Efficacy of triple therapy with rabeprazole for Helicobacter pylori infection and CYP2C19 genetic polymorphism.

BACKGROUND: Rabeprazole is a new, potent, proton pump inhibitor. The metabolism of rabeprazole is less dependent on CYP2C19 genetic polymorphism. METHODS: A total of 102 Helicobacter pylori-positive patients with gastric ulcer were randomly allocated to three groups: rabeprazole 10 mg (RAC10), rabeprazole 20 mg (RAC20) or rabeprazole 40 mg (RAC40) plus amoxicillin 750 mg and clarithromycin 200 mg twice daily for 7 days. CYP2C19 genotype was determined by the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: All-patients-treated-based eradication rates in patients treated with RAC10, RAC20 and RAC40 were 83%, 77% and 90%, respectively, and per protocol-based eradication rates were 83%, 80% and 90%, respectively. The eradication rates in the three groups were not significantly different. There was also no significant difference between the all-patients-treated-based eradication rate in CYP2C19 extensive metabolizers and that in poor metabolizers (86% vs. 77%). Adverse events were 12% in extensive metabolizers and 23% in poor metabolizers, and the difference in these incidence rates was also not statistically significant. CONCLUSIONS: Triple therapy with 10 mg of rabeprazole combined with amoxicillin/clarithromycin is effective for Japanese patients with H. pylori infection, and the H. pylori eradication rate is not affected by CYP2C19 genetic polymorphism.

Clinical relevance of the babA2 genotype of Helicobacter pylori in Japanese clinical isolates.

Genotypic variation of Helicobacter pylori is speculated to associate with different clinical outcomes. In Western countries, the gene encoding blood group antigen-binding adhesin (BabA), babA2, is of high clinical relevance and is a useful marker to identify patients who are at higher risk for peptic ulceration and gastric adenocarcinoma, as are vacA and cagA. We investigated the presence of babA2 and cagA in 179 Japanese clinical isolates by PCR and Southern blot analysis and looked for correlations with various clinical outcomes (nonulcer dyspepsia, duodenal ulcers, gastric ulcers gastric adenocarcinoma, and mucosa-associated lymphoid tissue lymphoma). The prevalence of the babA2 genotype was 84.9% and that of the cagA genotype was 96.1%. There was no correlation between the babA2 and cagA genotypes, and there was no association between the babA2 or cagA status and clinical outcome. These results indicate that babA2 status is not of high clinical relevance in Japan and that Japanese strains are different from those infecting Western populations.

Attributable risk of H. pylori in peptic ulcer disease: does declining prevalence of infection in general population explain increasing frequency of non-H. pylori ulcers?

Recent reports in the United States have found that fewer peptic ulcers are due to Helicobacter pylori than previously believed. The aim of this study is to determine if the declining prevalence of H. pylori infection in the general population can account for the apparent increase in the frequency of non-H. pylori ulcers. A total of 396 patients with peptic ulcer or ulcer scar were enrolled in this study. The pre-1950 population consisted of 149 patients with gastric ulcers and with 44 duodenal ulcers. The post-1950 population consisted of 96 patients with gastric ulcers and 107 with duodenal ulcers. The frequency of H. pylori-negative gastric ulcers was 5.4% in patients born before 1950 and 4.2% in patients born after 1950, and the frequency of H. pylori-negative duodenal ulcers was 0% and 1.9%, respectively. There are no statistical differences between the two populations in gastric and duodenal ulcers. H. pylori seropositivity was 74.9% in asymptomatic volunteers born before 1950 and 20.7% in those born after 1950 (P < 0.01) in the general population. The attributable risk of H. pylori infection in peptic ulcer diseases was not affected by the prevalence of H. pylori infection in the general population in Japan. This suggests that the apparent increase in frequency of non-H. pylori ulcers in the United States is not simply due to the declining prevalence of infection. Other explanations for non-H. pylori ulcers should be sought.

[Virulence gene of H. pylori].

H. pylori is a well-recognized pathogen that infects up to 50% of humans in the world. H. pylori lives for decades in the hostile environment of the human stomach. H. pylori is closely associated with histologic gastritis, gastric ulceration, duodenal ulceration, gastric cancer and MALT lymphoma. These various clinical outcomes are considered by 1) different virulence, 2) host response, 3) other environmental factors, and their interactions. Since the whole genome was sequenced in 1997, the virulence genes have been investigated in molecular genetic aspects. The cag pathogenicity island (cagPAI) is a complex of virulence genes, which code approximately 30 proteins. The cagPAI acquired by horizontal transfer and is coding for type 4 secretion machinery system. Via this system, many virulence gene products or other interactive proteins are transferred into the host cells.

