Shigeru Harasawa

A randomized, double-blind, placebo-controlled clinical trial of the effectiveness of the novel serotonin type 3 receptor antagonist ramosetron in both male and female Japanese patients with diarrhea-predominant irritable bowel syndrome

Objective. Irritable bowel syndrome is characterized by abdominal discomfort and/or pain associated with altered bowel habits. The neurotransmitter serotonin and serotonin type 3 receptors that are extensively distributed on enteric neurons in the human gastrointestinal tract play a role in increasing the sensation of pain and affecting bowel habits in patients with irritable bowel syndrome. The aim of this study was to evaluate the efficacy and safety of the serotonin type 3 receptor antagonist ramosetron hydrochloride in Japanese patients with diarrhea-predominant irritable bowel syndrome. Material and methods. In a double-blind, placebo-controlled, parallel group-comparative study with a 1-week run-in period, 539 patients with diarrhea-predominant irritable bowel syndrome meeting the Rome II diagnostic criteria received either 5 µg ramosetron hydrochloride (n=270) or placebo (n=269) once daily for 12 weeks. Results. Forty-seven percent of ramosetron hydrochloride-treated patients were monthly responders in the primary end-point, “Patient-reported global assessment of relief of irritable bowel syndrome symptoms”, compared with 27% for placebos (p<0.001). The most frequently reported adverse event in the ramosetron hydrochloride-treated group compared with the placebo group was hard stool. Conclusions. Ramosetron hydrochloride 5 µg once daily is effective and well tolerated in the treatment of abdominal pain, discomfort and bowel habits in patients with diarrhea-predominant irritable bowel syndrome.

A Phase II Trial of the Novel Serotonin Type 3 Receptor Antagonist Ramosetron in Japanese Male and Female Patients with Diarrhea-Predominant Irritable Bowel Syndrome

Background: Irritable bowel syndrome (IBS) is a common gastrointestinal disorder. Serotonin type 3 (5-HT3) receptor antagonist alosetron hydrochloride is indicated for women with chronic, severe diarrhea-predominant IBS who have not responded adequately to conventional therapy. However, whether or not the therapeutic efficacy of 5-HT3 receptor antagonists has gender difference is uncertain. Methods: A double-blind, placebo-controlled, parallel-group, comparative study was conducted to evaluate the effect of novel 5-HT3 receptor antagonist, ramosetron hydrochloride, in male and female patients with diarrhea-predominant IBS. 418 subjects were randomized (109 subjects: placebo, 105 subjects: 1 µg, 103 subjects: 5 µg, and 101 subjects: 10 µg) and administered the study drug once daily. Results: The monthly responder rates of ‘Patient-reported global assessment of relief of irritable bowel syndrome symptoms’ in the 5- and 10-µg ramosetron hydrochloride-administered groups were higher than the placebo group (26.92, 42.57, and 43.01% for placebo, 5 and 10 µg). Moreover, the difference of the responder rate in comparison with the placebo group was similar in males and females. As for safety, there was tolerability at doses up to 10 µg. Conclusion: Ramosetron is an effective and well-tolerated treatment not only for female IBS patients but also for male patients.

Dyspepsia and Dyspepsia Subgroups in Japan: Symptom Profiles and Experience with Cisapride: General Discussion

In 240 patients with symptoms of dyspepsia, recruited consecutively and investigated in 12 hospitals in Japan, 24.2% were diagnosed having organic dyspepsia; 75.8% had functional dyspepsia, of whom 63.2% were diagnosed by the investigator having dysmotility-like, 13.7% ulcer-like, 11.5% reflux-like, and 11.5% non-specific dyspepsia. There was, however, considerable overlap of symptom profiles. Cisapride therapy initiated in functional dyspeptic patients resulted in moderate or marked improvement in 79.1% of the patients with the highest response rates for dysmotility-like (85.2%), reflux-like (81.0%), and non-specific dyspepsia (76.1%) (versus 52.0% for ulcer-like dyspepsia).

