Mucosal Protective Drug Research Articles

Recovery from indomethacin-induced gastrointestinal bleeding by treatment with teprenone

BackgroundGastrointestinal injuries caused by nonsteroidal anti-inflammatory drugs (NSAIDs) is a serious side effect in patients with rheumatoid arthritis (RA). However, effective therapeutic strategies have yet to be established. In this study, we investigated the therapeutic effects of teprenone (TEP), a gastric mucosal protective drug, on NSAID-induced gastrointestinal injuries in rats with RA (AA rats).MethodsGastrointestinal injury was induced by oral administration of indomethacin (IMC), a typical NSAID. TEP was orally administered after IMC-induced gastrointestinal bleeding, and the stomach, jejunum, and ileum were excised.ResultsOn day 14 of IMC administration, lesion areas in the stomach, jejunum, and ileum were significantly larger in AA rats than in normal rats. When TEP was orally administered to AA rats, the lesion areas in the stomach, jejunum, and ileum significantly decreased compared with those in control rats (IMC-induced AA rats). Therefore, we measured NOS2 mRNA and NO levels, which were significantly decreased in rats with IMC-induced AA after treatment with TEP.ConclusionsThese results suggest that the oral administration of TEP may be useful for the treatment of NSAID-induced gastrointestinal injuries in patients with RA.

A comparison of different symptomatic reflux esophagitis treatments: A real-world study.

Proton pump inhibitors (PPIs) are currently the reference drugs for gastroesophageal reflux disease (GERD), but symptoms often recur after their withdrawal. Moreover, whether prokinetics or barrier drugs used alongside PPIs are more effective remains under debate. The aim of the study was to assess the efficacy of different therapeutic approaches to GERD treatment. We enrolled 211 grade A reflux esophagitis patients who consented to participate in this non-randomized, open-label trial. The study consisted of 6 sequentially administered medical treatments for GERD, lasting 2 months, with a 3-week washout period between each drug schedule: Group A: PPI (esomeprazole 40 mg/day before breakfast); Group B: mucosal protective drugs (a combination of hyaluronic acid, chondroitin sulfate and poloxamer 407, or a combination of hyaluronic acid, chondroitin sulfate and aluminum, 3 times daily after a meal); Group C: prokinetics (levosulpiride 25 mg or domperidone 10 mg, 3 times daily before a meal); Group D: barrier drug (alginate 3 times daily after a meal); Group E: PPI (esomeprazole 40 mg/day before breakfast) and mucosal protective drugs (a combination of hyaluronic acid, chondroitin sulfate and poloxamer 407, or a combination of hyaluronic acid, chondroitin sulfate and aluminum, before sleep); Group F: PPI (esomeprazole 40 mg/day before breakfast) and prokinetics (levosulpiride 25 mg or domperidone 10 mg before lunch and dinner). Symptoms were evaluated using the visual analogue scale (VAS) and global symptomatic score (GSS), as follows: heartburn: 0-3; retrosternal chest pain: 0-3; regurgitation: 0-3. All but 2 treatments (groups C and D) significantly improved VAS and GSS, with group E showing the most significant GSS improvement. Group C had the highest number of dropouts due to treatment failure and reported more side effects. Using PPIs and mucosal protective drugs resulted in significant symptom alleviation. However, the administration of prokinetics caused higher dropouts due to treatment failure.

An Unusual Cause of Esophagitis

An Unusual Cause of Esophagitis

Role of oral pentosan polysulfate in Bacillus Calmette-Guérin therapy in patients with non-muscle-invasive bladder cancer.