[Recent endoscopic treatment in gastroenterology].

Endoscopic diagnosis and treatment became to be necessary in gastroenterology for last two decades. Indication of endoscopic treatment is amazingly expanding because of developing new techniques and easy-to-use devices. Nowadays, the indication for endoscopic treatment includes the removal of foreign bodies in alimentary tract, the dilatation of stricture lesions by balloon or expandable metallic stent, the resection of polypoid and superficial tumors by polypectomy and EMR (endoscopic mucosal resection) techniques, the injection sclerotherapy and ligation method for gastroesophageal varices, the hemostasis of gastrointestinal hemorrhages by injection method or heat-burn method. In biliary and pancreatic area, there are some endoscopic treatments that are removal and destruction of stones in common bile duct, biliary and pancreatic drainage by tubing method. Our results of endoscopic resection for esophageal and gastric tumors are shown in this papers. In conclusion, complete resection that means histologically tumor negative of lateral and vertical margin of resected specimen is important to prevent recurrence of tumors after resection.

Non-Helicobacter pylori and non-NSAID peptic ulcer disease in the Japanese population.

BACKGROUND: Helicobacter pylori and non-steroidal anti-inflammatory drugs (NSAIDs) are recognized as the major causes of peptic ulcer disease. The status of H. pylori infection in the background population may influence the incidence of H. pylori-negative peptic ulcer disease. OBJECTIVE: To examine the incidence of H. pylori-negative peptic ulcer disease without intake of NSAIDs in Japan. PATIENTS: A total of 398 patients who had no eradication therapy for H. pylori prior to this study, including 246 patients with gastric ulcer (GU) and 152 patients with duodenal ulcer (DU), were enrolled. METHODS: H. pylori status was assessed by rapid urease tests, histological examinations (haematoxylin & eosin stain, Giemsa stain and/or immunostaining) and serum IgG antibody. Two biopsy specimens were taken from the antrum within 3 cm of the pyloric and two from the middle corpus of the stomach, along the greater curvature. Patients were asked a series of questions regarding risk factors, including the use of NSAIDs. The presence of gastritis, gastric atrophy and intestinal metaplasia was examined according to the updated Sydney system. RESULTS: Of the 246 patients with GU, 12 patients (4.9%) were considered to be H. pylori-negative. Of the 152 patients with DU, two patients (1.3%) were considered to be H. pylori-negative. Hence, a total of 14 patients were found to be H. pylori-negative. Nine of them were taking NSAIDs. Consequently, the frequency of H. pylori-negative ulcer without intake of NSAIDs was 1.3%. There was no significant difference in the frequencies of H. pylori-negative patients between the GU and DU groups. CONCLUSION: The incidence of H. pylori-negative peptic ulcer disease without intake of NSAIDs was very low in the Japanese population.

A prospective evaluation of new rapid urease tests before and after eradication treatment of Helicobacter pylori, in comparison with histology, culture and 13C-urea breath test.

BACKGROUND: The rapid urease test is a simple and cost-effective method to detect Helicobacter pylori in biopsy specimens. The aim of this study was to evaluate the accuracy of two new rapid urease tests, Helicocheck and PyloriTek, before and after eradication. METHODS: A total of 278 patients, including 115 patients who had not undergone eradication of H pylori and 163 patients after eradication treatment, were enrolled. Eight biopsy specimens were taken from both the antrum and the body of the stomach for histology, culture, and two rapid urease tests. Assessment of H pylori infection was determined by the combination of histology, culture, and (13)C-urea breath test. RESULTS: Overall sensitivity, specificity, and positive and negative predictive values of the Helicocheck before eradication were 91.0%, 100%, 100%, and 62.5%; PyloriTek, 92.0%, 100%, 100%, and 65.2%. Those of Helicocheck after eradication were, respectively, 60. 5%, 99.2%, 95.8%, and 89.2%; PyloriTek, 60.5%, 99.2%, 95.8%, and 89. 2%. For the Helicocheck, determination of the infection status of H pylori by biopsies from the gastric body had a significantly higher sensitivity than antral biopsies. After eradication, the combination of 1 antral biopsy and 1 biopsy from the body was not effective enough to improve the overall sensitivity. CONCLUSIONS: Helicocheck and PyloriTek have equally satisfactory overall sensitivity before eradication treatment. However, the sensitivity of these rapid urease tests was lower after eradication than before eradication.

[The long-term perfusion system on amylase release from dispersed acinar cells--comparative study with direct incubation techinique and residual stimulation].

