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 microg, 103 subjects: 5 microg, and 101 subjects: 10 microg) 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-microg ramosetron hydrochloride-administered groups were higher than the placebo group (26.92, 42.57, and 43.01% for placebo, 5 and 10 microg). 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 microg. CONCLUSION: Ramosetron is an effective and well-tolerated treatment not only for female IBS patients but also for male patients.

A case of late onset cardiac amyloidosis with a new transthyretin variant (lysine 92).

A new transthyretin (TTR) variant (lysine 92), which causes late onset cardiac amyloidosis, is described in a 71-year-old man. The patient at first had syncope due to ventricular tachycardia and was admitted our hospital. Typical findings of cardiac amyloidosis were observed by echocardiography, and a diagnosis of systemic amyloidosis was made by rectal biopsy. The man died approximately 3 years and 6 months after first admission, with gradually worsening congestive heart failure. Pathological examination showed prominent amyloid deposits in the heart and the vascular wall of many organs including the liver, pancreas, kidney, lung, and gastrointestinal tracts. Amyloid protein of transthyretin type was indicated by immunohistochemical study, and DNA sequencing identified a novel mutation in the transthyretin gene encoding 92 glutamine --> lysine. A polymerase chain reaction-induced mutation restriction analysis with a mismatched antisense primer showed that the patient was heterozygous for the TTR Lys92 allele.

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

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.

[Comparison between histamine H2-blocker and proton pump inhibitor on the effects of initial treatment in reflux esophagitis].

I have reviewed the comparison between histamine H2 blocker(H2-RA) and proton pump inhibitor(PPI) on the effects of initial treatment in patients with reflux esophagitis. Pathophysiology of reflux esophagitis has been thought to be gastroesophageal reflux of the gastric acid, due to motor dysfunctions of the esophagus and the stomach. Endoscopic healing rate of reflux esophagitis is significantly higher 84% on PPI treatment than 52% on H2-RA treatment at 8 weeks period. Because suppression of the gastric acid secretion is significantly stronger and longer on PPI than H2-RA, especially this suppression is markedly found in day time and also night time. On the initial treatment of reflux esophagitis, PPI is choice so-called "step down therapy" after healing, H2-RA and/or prokinetic drugs are treated as maintenance therapy.

[The effect of exogenous nitric oxide on endothelial dysfunction in two-kidney, one-clip renovascular hypertensive rats].

Previous studies have shown that hypertension causes endothelial dysfunction. To study the influence of exogenous nitric oxide(NO) on endothelial dysfunction produced by hypertension, we administered a non-depressor dose of nipradilol to two-kidney, one-clip renovascular hypertensive rats(2K1C). Sprague-Dawley rats underwent either sham surgery(G-1) or clipping of the left renal artery. From day seven, 2K1C were randomized into 3 groups, placebo treatment(G-2), nipradilol treatment(G-3,) and propranolol treatment(G-4). Urinary NO2- + NO3-(NOx) excretion (UNOx V) was measured 4 weeks after clipping, and then, acetylcholine(Ach), A23187, or sodium nitroprusside(SNP)-induced relaxation were measured in the aorta. Blood pressure was increased in G-2, G-3, and G-4 compared to G-1. UNOx V was lower in G-2, G-3, and G-4 compared to G-1, but UNOx V was higher in G-3 compared to G-2 and G-4. Although Ach or A23187-induced relaxation was significantly decreased in isolated artery from G-2, G-3, and G-4 compared with those from G-1. Ach- or A23187-induced relaxation was improved in G-3. SNP-induced relaxation did not differ among the 4 groups. These results suggest that exogenous NO from nipradilol reduces the endothelial dysfunction caused by hypertension without changing the blood pressure.

[Long-term endoscopic follow-up for peptic ulcer patients after eradication of H. pylori; comparison with the maintainance therapy by H2-blocker].

This study was aimed to clarify the endoscopic findings and the decline of serum IgG titer after successful eradication of H. pylori in long-term (from 2 to 7 years). Forty-six H. pylori-positive peptic ulcer (22 GU and 26 DU) cases were eradicated with antimicrobial therapy. Sixty-nine non-eradicated DU cases who received maintainance therapy with H2-blocker were control group. Biopsy urease test (BUT) and culturing was performed to diagnose the H. pylori infection. Anti-H. pylori IgG titer (EIA) were also measured in some cases, pre and 6, 12, 24 months after the eradication. In 3 cases, H. pylori were recrudescent and only in a case, DU recurred during 5 years after eradication. Meanwhile, in 55% of control cases, DU were recurred during same periods. In 62% of eradicated cases, serum IgG-antibody to H. pylori declined below the cut-off level during 2 years after eradication. It was certified that eradication therapy against H. pylori prevents ulcer recurrence for long time, and re-rise of serum IgG titer to H. pylori might predict a recrudescence of infection.

Effect of exogenous tetragastrin on gastric myoelectrical activity in humans.

It is known that cutaneous electrogastrography (EGG) undergoes a change after food ingestion, showing increases in frequency and amplitude compared with preprandial values, but the factors regulating such changes remain to be elucidated. Paying special attention to gastrin, one of gastrointestinal peptides released after food ingestion, we administered tetragastrin in an exogenous manner and evaluated its effects on EGG in the present study. In healthy subjects, the intramuscular injection of tetragastrin significantly increased EGG frequency dose-dependently, but caused no significant change in amplitude. These results suggest that the increase in endogenous gastrin release is one of the mechanisms which underlies the increase in EGG frequency after food ingestion.

Factors affecting depth of gastric ulcers.

