lafutidine and Stomach-Ulcer

Improving the quality of ulcer healing (QOUH) is one of the valid methods of prevention of relapse of gastric ulcers. We investigated the effect of lafutidine on the QOUH of gastric ulcer compared with famotidine in a randomized, multi-centre controlled trial. Consecutive 80 patients with a gastric ulcer were randomly assigned to receive twice daily either lafutidine (10 mg) or famotidine (20 mg) for 12 weeks. Esophagogastroduodenoscopy was performed to examine the ulcer healing rate and rate of flat type ulcer scars using dye-contrast. The gastric ulcer healing rate was 92.1% in the lafutidine group (35/38) and 94.7% in the famotidine group (36/38). The rate of flat-type ulcer scars was significantly higher in the lafutidine group (68.4%, 26/38) than in the famotidine group (42.1%, 16/38) (P = 0.021). In conclusion, the present study demonstrated that lafutidine, as compared to famotidine, yields a significantly superior QOUH in patients with gastric ulcers in the clinical setting.

Topics: Acetamides; Adult; Aged; Anti-Ulcer Agents; Drug Administration Schedule; Famotidine; Female; Gastroscopy; Humans; Male; Middle Aged; Piperidines; Pyridines; Stomach Ulcer; Treatment Outcome; Wound Healing

The aim of this study was to evaluate the pharmacokinetics (PK) of single and multiple doses of oral lafutidine tablets and the effect of food on the PK properties in healthy Chinese subjects. The tolerability and the effect of gender on the PK properties were also evaluated to acquire more PK information.. Three PK studies were conducted in 12 healthy Chinese subjects (6 male, 6 female). Study 1 was a single-dose, three-period, three-dose level (10, 20, and 40 mg), three-sequence cross-over study under fasting conditions. Study 2 was a repeat-dose study (10 mg twice daily over 6 days; all 12 subjects). Study 3 was a two-period, two-sequence cross-over single-dose (10 mg) food interaction study. All randomizations (study 1, study 3) were done to ascertain 1:1 gender ratio per sequence. A validated liquid chromatography tandem mass spectrometry (LC/MS/MS) method was used to determine plasma lafutidine concentrations. PK parameters were calculated by the non-compartmental method.. The area under the time-concentration curve (AUC) and maximum plasma concentration (C. The PK of lafutidine showed dose proportionality. There was no significant accumulation of lafutidine tablets with multiple dosing. Food did not affect the degree of lafutidine absorption, but it did reduce the rate of absorption. Further study is needed regarding the effect of gender on lafutidine. Lafutidine was well tolerated within the dose range 10-40 mg, and no serious adverse events were observed.

Topics: Acetamides; Administration, Oral; Adult; Anti-Ulcer Agents; Area Under Curve; Asian People; Cross-Over Studies; Dose-Response Relationship, Drug; Drug Monitoring; Female; Food-Drug Interactions; Healthy Volunteers; Humans; Male; Piperidines; Pyridines; Stomach Ulcer; Tablets; Tandem Mass Spectrometry

In this study, lafutidine (LAF) was used as a model compound to investigate the binding mechanism between antiulcer drugs and human serum albumin (HSA) through various techniques, including STD-NMR, WaterLOGSY-NMR, (1)H NMR relaxation times, tr-NOESY, molecule docking calculation, FT-IR spectroscopy, and CD spectroscopy. The analyses of STD-NMR, which derived relative STD (%) intensities, and WaterLOGSY-NMR, determined that LAF bound to HSA. In particular, the pyridyl group of LAF was in close contact with HSA binding pocket, whereas furyl group had a secondary binding. Competitive STD-NMR and WaterLOGSY-NMR experiments, with warifarin and ibuprofen as site-selective probes, indicated that LAF preferentially bound to site II in the hydrophobic subdomains IIIA of HSA. The bound conformation of LAF at the HSA binding site was further elucidated by transferred NOE effect (tr-NOESY) experiment. Relaxation experiments provided quantitative information about the relationship between the affinity and structure of LAF. The molecule docking simulations conducted with AutoDock and the restraints derived from STD results led to three-dimensional models that were consistent with the NMR spectroscopic data. The presence of hydrophobic forces and hydrogen interactions was also determined. Additionally, FT-IR and CD spectroscopies showed that LAF induced secondary structure changes of HSA.