We have modified the perfused guinea pig pancreatic acini system in order to obtain reproducible results in repeated secretagogue stimulation. No signs of tachyphylaxis were observed when cholecystokinin-8 (CCK-8) was administered as short pulse for 5 minutes and the interval between administrations were kept more than 90 minutes. Maximal amylase response was obtained at 10(-8) M of CCK-8 and a supra-maximal significant inhibition on amylase release was observed with higher doses of CCK-8. Twenty minutes stimulation with 10(-8) M of CCK-8 showed a biphasic response; while, 5 minutes stimulation showed a mono-phasic pattern. The results suggest that amylase response was highly influenced not only by the concentration of the secretagogue but also the duration of the stimulation in this perfusion system. The mechanism of this phenomenon may be comprehensive by the double-ligand-complex theory based on low and high affinity site on cell surface receptors.

Tropomodulin isolated from rabbit skeletal muscle inhibits filament formation of actin in the presence of tropomyosin and troponin.

Tropomodulin is a tropomyosin-binding protein, originally isolated from human erythrocytes. Tropomodulin is currently regarded as the sole actin pointed-end capping protein [Weber, A., Pennise, C.R., Babcock, G.G. & Fowler, V.M. (1994) J. Cell Biol. 127, 1627-1635]. This work first describes a procedure for the purification of tropomodulin from rabbit skeletal muscle. Tropomodulin almost completely inhibited filament formation of actin in the presence of tropomyosin and troponin. For the maximal inhibition of actin polymerization, approximately 0.10, 0.12 and 0.003 mol of tropomyosin, troponin and tropomodulin per mol of actin were required, respectively. Fluorescence-intensity measurements, electron-microscopy and sedimentation experiments revealed that only very short fragments and amorphous aggregates, but not filaments, were formed when actin was copolymerized with tropomyosin, troponin and tropomodulin by the addition of 50 mM KCl at pH 8.0. The effects of tropomyosin, troponin and tropomodulin were more remarkable on Ca-actin than on Mg-actin. It appears that tropomodulin caps both the pointed and barbed ends of tropomyosin- and troponin-bound actin filaments.

[The appropriate time for the assessment of Helicobacter pylori eradication].

As all of the guidelines on the management of H. pylori infection suggest, the assessment of the eradication is generally performed at least 4 weeks after the completion of eradication treatment. However, H. pylori occasionally re-appears after one month, even the successful eradication was confirmed by the guideline. In this study, we investigated the appropriate time for the assessment of H. pylori eradication, mainly by using 13C urea breath tests (UBT) as a positive standard. From July 1992 to December 1997, 386 patients with H. pylori infection received eradication treatments. The presence of H. pylori was assessed by rapid urease test, UBT, culture and histologic examination. Eradication of the bacteria was determined by the negative results in all of these four tests. At 4 weeks after completion of therapy, 312 cases (80.8%) were judged as being free of H. pylori. Mean observation period was up to 12 months, and 113 cases were followed up to more than 1 year, and 50 cases were followed up to more than 2 years. H. pylori had re-appeared in 3 cases after 3 months, 1 case after 6 months, 2 cases after 12 months, and 1 case 24 months after the treatment, respectively. For the purpose of more accurate diagnosis, the assessment of eradication of H. pylori should be performed at 1 year after the completion of therapy. Since all the recrudescence could be diagnosed with UBT earlier and be confirmed by the other tests later, UBT is recommended as a useful methods in the assessment of Helicobacter pylori eradication.

Eradication of Helicobacter pylori using 30 mg or 60 mg lansoprazole combined with amoxicillin and metronidazole: one and two weeks of a new triple therapy.

A new triple therapy using a proton pump inhibitor and two antibiotics shows high efficiency against Helicobacter pylori infection. The aim of this study was to determine the optimal dose and duration of lansoprazole (LA) administration in combination with amoxicillin (AMPC) and metronidazole (MNZ). A total of 91 patients were enrolled in this study. They were divided into four groups: group A, 2 weeks of 30mg LA once daily, 500mg AMPC tid, and 250mg MNZ tid; group B, 2 weeks of 30mg LA bid, 500mg AMPC tid, and 250mg MNZ tid; group C, 1 week of 30mg LA once daily, 500mg AMPC tid, and 250mg MNZ tid; group D, 1 week of 30mg LA bid, 500mg AMPC tid, and 250mg MNZ tid. H. pylori status was determined by the rapid urease test, culture, histology, and 13C-urea breath test before and at least 4 weeks after the end of therapy. The cure rates in a per-protocol analysis and the incidence of adverse events in the evaluated patients were, respectively, 89.5% and 21.1% in group A, 100% and 20.0% in group B, 96.8% and 12.9% in group C, and 92.3% and 26.9% in group D. Most of the adverse events were tolerated. All four regimens in this study showed the same cure rates, and they were effective and well tolerated. One week of triple therapy using once-daily administration of 30mg LA is a good alternative.

