metabolizers on day 1 (5357 +/- 883 vs 1131 +/- 512 ng x hr/ml and 1703 +/- 432 vs 561 +/- 358 ng x hr/ml, respectively; p<0.001) and on day 4 (5601 +/- 669 vs 1619 +/- 778 ng x hr/ml and 1914 +/- 378 vs 511 +/- 360 ng x hr/ml, respectively; p<0.001). However, no significant difference was noted between day 1 and day 4 of dosing within the same genotype groups. Only CYP2C19 poor metabolizers had significantly higher plasma gastrin levels on day 4 compared with those levels on day 1 (p<0.05). The pharmacokinetic-pharmacodynamic relationship of rabeprazole appears to be time dependent. CONCLUSION: The pharmacokinetic and pharmacodynamic data suggest that CYP2C19 poor metabolizers might be subject to advantageous conditions, especially after day 4, for treating H. pylori infection with rabeprazole.

Density of Helicobacter pylori may affect the efficacy of eradication therapy and ulcer healing in patients with active duodenal ulcers.

AIM: To evaluate the association of pre-treatment Helicobacter pylori (H. pylori) density with bacterial eradication and ulcer healing rates in patients with active duodenal ulcer. METHODS: One hundred and four consecutive duodenal ulcer outpatients with H. pylori infection ascertained by gastric histopathology and (13)C-urea breath test (UBT) were enrolled in this study. H. pylori density was graded histologically according to the Sydney system (normal, mild, moderate, and marked). In each patient, lansoprazole (30 mg b.i.d.), clarithromycin (500 mg b.i.d.) and amoxicillin (1 g b.i.d.) were used for 1 week, then 30 mg lansoprazole once daily was continued for an additional 3 weeks. Follow-up endoscopy was performed at 4 weeks after completion of the therapy, and UBT was done at 4 and 8 weeks after completion of the therapy. RESULTS: The H. pylori eradication rates were 88.9 %/100.0 %, 94.3 %/100.0 %, and 69.7 %/85.2 %; and the ulcer healing rates were 88.9 %/100.0 %, 94.3 %/100.0 %, and 63.6 %/77.8 % (intention-to-treat/per protocol analysis) in the mild, moderate, and marked H. pylori density groups, respectively. The association of pretreatment H. pylori density with the eradication rate and ulcer healing rate was both statistically significant (P=0.013/0.006 and 0.002/<0.001, respectively; using results of intention-to-treat/per protocol analysis). CONCLUSION: Intragastric bacterial load may affect both the outcome of eradication treatment and ulcer healing in patients with active duodenal ulcer disease.

Clinicopathologic significance of immunohistochemical fecal occult blood test in subjects receiving bidirectional endoscopy.

BACKGROUND/AIMS: Fecal occult blood test has been utilized to screen for lower gastrointestinal pathologies, such as colorectal cancer and polyps that bleed. Recent studies have revealed a relatively high frequency of upper gastrointestinal abnormalities in subjects with positive fecal occult blood by guaiac-based method. Although immunohistochemical tests of fecal occult blood were assumed to have greater diagnostic validity, the distribution of gastrointestinal pathology using such examinations is not well established. This study aims to investigate the efficacy of immunohistochemical analysis of fecal occult blood in detecting upper and lower gastrointestinal lesions in asymptomatic individuals. METHODOLOGY: Subjects who underwent regular health checkups were enrolled if they received both esophagogastroscopic and colonoscopic examinations. Each subject was tested by an immunohistochemical fecal occult blood test. The fecal occult blood results were evaluated and correlated with lesions identified in endoscopic examinations. RESULTS: In total 655 males and 722 females with age 46.2 +/- 12.1 years were enrolled, 287 cases (20.7%) had polypoid lesions of colon, including 6 colon cancers, 37 with polyps > or = 1 cm, 104 with polyp 5-9 mm, and 140 with polyp < 5 mm. FOB was positive in 31 cases, of which 15 (15/31, 48.4%) were polypoid lesions of colon, 1 was colonic ulcer, 9 (29.0%) were active gastroduodenal ulcers but 6 (19.4%) had no significant lesions. The positive and negative predictive value for colon polyps was 48.4% and 80%, respectively. The sensitivity was 50% (3/6) for colon cancer and varied among polyps with different sizes: 16.2% (6/37) for polyps > or = 1 cm; 5.8% (6/104) for polyps 5-9 mm and 0% (0/140) for polyps < 5 mm. CONCLUSIONS: A substantial portion of subjects (29%) with positive fecal occult blood reaction of immunohistochemical analysis but negative colonoscopy still needs esophagogastroscopic examination to disclose upper gastrointestinal lesions. Immunohistochemical determination of fecal occult blood remains imperfect for polypoid lesions of colon in view of its sensitivity and specificity.

Limited value of typical gastroesophageal reflux disease symptoms to screen for erosive esophagitis in Taiwanese.

