Randomized, double-blind, placebo-controlled crossover trial of famotidine in patients with functional dyspepsia.

BACKGROUND: Histamine 2-receptor antagonists were used as a first therapy against functional dyspepsia. However, few clinical studies with famotidine for functional dyspepsia have been reported. AIM: To evaluate the effectiveness of famotidine for functional dyspepsia patients. METHODS: A multicentre, randomized, double-blind, placebo-controlled crossover trail was conducted. Patients diagnosed with functional dyspepsia by the Roma II criteria were included. Subjects were randomized into two groups, and received either famotidine or placebo as the first 4 weeks medication. After a 1-week washout period, they were switched to the other regimen for another 4 weeks. Evaluation was made prior to the start of study, upon completion of the first drug cycle, and the second drug cycle, by Gastrointestinal Symptoms Rating Scale for the seriousness of abdominal symptoms, and by Short Form-36 for the level of quality of life. RESULTS: Nineteen of 21 enrolled patients successfully completed this study. Significant improvement in Gastrointestinal Symptoms Rating Scale scores was observed in abdominal pain (P = 0.007), indigestion and reflux syndrome after famotidine treatment. Also quality of life scores showed significant improvement in body pain, vitality and general health perceptions after famotidine treatment. There was no improvement of symptoms and quality of life scores after administration of placebo. CONCLUSIONS: Famotidine was effective for improving symptoms and quality of life in functional dyspepsia patients.

Validity of mutagenic activity as an indicator of river water pollution.

OBJECTIVES: To investigate if mutagenicity could be expressed by known water pollution indicators, we determined the mutagenic activity of blue rayon extracts from sampled river water with the Ames test utilizing new strains of bacteria, and compared the results with those of known indicators of water pollution. METHODS: Water samples were collected by the blue rayon adsorption method at sixteen sites in six rivers in the North Kyushu district. The Assay of mutagenicity was carried out using the Ames test. The test strains wereSalmonella typhimurium TA100, YG1024, YG1041 and YG1042. B(a)P, Trp-P-1 and Trp-P-2 were quantified by HPLC. Determinations of SS, BOD, COD, T-N, T-P, DOC, and A(260)/DOC were performed. RESULTS: The extracts from five sampling sites showed higher mutagenicity toward strain YG1024 with or without S9mix, and the extracts from two of these five sites showed higher mutagenicity toward strain YG1041 with and without S9mix. However, the water pollution indicators did not show specific trends that were consistent with the mutagenic activity. CONCLUSIONS: Since the mutagenic activity of river water could not be predicted using known water pollution indicators, we recommend that biological examinations such as mutagenicity tests be added to the indicators that are currently in use.

The mutagenicity of amino-derivatives of diphenyl ether herbicides in new Salmonella typhimurium YG tester strains.

In this study, we examined the mutagenicity of four diphenyl ether herbicides and their amino derivatives in Salmonella typhimurium TA tester strains and YG tester strains. YG tester strains have been newly developed for sensitive detection of specific chemicals. S. typhimurium YG 1021, YG 1024, YG 1026 and YG 1029 strains are sensitive to mutagenic nitoroarenes and hydroxyamines. S. typhimurium YG 3003 is a strain that is sensitive to some oxidative mutagens. And S. typhimurium YG 7108 is useful for detection of mutagenic alkylating agents. As a result, each amino derivative of diphenyl ether herbicides is more mutagenic than its parent herbicide in S. typhimurium TA and YG tester strains with metabolic activation by S9 mixture. Moreover, S. typhimurium YG tester strains are more useful for highly sensitive detection of mutagens than S. typhimurium TA tester strains. We also examined the production of amino derivatives in a water environment from parent herbicides. It was clear that diphenyl ether herbicides rapidly transform to amino derivatives in a water environment.

[Biodegradation of herbicide chlornitrofen (CNP) and mutagenicity of its degradation products].