PurposeIntravesical Bacillus Calmette–Guérin (BCG) instillation, although an important treatment for non-muscle-invasive bladder cancer, exerts local and systemic adverse effects. Pentosan polysulfate (PPS) is a bladder mucosal protective drug that acts by replacing mucus in the glycosaminoglycan layer of the damaged urothelium. We hypothesized that co-administration of oral PPS with BCG instillation would relieve BCG-related adverse effects without affecting its efficacy.Materials and MethodsA total of 217 patients receiving BCG instillation were enrolled. They were placed in two groups and analyzed retrospectively: group A (n=122) received BCG instillation only and group B (n=95) received 100 mg of PPS thrice daily during the BCG treatment.ResultsAfter BCG instillation, the rate of BCG-treatment discontinuation owing to adverse effects was 15.6% in group A and 6.3% in group B (p=0.034). The proportion of patients with bacteriuria after BCG was higher in group B; however, no statistical difference was observed (28.7% vs. 41.1%; p=0.057). The proportion of patients with pyuria was significantly higher in group B (81.1% vs. 91.6%; p=0.029). The proportion of patients using antibiotics was significantly higher in group A (73.8% vs. 43.2%; p=0.001). The recurrence rate within 1 year was 29 (23.8%) in group A vs. 19 (20.0%) in group B (p=0.507). Univariate and multivariate analyses showed that antibiotic use had a statistically significant effect on BCG discontinuation.ConclusionsOral PPS effectively decreased the discontinuation rate and antibiotic use without affecting the BCG efficacy.

Prevention of Rat Intestinal Injury with a Drug Combination of Melatonin and Misoprostol.

A healthy intestinal barrier prevents uptake of allergens and toxins, whereas intestinal permeability increases following chemotherapy and in many gastrointestinal and systemic diseases and disorders. Currently, there are no approved drugs that target and repair the intestinal epithelial barrier while there is a medical need for such treatment in gastrointestinal and related conditions. The objective of this single-pass intestinal perfusion study in rats was to investigate the preventive cytoprotective effect of three mucosal protective drugs—melatonin, misoprostol, and teduglutide—with different mechanisms of action on an acute jejunal injury induced by exposing the intestine for 15 min to the anionic surfactant, sodium dodecyl sulfate (SDS). The effect was evaluated by monitoring intestinal clearance of 51Cr-labeled ethylenediaminetetraacetate and intestinal histology before, during, and after luminal exposure to SDS. Our results showed that separate pharmacological pretreatments with luminal misoprostol and melatonin reduced acute SDS-induced intestinal injury by 47% and 58%, respectively, while their use in combination abolished this injury. This data supports further development of drug combinations for oral treatments of conditions and disorders related to a dysregulated or compromised mucosal epithelial barrier.

Histamine2-Receptor Antagonists, Proton Pump Inhibitors, or Potassium-Competitive Acid Blockers Preventing Delayed Bleeding After Endoscopic Submucosal Dissection: A Meta-Analysis.

Background: Endoscopic submucosal dissection (ESD) was commonly used for en bloc resection in gastric cancer and adenoma with the risk of delayed bleeding after ESD. We conducted a direct and indirect comparison meta-analysis to evaluate the best choice in preventing post-ESD bleeding among proton pump inhibitors (PPIs), histamine2-receptor antagonists (H2RAs), and the most widely used potassium-competitive acid blocker, vonoprazan. Methods: The Pubmed, Cochrane Library, and Embase were searched for randomized trials. We pooled odds ratios (OR) for preventing post-ESD bleeding using meta-analysis. Results: Sixteen randomized trials met the inclusion criteria including 2,062 patients. Direct comparisons showed slightly significant efficacy in PPIs rather than H2RAs in preventing post-ESD bleeding [OR: 1.83; 95% confidence interval (CI): 1.10 to 3.05] and vonoprazan was better than PPIs (OR: 0.46; 95% CI: 0.25 to 0.86). The adjusted indirect comparison indicated vonoprazan was superior to H2RAs (OR: 0.30, 95% CI: 0.12 to 0.74). In subgroup analysis, PPIs had similar efficacy as H2RAs in 4 weeks, while PPIs were better than H2RAs in 8 weeks’ treatment (OR: 1.91; 95% CI: 1.08 to 3.40). The superiority of vonoprazan than PPIs was more significant in combination therapy (OR: 0.18; 95% CI: 0.04 to 0.69). There was a significant difference in vonoprazan for 8 weeks of medication (OR: 0.44; 95% CI: 0.21 to 0.92). Conclusions: The effects of vonoprazan is better than PPIs than H2RAs in preventing bleeding after ESD. When vonoprazan combined with mucosal protective antiulcer drug in treatment or used in 8 weeks of medication, the efficacy may be even better.