High Prevalence of Irritable Bowel Syndrome in Medical Outpatients in Japan

Background and Goals The prevalence of irritable bowel syndrome (IBS) among Japanese patients who visit hospitals departments of internal medicine is thought to be high. However, no clear statistical evidence has been provided to support such a claim. We tested the hypotheses that the prevalence of IBS in medical outpatients clinics in Japan is high, and that IBS patients feel more psychosocial stress than patients without IBS. Study The subjects in this study were 633 patients who visited participating physicians. Patients were asked to fill in the Japanese version of the Rome II Modular Questionnaire (RIIMQ) for IBS diagnosis, the Self-reported Irritable Bowel Syndrome Questionnaire (SIBSQ) for severity of the disease and the demographic questionnaire for perceived stress and life style. Results Rome II-defined IBS was diagnosed in 196 patients (31%). Analysis of variance revealed significant difference in the IBS scores of SIBSQ among IBS subjects (39.0±11.1, mean±SD), functional bowel disorder subjects (27.1±10.2), and normal subjects (24.0±10.0, P<0.01). The prevalence of IBS depending on age formed 2 peaks, one among adolescents and the other among the elderly. IBS patients had significantly more perceived stress (P<0.0001), irregular sleep habit (P<0.0001), and irregular meal habit (P<0.0001) than those without IBS. Conclusions The prevalence of IBS among medical outpatients in Japan is high (31%). IBS subjects among medically ill patients are thought to have more perceived stress and less regular life styles.

Large‐scale randomized clinical study on functional dyspepsia treatment with mosapride or teprenone: Japan Mosapride Mega‐Study (JMMS)

Background and Aim:  Functional dyspepsia (FD) is a common condition seen in primary gastroenterology practice. The present study was conducted to compare the clinical effectiveness of mosapride and teprenone in patients with FD.

Gastric emptying in normal subjects and patients with peptic ulcer

SummaryGastric emptying in patients with peptic ulcer and normal subjects was studied using the acetaminophen method. The subjects consisted of 15 normal subjects, 52 gastric ulcer patients and 65 duodenal ulcer patients, who were studied in active stage of the ulcer. As an indicator of gastric emptying rate, the plasma acetaminophen concentration was measured by dye method (diphenylhydrazyl), as meg/ml, at 45 minutes after ingestion of a high calory pasty test meal (200 ml) with 1.5gr of acetaminophen.In normal subjects, the plasma acetaminophen concentration was 9.4±3.6mcg/ml. In gastric ulcer patients, the concentration was 7.4±3.2mcg/ml, which showed significantly delayed gastric emptying (P< 0.05). In duodenal ulcer patients, the concentration was 11.6±3.3mcg/ml, which suggested significantly rapid gastric emptying (P< 0.05).In consideration of gastric acid secretion, gastric ulcer cases with lower acid secretion have more delayed gastric emptying. In duodenal ulcer cases with hypersecretion, gastric emptying is more rapid than normoand/or hyposecretory cases (P< 0.005).The delayed gastric emptying may play a role in etiology of gastric ulcer. On the other hand, the rapid gastric emptying with gastric acid hypersecretion may be important in the pathogenesis of duodenal ulcer.

Lesions of the upper gastrointestinal tract in patients with chronic renal failure

SummaryEndoscopy of the upper gastrointestinal tract was performed on 84 patients with end-stage chronic renal failure undergoing hemodialysis. Gastric acid secretion and fasting plasma gastrin levels were also examined in these patients.Hemorrhagic gastritis was most frequently observed (23 cases) followed by erosive gastritis (18 cases). No patients had gastric ulcers. Duodenal ulcers were observed in only two patients. Gastrointestinal bleeding was observed in 15 cases (17.9%). Thirteen of these 15 cases had hemorrhagic gastritis, one of which had a duodenal ulcer as a complication.Fasting plasma gastrin levels (359.6 ± 336.5 pg/ml) were significantly higher than those of normal subjects (35.2 ± 37.1 pg/ml), but no acceleration in gastric acid secretion was observed either in the basal condition (BAO 0.8± 0.7 mEq/h) or following tetragastrin stimulation (MAO 9.0 ± 6.9 mEq/h).Our results were inconsistent with the previous reports that high frequencies of peptic ulcers and increased gastric acid secretion were observed in patients with chronic renal failure.Our data suggest that the defensive factors rather than the aggressive factors of the gastroduodenal mucosa may be involved in chronic renal failure.