Mutagenicities of three diphenyl ether-derived herbicides, chlornitrofen (CNP), nitrofen and chlormethoxynil, and their amino derivatives were assayed by the Ames test using TA98, TA100 and YG strains, recently developed tester strains. As for CNP, mutagenicities of its biodegradation products were also assayed, and biodegradation of CNP and change in mutagenic potency were examined using river water to which CNP was added. CNP was weakly mutagenic in YG1029, and nitrofen was weakly mutagenic in YG1029, while highly mutagenic in YG1026. But neither of three herbicides were mutagenic using TA98 and TA100. All of their amino derivatives were mutagenic especially in YG1024 and YG1029, acetyltransferase-rich mutants of TA98 or TA100. In YG1029, mutagenic potency of the amino derivatives was relatively high compared with that of each parent compound. Concerning biodegradation products of CNP, amino-CNP was highly mutagenic and acethylamino-CNP was moderately mutagenic in YG 1026, but others were non-mutagenic. In river water, CNP was degraded rapidly and converted to amino-CNP. Change in mutagenicity of river water to which CNP was added seemed to reflect changes in amino-CNP concentration in river water. Therefore, assessing health impact of chemicals released in natural environment, their degradation products must be considered along with parent compounds.

Site-specific formation of thyrotropin-releasing hormone-induced gastric ulcers through the vagal system.

The left and right dorsal motor nuclei (DMN) separately innervate the anterior and posterior gastric walls through the left and right gastric branches of the vagus nerve (GBVN) in rats. The present study was carried out to investigate the effects of selective centrally originated excitation of the unilateral vagal system on the gastric area in which vagus-induced gastric ulcers developed. Since intracisternally injected thyrotropin-releasing hormone (TRH) stimulates neurons in the bilateral DMNs to produce gastric ulcers, selective stimulation of the unilateral vagal system was produced by contralateral gastric branch vagotomy before intracisternal injection of TRH. Intracisternal injection of TRH (2 micrograms/rat) into left gastric branch-vagotomized rats resulted in lesion formation only on the posterior gastric wall and not on the anterior wall. In contrast, in right gastric branch-vagotomized rats TRH-induced gastric lesions were observed only on the anterior gastric wall and not on the posterior wall. These results suggest that selective stimulation of the left or right DMN induces site-specific ulcer formation through the left or right GBVN. Next, gastric acid secretion was determined in pylorus-ligated rats to examine a role of acid hypersecretion in site-specific ulcer formation caused by TRH. Of interest was that gastric acid secretion in unilaterally vagotomized rats given TRH intracisternally was significantly smaller than that in sham-operated rats given intracisternal saline, although the former rats developed gastric ulcers, whereas the latter did not. It is therefore speculated that gastric hyperacidity plays a less important role in the peripheral mechanisms of TRH-induced site-specific gastric ulceration.

Kainic acid injection into medullary raphe produces gastric lesions through the vagal system in rats.

There is little evidence of a role of nuclei in the brain stem, other than the dorsal motor nucleus of the vagus nerve in the medulla oblongata, in terms of central mechanisms for gastric ulcer formation. Recent reports suggest that the medullary raphe nuclei may be involved in the central regulation of gastric functions such as gastric acid secretion and motility. In the present study, we examined whether neurons in the nucleus raphe obscurus (NRO) played a significant role in the formation of gastric ulcers with the use of Sprague-Dawley rats. First, we determined whether excitation of the medullary raphe resulted in the development of gastric lesions. Chemical stimulation of neurons in the NRO by kainic acid produced gastric erosions within 4 h in 24-h fasted rats. Saline tested under the same conditions did not modify the integrity of the gastric mucosa. It was also demonstrated that kainic acid injection outside the raphe obscurus boundaries failed to develop gastric lesions. Next, we examined the effects of the vagal system on the gastric lesion formation induced by stimulation of the raphe nucleus. Bilateral gastric branch vagotomies completely prevented the development of the raphe nucleus-provoked gastric mucosal damage. All these results suggest, for the first time, that excitation of neurons in the medullary raphe obscurus induces gastric ulceration through vagal stimulation.

Evidence that gastric antisecretory action of lipopolysaccharide is not due to a toxic effect on gastric parietal cells.