Megaesophagus Secondary to Feline Dysautonomia (Key-Gaskell Syndrome) in a Cat

Background: Feline dysautonomia is a rare autonomic neuropathy of unknown cause, that has already been reported in Europe, the United States and Brazil. Cats usually show nonspecifc clinical signs that are associated with autonomic dysfunction of the nervous system. The diagnosis is based on the clinical signs and imaging tests, and confrmed by necropsy and histopathological fndings. The prognosis is poor and there is no defnitive treatment. The aim of this report is to describe a case of feline dysautonomia with emphasis in the clinical, diagnostic imaging and histopathological fndings. Feline dysautonomia must always be considered as a differential diagnosis in cases of megaesophagus in cats.Case: A mixed-breed young male cat was evaluated for anorexia, regurgitation, bilateral nasal discharge and dyspnoea for 24 h. The animal was dehydrated and had pale mucous membranes, abdominal distension and keratoconjunctivitis sicca. The neurological examination was normal. Abdominal ultrasound showed a distended bladder and normal intestinal motility. Chest radiography and esophageal contrast study exhibited megaesophagus in the intrathoracic region. Blood work showed mild neutrophilic leukocytosis and the presence of toxic neutrophils. The cat remained hospitalized for supportive care, including fluidtherapy, broad spectrum antibiotics, antiemetic and mucosal protective drugs. Twelve days after the admission, the cat presented prostration, hypoglycemia, hypothermia, hypokalemia and severe leukopenia. Chest radiography revealed increased radiopacity in the right hemithorax, suggesting aspiration pneumonia. The cat died and during necropsy there was marked megaesophagus, with areas of erosion/ulceration of the mucosa, in addition to pulmonary consolidation areas. The histopathological analysis showed an extensive area of ulceration in the esophageal epithelium, in addition to infltration of lymphocytes, macrophages and occasional neutrophils and numerous bacteria, compatible with ulcerative esophagitis. The lung analysis showed severe multifocal thrombosis, multifocal areas of athelectasia, moderate congestion and edema, vegetable material in the bronchi, basophilic myriad bacterial and multifocal necrosis. Hypereosinophilic neurons with pyknotic nuclei, mild cytoplasmic vacuolization, loss of granular appearance of Nissl substance and nuclei shifted to the periphery were observed in the esophageal ganglia. The post mortem diagnosis was megaesophagus and chronic active esophagitis with neuronal degeneration, confrming the diagnosis of feline dysautonomia and aspiration pneumonia.Discussion: This cat was presented with nonspecifc clinical signs, megaesophagus, constipation, keratoconjunctivitis sicca and regurgitation that are commonly observed in cases of feline dysautonomia. However, there were also expiratory dyspnoea, which is less common. Unlike most cases, this cat did not show mydriasis, prolapsed nictitating membranes, reduced pupillary light response or bradycardia. Considering the evolution of its clinical condition, it was suspected that the cat died due to sepsis, possibly as a result of aspiration pneumonia. Since feline dysautonomia is uncommon and requires histopathological analysis for diagnosis confrmation, the prevalence of the disease might be underestimated in our region. In this case, the clinical evaluation, diagnostic imaging, macroscopic and histopathological fndings were consistent with dysautonomia, therefore it is important to consider the disease as a differential diagnosis in cases of megaesophagus in cats, even in the absence of other classical signs of autonomic dysfunction.Keywords: ganglioneuropathy, autonomic neuropathy, neurology, cat.

Occult vs. overt upper gastrointestinal bleeding - inverse relationship and the use of mucosal damaging and protective drugs.