Topics: Acetamides; Binding Sites; Circular Dichroism; Humans; Magnetic Resonance Spectroscopy; Molecular Docking Simulation; Piperidines; Protein Binding; Protein Domains; Protein Structure, Secondary; Protons; Pyridines; Serum Albumin; Spectrophotometry; Spectroscopy, Fourier Transform Infrared; Stomach Ulcer; Warfarin

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Acetamides; Anti-Ulcer Agents; Central Nervous System Diseases; Clopidogrel; Histamine H2 Antagonists; Humans; Middle Aged; Piperidines; Pyridines; Rabeprazole; Stomach Ulcer; Ticlopidine

Sensory neuron activation reduces water-immersion restraint stress (WIR)-induced gastric mucosal injury by inhibiting neutrophil activation through increase in endothelial production of prostacyclin. This study was designed to examine whether lafutidine, which is an H(2)-receptor antagonist and activates sensory neurons, inhibits neutrophil activation, thereby reducing WIR-induced gastric mucosal injury. Lafutidine enhanced WIR-induced increases in gastric tissue levels of calcitonin gene-related peptide (CGRP) and 6-keto-PGF(1alpha), a stable metabolite of prostacyclin, whereas famotidine, another H(2)-receptor antagonist, did not. Such lafutidine-induced increases in gastric tissue levels of 6-keto-PGF(1alpha) were reversed by pretreatment with capsazepine, an inhibitor of sensory neuron activation, CGRP(8-37), a CGRP antagonist, and indomethacin. Lafutidine inhibited acid-induced exacerbation of gastric mucosal injury in animals subjected to WIR by inhibiting neutrophil activation, whereas famotidine did not. Lafutidine synergistically increased CGRP release from isolated rat dorsal root ganglion neurons in the presence of anandamide, but famotidine did not. These observations suggest that lafutidine might reduce WIR-induced gastric mucosal injury not only by inhibiting acid secretion but also by inhibiting neutrophil activation through enhancement of sensory neuron activation.

Topics: 6-Ketoprostaglandin F1 alpha; Acetamides; Animals; Anti-Ulcer Agents; Arachidonic Acids; Calcitonin Gene-Related Peptide; Capsaicin; Cells, Cultured; Cyclooxygenase Inhibitors; Disease Models, Animal; Endocannabinoids; Famotidine; Ganglia, Spinal; Gastric Acid; Gastric Mucosa; Histamine H2 Antagonists; Indomethacin; Male; Neurons, Afferent; Neutrophil Activation; Peptide Fragments; Piperidines; Polyunsaturated Alkamides; Pyridines; Rats; Rats, Wistar; Restraint, Physical; Stomach Ulcer; Stress, Psychological

We examined the prophylactic effect of lafutidine, a histamine H2 receptor antagonist, on the morphological and functional derangement of the rat stomach after the administration of 5-fluorouracil (5-FU) in the absence or presence of taurocholate Na (TC). Rats were given 5-FU p. o. once daily for 5 days. After 18 hr fasting, the animals were given omeprazole to inhibit acid secretion. Under urethane anesthesia, the stomach was mounted on an ex-vivo chamber, perfused with 100 mM HCl, and both the transmucosal potential difference (PD) and gastric mucosal blood flow (GMBF) were simultaneously measured before and after exposure of the mucosa to 20 mM TC for 30 min. The 5-FU treatment lowered the basal PD with a decrease in the mucosal height and caused few haemorrhagic lesions in the stomach when perfused with 100 mM HCl for 2 hr. The 5-FU treatment had no influence on the reduced PD response caused by TC, but significantly impaired the increase in GMBF after exposure to TC, resulting a marked aggravation of gastric lesions. Lafutidine, given together with 5-FU for 5 days, significantly antagonized the deleterious effect of 5-FU on the basal PD and the GMBF response to TC, and prevented the aggravation of gastric lesions. These effects of lafutidine were not mimicked by cimetidine and disappeared due to the chemical ablation of capsaicin-sensitive afferent neurons. We conclude that 1) 5-FU treatment caused the morphological and functional derangement of the stomach and increased the mucosal vulnerability against acid, and 2) lafutidine prevents such changes caused by 5-FU treatment, probably mediated through capsaicin-sensitive afferent neurons.