We have recently found that bacterial lipopolysaccharide (LPS) or endotoxin at minute doses inhibits the secretion of gastric acid and pepsin in rats. The present study was performed to determine whether this antisecretory action of LPS was a reversible biological response or a result of the destruction of gastric parietal cells by endotoxin. The intraperitoneal injection of LPS into pylorus-ligated rats resulted in a dose-related (40-4000 ng/kg) decrease in gastric acid secretion, with maximal inhibition being observed at a dose of 4000 ng/kg. The stomach then was examined both macroscopically and microscopically for the presence or absence of mucosal lesions or damaged gastric parietal cells. No morphological changes in the gastric mucosal structure including parietal cells were observed even in the rats injected with 4000 ng/kg of LPS. Next, basal gastric acid output was compared in the rats that had received LPS (4000 ng/kg, intraperitoneal) or saline alone 24 hr before. There was no significant difference in gastric acid secretion between the saline- and LPS-pretreated groups, indicating that the secretory capacity of gastric parietal cells returned to the control level at 24 hr after the injection of a maximal antisecretory dose of LPS. These results clearly suggest that the LPS-induced inhibition of gastric secretion results not from its toxic or destructive effect on the gastric secretory mechanism but from its reversible biological effect on gastric physiology.

Basic fibroblast growth factor (bFGF) acts centrally in the brain to inhibit gastric emptying in rats.

In the present study, we evaluated the central nervous system action of basic fibroblast growth factor (bFGF) on gastric emptying of a liquid meal in conscious rats using a Phenol red method. Intracisternal injection of bFGF dose-dependently inhibited gastric emptying, while intraperitoneal injection of bFGF at the same doses failed to alter gastric emptying. These results suggest for the first time that bFGF acts in the central nervous system to delay gastric emptying.

The gastric antisecretory action of lipopolysaccharide is blocked by indomethacin.

We have recently found that bacterial lipopolysaccharide (LPS) at minute doses inhibits the secretion of gastric acid and pepsin in rats. The present study was performed to examine the mechanism by which LPS exerts its antisecretory action. The i.p. injection of LPS resulted in a dose-dependent (40-4000 ng/kg) decrease in gastric acid output in pylorus-ligated rats. However, preinjection of indomethacin (2-10 mg/kg s.c.), an inhibitor of prostaglandin biosynthesis, prevented the LPS-induced inhibition of gastric secretion in a dose-related manner, while these concentrations of indomethacin by themselves did not affect gastric acid output. These results suggest that LPS requires an intact prostaglandin system to exhibit its inhibitory action on gastric secretion.

Gastric antisecretory and antiulcer actions of interleukin-1. Evidence for the presence of an "immune-brain-gut" axis.

Increasing evidence suggests that interleukin-1 (IL-1), a cytokine mainly produced by activated monocytes/macrophages, has various biological actions in addition to its immunological activities. In the present study, we examined the effect of IL-1 on gastric secretion and gastric ulcer formation in rats. Gastric secretion was assessed in conscious pylorus-ligated rats weighing approximately 200 g. The peripheral injection of IL-1 resulted in a dose-related inhibition of gastric acid output. The central injection of IL-1 similarly reduced gastric acid secretion at 100 times smaller doses than peripherally injected IL-1, suggesting that this gastric antisecretory action of IL-1 is mediated by the central nervous system. In addition, it was found that this inhibitory effect of IL-1, either peripherally or centrally administered, was still evident at 8 h after injection, indicating the long-lasting property of this IL-1 action. On the basis of these antisecretory actions of IL-1, we determined whether or not pretreatment with IL-1 would prevent experimentally induced gastric ulcer formation. As expected, the central administration of IL-1 dose-dependently suppressed the development of gastric mucosal lesions induced by water-immersion restraint stress, a well-established ulcerogenic procedure. These results clearly demonstrated that IL-1 has potent antisecretory and antiulcer effects that are mediated by the central nervous system. Moreover, these findings suggest that there may exist an "immune-brain-gut" axis, which is involved in the regulation of gastric secretion and mucosal homeostasis, especially under certain pathophysiological conditions that activate the immune system to release various cytokines including IL-1.

Central basic fibroblast growth factor inhibits gastric ulcer formation in rats.