While efforts have focused on the prevention of overt upper gastrointestinal bleeding (UGIB), little is known about occult GIB, which might also originate from sites not protected by acid inhibition. To measure the incidence and outcomes of both overt and occult GIB over a 6-year period (2007-2012), and to assess the use of NSAIDs, anti-thrombotic therapy (ATT), proton pump inhibitors (PPIs), and iron therapy. A sample of 300 patients (100 from each of three index years) with occult GIB was randomly selected and their outcomes were compared with those of patients with overt UGIB (N = 869). The incidence of overt UGIB fell from 140.1 per 100 000 population per annum in 2007 to 106.8 in 2010 and to 88.0 in 2012 (P < 0.001); while that of occult GIB rose from 243.1 to 263.6 and to 292.8 (P < 0.001) over the same period. The incidence of occult GIB was highly correlated with the number of prescriptions of PPIs per 1000 population (χ(2) trend = 11.80; P < 0.001). In the overt UGIB group, the median haemoglobin level on presentation was lowest (10.3) in patients taking NSAIDs/ATT plus PPIs compared with those taking PPIs alone (11.5), NSAIDs/ATT alone (10.4) or none of these drugs (12.7 g/dL) (P < 0.001, Kruskal-Wallis). An inverse trend seems to have formed in the incidence of overt vs. occult gastrointestinal bleeding in association with the wider use of PPIs and NSAIDs. An alternative approach to acid inhibition is needed to prevent gastrointestinal bleeding.

Repositioning Irsogladine to Hsp90 Inhibitor

|Heat shock protein 90 (Hsp90) is a ubiquitous adenosine triphosphate (ATP)‐dependent molecular chaperone and represents an attractive cancer therapeutic target due to its role in maintaining the correct folding and stability of many oncogenic proteins. In our effort to repurpose existing drugs to Hsp90 inhibitors, we screened Food and Drug Administration (FDA) approved drugs based on chemical structure similarity and discovered that a mucosal protective drug, irsogladine, inhibits the Hsp90 folding machinery. In vitro fluorescence polarization assay and cell‐based mechanism study demonstrate that irsogladine binds to the ATP‐binding pocket in N‐terminal domain of Hsp90 and impairs the Hsp90 chaperoning function. Consequently, irsogladine induces the downregulation of Hsp90 client proteins including Her2, Akt, and Cdk4 and upregulation of the co‐chapereone Hsp70.

Aggravation by Clopidogrel, An Antiplatelet Drug, of Antral Damage Induced by NSAID in Rats: A Prophylactic Effect of Antiulcer Drugs

Recent studies suggested a risk of gastric adverse reaction on the concomitant use of antithrombotic drugs with NSAIDs. We investigated whether clopidogrel, a P2Y12 receptor antagonist, aggravates antral damage induced in rats by indomethacin and examined the effects of several antiulcer drugs on these lesions. Male SD rats fasted for 24 h were refed for 1 h, and then administered indomethacin (30 mg/kg) s.c. 1 h after refeeding, and the stomachs were examined for lesions 6 h thereafter. Clopidogrel (3‐30 mg/kg) was given p.o. 3 times, 48, 24 h and 30 min before indomethacin. Famotidine or teprenone was given p.o. 1 h before indomethacin. Indomethacin alone produced damages, mostly nonhemorrhagic lesions, in the antrum of refed rats. Clopidogrel dose‐dependently worsened these lesions with convertion of nonhemorrhagic damages into hemorrhagic ones. The ulcerogenic response to indomethacin plus clopidogrel (30 mg/kg) was significantly suppressed by pretreatment with famotidine with a decrease in hemorrhagic lesions. The aggravating effect of clopidogrel was also attenuated by teprenone, though the effect was less pronounced than that of famotidine. These results suggest that 1) clopidogrel aggravates NSAID‐induced antral lesions, converting from nonhemorrhagic into hemorrhagic damage, and 2) these lesions are effectively prevented by both antisecretory and mucosal protective drugs.

