[Strategy to manage low dose aspirin-induced gastrointestinal injury].

Low dose aspirin, as an anti-platelet medication, has been increasingly prescribed to elderly patients for primary and secondary prevention of cardio- and cerebro-vascular events. Nonetheless, aspirin's effectiveness in such disease prevention is limited by the risk of upper and lower gastrointestinal (GI) complications such as ulceration, hemorrhage and perforation. Aspirin administration is associated with 2-fold increase in the GI risk in middle-aged users without prior history of peptic ulcer and without concomitant medications. However, such GI risk increases dramatically in patients with a prior history of peptic ulcer disease, advanced age, and concomitant use of NSAIDs, corticosteroids, clopidogrel, or anticoagulants. Mechanisms of aspirin-induced GI injury are believed to be through local effects within the GI mucosa that cause topical injury and through systemic inhibition of cyclo-oxygenase (COX) resulting in depletion of mucosal protective prostaglandins. Herein, we focus on the strategy to manage aspirin-induced peptic ulcerations and their complications, based on the scientific evidence.

[Role of proton pump inhibitor in the management of low dose aspirin related ulcerations].

Aspirin, as an anti-platelet medication, has been increasingly prescribed to elderly patients for primary and secondary prevention of cardio--and cerebro--vascular events. Nonetheless, aspirin's effectiveness in such disease prevention is limited by the risk of gastrointestinal (GI) complications such as ulceration, hemorrhage and perforation. Aspirin administration is associated with 2-fold increase in GI risk in middle-aged users without prior history of peptic ulcer and without concomitant medications. However, the GI risk increases dramatically in patients with a prior history of peptic ulcer disease, advanced age, and concomitant use of NSAIDs, corticosteroids, clopidogrel, or anticoagulants. Mechanisms of aspirin-induced GI injury are believed to be through local effects within the GI mucosa that cause topical injury and through systemic inhibition of cyclo-oxygenase (CO) resulting in depletion of mucosal protective prostaglandins. Herein, we focus on the role of proton pump inhibitor (PPI) in the strategy to prevent and to treat aspirin-induced peptic ulcerations and their complications, based on the scientific evidence.

[PPARgamma agonists for the diseases of gastrointestinal tract and liver].

Peroxisome proliferator-activated receptor gamma (PPARgamma), a member of the nuclear receptor superfamily, is expressed in colonic epithelial cells at high levels and is assumed to play an important physiological role in the gut. In vitro as well as animal model experiments showed considerable anti-cancer and anti-inflammatory effects of thiazolidinedione (TZD) PPARgamma agonists in the colon. Therefore, in the gastroenterology field, much attention has been focused on the efficacy of TZD on the treatment of colorectal cancer and inflammatory bowel diseases (IBD). Although we only have very limited clinical evidence at present, TZD might be useful for the chemoprevention of colorectal cancer and treatment of mild to moderately active inflammatory bowel diseases, which warrant further clinical studies.

Proton pump inhibitors and recurrent bleeding in peptic ulcer disease.

Peptic ulcer disease (PUD) is one of the main lesions responsible for upper gastrointestinal (GI) bleeding, as well as esophageal varices and Mallory-Weiss tear. Helicobacter pylori and non-steroidal anti-inflammatory drugs (NSAIDs)/aspirin are the major responsible causes. In cases of upper GI bleeding, urgent endoscopy is performed after stabilization of vital signs. There are several modalities for controlling bleeding in PUD, such as ethanol injection or hypertonic saline with epinephrine. Recurrent bleeding occurs in 20% of patients after endoscopic therapy. The combination of endoscopic intervention and a proton pump inhibitor (PPI) is necessary to achieve hemostasis of active bleeding. It has been reported that high-dose omeprazole (80 mg bolus injection, then 8 mg/h continuous infusion for 72 h, then 40 mg/day orally for 1 week) can reduce recurrent bleeding, the need for surgery and mortality from hemorrhagic shock in patients with high-risk peptic ulcer bleeding, as compared with standard-dose omeprazole. The metabolism of PPIs is dependent upon P450 2C19 genotypes and the clinical usefulness of genotypic analysis remains to be determined.

[Iron deficiency anemia and H. pylori].

Although Helicobacter pylori (H. pylori) is a causative agent for chronic gastritis, peptic ulcer, and gastric carcinoma, this pathogen is also responsible for some extra-gastric diseases. Both epidemiologic and clinical studies suggest that H. pylori infection is a risk factor for iron deficiency anemia (IDA). Several case reports and case series showed reversal of IDA after eradication of H. pylori. Although the mechanisms for H. pylori-associated IDA is not fully understood, H. pylori-induced chronic pangastritis with resultant achlorhydria and reduced ascorbic acid secretion in the gastric mucosa may lead to reduced iron absorption. Uptake of iron by H. pylori is also suggested. Further properly designed trials are needed to confirm a causal relationship between H. pylori and IDA.

