Kei Matsueda

Patients with Constipation-Predominant Irritable Bowel Syndrome (IBS) May Have Elevated Serotonin Concentrations in Colonic Mucosa as Compared with Diarrhea-Predominant Patients and Subjects with Normal Bowel Habits

Background: Serotonin (5-HT) may play an important role in the regulation of colonic motility in humans. However, it is not known whether alterations in the colonic 5-HT system are involved in the pathophysiology of irritable bowel syndrome (IBS). Methods: Colonic mucosal specimens ranging from the ascending colon to the rectum were obtained from patients with diarrhea- or constipation-predominant IBS (n = 7 and n = 8, respectively) and from subjects with normal bowel habits (n = 7) by endoscopic biopsy in order to determine whether patients with different clinical manifestations of IBS have different mucosal disposition of 5-HT. The tissue concentrations of 5-HT and its major metabolite, 5-hydroxyindoleacetic acid, were determined by reversed-phase high-performance liquid chromatography with fluorescence detection. Results: In all study groups, the mean mucosal 5-HT concentrations obtained from the rectum were significantly (p < 0.05) higher than those obtained from more cephalic regions of the colon. In addition, the overall mean mucosal 5-HT concentrations obtained from patients with constipation-predominant IBS were significantly (p < 0.05) higher than those obtained from the control subjects and patients with diarrhea-predominant IBS. No significant differences were observed in 5-hydroxyindoleacetic acid concentrations among the three groups. Conclusions: The mucosal 5-HT concentrations in the colon showed an ascending cephalocaudal gradient in all study groups. Although the mucosal 5-HT concentrations were elevated in patients with constipation-predominant IBS as compared with those with diarrhea-predominant IBS and the control subjects, further studies are necessary to determine whether the elevated mucosal 5-HT is a cause or a result of abnormal colonic motility.

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.

Clinical trial: dose-dependent therapeutic efficacy of acotiamide hydrochloride (Z-338) in patients with functional dyspepsia - 100 mg t.i.d. is an optimal dosage.

Background  Acotiamide is a selective acetylcholinesterase inhibitor and enhances the actions of cholinergic neurons localized in the stomach.

A Long-Term Study of Acotiamide in Patients with Functional Dyspepsia: Results from an Open-Label Phase III Trial in Japan on Efficacy, Safety and Pattern of Administration

Background: This long-term 48-week study of acotiamide was carried out to investigate the efficacy, safety and administration pattern in patients with functional dyspepsia (FD). Methods: This was a multicenter, open-label, single-arm, long-term phase III study in which patients with FD were given acotiamide, 100 mg t.i.d., for 48 weeks. The two major efficacy endpoints were global overall treatment efficacy (OTE) and the elimination rate of three cardinal symptoms (i.e. postprandial fullness, early satiation and upper abdominal bloating), which were evaluated weekly and daily by the patients, respectively. The long-term administration patterns were investigated by following the patients based on cessation and readministration criteria. Results: Efficacy was analyzed in 405 patients. The OTE improvement rate was 26.1% at week 1 and increased with time. It was 60.6% at week 8 and subsequently maintained. Similarly, the symptom elimination rate increased up to week 8. Many patients who met the cessation criterion achieved remission of FD symptoms after experiencing dose interruption and readministration. The incidence rate of adverse drug reactions was 11.5% and most of the adverse drug reactions were mild in severity except increased ALT in 1 patient. Conclusion: FD symptoms were controlled by intermittent administration of acotiamide even in patients with relapsing FD.

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.

Efficacy of treatment with chimeric monoclonal antibody (Infliximab) to tumor necrosis factor-α for Crohn's disease in Japan: Evaluation by rapid turnover proteins, and radiologic and endoscopic findings

Background: Several studies have reported that the chimeric monoclonal antibody to tumor necrosis factor (TNF)‐α (Infliximab) is extremely valuable in the treatment of Crohns disease. The aim of this study was to clarify the efficacy of this treatment in Japanese patients with Crohns disease.

Marked clinical improvement in patients with hepatocellular carcinoma by surgical removal of extended tumor mass in right atrium and pulmonary arteries

Two patients with advanced hepatocellular carcinoma presented severe exertional dyspnea because of extension of a tumor into the right side of the heart. Removable of the tumor thrombus by open-heart surgery ameliorated the symptoms in each case, but their subsequent courses differed considerably. One patient survived for as long as 8 months thanks to successive multidisciplinary treatments, whereas the other patient died suddenly 1 month after the surgery. The first patients hepatocellular carcinoma was more differentiated, and the dyspnea was caused by a low cardiac output due to the intracardiac tumor mass, not by pulmonary embolism as in the second patients case. We conclude that successive multidisciplinary treatments to control the growth of hepatocellular carcinoma is the most important approach and is indispensable for improving the prognosis.

Malabsorption with idiopathic hypoparathyroidism responding to treatment for coincident celiac sprue.

SummaryOur study suggests that coexisting celiac sprue is one of the mechanisms responsible for the malabsorption associated with idiopathic hypoparathyroidism. Celiac sprue is relatively common, and this association could occur by coincidence. Alternately there may be shared determinants of susceptibility or perhaps a direct immunological relationship. In such patients, both gluten-free diet and correction of the hypoparathyroid state may be necessary to correct malabsorption. In our literature survey, this is the first case in which celiac sprue associated with idiopathic hypoparathyroidism was documented. The importance of intestinal biopsy in evaluating malabsorption in patients with idiopathic hypoparathyroidism is emphasized.

In Vitro Measurement of the pH Gradient and Thickness of the Duodenal Mucus Gel Layer in Rats

The mucus bicarbonate barrier of the duodenum has lately been reported to be one of the most important defensive factors for the duodenal mucosa. We established an in vitro system for evaluating the mucus bicarbonate barrier in the rat duodenum. Our method allows direct measurement of the pH gradient as well as the thickness of the mucus gel layer of the rat duodenum in vitro. The obtained results suggest that alkali secretion in response to acid-loading as well as the thickness of the duodenal mucus gel layer are greater than those in the stomach.

Effect of acotiamide on gastric emptying in healthy adult humans

Acotiamide is a first‐in‐class drug that is used to treat functional dyspepsia (FD). It is considered that acotiamide acts as an antagonist on muscarinic autoreceptors in the enteric nervous system and inhibits acetylcholinesterase activity. We examined the effect of acotiamide on gastric emptying in healthy adult humans.