414 Occult vs. Overt Upper Gastrointestinal Bleeding - Inverse Relationship and the Use of Mucosal Damaging and Protective Drugs

Introduction Efforts have been focused on the prevention of overt upper gastrointestinal bleeding (UGIB), using acid inhibitors, particularly in users of NSAIDs and anti-thrombotic therapy (ATT). Little is known about the impact of such efforts on occult GIB which might also originate from sites not protected by acid inhibition. We aimedto measure the incidence of both overt and occult GIB in a well-defined geographical region over a 5-year period, 2007–2012; assess the use of NSAIDs, ATT, PPIs, and iron therapy; and compare the outcomes of patients with occult vs. overt GIB. Method The incidence was analysed in 2007, 2010 and 2012. Overt UGIB included haematemesis and melena. A sample of 300 patients (100 from each of the 3 index years) with occult GIB was randomly selected and their outcomes and details were compared with those of patients with overt UGIB (N = 869) using the Mann-Whitney and Fisher’s exact tests. Trends with time in incidence were assessed using the chi-squared test for trend. Numbers of prescriptions issued per 1000 population were recorded for each year from 2007 to 2012 and trends were assessed using Pearson correlation analysis. Results The incidence of overt UGIB and occult GIB and details of drug use are shown in Table 1. Demography: Compared with patients with occult GIB (N = 300) randomly selected in the 3 index years, those with overt UGIB (N = 869) had a median (IQR) age of 63 (47–77) years vs. 67 (53–75) in the occult group (NS), 62.5% males vs. 39.3% (P Conclusion (1) The incidence of occult GIB continues to rise while that of overt UGIB continues to fall. (2) This is accompanied by a rise in the use of NSAIDs, PPIs, and iron therapy. (3) Patients with occult GIB have similar 30-day mortality to overt UGIB but are less likely to require blood transfusion. (4) An alternative approach to acid inhibition might be needed to prevent occult GIB. Disclosure of interest None Declared.

Rebamipide protects small intestinal mucosal injuries caused by indomethacin by modulating intestinal microbiota and the gene expression in intestinal mucosa in a rat model.

The effect of rebamipide, a mucosal protective drug, on small intestinal mucosal injury caused by indomethacin was examined using a rat model. Indomethacin administration (10 mg/kg, p.o.) induced intestinal mucosal injury was accompanied by an increase in the numbers of intestinal bacteria particularly Enterobacteriaceae in the jejunum and ileum. Rebamipide (30 and 100 mg/kg, p.o., given 5 times) was shown to inhibit the indomethacin-induced small intestinal mucosal injury and decreased the number of Enterococcaceae and Enterobacteriaceae in the jejunal mucosa to normal levels. It was also shown that the detection rate of segmented filamentous bacteria was increased by rebamipide. PCR array analysis of genes related to inflammation, oxidative stress and wound healing showed that indomethacin induced upregulation and downregulation of 14 and 3 genes, respectively in the rat jejunal mucosa by more than 5-fold compared to that of normal rats. Rebamipide suppressed the upregulated gene expression of TNFα and Duox2 in a dose-dependent manner. In conclusion, our study confirmed that disturbance of intestinal microbiota plays a crucial role in indomethacin-induced small intestinal mucosal injury, and suggests that rebamipide could be used as prophylaxis against non-steroidal anti-inflammatory drugs -induced gastrointestinal mucosal injury, by modulating microbiota and suppressing mucosal inflammation in the small intestine.

Observational study of the effects of dabigatran on gastrointestinal symptoms in patients with non-valvular atrial fibrillation

