Background: The eradication of Helicobacter pylori decreases the antisecretory activity of omeprazole and lansoprazole. Rabeprazole is a potent proton pump inhibitor that may not be affected as greatly by H. pylori status.Aim: To compare the effect of H. pylori eradication on intragastric acidity and plasma gastrin during dosing with lansoprazole, omeprazole, rabeprazole and placebo.Methods: Twenty-four healthy H. pylori -infected volunteers were studied on day 7 of dosing with placebo, lansoprazole 30 mg, omeprazole 20 mg and rabeprazole 20 mg, before and at least 5 weeks after H. pylori eradication. On each occasion, the 24-h intragastric acidity was measured by gastric aspiration. Plasma gastrin concentrations were measured hourly from 08.00 to 13.00 h.Results: Sixteen subjects completed the study. For all three drugs and placebo, H. pylori eradication increased intragastric acidity, particularly nocturnal acidity, and decreased plasma gastrin. There were no differences between the three drugs with respect to 24-h acidity, percentage of time pH > 4 or 5-h plasma gastrin, either before or after H. pylori eradication. Before eradication, the percentage nocturnal time at pH > 3 was significantly greater during rabeprazole than during lanso-prazole dosing.Conclusions: The increase in intragastric acidity seen after H. pylori eradication during dosing with proton pump inhibitors is a drug-class effect, particularly affecting nocturnal acid control. This is related to increased spontaneous intragastric acidity after H. pylori eradication.

Barrett’s esophagus (BE) is composed of multiple lineages including Paneth cells and endocrine cells in addition to gastric and intestinal cells. Although the origin of the BE stem cell is a matter of conjecture, the stem cells are clearly multipotent, and therefore the phenotype is restricted by genomic imprinting (termed restricted potency). Recent evidence suggests that the microenvironment may select various lineages. In this regard the proportion of gastric and specialized intestinal metaplastic cells has been attributed to the composition of the refluxate, acid or bile, respectively. Experimental evidence also implicates specific xenobiotics in this process, including bile acids. In particular we discuss the potential biologic roles of bile acids in epithelial adaptation from in vivo and in vitro models.

BACKGROUND:The ribonucleoprotein telomerase has been proposed as a potential prognostic marker for malignancy. Whether telomerase activity of clinical specimens correlates with other clinico-pathological variables, however, remains controversial. This is at least in part due to the varying contribution that nonmalignant cells will make to the net activity when extracts are assayed for telomerase activity. We therefore designed experiments to assay telomerase activity of isolated malignant cells of primary colorectal cancers.METHODS:Thirty colorectal cancer and 20 corresponding specimen taken from macroscopically normal regions of the colon were mechanically disaggregated and digested with collagenase, DNase and hyaluronidase. The epithelial cell population was separated using Ber-EP4 pan-epithelial antibody and Magnetic Activated Cell Sorting technique. Haematoxylin and eosin staining was used to assess the proportion of recovered epithelial cells which were malignant. Telomerase activity was assayed by the Telomeric Repeat Amplification Protocol, which was quantified by PhosphorImager with Image Quant software.RESULTS:Epithelial cells of three of 20 normal mucosa specimens were telomerase positive with weak activity (mean 3.7 TPGs, Total Product Generated, range 1.4-5.1TPGs). In the cancer group the vast majority (>95%) of the epithelial cells recovered were malignant by cytological criteria. Epithelial cells were telomerase positive in all the cancers, with a wide range of telomerase activity values (mean 22.7 TPGs, range 0.19-308 TPGs). Telomerase activity correlated with Dukes' stage (r = 0.52, P=0.004, Spearman's rank).CONCLUSIONS:Pathological stage correlates with telomerase activity of the malignant cell population of the primary tumour in colorectal cancer. This suggests that telomerase activity increases during the progression of a cancer and may have implications for the design of anticancer (antitelomerase) agents.

Increased expression of telomerase is critical in the pathogenesis of cancer. Telomerase expression is reported variably in foregut cancers, possibly as a result of telomerase inhibition or ribonucleases. We performed experiments to assess telomerase and telomerase RNA expression in foregut cancers and to quantify and characterize telomerase inhibition. Cancer specimens were obtained from 27 patients. Telomerase activity of cancers was determined by the telomeric repeat amplification protocol, the presence of telomerase RNA component (hTERC) by reverse transcription PCR, and the quantity of telomerase inhibitors in mixing experiments. Ribonuclease activity was measured by assessing degradation of labeled RNA by cancers. Telomerase was found in 8/11 adenocarcinomas of the esophagus or gastroesophageal junction and 6/16 distal gastric adenocarcinomas; hTERC was detectable in all cancers. Telomerase inhibition was more marked in distal compared to proximal adenocarcinomas (P = 0.01) and correlated with ribonuclease activity (rs= 0.65). Ribonucleases contribute significantly to telomerase inhibitory activity detectable in foregut cancer specimens. In vitro, the presence of telomerase inhibitors in some specimens did not prevent the detection of telomerase by the TRAP assay. This suggests a more complex relationship between telomerase and its inhibitors. Site-specificity of telomerase inhibitors generally and ribonuclease activity specifically suggests a putative regulatory role in vivo.