Topics: Acetamides; Animals; Anti-Ulcer Agents; Cimetidine; Dinoprostone; Drug Interactions; Fluorouracil; Gastric Mucosa; Hydrochloric Acid; Male; Membrane Potentials; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Stomach; Stomach Ulcer; Taurocholic Acid

Effects of vanilloid-receptor agonists and antagonists on HCl-induced gastric lesions in rats were investigated to elucidate the role of vanilloid receptor type 1 (VR1) in gastric mucosal defense mechanisms.. Gastric lesions in rats were evaluated after intragastric administration of 0.6 N HCl. The localization of VR1 in the stomach was investigated immunohistochemically.. Intragastric administration of capsaicin inhibited the formation of gastric lesions in a dose-dependent manner (0.1-2.5 mg/kg). The functional VR1 antagonists ruthenium red and capsazepine markedly aggravated HCl-induced gastric lesions in rats. The gastroprotective effect of capsaicin was attenuated by ruthenium red or capsazepine. It is reported that resiniferatoxin, [6]-gingerol and lafutidine are compounds that activate VR1 and/or capsaicin-sensitive afferent neurons. These compounds significantly inhibited the formation of HCl-induced gastric lesions, and their gastroprotective effects were inhibited by treatment with ruthenium red. The immunohistochemical studies revealed that nerve fibers expressing VR1 exist along gastric glands in the mucosa, around blood vessels in the submucosa, in the myenteric plexus, and in the smooth muscle layers, especially the circular muscle layer.. The results of this study suggest that VR1 plays a protective role in the gastric defensive mechanism in rats.

Topics: Acetamides; Animals; Anti-Ulcer Agents; Capsaicin; Catechols; Diterpenes; Famotidine; Fatty Alcohols; Gastric Mucosa; Hydrochloric Acid; Male; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Receptors, Drug; Stomach Ulcer

Lafutidine is a novel histamine H(2)-receptor antagonist with a potent and long-lasting anti-acid secretory effect that has also been found to have a potent gastroprotective effect. We investigated the effect of lafutidine on gastric mucosal injury induced in rats with the use of water-immersion restraint stress (WRS) by examining serum calcitonin gene-related peptide (CGRP) concentrations, which we measured with the use of an enzyme immunometric assay. WRS-induced mucosal erosive injury in the stomach was reduced significantly by both lafutidine and famotidine pretreatment (from 7.79 +/- 2.02 mm(2) to 3.09 +/- 0.74 mm(2) and 4.05 +/- 1.18 mm(2), respectively). A single administration of lafutidine or famotidine did not change the serum CGRP concentration from the control value when these drugs were administered without WRS. Lafutidine pretreatment before WRS caused a significant increase in serum CGRP concentration compared with famotidine (lafutidine, 86.64 +/- 9.52 pg/mL; famotidine, 47.55 +/- 4.35 pg/mL; control, 58.43 +/- 6.07 pg/mL). Our results suggest that lafutidine augments CGRP release from the rat stomach when administered before the induction of WRS.

