Pylori-negative Healthy Subjects Research Articles

Effects of Helicobacter pylori Infection on the Expressions and Functional Activities of Human Duodenal Mucosal Bicarbonate Transport Proteins.

The mechanisms for Helicobacter pylori (H. pylori)-induced duodenal ulcerogenesis are not fully understood. In this study, we investigated the effects of H. pylori infection on the expressions and functional activities of human duodenal mucosal bicarbonate transport proteins and hope to further clarify the pathogenesis of H. pylori-associated duodenal ulcer. The experiments were performed in the patients with H. pylori-associated duodenal ulcers, H. pylori-associated chronic gastritis, and H. pylori-negative healthy subjects. Duodenal mucosal bicarbonate secretion was measured by Ussing Chamber technology. The expressions of duodenal mucosal bicarbonate transport proteins, CFTR (cystic fibrosis transmembrane conductance regulator) and SLC26A6 (solute-linked carrier 26 gene A6), in the patients with H. pylori-associated duodenal ulcers were markedly lower than those in healthy controls. Basal and both forskolin- and prostaglandin E2 -stimulated duodenal mucosal bicarbonate secretions in the patients with H. pylori-associated duodenal ulcers were also lower than those in healthy controls. After anti-H. pylori treatment for H. pylori-associated duodenal ulcers, duodenal mucosal bicarbonate secretion and CFTR and SLC26A6 expressions in H. pylori-eradicated patients recovered to levels comparable to healthy controls, but those were found to be not significantly altered in non-H. pylori-eradicated patients. The further results showed that decreases in the H. pylori-induced CFTR and SLC26A6 expression were related to the severity and virulent factors of H. pylori infection. H. pylori infection impairs the expressions and functional activities of duodenal mucosal bicarbonate transport proteins, CFTR and SLC26A6, which contributes to the development of duodenal ulcer.

An open-label, parallel, multiple-dose study comparing the pharmacokinetics and gastric acid suppression of rabeprazole extended-release with esomeprazole 40 mg and rabeprazole delayed-release 20 mg in healthy volunteers

Novel rabeprazole extended-release (ER) formulations were developed to provide prolonged gastric acid suppression and potentially improved clinical outcomes in GERD patients. To evaluate the pharmacodynamics and pharmacokinetics of six rabeprazole-ER formulations vs. esomeprazole 40 mg and rabeprazole delayed-release (DR) 20 mg. Helicobacter pylori-negative healthy subjects were randomised to receive one of eight treatments once daily for 5 days. Twenty-four-hour intragastric pH was monitored on days -1, 1 and 5. Rabeprazole plasma concentrations were measured on day 5. A total of 248 subjects (N=31/group) were enrolled in the study. On day 5, rabeprazole-ER groups provided mean durations of 18.5-20.2 h (77.0-84.1% of 24-h) with intragastric pH >4.0 vs. esomeprazole 40 mg (15.9 h/66.1% of 24-h) and rabeprazole-DR 20 mg (15.2 h/63.2% of 24-h). A similar increase was observed on day 1. While percentage of daytime (8 am-10 pm) with intragastric pH >4.0 on day 5 was overall similar across the groups, percentage of night-time (10 pm-8 am) with intragastric pH >4.0 was higher with the rabeprazole-ER groups (57.0-72.4%) vs. esomeprazole 40 mg (32.8%) and rabeprazole-DR 20 mg (34.0%). Rabeprazole-ER once daily for 5 days demonstrated a significantly longer duration of gastric acid suppression in 24 h vs. esomeprazole 40 mg and rabeprazole-DR 20 mg. The increase in acid suppression was predominantly due to prolonged acid suppression during the night-time; this was supported by the extended-release pharmacokinetic characteristics.