BackgroundDyspepsia (including upper abdominal pain, abdominal pain, abdominal discomfort, epigastric discomfort, and dyspepsia) is a symptom that is carefully monitored during dabigatran treatment. However, detailed information on dyspepsia, including onset, duration, severity, and use of drug treatment, has not yet been established in Japanese patients. MethodsWe conducted a multi-center, prospective, open-label, randomized, and parallel-group-comparison observational study of 309 patients with non-valvular atrial fibrillation who had been newly prescribed dabigatran at 19 institutes in Japan. Gastrointestinal adverse events were evaluated using the Global Overall Severity (GOS) scale self-reports to describe symptoms and to assess frequency and severity of symptoms (Part 1). Thereafter, patients with a GOS score ≥3 were randomized to receive a 4-week course of a proton pump inhibitor, an H2-receptor antagonist or a gastric mucosal protective drug (Part 2). ResultsThe incidence of dyspepsia symptoms due to dabigatran was 17.2% (53/309, 95% confidence interval 13.1–21.8%), with 77% of events occurring within 10 days of initiation. Five patients discontinued the study because of dyspepsia. At the end of the observation period, the mean GOS score of those reporting dyspepsia was 3.5±1.7, with 11.3% (35/309) reporting a score ≥3. Substantial differences in the incidence of dyspepsia were observed between the study institutes (0–41%). In the multivariate regression analysis, no significant factor was found to affect incidence or severity of dyspepsia. The majority (83–100%) reported that symptoms improved with treatment (GOS score ≤2), and there was no significant difference between the three different treatment groups. ConclusionsThe reported symptoms of dyspepsia were generally mild, but were moderate in approximately 10% of patients. Proton pump inhibitors, H2-receptor antagonists, and rebamipide seemed to be equally effective in relieving dabigatran-related dyspepsia (umin-CTR UMIN000007579).

P3–036 - Irsogladine Maleate Prevents Oral Candidiasis Associated with Radiotherapy in Patients with Head and Neck Cancer

Background: Previously, we reported that oral mucosal damage induced by radiotherapy is related to Candida-associated opportunistic infection (JSMO; 2011). Irsogladine maleate, a mucosal protective drug, has a preventive effect on radiotherapy-induced mucositis (JSMO; 2012). In the present study, we investigated the benefit of irsogladine maleate for oral mucositis and candidiasis induced by radiotherapy in patients with head and neck cancer. Methods: A prospective randomized study of 43 patients (10 female, 33 male) with advanced head and neck cancer was conducted from November 2010 to December 2011. Group A (n = 21) received irsogladine 4 mg during radiotherapy and Group B (n = 22) received radiotherapy without irsogladine. We evaluated oral health retrospectively by using the Revised Oral Assessment Guide (ROAG) and assessing tongue fur. Results: After 30 Gy of radiotherapy, the ROAG score for the lips in group A was significantly lower than in group B. Moreover, after 20 Gy of radiotherapy, the score for the oral mucosa and gingiva in group A was significantly lower than in group B. A significant increase in tongue fur compared with electronic medical records was observed in both groups. However, the score in group A was significantly lower than in group B at 20, 30 and 50 Gy of radiotherapy. Conclusion: Irsogladine appears to be useful for the prevention of oral mucositis and candidiasis associated with radiotherapy in patients with head and neck cancer.

59 Can Irsogladine Maleate, a Mucosal Protective Drug, Promotes the Healing of Ulcers After Endoscopic Submucosal Dissection? a Randomized, Prospective, Multicenter Study

6 (15.4%) 33 (84.6%) 39 Flat or depressed 10 (21.7%) 36 (78.3%) 46 Size (mm) 0.22** 30 11 (16.4%) 56 (83.6%) 67 30 5 (27.8%) 13 (72.2%) 18 Depth 0.09** Mucosa 12 (16.0%) 63 (84.0%) 75 Submucosa (SM1) 4 (40.0%) 6 (60.0%) 10 Ulcerative finding 0.20** Present 4 (30.8%) 9 (69.2%) 13 Absent 12 (16.7%) 60 (83.3%) 72 En bloc or piecemeal resection 0.50** En bloc 13 (19.7%) 53 (80.3%) 66 Piecemeal 3 (15.8%) 16 (84.2%) 19 LM positive length (mm) 0.001** 6 10 (66.7%) 5 (33.3%) 15 6 6 (8.6%) 64 (91.4%) 70 SM1, tumor infiltration into the submucosal layer 500 m from the muscularis mucosae. *P values were calculated using the chi-square test. **P values were calculated using the Fisher exact test.