A human gastric cancer cell line possesses a functional receptor for gastrin-releasing peptide.

Bombesin (BBS) exhibits diverse biological functions including those of neurotransmitter, regulator of gastrointestinal hormone release, and mitogen. Gastrin-releasing peptide (GRP, the mammalian equivalent of BBS) is found in mucosal cells of the gastric fundus and antrum. We determined whether a human gastric cancer cell line (SIIA) expresses a functional GRP-receptor (GRP-R). BBS increased intracellular calcium ([Ca2+]i), and a specific GRP-R antagonist, ([D-Phe6, Des-Met14]-BBS (6-14)-ethylamide), blocked BBS-induced increase in [Ca2+]i. SIIA cells possess GRP-R mRNA by reverse transcriptase-PCR. Furthermore, these cells possess an 80-kDa cell surface protein that specifically binds BBS with two high-binding affinities (Kd1 = 0.6 nM, Kd2 = 6.7 nM). These findings indicate that SIIA cells possess a GRP-R that is capable of physiological signal transduction, though the cellular response remains unknown.

Bombesin stimulates in vitro growth of human breast cancer independent of estrogen receptors status.

BACKGROUND: Approximately 180,000 women will be found to have breast cancer this year in the United States. Chemotherapy has limited success in advanced disease and the effect of tamoxifen appears to require a functional estrogen-receptor (ER). Our aim was to determine whether bombesin (BBS) regulates growth of human breast cancer cells. METHODS: Estrogen-dependent (MCF-7), estrogen-responsive (ZR-75-1) and estrogen-independent (MDA-MB-231) human breast cancer cells were studied. Receptors were identified by cross-linking methods and radioligand binding assays; intracellular calcium ([Ca2+]i) was measured after BBS treatment to confirm functional status of the receptor; and the effect of BBS on cell growth was measured directly. RESULTS: All three cell lines had a high affinity BBS receptor (Kd = 1-7 nM; molecular weight 75 kDa). BBS stimulated [Ca2+]i levels as well as cell growth in all three cell lines; the trophic effect was blocked by BBS receptor antagonists. CONCLUSIONS: We conclude that BBS is trophic for human breast cancers independent of ER status, and that antagonism of the BBS receptor may be a useful target for hormonal therapy in ER-negative breast cancer.

Mechanisms of bombesin on growth of gastrinoma (PT) in vivo.

The growth of the human gastrinoma model (PT) in athymic nude mice is stimulated by bombesin (BBS), an amphibian peptide homologous to both human gastrin-releasing peptide (GRP) and neuromedin B (NMB). The mechanism is not known, and a potent and specific GRP-R antagonist BIM26226, which has low affinity for NMB-R, was used in vivo in athymic nude mice bearing gastrinoma subcutaneously. Both the BBS and BIM26226 stimulated the growth of PT, and the growth stimulation was even greater when given together. RT-PCR study of gastrinoma revealed the presence of both GRP-R and NMB-R mRNA, but much more abundant NMB-R mRNA. We conclude that BBS-stimulated growth of gastrinoma involves both GRP-R and NMB-R, and our findings suggest that GRP-R mediates negative and NMB-R produces positive growth effects on gastrinoma.

Hyperphosphorylation of retinoblastoma protein and stimulation of growth by okadaic acid in human pancreatic cancer.

Phosphorylation/dephosphorylation of intracellular proteins are important steps in the regulation of cell growth. Okadaic acid, an inhibitor of the serine/threonine protein phosphatases 1 and 2A, is a potent tumor promoter. This effect may be through the inhibition of dephosphorylation (termed "hyperphosphorylation") and subsequent inactivation of tumor-suppressor proteins. We examined whether okadaic acid regulates growth of human pancreatic cancer cells (MIA PaCa-2 and Panc-1) or alters the phosphorylation of the retinoblastoma tumor-suppressor protein. Growth studies, nuclear labeling analyses, and Western blotting for retinoblastoma protein were performed. Okadaic acid stimulated cell growth and induced hyperphosphorylation of the retinoblastoma protein. The growth-stimulatory effect of okadaic acid on these human pancreatic cancer cells may be mediated by inactivation of the growth suppressive effect of the retinoblastoma protein by hyperphosphorylation. These studies suggest that the growth of these human pancreatic cancer cells is still regulated by tumor-suppressor proteins.

