[Heparin-induced thrombocytopenia with pseudo-pulmonary embolism in a patient who was newly introduced to hemodialysis treatment].

Pseudo-pulmonary embolism (PPE) superimposed on heparin-induced thrombocytopenia (HIT) is an important complication in patients undergoing hemodialysis (HD) treatment. We report the clinical profile of an HD patient with acute respiratory distress induced by PPE and HIT. A 67-year-old man with diabetic nephropathy and end-stage renal failure developed congestive heart failure. He was admitted to Kitasato University Hospital. He was introduced to HD treatment using low-molecular-weight heparin as an anticoagulant for an HD session on day 1 of admission. On day 11 after admission, he suddenly developed respiratory distress and hypoxia at 30 min after the start of the fifth HD session. The HD session was immediately discontinued, and oxygen inhalation improved his complaints and hypoxia. The platelet count decreased from 220 x 10(9)/L at the start of the HD session to 80 x 10(9)/L at the end of the HD session. We suspected HIT when blood clotting occurred in his hemodialyzer and blood circuit for HD during the HD session on day 12. Chest X-ray, electrocardiogram, echocardiography, and pulmonary microcirculation scintigraphy were normal. Serum analysis was positive for heparin-platelet factor 4 (PF4) antibody. We then diagnosed him with PPE superimposed on HIT. After the anticoagulant agent for HD was changed from low-molecular-weight heparin to nafamostat mesilate, his clinical symptoms and thrombocytopenia disappeared. PPE superimposed on HIT appeared approximately 7-10 days after the initial use of heparin for the HD session. PPE also led to acute respiratory distress, blood coagulation in the hemodialyzer and blood circuit for HD, as well as thrombocytopenia with less than a 50% decrease in platelet counts. The prognosis of PEE and HIT is good after discontinuing the use of heparin.

Possible involvement of host defense mechanism in the suppression of rat acute reflux esophagitis by the particular histamine H2 receptor antagonist lafutidine.

AIMS: Gastroesophageal reflux disease is considered to be caused primarily by gastric juice refluxed into the esophagus. Here, we investigated the possible involvement of host defense mechanisms in the development of acute reflux esophagitis using lafutidine, a histamine H(2) receptor antagonist (H(2)RA) with proven gastric mucosal protective effects. METHODS AND RESULTS: The ligation of both the pylorus and the forestomach of SD rats under anesthesia caused hemorrhagic lesions in the esophageal mucosa at 6 h. Lesion formation was significantly inhibited by treatment with H(2)RAs, including the conventional H(2)RAs famotidine and cimetidine as well as lafutidine. The maximum suppressive abilities of these agents were similar to that of the proton pump inhibitor lansoprazole. Interestingly, unlike famotidine, lafutidine at low doses significantly suppressed esophagitis without inhibiting gastric acid secretion. Note that neither lafutidine nor famotidine inhibited hexosamine output in gastric juice samples obtained 3 h after ligation. Additionally, the protective effect of lafutidine, but not of famotidine, was partly attenuated by the denervation of capsaicin-sensitive afferent nerves with a large dose of capsaicin. CONCLUSION: The present results indicate that esophageal host-defense via capsaicin-sensitive afferent nerves may contribute to the therapeutic action of lafutidine.

Lafutidine, a unique histamine H2-receptor antagonist, inhibits distention-induced gastric acid secretion through an H2 receptor-independent mechanism.

Gastric acid secretion during the daytime has been implicated in the pathogenesis of acid-related diseases. Although daytime acid secretion is mainly governed by the parasympathetic vagal nerve, clinical observations have been accumulated that the H(2)-receptor antagonist lafutidine may have a strong effect. Here, we examined the actions of H(2)-receptor antagonists in a rat model of gastric acid secretion induced by stomach distention, a major post-meal stimulus. Indeed, the acid output during a 3h period after the instillation of saline into pylorus-ligated SD rats under urethane anesthesia was dependent on the instilled volume and was strongly suppressed by a vagotomy or the intraduodenal administration of atropine. Interestingly, lafutidine, but not famotidine or cimetidine, administered at a sufficient dose to block histamine-dependent acid secretion was capable of inhibiting distention-induced acid secretion. Moreover, gastric acid secretion induced by the intravenous perfusion of carbachol into SD rats was strongly inhibited by lafutidine but only partially inhibited by famotidine. The antisecretory action of lafutidine under these conditions was partly reversed by the co-administration of the nitric oxide synthase inhibitor L-NMMA, but was hardly affected by denervation with capsaicin or by the administration of the transient receptor potential channel V1 (TRPV1) antagonist capsazepine. Together with the observation that lafutidine increased the amount of intragastric nitric oxide, the present results suggest that lafutidine inhibits daytime gastric acid secretion not only by blocking H(2) receptors, but also through nitric oxide-mediated and histamine-independent indirect actions.

Afferent signalling from the acid-challenged rat stomach is inhibited and gastric acid elimination is enhanced by lafutidine.