Ursodeoxycholic acid for treatment of bile reflux gastritis: A systematic review

AIM: To systematically evaluate the efficacy of ursodeoxycholic acid(UDCA) in the treatment of bile reflux gastritis.METHODS: We searched PubMed, Cochrane Library, Chinese Academic Journal(CJFD), Chinese Biomedical Literature Database(CBM), Chinese Journal Full-Text Database(CNKI), Wanfang database, and VIP database(until December 2012)to collect randomized controlled trials(RCTs) that evaluated the efficacy of UDCA in the treatment of bile reflux gastritis. Other relevant journals were also searched manually. Literature screening, quality assessment and data extraction were conducted by two reviewers according to inclusion and exclusion criteria. Meta-analyses were conducted using RevMan 5.0.RESULTS: A total of 17 RCTs involving 1365patients were identified. According to the results of meta-analyses, trial groups was better than control groups in terms of overall efficacy(OR = 4.16, 95% CI: 2.68-6.46, P < 0.00001), rate of clinical symptom remission(OR = 4.99, 95%CI: 2.71-9.16, P < 0.00001) and cure rate(OR =1.92, 95% CI: 1.24-2.99, P = 0.004). In terms of improvement of mucosal inflammation revealed by gastroscopy, the UDCA + PPI + prokinetic drug group was better than the control group(OR = 4.45, 95% CI: 2.04-9.69, P = 0.0002), but the groups of UDCA + prokinetic drug + mucosal protective drug(P = 0.13) and UDCA + prokinetic drug(OR = 2.34, 95% CI: 0.78-6.98, P = 0.13)showed no significant difference compared to the control group. Six RCTs reported adverse effects and the UDCA group did not report adverse events.CONCLUSION: Our results show that UDCA is much more effective in the treatment of bile reflux gastritis than control drugs. However, there is a moderate risk of bias due to methodological quality problems in all 17 included RCTs.More strictly-designed, large-scale, high-quality,multi-centered RCTs are needed to confirm this result.

Irsogladine : Overview of the Mechanisms of Mucosal Protective and Healing- Promoting Actions in the Gastrointestinal Tract

Irsogladine, a mucosal protective drug, was developed in Japan for the treatment of peptic ulcer disease and acute gastritis. This drug is superior to gefarnate, the same therapeutic category drug, in a randomized, controlled and double-blind clinical study in 1987. The mechanisms of irsogladine's actions are apparently different from those of antisecretory drugs. Irsogladine increases intracellular cyclic adenosine 3',5'-monophosphate content via non-selective inhibition of phosphodiesterase isozymes and exhibits gastric cytoprotection partly mediated by endogenous nitric oxide. These effects may account for a variety of actions of irsogladine in the gastrointestinal tract, including facilitation of gap junctional intercellular communication, inhibition of the reduced gastric mucosal blood flow response, suppression of reactive oxygen generation and so on. Since 1984, more than 60 papers have been published to further verify the effects of irsogladine on gap junctional intercellular communication, tight junction, nitric oxide production and neutrophil migration as well as Helicobacter pylori-related pathological changes in the stomach as well as the adverse reactions induced in the stomach or the small intestine by various drugs, including nonsteroidal anti-inflammatory drugs, bisphosphonates or selective serotonin re-uptake inhibitors. In this article, we review recent advances in understanding the mechanisms of irsogladine's actions and the most recent data in experimental as well as clinical studies.

WS10-3 - Irsogladine Maleate Prevents Oral Mucositis Associated with Radiotherapy in Patients with Head and Neck Cancer