Comparison of the effects of fasting morning, fasting evening and fed bedtime administration of tenatoprazole on intragastric pH in healthy volunteers: a randomized three‐way crossover study

The effectiveness of proton pump inhibitors is influenced by meals and administration time. To compare the effects on intragastric acidity of times of dosing of tenatoprazole, a novel imidazopyridine-based proton pump inhibitor with a prolonged plasma half-life. This randomized three-period crossover study included 12 Helicobacter pylori-negative healthy subjects, who received tenatoprazole 40 mg either fasting at 7.00 AM, fasting at 7.00 PM or fed at 9.30 PM for 7 days, with a 2-week washout between periods. Twenty-four hour intragastric pH was monitored on day 7 of each period. On day 7, median 24-h pH was 4.7, 5.1 and 4.7 after breakfast, dinner and bedtime dosing, respectively (P = 0.11), whereas night-time pH was 4.2, 5.0 and 4.4 (P = 0.13). The mean 24-h percentage of time over pH 4 was 62, 72 and 64 after breakfast, dinner and bedtime dosing, respectively (N.S.), and 54, 68 and 56 during night-time (P = 0.06). Nocturnal acid breakthrough incidence decreased from 100% at baseline to 83%, 55% and 75% after 7.00 AM, 7.00 PM and 9.30 PM dosing, respectively (P = 0.18), and its mean duration dropped from 6.2 to 2.8, 1.0 and 2.2 h, respectively (P < 0.05). Seven-day administration of tenatoprazole provides a prolonged duration of acid suppression, especially during the night-time, with little effect of food or time of dosing.

Pharmacodynamic and kinetic effect of rabeprazole on serum gastrin level in relation to CYP2C19 polymorphism in Chinese Hans

To observe the pharmacokinetics and pharmaco-dynamics of rabeprazole and compare serum gastrin concentrations in different CYP2C19 genotype groups. The CYP2C19 genotype status of Chinese Han healthy volunteers was determined by polymerase chain reaction-restriction fragment length polymorphism method. Twenty H pylori-negative healthy subjects voluntary participated in the study. They were divided into the following three groups: homozygous extensive metabolizers (homEM), heterozygous extensive metabolizers (hetEM) and poor metabolizers (PM). After they orally received rabeprazole 20 mg once daily in the morning of d 1 and d 8, blood samples were collected at various time-points until 24 h after administration and intragastric pH values were monitored for 24 h by Digitrapper pH. Serum gastrin concentrations were measured by radioimmunoassay. Serum concentrations of rabeprazole were measured by high performance liquid chromatography. The mean AUC values for rabeprazole after a single and repeated doses were significantly different between the homEM and PM groups, but not between the homEM and hetEM, or the hetEM and PM groups. No significant differences in intragastric pH medians were observed among the three different genotype groups after a single dose or repeated doses. The ratio of pH medians between d 1 and d 8 ranged from 84% to 108%. The mean gastrin AUC values were also different among the three genotype groups, with a relative ratio of 1.0, 1.2 and 1.5 after a single dose and 1.0, 1.5 and 1.6 after repeated doses in the homEM, hetEM and PM groups, respectively. The gastrin AUC values among the three different genotype groups showed no significant difference either after a single dose or repeated doses. The subject who had lower intragastric acidity showed higher serum gastrin levels and concentrations of rabeprazole. In Chinese Han healthy people, the pharmacokinetics of rabeprazole are dependent on the CYP2C19 genotype status, but acid-inhibitory efficacy of rabeprazole and the gastrin level are not influenced significantly.

Esomeprazole 20mg Provides More Effective Intragastric Acid Control than Maintenance-Dose Rabeprazole, Lansoprazole or Pantoprazole in Healthy Volunteers

A high proportion of patients with gastro-oesophageal reflux disease experience recurrence of symptoms within a year of initial treatment. The key to preventing relapse is an effective maintenance therapy that maintains intragastric pH >4. This study was conducted to compare the effects on intragastric pH of maintenance doses of four proton pump inhibitors: esomeprazole 20mg, lanso-prazole 15mg, rabeprazole 10mg and pantoprazole 20mg. Three standardised, randomised, two-way crossover studies were performed in a total of 108 Helicobacter pylori-negative healthy subjects. Intragastric pH was monitored on day 5 of once-daily oral dosing. The percentage of time of a 24-hour period with intragastric pH >4 and 24-hour median pH were measured on day 5. The mean percentage of time with intragastric pH >4 on day 5 was significantly longer following esomeprazole 20mg compared with either lansoprazole 15mg (esomeprazole 50.4% vs lansoprazole 43.0%, p = 0.026), rabeprazole 10mg (esomeprazole 59.8% vs rabeprazole 51.7%, p = 0.011) or pantoprazole 20mg (esomeprazole 59.6% vs pantoprazole 39.5%, p < 0.0001). Maintenance dose esomeprazole 20mg provided greater acid control and maintained intragastric pH >4 for a longer period of time than maintenance dose lansoprazole 15mg, rabeprazole 10mg and pantoprazole 20mg in healthy subjects.