BACKGROUND AND PURPOSE: The predictive value of gastroesophageal reflux disease (GERD) symptoms for erosive esophagitis is controversial. This study evaluated the sensitivity of heartburn and acid regurgitation as indicators of erosive esophagitis in Taiwanese. METHODS: Data collected from 521 consecutive health check-up participants who received panendoscopy and completed a self-administered questionnaire for GERD were analyzed. A classification system was used based on the presence of typical symptoms (heartburn or acid regurgitation) experienced 1 or more times per week (I), less than once per week, but more than once per month (II), and in the past (III), and in subjects free of typical symptoms, comprised those with atypical symptoms (IV), extraesophageal symptoms (V), both atypical and extraesophageal symptoms (VI), and lack of all of the above symptoms (VII). The Los Angeles classification was used for the endoscopic assessment of erosive esophagitis. RESULTS: The sensitivity, positive predictive value (PPV), and specificity of criteria I+II were 30.5%, 32%, and 78.9%, respectively, for erosive esophagitis in Taiwanese. Inclusion of symptoms in category III increased sensitivity by 13.3%. Combined symptoms in categories IV+V+VI had the highest negative predictive value of 85.5% and a fair specificity of 73.8% for those free of typical symptoms. In the overall classification system, the combination of symptoms in categories IV+V+VI increased sensitivity by 17.9 to 61.7%, and decreased specificity by 26.3 to 40.4%. The most specific indicator was symptoms in category I (with a PPV of 45% for erosive esophagitis in symptomatic patients). About two-fifths (38.3%) of patients with erosive esophagitis had none of the symptoms in the classification system. CONCLUSIONS: Heartburn and acid regurgitation are insensitive predictors of erosive esophagitis in Taiwanese. Step-wise addition of previous typical symptoms, currently atypical and extraesophageal symptoms to the "heartburn and acid regurgitation" criterion can greatly increase sensitivity, but endoscopy remains the method of choice to detect erosive esophagitis.

Correlation between the degree of duodenal bulbar deformity and the density of Helicobacter pylori infection in patients with active duodenal ulcers.

BACKGROUND: Duodenal ulcer with deformity of the bulb is evidence of a chronic process of ulcer disease. This prospective study was carried out to investigate the relationship between the degree of bulbar deformity and the density of Helicobacter pylori infection in patients with duodenal ulcer. METHODS: Patients with endoscopically proven active duodenal ulcers and a positive diagnosis of H. pylori infection were enrolled. Duodenal ulcers were divided into three types according to the degree of deformity of the bulb: type I, normal bulb; type II, mildly deformed; type III, markedly deformed. In each case, we evaluated the H. pylori density histologically. The density was graded according to the Sydney system (normal, mild, moderate, and marked). RESULTS: A total of 95 duodenal ulcer patients were studied, including 25 with type I, 40 with type II, and 30 with type III duodenal ulcers. H. pylori density was correlated with deformity of the duodenal bulb: 16/25 (64%) patients with a type I ulcer had mild infection, 19/40 (47.5%) patients with a type II ulcer had moderate infection, and 15/30 (50%) patients with a type III ulcer had marked infection. CONCLUSION: Patients with active type II or III duodenal ulcers had greater densities of H. pylori than did those with type I ulcers. A tendency for higher H. pylori density was seen as the degree of deformity of the duodenal bulb increased.

Catechins and Sialic Acid Attenuate Helicobacter pylori-Triggered Epithelial Caspase-1 Activity and Eradicate Helicobacter pylori Infection.

The inflammasome/caspase-1 signaling pathway in immune cells plays a critical role in bacterial pathogenesis; however, the regulation of this pathway in the gastric epithelium during Helicobacter pylori infection is yet to be elucidated. Here, we investigated the effect of catechins (CAs), sialic acid (SA), or combination of CA and SA (CASA) on H. pylori-induced caspase-1-mediated epithelial damage, as well as H. pylori colonization in vitro (AGS cells) and in vivo (BALB/c mice). Our results indicate that the activity of caspase-1 and the expression of its downstream substrate IL-1 ß were upregulated in H. pylori-infected AGS cells. In addition, we observed increased oxidative stress, NADPH oxidase gp91phox, CD68, caspase-1/IL-1 ß , and apoptosis, but decreased autophagy, in the gastric mucosa of H. pylori-infected mice. We have further demonstrated that treatment with CASA led to synergistic anti-H. pylori activity and was more effective than treatment with CA or SA alone. In particular, treatment with CASA for 10 days eradicated H. pylori infection in up to 95% of H. pylori-infected mice. Taken together, we suggest that the pathogenesis of H. pylori involves a gastric epithelial inflammasome/caspase-1 signaling pathway, and our results show that CASA was able to attenuate this pathway and effectively eradicate H. pylori infection.

Role of omeprazole dosage and cytochrome P450 2C19 genotype in patients receiving omeprazole-amoxicillin dual therapy for Helicobacter pylori eradication.

