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Notes: 1. A controlled-release preparation of mesalazine microgranules (PentasaR; Ferring AS, Vanlose, Denmark) releases the active ingredient over a wide area from the small intestine to the rectum and is consequently expected to bring about therapeutic benefits to patients with ulcerative colitis and Crohn's disease.2. Mesalazine microgranules (50 or 150 mg/kg per day) were administered orally to each rabbit with carrageenan-induced colitis for six weeks. Its inhibitory effect on colonic mucosal damage was assessed in terms of the microscopic damage scores, leukotriene B4 concentrations and concentrations of mesalazine derivatives.3. At the end of the experiment, the mesalazine 150 mg group had gained a significantly greater bodyweight than the control group. Microscopic damage was significantly lower in the 150 mg group than in the untreated control group. Tissue concentrations of 5-aminosalicylic acid and acetyl-5-aminosalicylic acid in the small and large intestine were higher in the 150 mg group than in the 50 mg group. Mucosal leukotriene B4 levels tended to be lower in rabbits receiving the larger dose of mesalazine.4. The present study indicates that slow release 5-aminosalicylic acid at the larger dose reaches the large bowel in sufficiently high concentrations following oral administration and significantly reduces carrageenan-induced colitis in the rabbit.

Notes: Epidermal growth factor (EGF), which binds to EGF receptors (EGF-R), stimulates oesophageal epithelial cell proliferation, enabling rapid repair after mucosal injury. In the normal human oesophageal epithelium, EGF-R expression is present and confined to the basal layer.〈section xml:id="abs1-2"〉〈title type="main"〉Aim:To examine histological changes in and dynamics of EGF-R expression during healing after acid reflux oesophagitis in a rat model.〈section xml:id="abs1-3"〉〈title type="main"〉Methods:Gastric acid reflux oesophagitis was induced in Wistar rats by ligation of the pylorus and the transitional region between the forestomach and the grandular portion for 5 h, followed by release of both ligations. Rats were killed 7 and 14 days after production of oesophagitis to examine macroscopic and histological changes as well as dynamics of EGF-R expression. Epithelial cell proliferation was assessed by bromodeoxyuridine (BrdU) uptake, and expression of EGF-R mRNA and protein by RT–PCR and Western blotting or immunohistochemistry.〈section xml:id="abs1-4"〉〈title type="main"〉Results:Gastric acid reflux induced erosive and ulcerative mucosal lesions in the lower and middle part of the oesophagus. These lesions were healed by 14 days and histologically showed thickening of the oesophageal epithelium from 41.11 ± 3.09 μm in controls to 142.73 ± 11.59 μm (P 〈 0.001) in ligated rats, as well as elongation of papillae and basal cell hyperplasia. The number of BrdU-positive cells among basal cells on day 14 was significantly increased from 7.1 ± 0.8/field in controls to 30.9 ± 3.0/field in ligated rats. Expression of EGF-R mRNA and protein was significantly increased on day 14 and most basal cells were immunohistochemically positive in both BrdU and EGF-R staining.〈section xml:id="abs1-5"〉〈title type="main"〉Conclusion:Acid reflux-induced oesophageal injury caused basal cell hyperplasia with an increase in cell proliferation and EGF-R expression. Activation of EGF-R gene and protein in response to acid reflux-induced injury may facilitate mucosal healing. These results suggest that epidermal growth factor receptors play a crucial role in healing after acid reflux oesophagitis in rats.

Notes: Ornithine decarboxylase (ODC), a rate-limiting enzyme of polyamine biosynthesis, mediates epithelial cell proliferation and plays a critical role in the optimal repair of gastric mucosal damage. Several studies have shown that Helicobacter pylori inhibits the growth and proliferation of gastric cells in vitro.〈section xml:id="abs1-2"〉〈title type="main"〉Aim:To test whether H. pylori extract affects ODC mRNA expression and its enzyme activity in gastric cells and to examine the partial characterization of the molecule responsible for this effect.〈section xml:id="abs1-3"〉〈title type="main"〉Methods:Human gastric cells (MKN-45) were used. Bacterial extracts from various E. coli or H. pylori strains, namely (1) cagA+, vacA+, CagA+, VacA+; (2) cagA+, vacA+, CagA+ VacA–; or (3) cagA–, vacA+, CagA–, VacA– were added to the cells. Cell proliferation was assessed by [3H]-thymidine incorporation, viability by MTT assay and LDH release test, ODC enzyme activity by 14CO2 counts from L-[114C]ornithine, and ODC mRNA by Northern blotting.〈section xml:id="abs1-4"〉〈title type="main"〉Results: H. pylori and E. coli extract did not affect viability of gastric cells. H. pylori extract, especially extracts containing a protein greater than 50 kDa, significantly inhibited proliferation and ODC activity of gastric cells while E. coli extract had no effect. Inhibition of ODC activity was found in extracts of all H. pylori strains, irrespective of CagA and VacA protein expression. Serum stimulation induces an increase in ODC mRNA while H. pylori extract did not affect ODC mRNA expression.〈section xml:id="abs1-5"〉〈title type="main"〉Conclusion:High molecular weight (greater than 50 kDa) proteins of H. pylori extract without CagA or VacA protein inhibited proliferation and ODC activity of human gastric cells, but did not affect ODC mRNA expression, suggesting that inhibition of ODC activity is regulated at the post-transcriptional level.