Objective The ribonucleoprotein telomerase extends telomeres in cancer cells and has been proposed as a prognostic marker for cancer. We measured telomerase expression in proximal adenocarcinomas (those arising in the distal oesophagus or at the gastro-oesophageal junction) and distal adenocarcinomas (those arising in the corpus or antrum of the stomach) of the foregut, and correlated telomerase activity with pathological stage and post-operative survival.Design Surgical specimens were collected from patients undergoing resections for gastric and oesophageal carcinomas. Haematoxylin and eosin histology provided data on the pathological tumour stage and pathological node stage.Methods The telomerase activity of cancer specimens was determined using the telomeric repeat amplification protocol. A single pathologist, blinded to the results of the telomerase assays, reviewed all slides of cancers to assign T and N stages.Results The cancers exhibited a wide range of telomerase expression. There was no significant difference between the telomerase activity of proximal adenocarcinomas (median, 551 U; 95% confidence interval, 154-2394 U; n = 26) and distal adenocarcinomas (median, 703 U; 95% confidence interval, 139-1618 U; n = 20). Distal adenocarcinomas expressing high telomerase activity (greater than the median) were significantly more advanced with regard to T stage than distal cancers expressing low telomerase levels (less than the median; P = 0.03, Mann-Whitney test). in distal adenocarcinomas, high telomerase activity was associated with poor patient survival (median 3 months) compared to low telomerase activity (median survival 22.4 months; P = 0.01, log-rank test). No such differences were observed for proximal adenocarcinomas.Conclusions There is a difference between gastric and oesophageal/gastro-oesophageal junction adenocarcinomas in terms of the relationship with telomerase expression and clinico-pathological variables. Among patients with distal gastric adenocarcinoma, telomerase activity correlates with markers of advanced disease, whereas this relationship does not hold true in oesophageal/gastro-oesophageal junction adenocarcinomas. Telomerase activation may occur at different stages of the formation of the malignant phenotype in these two cancers and may reflect differences in their pathogenesis. Telomerase could be a prognostic marker in gastric but not in oesophageal adenocarcinoma. Eur J Gastroenterol Hepatol 13:903-908 (C) 2001 Lippincott Williams & Wilkins.

OBJECTIVE: GI epithelial cells express telomerase, a ribonucleoprotein that prevents telomeric shortening in proliferating cells. Telomerase levels are high in cancer, but little is known about telomerase expression in other diseases. We, therefore, designed experiments to determine telomerase expression in different colonic segments and to compare this with corresponding segments in patients with ulcerative colitis. Colorectal cancers and adenomatous polyps were included as disease controls. METHODS: In total, telomerase expression was determined in colonic tissues obtained from 62 patients. Twenty-five patients had ulcerative colitis, 21 had normal colons, 11 had colorectal cancer, and nine had adenomatous polyps. Endoscopic biopsies were collected prospectively at colonoscopy, processed for telomerase assays (Telomeric Repeat Amplification Protocol), hematoxylin and eosin staining, and scored for inflammation. RESULTS: Telomerase activity is expressed in arbitrary units (median 95% confidence interval). In the normal colon, telomerase activity in the cecum, transverse, sigmoid, and rectum was 255 (171–449), 707 (374–895), 561 (468–1426), and 563 (402–846), respectively. Telomerase was higher in the distal three segments when compared with the cecum (p = 0.005). In ulcerative colitis, there was a marked decrease in telomerase activity in the cecum 152 (59–272), p = 0.04, transverse 180 (129–365), p <0.001, sigmoid 352 (114–464), p = 0.005, and rectum 180 (70–337), p = 0.001 when compared with normals. Telomerase activity correlated negatively with inflammation (r = − 0.32, p = 0.001) and was also decreased in microscopically normal areas. Cancers expressed high levels of telomerase. CONCLUSIONS: Colonic mucosal expression of telomerase is reduced in ulcerative colitis. Levels are low even in microscopically normal mucosa, suggesting that telomerase deficiency may contribute to the pathogenesis of the disease.

Background:Amongst the low‐dose H2‐receptor antagonists available for the self‐medication of dyspepsia, both famotidine 10 mg and cimetidine 200 mg have been shown to raise intragastric pH, but there is a delay after ingestion before significant effects can be demonstrated. A new effervescent preparation of cimetidine 200 mg releases an acid buffer which has a more rapid effect on intragastric pH.Aim:To investigate the relative abilities of low‐dose famotidine and effervescent cimetidine to raise intragastric pH after a single postprandial evening dose.Methods:Twenty‐four healthy subjects (12 men, 12 women, median age 32 years) completed a three‐period crossover trial of famotidine 10 mg, effervescent cimetidine 200 mg and placebo. After a standard meal was given at 18.30 h to subjects fasted for 5.5 h, drug or placebo was given at 19.30 h. Intragastric pH was recorded with combined glass electrodes from 18.00 to 07.30 h by digital recorders.Results:Over the 12 h post‐dose period the mean area under the pH/time curve (AUC ) after famotidine 10 mg was 3.73, after cimetidine 200 mg effervescent 2.79, and after placebo 2.07. Over the same period the median pH and percentage of time that recordings were above pH 3 were 3.45 and 52.5 after famotidine 10 mg, 2.40 and 33.8 after cimetidine 200 mg effervescent, and 1.68 and 15.9 after placebo. Both active treatments were significantly different from placebo by each measure (P < 0.001), and famotidine 10 mg was significantly more effective than cimetidine 200 mg effervescent by each measure over the 0–12 h period (P < 0.001). Comparisons of mean AUCs for each 15 min period after dosing showed that decrease in acidity was significantly greater after cimetidine 200 mg effervescent than after famotidine 10 mg for the first 60 min. In the later post‐dose period only famotidine 10 mg raised pH for all time points to 12 h, whilst the effect of effervescent cimetidine 200 mg was detectable to ≈ 8 h.Conclusions:Inhibition of gastric acidity over the 12 h post‐dose period was significantly greater and endured longer after famotidine 10 mg than after effervescent cimetidine 200 mg, but for the 60 min period immediately after dosing the effect on intragastric pH was significant following effervescent cimetidine 200 mg but not famotidine 10 mg. This suggests effervescent formulations of H2‐receptor antagonists with an acid buffer have a more rapid effect on intragastric pH than film‐coated tablets.