Intraluminal tumor of the common bile duct as a metastasis of renal cell carcinoma.

A 57-year-old woman was admitted for evaluation of liver dysfunction. A physical examination revealed jaundice and a left abdominal mass, which was diagnosed as being a large renal tumor. Cholangiography showed a smooth filling defect 1 cm in diameter at the common bile duct. Left nephrectomy, and resection of the common bile duct were performed. The pathological diagnosis was metastasis of the common bile duct wall resulting from renal cell carcinoma. Metastatic common bile duct tumors are extremely rare. However, it is important to consider that this is one of the causes of obstructive jaundice.

Stimulation of pancreatic growth. Distal small bowel resection mediated by increased levels of cholecystokinin.

SUMMARY BACKGROUND DATA: Distal, but not proximal, resection of the small bowel induces growth of rat pancreas, but the mechanism of this phenomenon is poorly clarified. The release of cholecystokinin (CCK), a trophic hormone for the pancreas, is regulated by a negative-feedback control of bile salts. The ileum is a major site for reabsorption of bile salts. Thus, unsuppressed release of CCK due to deleted reabsorption of bile salts after distal small bowel resection may be a cause of pancreatic growth. In this study, the authors have examined whether pancreatic growth after distal small bowel resection was mediated by endogenous CCK and have determined whether the mechanism of this pancreatic growth required biosynthesis of polyamine. METHODS: Male Fischer 344 rats underwent 70% distal small bowel resection or transection of the ileum. Beginning 48 hours after surgery, CR1409 (a CCK-receptor antagonist) or saline was injected subcutaneously every 8 hours. All animals were pair-fed and killed 14 days after surgery. The pancreas from each rat was excised, weighed, and assayed for DNA, RNA, protein, and polyamine content. RESULTS: Distal small bowel resection increased pancreatic weight, DNA, RNA, and protein, as well as polyamine levels; all of these increases were significantly suppressed by CR1409. Postprandial release of CCK into the circulation was significantly increased after distal small bowel resection. CONCLUSIONS: Pancreatic growth after distal small bowel resection was associated with the stimulation of polyamine biosynthesis; growth appeared to be mediated by endogenous CCK.

Short-term caloric restriction augments age-related decreases in gastrin content and release.

Aging is associated with significant structural and functional changes in the gastrointestinal tract. Gastrin, a hormone produced by G cells in the antrum of the stomach, stimulates proliferation of gastric mucosa; its synthesis appears to decrease with age. Life-long restriction of caloric intake is the only experimental manipulation that has been shown to retard aging processes in rats. The purpose of this study was to examine the effect of short-term caloric restriction (CR) on the production and release of the hormone gastrin with aging. Aging causes a fall in both fasting plasma levels of gastrin and antral content of gastrin in Fischer 344 rats; short-term CR appears to augment this age-related decrease. Steady state levels of antral gastrin mRNA were decreased with aging, and short-term CR resulted in an augmented decrease in aged, but not in young rats. Our findings indicate that gastrin release, synthesis and gene expression decrease with age. Restriction of the caloric intake for a short period (i.e. 8 weeks) augments this age-related decrease in antral gastrin and fasting plasma levels. Short-term CR appears to decrease the production of gastrin at the level of gene expression.

All-trans-retinoic acid inhibits growth of human pancreatic cancer cell lines.

Retinoids are a class of molecules structurally related to vitamin A that have potent antiproliferative and differentiating effects on a variety of normal and neoplastic tissues. All-trans-retinoic acid (ATRA) has become a first-line chemotherapeutic agent in the treatment of certain leukemias; however, the effect of ATRA on pancreatic tumors is unknown. The purpose of this study was to determine the effect of ATRA on the growth characteristics of both exocrine and endocrine human pancreatic cancer cell lines. The in vitro growth of four cell lines was examined after treatment with a wide dose range of ATRA. The growth of all tumor cell lines was inhibited by ATRA in a dose-dependent fashion beginning at 0.1 microgram M. The in vivo growth of functioning human pancreatic carcinoid (BON) xenografts in Balb/c athymic mice was determined by treatment with several doses of ATRA over 1 month. The growth of BON tumors was inhibited in a dose-dependent fashion. These results suggest that ATRA exerts direct antiproliferative effects on both exocrine and endocrine human pancreatic cancers and may be useful in the chemotherapy of these tumors.