Notes: Background : In Helicobacter pylori infection, the effect of short-term triple therapy with proton pump inhibitor plus two antibiotics on gastric ulcer healing is not well known.Aim : To compare 1-week triple therapy with 8-week proton pump inhibitor therapy on gastric ulcer healing in infected patients.Patients and methods : We randomly assigned 120 patients with H. pylori and gastric ulcers to proton pump inhibitor plus amoxicillin and clarithromycin for 1 week (n = 61) or proton pump inhibitor alone for 8 weeks (n = 59), with endoscopic assessment of ulcer healing 8 weeks after the start of treatment.Results : Triple therapy eradicated H. pylori in 51 patients [intention-to-treat, 84%; 95% confidence interval (CI), 75–93%]. At 8 weeks, gastric ulcers were healed in 30 patients given triple therapy (49%; 95% CI, 37–62%) and in 49 patients given proton pump inhibitor (83%; 95% CI, 73–93%, P 〈 0.001). Healing rates in the triple therapy and proton pump inhibitor-only groups were 89% and 100%, respectively, for ulcers of 〈 1.0 cm in diameter, 54% and 77% for ulcers of 1.0 to 〈 1.5 cm in diameter, and 5% and 77% (P 〈 0.001) for ulcers of ≥ 1.5 cm in diameter.Conclusions : One-week triple therapy healed most ulcers of 〈 1.0 cm, but not ulcers of ≥ 1.5 cm. Short-term therapy is effective for gastric ulcers of 〈 1.0 cm, but, for larger ulcers, follow-up therapy to suppress acid is needed.

Notes: Background : Several studies in Western countries showed that proton-pump inhibitors are superior to histamine2-receptor antagonists or placebo in the treatment of non-erosive gastro-oesophageal reflux disease. The efficacy of acid-suppressive drugs for non-erosive gastro-oesophageal reflux disease in Japan, in which the prevalence of Helicobacter pylori infection is higher compared with Western countries, is unknown.Aim : To compare the efficacy of famotidine and omeprazole in Japanese patients with non-erosive gastro-oesophageal reflux disease by a prospective randomized multicentre trial.Methods : A total of 98 patients received either famotidine 20 mg b.d. (n = 48) or omeprazole once daily (n = 50). Frequency of gastro-oesophageal reflux disease symptoms and health-related quality of life were evaluated at baseline and after 4 weeks of treatment. Complete relief was defined as no gastro-oesophageal reflux disease symptoms during the 7-day interval in week 4.Results : Complete relief was achieved in 23 (48%) of patients receiving famotidine and 28 (56%) of patients treated with omeprazole. In the famotidine group, complete relief rate in H. pylori-negative patients was significantly lower than H. pylori-positive patients (35% vs. 64%). Both famotidine and omeprazole improved most scales of health-related quality of life. Omeprazole significantly improved reflux score irrespective of H. pylori infection while famotidine significantly improved reflux score in H. pylori-positive patients but not in H. pylori-negative patients.Conclusions : Omeprazole is more effective than famotidine for the control of gastro-oesophageal reflux disease symptoms in H. pylori-negative patients, while similar efficacy is observed in H. pylori-positive patients with non-erosive gastro-oesophageal reflux disease.