Peroxisome proliferator-activated receptor gamma (PPARgamma) regulates trefoil factor family 2 (TFF2) expression in gastric epithelial cells.

Although trefoil factor family 2 (TFF2) plays a critical role in the defense and repair of gastric mucosa, the regulatory mechanism of TFF2 expression is not fully understood. In this study, we investigated the regulation of TFF2 expression by peroxisome proliferator-activated receptor gamma (PPARgamma) in gastric epithelial cells. MKN45 gastric cells were used. TFF2 mRNA expression was analyzed by real-time quantitative RT-PCR. The promoter sequence of the human TFF2 gene was cloned into pGL3-basic vector for reporter gene assays. Ciglitazone was mainly used as a specific PPARgamma ligand. MKN45 cells expressed functional PPARgamma proteins. Endogenous TFF2 mRNA expression and TFF2 reporter gene transcription was significantly up-regulated by ciglitazone in a dose-dependent manner. Reporter gene assays showed that two distinct cis-elements are involved in the response to PAPRgamma activation. Within one of these element (nucleotides -558 to -507), we identified a functional peroxisome proliferator responsive element (PPRE) at -522 (5'-GGGACAAAGGGCA-3'). Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assay confirmed the binding of PPARgamma to this sequence. Another element (nucleotides -407 to -358) appeared to be a composite enhancer element indirectly regulated by PPARgamma and a combination of these two cis-elements was required for the full response of the human TFF2 gene expression to PPARgamma. These data demonstrate that human TFF2 gene is a direct target of PPARgamma in gastric epithelial cells. Since TFF2 is a critical gastroprotective agent, PPARgamma may be involved in the gastric mucosal defense through regulating TFF2 expression in humans.

Regulation of TFF3 expression by homeodomain protein CDX2.

Although trefoil factor family 3 (TFF3) plays an important role in protecting the intestinal mucosa, the regulatory mechanisms of its expression are not fully understood. Since homeodomain protein CDX2 has been reported to be critically involved in the development and differentiation of intestinal epithelium, we examined whether CDX2 affects the expression of TFF3. The transcription of human TFF3 reporter genes was significantly up-regulated by the transient overexpression of CDX2 in COS-7 cells and AGS gastric cells. Electrophoretic mobility shift assay revealed the presence of at least two CDX-binding sites within the human TFF3 promoter. Deletion analysis showed the relative importance of the proximal CDX-binding site at -63. We also detected the up-regulation of endogenous TFF3 mRNA expression in AGS cells stably transfected with CDX2 expression vectors. These results suggest that CDX2 plays a key role in the expression of TFF3 in the intestine and perhaps in intestinal metaplasia of the stomach.

Comparison between endoscopic papillary balloon dilatation and endoscopic sphincterotomy for the treatment of common bile duct stones.

BACKGROUND: This study was designed to evaluate the therapeutic outcome and early postoperative complications, especially pancreatitis, of endoscopic papillary balloon dilation (EPBD) and endoscopic sphincterotomy (EST) in patients with common bile duct stones in our department. METHODS: One hundred eighty patients with common bile duct stones were randomized to undergo EPBD or EST. An 8-mm dilatation balloon was used for EPBD. Modified Cotton's criteria, in which relatively mild pancreatitis is also included as a complication, were used to determine the incidence of postoperative complications. RESULTS: The rate of complete removal of stones was significantly higher in the EST group (95.6%) than in the EPBD group (86.6%); for stones less than 10 mm in diameter, however, the rate with EPBD (93.8%) was almost equivalent to that with EST (98.1%). According to modified Cotton's criteria, the incidence of postoperative pancreatitis was significantly higher in the EPBD group (16.7%) than in the EST group (6.7%). Bleeding was encountered in one patient (1.1%) in the EST group, but in none in the EPBD group. No fatal complication occurred in either the EPBD or the EST group. CONCLUSIONS: Although EPBD appears to be comparable to EST for removal of small common bile duct stones, mild postoperative pancreatitis is more likely to occur with EPBD than with EST.

[Role of Helicobacter pylori eradication in the prevention of peptic ulcer in NSAID users].

Helicobacter pylori (H. pylori) and non-steroidal anti-inflammatory drug (NSAID) are independent risk factors for peptic ulcers and ulcer complications and they have additive or synergistic effects. A meta-analysis showed that the OR for the incidence of peptic ulcer was 61.1 in patients infected with H. pylori and also taking NSAID when compared to patients uninfected with H. pylori and not taking NSAID. H. pylori eradication may prevent NSAID-induced ulcers in NSAID naive patients. In patients receiving long-term NSAID, proton pump inhibitor(PPI) is more effective in the prevention of ulcer recurrence and bleeding. However, H. pylori eradication should be considered in patients receiving long -term PPI maintenance treatment to prevent the development of corpus gastritis and gastric atrophy.