Topics: Acetamides; Animals; Calcitonin Gene-Related Peptide; Famotidine; Histamine H2 Antagonists; Immersion; Male; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Restraint, Physical; Stomach Ulcer; Stress, Physiological; Water

It is well known that capsaicin-sensitive nerve signaling acts as a protective factor against various ulcerogens. However, the contribution of topical capsaicin-sensitive nerves within the stomach to rapid restitution has not been fully investigated. The present study was therefore conducted focusing on recovery from gastric mucosal damage induced by ethanol in vivo.. Male Sprague-Dawley rats were fasted and anesthetized. 51Cr-EDTA was administered intravenously and gastric mucosal integrity was continuously monitored by measuring the blood to lumen 51Cr-EDTA clearance. Capsaicin or vehicle was irrigated before, together with or after the perfusion of 20% ethanol, followed by perfusion with saline. In another experiment, ruthenium red, a capsaicin-sensitive cation antagonist, was given before the ethanol-capsaicin perfusion. Furthermore, this study was verified using lafutidine, a histamine H2-receptor antagonist, which has a gastric mucosal protective action through the capsaicin-sensitive afferent nerves.. When capsaicin was administered before ethanol treatment, mucosal damage was significantly reduced and recovery was significantly rapid compared to the control. When capsaicin (160 micro M) and ethanol were administered simultaneously, the mucosal damage was exacerbated but recovery was nevertheless more rapid than the control group. With a lower dose of capsaicin (80 micro M), mucosal damage was not exacerbated and recovery was enhanced. When capsaicin or lafutidine was administered after the induction of ethanol injury no change was detected regarding the damage. However, recovery was significantly accelerated. Ruthenium red reversed the action of post-treatment with capsaicin on restitution.. These results indicate that luminal administration of capsaicin exerts protection against and accelerates restitution from gastric damage in the very early phase after ethanol injury. This action is probably due to activation of topical capsaicin-sensitive afferent nerves in the rat.

Topics: Acetamides; Animals; Anti-Ulcer Agents; Capillary Permeability; Capsaicin; Edetic Acid; Ethanol; Gastric Mucosa; Male; Neurons, Afferent; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Ruthenium Red; Stomach Ulcer

Defunctionalization of capsaicin-sensitive afferent nerves by pretreatment with a neurotoxic dose of capsaicin aggravates gastric ulcers in rats. In the present study, we investigated the roles of vanilloid receptors in gastric antral ulcers, using vanilloid receptor agonists and antagonists. Gastric antral ulcers were induced by a combination of diethyldithiocarbamate and 1 N HCl in refed rats. The administration of ruthenium red (1.5 mg/kg, s.c., twice daily) aggravated gastric antral ulcers (ulcer index: control, 33.7+/-13.7 mm(2); ruthenium red, 99.9+/-11.0 mm(2)). A similar result was observed in rats pretreated with a neurotoxic dose of capsaicin. On the other hand, capsaicin (1-10 mg/kg, p.o., twice daily) inhibited antral ulcer formation (ulcer index: control, 99.2+/-20.6 mm(2); capsaicin 10 mg/kg, 37.0+/-11.7 mm(2)). A similar effect was obtained in rats treated with the novel antiulcer drug, lafutidine (3-10 mg/kg, p.o., twice daily), which has gastroprotective activity mediated by capsaicin-sensitive afferent nerves. The antiulcer effects of capsaicin and lafutidine were abolished by ruthenium red and by pretreatment with a neurotoxic dose of capsaicin. These results suggest that vanilloid receptors play a gastroprotective role in gastric antral ulcers. In addition, treatment with ruthenium red may be an alternative tool for defunctionalization of capsaicin-sensitive afferent nerves.

Topics: Acetamides; Animals; Anti-Ulcer Agents; Capsaicin; Cations; Ditiocarb; Famotidine; Ion Channels; Male; Piperidines; Pyloric Antrum; Pyridines; Rats; Rats, Sprague-Dawley; Receptors, Drug; Ruthenium Red; Stomach Ulcer