BACKGROUND: Lafutidine is a histamine H2 receptor antagonist, the gastroprotective effect of which is related to its antisecretory activity and its ability to activate a sensory neuron-dependent mechanism of defence. The present study investigated whether intragastric administration of lafutidine (10 and 30 mg/kg) modifies vagal afferent signalling, mucosal injury, intragastric acidity and gastric emptying after gastric acid challenge. METHODS: Adult rats were treated with vehicle, lafutidine (10 - 30 mg/kg) or cimetidine (10 mg/kg), and 30 min later their stomachs were exposed to exogenous HCl (0.25 M). During the period of 2 h post-HCl, intragastric pH, gastric volume, gastric acidity and extent of macroscopic gastric mucosal injury were determined and the activation of neurons in the brainstem was visualized by c-Fos immunocytochemistry. RESULTS: Gastric acid challenge enhanced the expression of c-Fos in the nucleus tractus solitarii but caused only minimal damage to the gastric mucosa. Lafutidine reduced the HCl-evoked expression of c-Fos in the NTS and elevated the intragastric pH following intragastric administration of excess HCl. Further analysis showed that the gastroprotective effect of lafutidine against excess acid was delayed and went in parallel with facilitation of gastric emptying, measured indirectly via gastric volume changes, and a reduction of gastric acidity. The H2 receptor antagonist cimetidine had similar but weaker effects. CONCLUSION: These observations indicate that lafutidine inhibits the vagal afferent signalling of a gastric acid insult, which may reflect an inhibitory action on acid-induced gastric pain. The ability of lafutidine to decrease intragastric acidity following exposure to excess HCl cannot be explained by its antisecretory activity but appears to reflect dilution and/or emptying of the acid load into the duodenum. This profile of actions emphasizes the notion that H2 receptor antagonists can protect the gastric mucosa from acid injury independently of their ability to suppress gastric acid secretion.

Effects of acid antisecretory drugs on mucus barrier of the rat against 5-fluorouracil-induced gastrointestinal mucositis.

OBJECTIVE: Acid antisecretory agents are used for the prophylaxis of cancer chemotherapy (CT)-induced gastrointestinal (GI) mucositis. Although these drugs seem to be clinically beneficial, data on their effects on the GI mucosal defense during CT treatment are scant. The objective of this study was to compare the effects of omeprazole, lansoprazole, and lafutidine on mucin, a major mucus component, during 5-fluorouracil (5-FU) treatment, as a CT regimen. MATERIAL AND METHODS: Rats, weighing approximately 230 g, were divided into five groups. The control group was administered 0.5% carboxymethylcellulose orally once daily for 5 days. The second, third, fourth, and fifth groups were treated with 5-FU (50 mg/kg), 5-FU plus omeprazole (10 mg/kg), 5-FU plus lansoprazole (10 mg/kg), and 5-FU plus lafutidine (30 mg/kg) in the same way, respectively. The rats were sacrificed on the sixth day, and their stomachs and small intestines were removed. Using anti-mucin monoclonal antibodies, we compared the immunoreactivity in different areas of the rats' GI tracts as well as the mucin content. RESULTS: Body-weight decreased in rats in the 5-FU group. Lafutidine, but neither omeprazole nor lansoprazole, inhibited the 5-FU-induced weight loss. Mucosal damage and reduced mucin content in stomach and small intestine were observed in rats receiving 5-FU alone. In the stomach, all antisecretory drugs caused the protective effects against 5-FU-induced mucosal injury and alleviation of the decreased mucin accumulation. In the jejunum and ileum, lafutidine, but neither omeprazole nor lansoprazole, ameliorated the 5-FU-induced mucosal damage and decreased mucin accumulation. CONCLUSION: Lafutidine could offer the possibility of more effective prevention of CT-induced mucositis through the activation of GI mucus cells.

Lafutidine inhibits Helicobacter pylori-induced interleukin-8 production in human gastric epithelial cells.

BACKGROUND AND AIM: Attachment of Helicobacter pylori to gastric epithelial cells leads to the production of chemokines, such as interleukin-8 (IL-8), which in turn activate and recruit neutrophils to the site of infection. Lafutidine [(+/-)-2-(furfurylsulfinyl)-N-(4-(4-(piperidinomethyl)-2-pyridyl)oxy-(Z)-2-butenyl)acetamide] is a new type of antiulcer drug that possesses an antisecretory action as well as gastroprotective activity, independent of its antisecretory action. In the present study, we examined the effects of lafutidine on H. pylori-induced IL-8 release and H. pylori adhesion to MKN45 cells. METHODS: MKN45 cells were stimulated with H. pylori, tumor necrosis factor (TNF)-alpha, or IL-1beta, then IL-6 and IL-8 levels in the culture supernatants were determined with a specific enzyme-linked immunosorbent assay kit. RESULTS: Lafutidine significantly inhibited both the release of IL-8 induced by H. pylori and the adhesion of H. pylori to cells in a dose-dependent manner. These properties of lafutidine are unrelated to the blockade of histamine H(2)-receptors, because the same effects have not been observed with other H(2)-receptor antagonists, such as cimetidine and famotidine. Lafutidine also significantly inhibited H. pylori-induced IL-6 release. Both TNF-alpha and IL-1beta-induced IL-8 releases, conversely, were little affected by lafutidine up to a concentration of 10(-5) M. CONCLUSIONS: These results suggest that lafutidine inhibits IL-8 release by inhibiting H. pylori adherence to gastric epithelial cells, indicating a novel mechanism by which lafutidine protects against the mucosal inflammation associated with H. pylori infection.