Anaphylactoid purpura with intestinal perforation: Report of a case and review of the Japanese literature

A 78 year old man suffering from anaphylactoid purpura complained of abdominal pain and bloody stools. Combined therapy with Prednisolone and cyclophosphamide had been given against nephrotic syndrome caused by purpura nephritis. Severe abdominal pain with symptoms and signs of panperitonitis necessitated laparotomy. Rectosigmoid perforation due to necrotizing angiitis (phlebitis) was also demonstrated histologically. The patient died of septicemia 18 days after surgery. Perforation of the alimentary tract rarely occurs in anaphylactoid purpura. Twenty similar cases were briefly reviewed from the Japanese literature.

Peptic ulcer recurrence during maintenance therapy with H2-receptor antagonist following first-line therapy with proton pump inhibitor

Abstract: We investigated the peptic ulcer recurrence rates during maintenance therapy with H2-receptor antagonists (H2RAs) following first-line therapy with a proton pump inhibitor (PPI). Patients with gastric ulcer (GU) or duodenal ulcer (DU) were enrolled in this study; 583 eligible patients (GU, 325; DU, 258) were administered lansoprazole (30 mg/day for 8 weeks for GU, and the same dosage for 6 weeks for DU) as first-line therapy, and a half dose of H2RA as maintenance therapy for 12 months. Endoscopic photographs were taken before administration and after 8 (GU) and 6 (DU) weeks of lansoprazole administration. Ulcer stage was evaluated using the classification of Sakita and Miwa. Endoscopic examinations were performed 6 months or 12 months after the start of maintenance therapy or when a recurrence was suspected because of the appearance of subjective symptoms. The healing rates for GU and DU patients after completion of lansoprazole therapy were 79% in both groups, while the S2-stage healing rates were 18% and 31%, respectively. At 1 year after the start of maintenance therapy, the recurrence rates were 25% for GU and 39% for DU patients. In DU patients, the recurrence rates from S1-stage and S2-stage were 49% and 20%, respectively (P = 0.004), but no significant difference was found between these rates in GU patients. The recurrence rates in H. pylori-positive patients before lansoprazole administration were 27% for GU and 43% for DU patients. We concluded that the maintenance therapy with a half-dose of H2RA following PPI therapy was insufficient to prevent recurrences of GU and DU.

GASTRIC METAPLASIA IN DUODENAL ULCER. Histochemical Considerations of Its Pathophysiological Significance

Gastric metaplasia of the duodenal mucosa in biopsy specimens of healed duodenal ulcer and in surgical specimens of perforated duodenal ulcer was investigated using mucin histochemistry and the indirect immunoperoxidase method. Endoscopic methylene blue test was performed prior to biopsy. All specimens from areas showing no dye absorption revealed varying degrees of gastric metaplasia characterized by heterotopic occurrence of gastric‐type foveolar cells mainly at the tips of stunted intestinal villi. On average, 31.8% of the total surface length of duodenal mucosa taken from areas showing no dye absorption was occupied by the metaplastic cells. They showed strong reactivities for periodic acid‐Schiff (PAS) and galactose oxidase‐Schiff sequences, while alcian blue and paradoxical concanavalin A staining, class III, were negative. Immunoperoxidase‐PAS double staining revealed a few gastrin and somatostatin cells in foci of gastric metaplasia, but almost no cells containing motilin, secretin, cholecystokinin and gastric inhibitory peptide. Such endocrine cells were scattered in nonmetaplastic mucosa. While such metaplastic change has been regarded as a self‐defence mechanism or adaptation of the duodenal mucosa against acid, a local decrease of normal endocrine cells, which allegedly function as acid receptors, may lead to alterations of gastroduodenal interaction. It is suggested that gastric metaplasia is important as one of the pathophysiological mechanisms involved in the recurrence of duodenal ulcer. ACTA PATHOL JPN 38 : 1011 ∼ 1018, 1988.