Somatic mutation of mitochondrial DNA in Helicobacter pylori-associated chronic gastritis in patients with and without gastric cancer

Somatic mutations of the mitochondrial DNA (mtDNA) are associated with development of various types of human cancer. To elucidate the significance of somatic mutations of the mtDNA in gastric carcinogenesis, we examined mtDNA mutations in gastric cancers and in Helicobacter pylori-associated chronic gastritis (H. pylori-CG), which is associated with an increased risk for gastric cancer development. Specimens of gastric cancer and gastric mucosa were obtained from 73 gastric cancer patients with H. pylori-CG, 75 cancer-free H. pylori-CG patients and 30 H. pylori-negative healthy subjects. Mutations of a specific mononucleotide repeat (D310) of the mtDNA were examined by microsatellite assay. mtDNA mutations were detected in 9 of 56 (16%) gastric cancers, in 10 of 148 (7%) H. pylori-CG and none of the 30 H. pylori-negative healthy subjects. mtDNA mutations in H. pylori-CG were significantly more frequent in gastric cancer patients than in cancer-free patients (12% vs. 1%, p=0.008). In addition, mtDNA mutations in H. pylori-CG were significantly more frequent in patients with mtDNA mutated gastric cancer than in patients with mtDNA unmutated gastric cancer (66% vs. 4%, p<0.001). These data suggest that somatic mutations of the mtDNA may be involved in the early stages of gastric carcinogenesis.

Comparison of rabeprazole 10mg twice daily and 20mg twice daily on intragastric PH in Helicobacter Pylori-negative healthy subjects in three different CYP2C19 genotype groups

Comparison of rabeprazole 10mg twice daily and 20mg twice daily on intragastric PH in Helicobacter Pylori-negative healthy subjects in three different CYP2C19 genotype groups

K-ras mutation in helicobacter pylori-associated chronic gastritis in patients with and without gastric cancer

Mutations of an oncogene, K-ras, are associated with the development and progression of many types of human cancer. To elucidate the significance of K-ras mutations in gastric carcinogenesis, we examined K-ras mutations in gastric cancers and in Helicobacter pylori-associated chronic gastritis (H. pylori-CG), which is associated with an increased risk for the gastric cancer development. Specimens of gastric cancer and H. pylori-CG were obtained from 64 gastric cancer patients with H. pylori-CG, 99 cancer-free H. pylori-CG patients and 30 H. pylori-negative healthy subjects. K-ras mutations were examined by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP), followed by DNA sequencing analysis. K-ras mutations were detected in 4 of 48 (8.3%) gastric cancers, in 10 of 163 (6.1%) H. pylori-CG and none of the 30 H. pylori-negative healthy subjects. In the gastric cancer patients, mutated K-ras was detected in differentiated type cancers but not in any of the undifferentiated type cancers. K-ras mutations in H. pylori-CG were significantly more frequent in gastric cancer patients than in cancer-free patients (10.9% vs. 3.0%, p = 0.044). In addition, K-ras mutations in H. pylori-CG were significantly more frequent in patients with K-ras mutated gastric cancer than in patients with K-ras unmutated gastric cancer (50.0% vs. 3.7%, p = 0.037). These data suggest that the genetic mechanism(s) of carcinogenesis differs between the differentiated type and the undifferentiated type of gastric cancer and that K-ras mutations may be involved in the early stages of gastric carcinogenesis of the differentiated type. © 2001 Wiley-Liss, Inc.