[Guideline for prophylaxis and treatment of NSAID-associated gastric ulcerations].

Both Helicobacter pylori (H. pylori) infection and non-steroidal anti-inflammatory drug (NSAID) administration independently and significantly increase the risk of peptic ulceration and ulcer bleeding as its complication. Because of increasing ratio of the senior generation in Japan, the relative role of NSAID including low-dose aspirin as an anti-platelet therapy, will be more important in the pathogenesis of peptic ulcerations. In order to prevent peptic ulcerations, one of the major adverse events of NSAID, a series of selective COX-2 inhibitors has been developed and some of them have been widely used clinically. However, long-term use of a COX-2 inhibitor may be associated with higher risk of cardiovascular events and strokes. Herein, we focus on prophylaxis and treatment of NSAID-associated gastric ulcerations.

Central thyrotropin-releasing hormone increases hepatic cyclic AMP through vagal-cholinergic and prostaglandin-dependent pathways in rats.

Central neuropeptides play roles in many physiologic regulations through the autonomic nervous system. We have demonstrated that central thyrotropin-releasing hormone (TRH), one of neuropeptides, induces a stimulation of hepatic proliferation through vagal-cholinergic pathways. Since cAMP is known to play an important role in the hepatic proliferation, effect of central TRH on hepatic cAMP was investigated. Rats were intracisternally injected with either a TRH analog, RX-77368 (1-100 ng), or saline. The liver was removed 2-72 h after the TRH analog and hepatic cAMP content was determined by radioimmunoassay. In some experiments, pretreatment with hepatic vagotomy, atropine methyl nitrate, or 6-hydroxydopamine (6-OHDA) was performed. Hepatic cAMP was dose-dependently increased by intracisternal TRH analog (5-100 ng) with a peak response occurring 12 h postinjection. The central TRH-induced increase in hepatic cAMP was abolished by vagotomy, atropine and indomethacin, but not by 6-OHDA. Intravenous injection of the TRH analog (10 ng) did not affect hepatic cAMP. These results demonstrate that TRH acts in the brain to increase hepatic cAMP through vagal-cholinergic and prostaglandin-dependent pathways, suggesting that central TRH modulates hepatic functions through cAMP-mediated signaling pathways.

Thyrotropin-releasing hormone in the dorsal vagal complex stimulates pancreatic blood flow in rats.

Central administration of thyrotropin-releasing hormone (TRH) enhanced pancreatic blood flow in animal models. TRH nerve fibers and receptors are localized in the dorsal vagal complex (DVC), and retrograde tracing techniques have shown that pancreatic vagal nerves arise from the DVC. However, nothing is known about the central sites of action for TRH to elicit the stimulation of pancreatic blood flow. Effect of microinjection of a TRH analog into the DVC on pancreatic blood flow was investigated in urethane-anesthetized rats. After measuring basal flow, a stable TRH analog (RX-77368) was microinjected into the DVC and pancreatic blood flow response was observed for 120 min by laser Doppler flowmetry. Vagotomy of the several portions, or pretreatment with atoropine methyl nitrate or N(G)-nitro-l-arginine-methyl ester was performed. Microinjection of RX-77368 (0.1-10 ng) into the left or right DVC dose-dependently increased pancreatic blood flow. The stimulation of pancreatic blood flow by RX-77368 microinjection was eliminated by the same side of cervical vagotomy as the microinjection site or subdiaphragmatic vagotomy, but not by the other side of cervical vagotomy. The TRH-induced stimulation of pancreatic blood flow was abolished by atropine or N(G)-nitro-l-arginine-methyl ester. These results suggest that TRH acts in the DVC to stimulate pancreatic blood flow through vagal-cholinergic and nitric oxide dependent pathways, indicating that neuropeptides may act in the specific brain nuclei to regulate pancreatic function.

Protective effect of central thyrotropin-releasing hormone analog on cerulein-induced acute pancreatitis in rats.