ABSTRACT Background Oral mucositis is a frequent and serious adverse event associated with radiotherapy. Although a number of compounds have been tested for prophylaxis of oral mucositis, few are satisfactory now. Several studies have shown that irsogladine, a gastric mucosal protective drug which facilitates gap-junctional intercellular communications, is effective for oral mucositis. Therefore we investigated the effect of irsogladine on radiotherapy-induced oral mucositis. Methods A prospective randomized study of 43 patients (10 females, 33 males) with advanced head and neck cancer was conducted from November 2010 to December 2011. Group A (n = 21) received irsogladine 4 mg during radiotherapy and Group B (n = 22) received radiotherapy without irsogladine. Oral Mucositis Weekly Questionnaire-Head and Neck Cancer (OMWQ-HN), Revised Oral Assessment Guide (ROAG) and Common Terminology Criteria for Adverse Events (CTCAE) scores were analyzed by the Mann Whitney U-test. Results A significant decline in health and quality of life was observed in both groups as measured by the OMWQ-HN. However, the score for group A was significantly greater than that for group B at 50 Gy of radiotherapy (P = 0.03). Moreover, a significant increase in ROAG score was observed in both groups. Nevertheless, the ROAG score for group A was significantly lower than that for group B after 20 Gy of radiotherapy. There was no difference in safety score between the two groups as measured by CTCAE ver. 4. Conclusion Irsogladine appears to be useful for the prevention of oral mucositis associated with radiotherapy in patients with head and neck cancer.

Impact of proton pump inhibitor omeprazole on the antiplatelet effect of clopidogrel in individuals with various CYP2C19*2 genotypes

To investigate the impact of omeprazole on platelet response to clopidogrel and the effect of polymorphisms of CYP2C19 on the antiplatelet effect of clopidogrel. Platelet aggregation (PA) was assessed before 300 mg aspirin plus 300 mg loading dose of clopidogrel and after 300 mg aspirin plus 75 mg maintenance dose of clopidogrel 7 days later in 414 patients with acute coronary syndrome who have undergone percutaneous coronary intervention (PCI). Thereafter, gastric mucosal protective drugs were given (omeprazolem 20 mg, n=224 or cimetidine 800 mg, n=190). Fourteen days later, PA was measured again. Genotypes of CYP2C19*2 were analyzed with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). After taken aspirin and clopidogrel, PA has decreased significantly in both groups. Compared with cimetidine, omeprazole had no significant impact on PA on 7 and 21 days post PCI. Compared with homozygotes or heterozygotes for the wild-type CYP2C19*2, patients with CYP2C19*2 AA genotype had significantly higher PA on 7 and 21 days post PCI (P<0.05). No attenuating effect on platelet response to clopidogrel has been observed for Omeprazole. The variant of CYP2C19*2 AA genotype is significantly associated with attenuated response to clopidogrel.

Quality of ulcer healing in gastrointestinal tract: Its pathophysiology and clinical relevance

In this paper, we review the concept of quality of ulcer healing (QOUH) in the gastrointestinal tract and its role in the ulcer recurrence. In the past, peptic ulcer disease (PUD) has been a chronic disease with a cycle of repeated healing/remission and recurrence. The main etiological factor of PUD is Helicobacter pylori (H. pylori), which is also the cause of ulcer recurrence. However, H. pylori-negative ulcers are present in 12%-20% of patients; they also recur and are on occasion intractable. QOUH focuses on the fact that mucosal and submucosal structures within ulcer scars are incompletely regenerated. Within the scars of healed ulcers, regenerated tissue is immature and with distorted architecture, suggesting poor QOUH. The abnormalities in mucosal regeneration can be the basis for ulcer recurrence. Our studies have shown that persistence of macrophages in the regenerated area plays a key role in ulcer recurrence. Our studies in a rat model of ulcer recurrence have indicated that proinflammatory cytokines trigger activation of macrophages, which in turn produce increased amounts of cytokines and chemokines, which attract neutrophils to the regenerated area. Neutrophils release proteolytic enzymes that destroy the tissue, resulting in ulcer recurrence. Another important factor in poor QOUH can be deficiency of endogenous prostaglandins and a deficiency and/or an imbalance of endogenous growth factors. Topically active mucosal protective and antiulcer drugs promote high QOUH and reduce inflammatory cell infiltration in the ulcer scar. In addition to PUD, the concept of QOUH is likely applicable to inflammatory bowel diseases including Crohn's disease and ulcerative colitis.