K‐ras mutation in helicobacter pylori‐associated chronic gastritis in patients with and without gastric cancer

Mutations of an oncogene, K-ras, are associated with the development and progression of many types of human cancer. To elucidate the significance of K-ras mutations in gastric carcinogenesis, we examined K-ras mutations in gastric cancers and in Helicobacter pylori-associated chronic gastritis (H. pylori-CG), which is associated with an increased risk for the gastric cancer development. Specimens of gastric cancer and H. pylori-CG were obtained from 64 gastric cancer patients with H. pylori-CG, 99 cancer-free H. pylori-CG patients and 30 H. pylori-negative healthy subjects. K-ras mutations were examined by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP), followed by DNA sequencing analysis. K-ras mutations were detected in 4 of 48 (8.3%) gastric cancers, in 10 of 163 (6.1%) H. pylori-CG and none of the 30 H. pylori-negative healthy subjects. In the gastric cancer patients, mutated K-ras was detected in differentiated type cancers but not in any of the undifferentiated type cancers. K-ras mutations in H. pylori-CG were significantly more frequent in gastric cancer patients than in cancer-free patients (10.9% vs. 3.0%, p = 0.044). In addition, K-ras mutations in H. pylori-CG were significantly more frequent in patients with K-ras mutated gastric cancer than in patients with K-ras unmutated gastric cancer (50.0% vs. 3.7%, p = 0.037). These data suggest that the genetic mechanism(s) of carcinogenesis differs between the differentiated type and the undifferentiated type of gastric cancer and that K-ras mutations may be involved in the early stages of gastric carcinogenesis of the differentiated type.

H. pylori and transient lower esophageal sphincter relaxations induced by gastric distension in healthy humans

The role of Helicobacter pylori infection in the control of lower esophageal sphincter (LES) motility, especially the occurrence of transient LES relaxations (TLESRs), was studied in eight H. pylori-positive and eight H. pylori-negative healthy subjects. During endoscopy, biopsy specimens were taken from the cardia, fundus, and antrum for determinations of H. pylori status, gastritis, and proinflammatory cytokine mucosal concentrations. LES motility was monitored during three different 30-min periods: baseline, gastric distension (barostat), and gastric distension with CCK infusion. Gastric distension significantly increased the TLESR rate, whereas CCK increased the rate of distension-induced TLESRs further and reduced resting LES pressure without significant differences between infected and noninfected subjects. H. pylori status did not influence resting LES pressure or gastric compliance. Cytokine mucosal concentrations were increased in infected patients, but no correlation was found with the TLESR rate, which was also independent of inflammation at the cardia, fundus, and antrum. These results suggest that H. pylori-associated inflammation does not affect the motor events involved in the pathogenesis of gastroesophageal reflux.

Localisation of cyclooxygenase 1 and cyclooxygenase 2 inHelicobacter pylori related gastritis and gastric ulcer tissues in humans

BACKGROUNDProstaglandin endoperoxide synthase/cyclooxygenase (COX) is the key enzyme in gastric mucosal protection and repair but its cellular localisation in the human stomach is still unclear.AIMSTo investigate immunohistochemically the cellular distribution...

Intraindividual variability of paracetamol absorption kinetics after a semi-solid meal in healthy volunteers.

The absorption kinetics of paracetamol is dependent on gastric emptying and its measurement was proposed as a non-invasive method to estimate gastric emptying rate. The objective of this study was to evaluate the intraindividual variability of paracetamol absorption kinetics after a semi-solid meal. The pharmacokinetics of paracetamol was studied on two occasions in 15 healthy volunteers without Helicobacter pylori antibodies. A 1-g dose of paracetamol was given as a solution together with a standardised semi-solid meal and the subjects stayed in the supine position. For most of the subjects, the time course of paracetamol concentrations was similar on the two occasions. The intraindividual variability was low, with coefficients of variation of 38.3%, 8.0% and 3.8% for time to maximum plasma concentration, maximum concentration and area under the plasma concentration - time curve until 6 h, respectively. The assessment of paracetamol absorption kinetics is reproducible when the drug is given together with a semi-solid meal in Helicobacter pylori-negative healthy subjects.