Protein kinase C activation by Helicobacter pylori in human gastric epithelial cells limits interleukin-8 production through suppression of extracellular signal-regulated kinase.

Helicobacter pylori (H. pylori) infection of gastric epithelial cells has been shown to induce interleukin (IL)-8 production, but the signal transduction mechanism leading to IL-8 production has not been clearly defined. Here, we investigate the role of protein kinase C (PKC) in the mechanism of induction of IL-8 release by H. pylori in human gastric epithelial cells. In MKN45 cells, H. pylori-induced IL-8 release was enhanced by treatment with PKC inhibitors (GF109203X and calphostin C) and PKC depletion, which completely inhibited PKC activity. Moreover, PKC inhibitors and PKC depletion increased extracellular signal-regulated kinase (ERK) activity and phosphorylation, but not calcium/calmodulin-dependent protein kinase II (CaMK II) activity, in response to H. pylori infection. PKC activated by H. pylori inhibited activation of ERK induced by H. pylori without affecting the CaMK II activity and negatively regulated IL-8 production in human gastric epithelial cells.

Identification of a signaling cascade for interleukin-8 production by Helicobacter pylori in human gastric epithelial cells.

Infecting gastric epithelial cells with Helicobacter pylori (H. pylori) has been shown to induce interleukin-8 (IL-8) production, but the signal transduction mechanism leading to IL-8 production is not defined clearly. In the present study, we investigated the molecular mechanism responsible for H. pylori-induced IL-8 release in human gastric epithelial cells. IL-8 levels in culture supernatants were determined by an enzyme linked-immunosorbent assay. Extracellular signal-regulated kinase (ERK) activity was tested using an in vitro kinase assay, which measured the incorporation of [gamma-33P]ATP into a synthetic peptide that is a specific ERK substrate. ERK phosphorylation and IkappaBalpha degradation by H. pylori infection were assessed by western blotting. In MKN45 cells, H. pylori-induced IL-8 release in a time-dependent manner. This IL-8 release was abolished by treatment with intracellular Ca2+ chelators (BAPTA-AM and TMB-8) but not by EGTA or nifedipine. The Ca2+ ionophore A23187 also induced IL-8 release to an extent similar to that of H. pylori infection. Calmodulin inhibitors (W7 and calmidazolium) and tyrosine kinase inhibitors (genistein and ST638) completely blocked IL-8 release by H. pylori and A23187. PD98059, an ERK pathway inhibitor, completely abolished H. pylori-induced IL-8 release. Moreover, BAPTA-AM, calmidazolium, and genistein, but not nifedipine, suppressed the ERK activation induced by H. pylori infection. PD98059 as well as MG132, an NF-kappaB pathway inhibitor, blocked both IL-8 production and degradation of IkappaBalpha induced by H. pylori infection, whereas only PD98059 inhibited ERK activity in response to H. pylori. There was no significant difference between IL-8 production induced by the cagA positive wild-type strain and the cagA negative isogenic mutant strain of H. pylori; therefore, CagA is not involved in the IL-8 production pathway. H. pylori-induced IL-8 production is dominantly regulated by Ca2+/calmodulin signaling, and ERK plays an important role in signal transmission for the efficient activation of H. pylori-induced NF-kappaB activity, resulting in IL-8 production.

Sensitizing effects of lafutidine on CGRP-containing afferent nerves in the rat stomach.

1. Capsaicin sensitive afferent nerves play an important role in gastric mucosal defensive mechanisms. Capsaicin stimulates afferent nerves and enhances the release of calcitonin gene-related peptide (CGRP), which seems to be the predominant neurotransmitter of spinal afferents in the rat stomach, exerting many pharmacological effects by a direct mechanism or indirectly through second messengers such as nitric oxide (NO). 2. Lafutidine is a new type of anti-ulcer drug, possessing both an antisecretory effect, exerted via histamine H(2) receptor blockade, and gastroprotective activities. Studies with certain antagonists or chemical deafferentation techniques suggest the gastroprotective actions of lafutidine to be mediated by capsaicin sensitive afferent nerves, but this is an assumption based on indirect techniques. In order to explain the direct relation of lafutidine to afferent nerves, we conducted the following studies. 3. We determined CGRP and NO release from rat stomach and specific [(3)H]-resiniferatoxin (RTX) binding to gastric vanilloid receptor subtype 1 (VR1), which binds capsaicin, using EIA, a microdialysis system and a radioreceptor assay, respectively. 4. Lafutidine enhanced both CGRP and NO release from the rat stomach induced by a submaximal dose of capsaicin, but had no effect on specific [(3)H]-RTX and capsaicin binding to VR1. 5. In conclusion, our findings demonstrate that lafutidine modulates the activity of capsaicin sensitive afferent nerves in the rat stomach, which may be a key mechanism involved in its gastroprotective action.