Notes: Background : The association between cure of Helicobacter pylori infection and the development of gastro-oesophageal reflux disease is controversial.Aim : To examine the prevalence of symptomatic GERD (sGERD) in Japanese patients with peptic ulcer disease after successful eradication and identify associated factors affecting sGERD development.Methods : We retrospectively examined 72 patients (40 gastric ulcer and 32 duodenal ulcer) with successful eradication. Associated factors such as age, gender, drinking and smoking habits, body mass index, presence of gastric atrophy and hiatal hernia were analysed.Results : Seven (9.7%) of 72 peptic ulcer patients newly developed sGERD. There were no differences in mean age, gender, smoking habit, drinking habit, body mass index, or presence of gastric atrophy and hiatal hernia between the sGERD and non-sGERD groups, while the proportion of subjects aged over 70 was significantly higher in the sGERD than the non-sGERD group. Six of 40 patients with gastric ulcer newly developed sGERD while only one of 32 patients with duodenal ulcer developed it.Conclusion : Approximately 10% of Japanese patients with peptic ulcer disease newly developed sGERD after cure of H. pylori infection. Age 〉 70 years was associated with development of sGERD. Eradication in patients in this age group should be carefully determined.

Notes: Background and Aims : The effects of rebamipide on chronic gastritis associated with Helicobacter pylori have not been well-defined. We compared these effects of rebamipide with those of cimetidine in Mongolian gerbils infected with H. pylori.Methods : Mongolian gerbils with or without H. pylori were divided into 10 groups 6 weeks after inoculation and fed diets containing a drug (rebamipide or cimetidine) or control diet. All animals were sacrificed 4 weeks after grouping. Their stomachs were examined for histology, colonization by H. pylori, myeloperoxidase activity (myeloperoxidase), production of neutrophil chemokine (CINC/KC) and tumour necrosis factor-α (TNF-α), and serum gastrin levels.Results : H. pylori colonized all of the inoculated animals. Neither rebamipide nor cimetidine decreased myeloperoxidase activity, but each reduced wet stomach weight in H. pylori-infected animals. The amount of increase in CINC/KC and TNF-α in gastric tissue caused by H. pylori infection was decreased by treatment with rebamipide or cimetidine. H. pylori infection increased serum gastrin levels, and this increase was significantly enhanced by cimetidine but not rebamipide.Conclusions : Rebamipide may improve H. pylori-infected chronic gastritis by preventing the production of inflammatory cytokines and chemokines, as does cimetidine, but may be preferable to cimetidine for long-term administration for treatment of H. pylori-infected chronic gastritis due to its effect on serum gastrin levels.

Notes: Background : Mitogen-activated protein (MAP) kinases, including extracellular signal-regulated kinases (ERK),c-Jun NH2-terminal kinases (JNK) and p38 MAP kinase (p38 MAPK) are important intermediates of the signal-transduction pathway from the cell surface to the nucleus. Expression of cyclooxygenase (COX)-2, associated with proliferation, apoptosis or both of gastrointestinal cancer cells, is mediated through MAP kinase families. However, the correlation between respective MAP kinase signals and COX-2 in the proliferation of gastric and colon cancer cells has not been well elucidated.Aim : We examined the effect of selective inhibitors of MAP kinases and COX-2 on serum-induced proliferation of gastric (MKN45) and colon (HT29) cancer cells.Methods : After 24-h serum starvation, cancer cells were stimulated with 2% serum and COX-2 inhibitors (NS398 10 µmol/L, or etodolac 100 µmol/L) or 1 h after preincubation with inhibitors for ERK (PD98059 20 µmol/L) or p38 MAPK (SB203580 10 µmol/L). Phosphorylated MAP kinases and COX-2 protein were evaluated by Western blotting, and the proliferation of cancer cells was estimated by 3H-thymidine incorporation. Transcription factors nuclear factor-κB and CREB were assayed by an electorophoretic mobility shift assay.Results : Serum increased the proliferation of MKN45 and HT29 cells by 280% and 200%, respectively, compared with the control levels (100%). In both cancer cells, phosphorylated MAP kinases were increased within 30 min after stimulation. PD98059 and SB203580 inhibited the serum-induced proliferation of MKN45 by 21% and 51% and of HT29 by 81% and 69%, respectively. NS398 and etodolac inhibited the proliferation of HT29 by 21% and 41%, respectively, but not that of MKN45. PD98059 and SB203580 also suppressed serum-induced expression of COX-2 protein in HT29 cells. In addition to the activation of MAP kinases and COX-2, activities of nuclear factor-κB and CREB were also increased during HT29 cell proliferation.Conclusions : These results suggest that the correlation of MAP kinases with COX-2 induction for cell proliferation differs between MKN45 and HT29 cells.