We investigated the recurrence of ulcers in rats after treatment with FRG-8813, (+/-)-2-(furfurylsulfinyl)-N-[4- [4-(piperidinomethyl)-2-pyridyl] oxy-(Z)-2-butenyl] acetamide, a novel histamine H(2)-receptor antagonist. Chronic gastric ulcers were induced by serosa-searing with a hot metal bar, and the ulcer healing and recurrence after treatment with FRG-8813 or famotidine were evaluated by endoscopy for 160 days. At the dose of 30 mg/kg p. o., once daily, the treatment with FRG-8813 or famotidine for 60 days, which was stopped earlier if the ulcer had healed, accelerated the ulcer healing significantly. A subsequent follow-up study on the healed rats showed that the cumulative recurrence rate of rats healed by FRG-8813 was lower than that of naturally healed rats or rats healed by famotidine. In many cases of rats healed by FRG-8813, the regenerated mucosa was normal in contrast with the control of famotidine-healed animals. The mucosal regeneration index of the gastric ulcer after 10 days' administration of FRG-8813 was significantly higher than that obtained with famotidine. After cessation of the treatment with famotidine for 7 days, rebound hyperacidity was induced; but such rebound did not occur with FRG-8813. Considering the low recurrence rate of ulcers after FRG-8813 treatment, we suggest that FRG-8813 treatment may provide additional benefits in peptic ulcer therapy.

Topics: Acetamides; Animals; Disease Models, Animal; Endoscopy, Gastrointestinal; Famotidine; Gastric Acidity Determination; Gastrins; Histamine H2 Antagonists; Male; Outcome Assessment, Health Care; Piperidines; Pyridines; Rats; Rats, Wistar; Secondary Prevention; Stomach Ulcer

Lafutidine (CAS 118288-08-7, FRG-8813) is a novel histamine H2-receptor antagonist with gastroprotective activity. The aim of this study was to investigate the property of the gastro-protective activity of lafutidine by examining the effect on ammonia-induced change in transmucosal potential difference (PD), basal gastric mucosal blood flow (GMBF) and noxious agent-induced cell damage. Intragastrical application of lafutidine accelerated the recovery of the PD reduction after exposure of the mucosa to 0.25% ammonia solution and the accelerating effect was abolished by chemical deafferentation, but not with indometacin, a cyclooxygenase inhibitor. The application of capsaicin, as a reference compound, significantly promoted the recovery of the ammonia-induced PD reduction and this effect was not altered with indometacin. Lafutidine given intragastrically caused a sustained increase in GMBF in a dose-dependent fashion, which was also completely inhibited in the deafferentated rats. In vitro studies revealed that, in contrast to 16,16-dimethyl prostaglandin E2, lafutidine did not protect isolated gastric superficial epithelial cells from ethanol- or ammonia-induced damage. In conclusion, the gastroprotection of lafutidine is induced by promoting the restitution of the damaged mucosa after a noxious agent, not by directly protecting the epithelial cells and this effect may be caused through the mechanism of capsaicin-sensitive afferent nerves.

Topics: 16,16-Dimethylprostaglandin E2; Acetamides; Ammonia; Animals; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Capsaicin; Central Nervous System Depressants; Ethanol; Gastric Mucosa; Histamine H2 Antagonists; Indomethacin; Male; Membrane Potentials; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Stomach Ulcer

Lafutidine is a new type antiulcer agent with antisecretory and gastroprotective activities. We investigated the effect of lafutidine on indomethacin-induced antral ulcer in refed rats. Subcutaneous indomethacin injection resulted in the formation of gastric antral ulcer. Lafutidine (1-10 mg/kg, p.o.) reduced the area of ulcer in a dose-dependent manner when administered immediately after the indomethacin injection. Capsaicin at 3 mg/kg, p.o. and 16,16-dimethyl prostaglandin E2 at 3 microg/kg, p.o. also reduced the ulcer area. Chemical deafferentation of capsaicin-sensitive neurons or N(G)-nitro-L-arginine treatment aggravated the ulcer formation and abolished the preventive effect of lafutidine and capsaicin. After the induction of gastric ulcer, lafutidine given twice daily for 2.5 days reduced the area of ulcer in a dose-dependent manner with a significant effect at 10 mg/kg, p.o., as compared with that of the control group. In chemically-deafferentated rats, lafutidine did not show any healing effect. Cimetidine (30 mg/kg, p.o.) and famotidine (1 mg/kg, p.o.) had no significant effect on indomethacin-induced antral ulcer. These results may suggest that lafutidine, unlike cimetidine and famotidine, can prevent the indomethacin-induced antral ulcer formation and accelerate the healing of the ulcer in refed rats through mechanisms involving the capsaicin-sensitive afferent neurons and nitric oxide.