We have recently reported that basic fibroblast growth factor (bFGF) acts in the brain to inhibit the secretion of gastric acid and pepsin, two major aggressive factors in the pathogenesis of gastric ulcer formation. In the present study, we determined whether or not bFGF has an anti-ulcer action via the central nervous system, using male Wistar rats. The intracisternal injection of bFGF dose-dependently (0.1-1.0 microgram(s)/rat) inhibited the severity of gastric ulcers induced by water-immersion restraint stress or central thyrotropin-releasing hormone. The same doses of peripherally injected bFGF failed to protect the gastric mucosa from these ulcerogenic procedures. These results suggest for the first time that bFGF has a mucosal protective effect through a mechanism involving the central nervous system. It is speculated that this anti-ulcer action of bFGF is, at least in part, dependent upon its gastric antisecretory effect.

Prevention by interleukin-1 of intracisternally injected thyrotropin-releasing hormone (TRH)-induced gastric mucosal lesions in rats.

We have recently found that interleukin-1 (IL-1) acts in the central nervous system to potently inhibit gastric acid and pepsin secretion in rats. In the present study, we examined the effects of IL-1 on the development of gastric mucosal lesions induced by intracisternal (i.c.) thyrotropin-releasing hormone (TRH), a neuropeptide known to centrally stimulate gastric secretion. Pretreatment with i.c. injected IL-1 (10 ng/rat) significantly suppressed the severity of TRH-induced gastric erosions. On the other hand, the same dose of i.c. injected IL-1 failed to exert a cytoprotective action for the gastric mucosa against orally administered absolute ethanol. These results suggest that IL-1 has an anti-ulcer effect mainly through its inhibitory action on gastric secretion.

Central nervous system action of basic fibroblast growth factor: inhibition of gastric acid and pepsin secretion.

To examine the effects of basic fibroblast growth factor (bFGF) on gastric secretion, the present study was carried out using pylorus-ligated rats. Intracisternally injected bFGF inhibited the secretion of both gastric acid and pepsin, and this gastric antisecretory action of bFGF was a dose-related response. On the other hand, the intraperitoneal injection of bFGF did not change gastric secretion. These results strongly suggested for the first time that bFGF, a growth factor that promotes the proliferation of various cell types, might also be a chemical messenger that is involved in the central regulation of gastric secretion. This biological action of bFGF may be considered as a novel nonmitogenic activity of this growth factor.

Interleukin-1: a cytokine that has potent antisecretory and anti-ulcer actions via the central nervous system.

The present study was performed to determine if interleukin-1 (IL-1) acts as a chemical messenger in the central nervous system (CNS) regulation of gastric secretion and ulcer formation, using male Wistar rats. The central injection of IL-1 dose-dependently inhibited gastric acid secretion in pylorus-ligated rats at 100 times smaller doses than the peripheral injection of the cytokine. The action of IL-1 was long-lasting because its antisecretory effect was still evident at 8 hr after injection. Furthermore, it was observed that pretreatment with central IL-1 dose-dependently suppressed the development of gastric ulcers induced by water-immersion restraint stress, a well-established ulcerogenic procedure. These results clearly suggested for the first time that IL-1, a cytokine produced by activated monocytes/macrophages, acts centrally in the brain to exert gastric antisecretory and anti-ulcer actions.

[Analysis of subsets of colonic mucosal lymphocyte in ulcerative colitis by two color flow cytometry].

To assess how the immunological events occur in the colonic mucosa in patients with ulcerative colitis, it is thought to be important to evaluate the subpopulations and/or subsets of mucosal lymphocytes. In this point of view, we assayed those by lymphocyte isolation techniques and two color flow cytometry. Although our results showed no disease-specific abnormalities of the percentages of CD3, CD4, CD8, CD20, and HLA-DR (+) cells in PBL (peripheral blood lymphocyte) nor CML (colonic mucosal lymphocyte), these subsets of CML appeared to be altered according to the grade of severity of inflammation. In our cases, the HLA-DR (+) cell and CD4 population were larger in severely inflamed mucosa. Furthermore, fluorescence intensities of HLA-DR antigen of CD20 population in CML were greater than those in PBL. These results suggest that the B cell-mediated mechanisms may play an important role in maintaining the severe inflammation, and the clinical significance of these studies are discussed.