Central neuropeptides play a role in many physiological functions through the autonomic nervous system. We have recently demonstrated that central injection of a thyrotropin-releasing hormone (TRH) analog increases pancreatic blood flow through vagal and nitric oxide-dependent pathways. In this study, the central effect of a TRH analog on experimental acute pancreatitis was investigated in rats. Acute pancreatitis was induced by two intraperitoneal injections of cerulein (40 microg/kg) at 1-h interval. Either stable TRH analog, RX 77368 (5-100 ng), or saline was injected intracisternally 15 min before the first cerulein injection under ether anesthesia. Serum amylase level was measured before and 5 h after the first cerulein injection. Pancreatic wet/dry weight ratio and histological changes were also evaluated. Intracisternal TRH analog inhibited cerulean-induced elevation of serum amylase level, increase in pancreatic wet/dry weight ratio and pancreatic histological changes, such as interstitial edema, inflammation and vacuolization. The pancreatic cytoprotection induced by central TRH analog was abolished by subdiaphragmatic vagotomy and N(G)-nitro-L-arginine-methyl ester (L-NAME), but not by 6-hydroxydopamine (6-OHDA). Intravenous administration of the TRH analog did not influence cerulein-induced acute pancreatitis. These results indicate that the TRH analog acts in the central nervous system to protect against acute pancreatitis through vagal and nitric oxide-dependent pathways.

PPARgamma mediates NSAIDs-induced upregulation of TFF2 expression in gastric epithelial cells.

Trefoil factor family (TFF) is a group of peptides that play critical roles in maintaining gastric mucosal integrity. In real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) and reporter gene assays, we show that indomethacin and aspirin upregulate TFF2 expression in MKN45 gastric cells. These drugs also activated peroxisome proliferator-activated receptor gamma (PPARgamma) at concentration ranges that increase TFF2 expression, and upregulated TFF2 expression was suppressed by GW9662, a specific inhibitor of PPARgamma. These results suggest that indomethacin and aspirin upregulate gastric expression of TFF2 through activation of PPARgamma. This mechanism may be important in reducing the extent of gastric mucosal injury caused by the administration of non-steroidal anti-inflammatory drugs (NSAIDs).

[Guidelines in the management of Helicobacter pylori infection in Japan--in comparison with the guidelines published in other countries].

Helicobacter pylori(H. pylori) is a causative agent for chronic gastritis and is an important risk factor for peptic ulcers, gastric carcinomas, and gastric MALT lymphomas. In 2000, the Japanese Society for Helicobacter Research published a guideline on the diagnosis and treatment of H. pylori infection for physicians in routine medical practice. In this guideline, H. pylori eradication therapy is recommended in gastric or duodenal ulcer patients. H. pylori eradication is also recommended in gastric MALT lymphoma patients but the guideline says it should be done at specialist institutions. Considering the high prevalence of gastric carcinomas in Japan. H. pylori eradication for the prevention of gastric carcinomas should be discussed urgently.

Surface potential studies on adsorption processes of clay nanosheets onto a floating molecular film of an amphiphilic alkylammonium cation.

A floating molecular film was formed when a chloroform solution of dimethyldioctadecylammonium bromide (DMDOA(+)Br(-)) was spread on an aqueous dispersion of a clay mineral (sodium montmorillonite). At a low concentration (<50 ppm: ppm = mg dm(-3)), a clay mineral was exfoliated into negatively charged layers (denoted by clay nanosheets). Clay nanosheets in a dispersion were adsorbed onto a floating film because of electrostatic interactions. At various clay concentrations (0-50 ppm), surface potential was measured as a function of time to obtain the quantitative information about the adsorption of clay nanosheets on a condensed floating film of DMDOA(+) ions. It was concluded that the adsorption equilibrium obeyed the Langmuir adsorption isotherm, which was supported by the atomic force microscopy (AFM) observation. The rate constants of adsorption and desorption processes were determined by the fitting analyses based on the Langmuir type kinetics. Interestingly, the delay of the adsorption was observed in the early stage indicating that clay nanosheets were removed from the surface region through the repulsion by a counteranion (Br(-)). This explanation was supported by the model simulation using the forward difference method.

Frequency of nonsteroidal anti-inflammatory drug-associated ulcers.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for treatment of orthopedic diseases, inflammatory diseases, etc., and low-dose aspirin is a common antiplatelet therapy given mainly for secondary prevention of atherothrombosis (e.g., myocardial infarction and cerebral infarction). As to the history of NSAID-induced gastric mucosal injury in Japan, the first case of an aspirin-induced gastric ulcer was reported as early as 1934. Based on a meta-analysis of risk factors for peptic ulcers, Helicobacter pylori infection and NSAIDs are the main etiologies of peptic ulcers. NSAIDs alone increase the odds ratio for ulcer development to 19.4 and that for ulcer bleeding to 4.85. In fact, the Japan Rheumatism Foundation reported in 1991 that active gastric ulcers and active duodenal ulcers were detected in 15.5 and 1.9 % of 1008 patients, respectively, taking oral NSAIDs for 3 months or longer. In Japan, which is becoming an increasingly aged society, the numbers of patients taking NSAIDs and low-dose aspirin are expected to increase dramatically in the future. It is hoped that accumulation of evidence on gastrointestinal risk will allow many patients to rationally avoid gastrointestinal complications while receiving the benefits of NSAIDs and low-dose aspirin.