Topics: 16,16-Dimethylprostaglandin E2; Acetamides; Administration, Oral; Animals; Anti-Ulcer Agents; Capsaicin; Cimetidine; Denervation; Dose-Response Relationship, Drug; Enzyme Inhibitors; Famotidine; Food; Indomethacin; Male; Nitroarginine; Piperidines; Pyloric Antrum; Pyridines; Rats; Rats, Sprague-Dawley; Stomach Ulcer; Wound Healing

Lafutidine ((+/-)-2-(furfurylsulfinyl)-N-(4-(4-(piperidinomethyl)-2-pyr idyl)oxy-(Z)-2-butenyl)acetamide) is a novel histamine H2-receptor antagonist and has been shown to exhibit a potent gastroprotective activity in addition to its antisecretory action. In the present study, we examined the effects of lafutidine on the mucosal ulcerogenic and potential difference (PD) responses induced by monochloramine (NH2Cl) in rat stomachs.. Oral administration of NH2Cl at 120 mmol/L produced haemorrhagic lesions in the stomach in unanaesthetized rats.. Lafutidine (3-30mg/kg), given p.o., showed a dose-dependent and significant inhibition against damage caused by NH2Cl: the effect was significant at 10 mg/kg or greater but disappeared almost totally in the sensory deafferented animals following capsaicin pretreatment. Likewise, capsaicin (10 mg/kg, p.o.), but not cimetidine (100 mg/kg, p.o.) exhibited a potent protection against NH2Cl-induced gastric lesions. Topical application of NH2Cl (10 mmol/L) reduced transmucosal PD in ex-vivo stomachs of anaesthetized rats, but this PD response was also prevented by pre-exposure to lafutidine, in a dose-dependent and sensory neuron-sensitive manner. Mucosal exposure to NH4OH (60 mmol/L) also caused PD reduction in ex-vivo stomachs made ischaemic by bleeding from the carotid artery (1 mL/100 g bodyweight), resulting in severe gastric lesions. These ulcerogenic and PD responses caused by NH4OH plus ischaemia were attenuated by prior application of lafutidine as well as taurine, a scavenger of NH2Cl. The former effect was, again, dependent on the sensory neurons. Intraluminal capsaicin but not cimetidine was also effective in preventing a PD response to NH2Cl.. These results suggest that lafutidine, but not cimetidine, protects the stomach against NH2Cl, whether occurring endogenously or administered exogenously and that this action may be mediated by capsaicin-sensitive sensory neurons.

Topics: Acetamides; Animals; Anti-Ulcer Agents; Capsaicin; Chloramines; Cimetidine; Gastric Mucosa; Histamine H2 Antagonists; Ischemia; Membrane Potentials; Neurons, Afferent; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Stomach; Stomach Ulcer

Effect of lafutidine ((+/-)-2-(furfurylsulfinyl)-N-[4-[4-(piperidinomethyl)-2-pyr idyl] oxy-(Z)-2-butenyl] acetamide, FRG-8813), a novel antiulcer agent, on the healing and relapse in acetic acid-induced gastric ulcer in rats was investigated. Lafutidine at 1, 3 or 10 mg/kg, twice daily for 10 days reduced the ulcer area in a dose-dependent manner, and the effect by 10 mg/kg of lafutidine was significant. The effect of famotidine at 1 mg/kg and cimetidine at 30 mg/kg, which have almost equal antisecretory activity to lafutidine at 10 mg/kg, on the ulcer area was not significant. Effect on the healing and relapse was assessed by endoscopy for 25 weeks after the induction of gastric ulcer. Drugs were administered twice daily for 11 weeks. Lafutidine at 3 mg/kg and famotidine at 1 mg/kg accelerated the healing, but cimetidine at 30 mg/kg did not. Cumulative relapse rate and inflammatory cell infiltration were significantly reduced in rats initially treated with lafutidine. Famotidine and cimetidine had no effect. In conclusion, lafutidine accelerated ulcer healing and prevented ulcer relapse in rats.