PURPOSE: We investigated the differences in background factors, clinical features, and gastric function tests among gastric ulcers of various depths. PATIENTS AND METHODS: The subjects were 68 patients (male 64, female 4) who were diagnosed as having a gastric ulcer at the angulus. The ulcers were classified according to depth based on the following: UL2 (shallow) ulceration to the submucosa; UL3 (intermediate), to the muscularis propria; and UL4 (deep excavation), beyond the muscularis propria. The depth of each ulcer was determined by endoscopic ultrasonography and/or ordinary endoscopic findings. We assessed clinical features, age, gender, smoking habit, alcohol consumption, ulcer history, presence of H. pylori, gastric acid secretion, gastric emptying, serum gastrin level, healing rate, and recurrence rate. RESULTS: Patients with UL4-type ulcers had a higher rate of recurrence and a significantly higher incidence of H. pylori infection. Patients with hyperacidity and currently smoking or consuming alcohol were significantly more likely to have UL4-type ulcers than of UL2 or 3 ulcers. Furthermore, a close relationship was recognized between recurrence, intractability and deeply excavated ulcers. Ulcer depth was not correlated significantly with any of the following factors: 1) patient's profile; including gender and hemorrhagic symptoms; 2) gastric function; including gastric emptying and serum gastrin levels. CONCLUSIONS: Smoking, alcohol consumption, recurrence of ulcers, hyperacidity and H. pylori infections are important factors associated with deep ulcers.

Analysis of interleukin-8 secretion induced by Helicobacter pylori from the gastric epithelial cell line MKN45: a mechanism independent of the intensity of cytotoxicity.

Interleukin (IL)-8, a potent chemoattractant and activator of neutrophils, has been implicated to have a major role in the pathogenesis of gastric mucosal injury by Helicobacter pylori infection. We examined the relationship between cytotoxicity and IL-8 secretion induced by H. pylori. Furthermore, whether the vacuolating cytotoxin of H. pylori mediates IL-8 secretion from gastric epithelial cell lines was examined. Among the inflammatory cytokines, messages for IL-6, IL-8 and transforming growth factor-beta 1 were produced by gastric cancer (MKN45) cells in response to exposure to the cytotoxic strain of H. pylori. MKN45 incubated with the viable cytotoxic strain of H. pylori secreted IL-8. In contrast, the supernatant of neither the cytotoxic nor the non-cytotoxic strain induced IL-8 secretion. There was no correlation between IL-8 secretion and the intensity of cytotoxicity. In conclusion, these findings suggest that IL-8 secretion from MKN45 induced by H. pylori is mediated by factors other than cytotoxicity.

The role of histamine in ethanol-induced gastric mucosal injury in the rat.

It has been suggested that changes in the micro circulatory system are related to the early production of acute gastric mucosal injury and inflammatory factors such as prostaglandins, histamine, etc., have been considered as contributing to the development of the injury. We assessed the permeability of the gastric mucosa in rats with ethanol-induced acute mucosal injury by measuring the leakage rate of 51chronium-ethylene-diamine-tetraacetic acid (51Cr-EDTA) into the gastric juice. Histamine concentrations in the gastric mucosa was measured by high performance liquid chromatography. The enterochromaffin-like (ECL) cell counts in the gastric mucosa was performed following histamine staining with an enzyme-labeled antibody, and the histamine released due to degranulation was observed. We also investigated the kinetics of endogenous histamine in the gastric mucosa. Five minutes after the administration of ethanol, an increase in permeability, an increase in histamine concentration, and a decrease in ECL cell count were found in the gastric mucosa. These results suggest that endogenous histamine in the gastric mucosa is closely related to the early development of acute gastric mucosal injury.

[Involvement of endogenous nitric oxide in the regulation of distal colonic motility in anaesthetized rat].

The contribution of the endogenous nitric oxide (NO) to the distal colonic motility was investigated by inhibiting NO production using NO synthase inhibitor, NG-monomethyl-L-arginine (L-NMMA). The experiment was carried out in the anaesthetized rat, which was vagotomized and pretreated with guanethidine, phentolamine and propranolol. The colonic motility was evaluated by changes in the increase in intraluminal pressure of the distal colon. L-NMMA infusion (100mg/kg iv) in the presence of atropine (1 mg/kg iv) resulted in a significant increase in arterial blood pressure and intraluminal pressure. The following L-arginine infusion (100mg/kg iv) restored blood pressure and intraluminal pressure to the control level. In contrast, L-NMMA infusion in the absence of atropine resulted in no change in intraluminal pressure with a significant increase in arterial blood pressure. These results indicate that there are NO-dependent and nondependent mechanisms to regulate the distal colonic motility.

The effect of Helicobacter pylori on gastric acid secretion by isolated parietal cells from a guinea pig. Association with production of vacuolating toxin by H. pylori.

BACKGROUND: One of the features of Helicobacter pylori infection in the human stomach seems to be disordered gastric acid secretion. The effect of vacuolating toxin (VT) produced by H. pylori on gastric acid secretion was examined. METHODS: VT(+)(toxigenic) and VT(-)(nontoxigenic) strains of H. pylori were cultured in brucella broth. The culture supernatant was added to isolated parietal cells, and acid secretion and intracellular adenosine 3'5'-cyclic phosphate (cAMP) and Ca2+ levels were measured with the 14C-aminopyrine (14C-AP) method, with 125I radioimmunoassay (RIA), and with the fura-2 fluorescence method, respectively. RESULTS: In the VT(+) strain a considerable inhibitory effect on 14C-AP accumulation was observed. However, the VT(-) strain had no significant effect on intracellular c-AMP and Ca2+. CONCLUSIONS: The VT(+) strain of H. pylori has an inhibitory effect on gastric acid secretion, whereas the VT(-) strain does not. This inhibitory effect was not associated with the response of second messengers. It is speculated that VT produced by H. pylori has a direct action on H(+)-K+ adenosine triphosphatase in parietal cells.