STUDY OBJECTIVE: To determine the factors that may influence Helicobacter pylori eradication in patients receiving omeprazole-amoxicillin dual therapy. DESIGN: Prospective, randomized study. SETTING: University-affiliated hospital in Taiwan. PATIENTS: A total of 128 adults (age range 20-75 yrs) with H. pylori-positive duodenal ulcer were enrolled; 121 completed the final evaluation. INTERVENTION: Patients were randomly assigned to one of four omeprazole-amoxicillin treatment groups, with each treatment administered for 2 weeks: O2A2 group (33 patients)--omeprazole 20 mg twice/day plus amoxicillin 500 mg 4 times/day; O2A1 group (32 patients)--omeprazole 20 mg twice/day plus amoxicillin 250 mg 4 times/day; O1A2 group (32 patients)--omeprazole 20 mg once/day plus amoxicillin 500 mg 4 times/day; and O1A1 group (31 patients)--omeprazole 20 mg once/day plus amoxicillin 250 mg 4 times/day. MEASUREMENTS AND MAIN RESULTS: Data were collected on H. pylori status, histologic parameters, antibiotic resistance, intragastric pH, cytochrome P450 (CYP) 2C19 genotype, and adverse reactions. The intent-to-treat cure rates (95% confidence interval [CI]) in groups O2A2, O2A1, O1A2, and O1A1 were 76% (95% CI 59-87%), 72% (95% CI 54-84%), 50% (95% CI 34-66%) and 52% (95% CI 35-68%), respectively. Eradication of H. pylori infection was statistically significantly dependent on omeprazole dosage, CYP2C19 genotype, age, gastritis status, and H. pylori density. All CYP2C19 poor metabolizers were cured, whereas the H. pylori cure rate in CYP2C19 extensive metabolizers varied from 44-76% in the different treatment groups. Eradication of H. pylori was favored in the omeprazole higher dose groups versus the lower dose groups (79% vs 53%, p=0.004). No secondary antibiotic resistance was found. Thirty-seven (95%) of 39 patients who failed with the initial treatment were cured by subsequent antibiotic susceptibility-driven proton pump inhibitor-based triple therapy. CONCLUSION: Provided a maintenance dose of amoxicillin is given every 6 hours, eradication of H. pylori infection was significantly dependent on omeprazole dosage, CYP2C19 genotype, age, gastritis status, and H. pylori density.

Abnormal gastroesophageal flap valve is highly associated with gastroesophageal reflux disease among subjects undergoing routine endoscopy in Taiwan.

OBJECTIVE: Gastroesophageal flap valve (GEFV) grade predicts severe gastroesophageal reflux disease in Caucasians, but its role in other populations is unclear. This study evaluated the significance of endoscopic grading of the GEFV in Taiwanese subjects. METHODS: Five hundred and six consecutive patients undergoing routine check-ups at the National Taiwan University Hospital were enrolled. Symptoms of upper gastrointestinal disease and endoscopic severity of esophageal mucosal injury were correlated to GEFV grades according to the Hill classification. RESULTS: The frequency of abnormal valves (Hill grades III or IV) was 27.3%. Of these, 42.7% had erosive esophagitis (EE). The majority of patients with EE were classified as Los Angeles grades A and B (79.7 and 16.9%, respectively). The prevalence of EE, hiatal hernia and, to a lesser degree, non-erosive reflux disease, increased with altered GEFV. Patients with abnormal valves were younger and more likely to be male, overweight, and to have atypical and extraesophageal symptoms. CONCLUSIONS: Taiwanese patients with abnormal GEFVs share similar characteristics and risk factors with the patients who have EE. Endoscopic grading of the GEFV is highly associated with GERD, and in particular EE, in subjects undergoing routine endoscopy.

Transfusion-transmitted HBV infection in an endemic area: the necessity of more sensitive screening for HBV carriers.

BACKGROUND: By NAT, HBV DNA is occasionally detectable in blood donors with past HBV infection but negative for HBsAg. Whether or not these donors can cause transfusion-transmitted HBV infections is uncertain. STUDY DESIGN AND METHODS: To determine whether or not donors with past HBV infection but negative for HbsAg can cause HBV transfusion-transmitted infections, recipients followed for blood transfusion in a university medical center in Taiwan were studied. HBV DNA and serologic markers were tested in donors and recipients. RESULTS: Of 1,038 enrolled recipients, 910 completed the 6-month post-transfusion follow-up visit. Of these, only 39 patients (4.3%) tested negative on the pretransfusion sample for HBsAg, anti-HBs, anti-HBc, and HBV DNA by PCR. These 39 HBV-naive recipients had been transfused with blood from 147 donations for which stored samples were available for HBV DNA testing by PCR; 11 of these HBsAg-negative samples tested positive for HBV DNA and anti-HBc. Two of the 11 patients who received the HBV-DNA-positive donations (18%) became positive for HBV DNA, and one seroconverted to anti-HBc and finally to anti-HBs, with a mild transient elevation of serum ALT activities. Based on the one confirmed case of HBV transmission, a projection was made that approximately 200 post-transfusion HBV infections could occur in one million units of transfused blood in Taiwan. CONCLUSIONS: In HBV-endemic areas like Taiwan, where blood donors are screened for HBsAg only, the risk of transfusion-transmitted HBV appears to be substantial. Implementation of NAT for blood screening in these settings warrants consideration.