Topics: Acetamides; Acetic Acid; Animals; Anti-Ulcer Agents; Cimetidine; Dose-Response Relationship, Drug; Famotidine; Histamine H2 Antagonists; Male; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Recurrence; Stomach Ulcer

FRG-8813 ((+/-)-2-(furfurylsulfinyl)-N-[4-[4-(piperidinomethyl)-2- pyridyl]oxy-(Z)-2-butenyl]acetamide) is a novel histamine H2-receptor antagonist with gastric antisecretory and gastroprotective activities. The present study was designed to investigate the property of gastroprotective action. The oral ED50 values for inhibition of mucosal lesions against 1% NH3-, 60% ethanol in 0.15 N HCl-, 100% ethanol-, 0.6 N HCl- and sodium taurocholate in 0.4 N HCl-induced damage were 3.3, 11.1, 14.9, 23.3 and 23.1 mg/kg, respectively. FRG-8813 was gastroprotective despite pretreatment with omeprazole, suggesting that the protective effect is independent of its antisecretory activity. It is unlikely that FRG-8813 works as a mild irritant because it showed a gastroprotective effect after intraperitoneal injection, but oral administration itself did not influence the rat gastric mucosa. Although pretreatment with indomethacin or N-ethylmaleimide did not affect the gastroprotection of FRG-8813, chemical deafferentation induced by capsaicin abolished the gastroprotection. Furthermore, prior administration of tetrodotoxin, the calcitonin gene-related peptide (CGRP) antagonist hCGRP or NG-nitro-L-arginine attenuated the gastroprotection of FRG-8813 as well as that of capsaicin. In contrast to capsaicin, repeated administration of FRG-8813 neither enhanced the susceptibility of the mucosa to damage nor affected the gastroprotective action of short-term treatment. In conclusion, these results suggest that FRG-8813 has gastroprotective activity independently of acid antisecretory activity and that capsaicin-sensitive nerves may be partially or fully involved in the gastroprotective mechanisms of FRG-8813.

Topics: Acetamides; Animals; Anti-Ulcer Agents; Drug Interactions; Gastric Mucosa; Gastrointestinal Motility; Histamine H2 Antagonists; Male; Omeprazole; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Stomach Ulcer

It is not presently well understood whether the histamine H2 receptor antagonist has a function other than the inhibition of gastric acid secretion, such as the effect on the gastric mucosal defence mechanism. In this paper, we report the effect of FRG-8813 (N-[4-[4-(piperidinylmethyl)pyridyl-2-oxy]-(Z)-2-butenyl]-2- (furfurylsulfinyl) acetamide), a new histamine H2 receptor antagonist, on the rat gastric mucin content with or without 0.15N HCl-ethanol (60 %)-induced gastric damage. The prior administration of FRG-8813 significantly inhibited the occurrence of macroscopically observable hemorrhagic lesions induced by the acidified ethanol treatment. Using a newly developed biochemical method, the mucin content of the deep corpus and antral mucosa of the acidified ethanol-treated animals was significantly reduced to 50% and 32% of the control, respectively. These reductions were inhibited by the pretreatment with FRG-8813. Total mucin content in the entire stomach recovered to about 80% of the control value after pretreatment with FRG-8813. A single oral administration of FRG-8813 (30 mg/kg) caused no significant change in the total mucin content, but mucin in the adherent mucus gel layer selectively and significantly increased to 250% of the control. These results suggest that FRG-8813 not only inhibits acid secretion but may also affect the gastric mucosal defensive mechanism as well.

Topics: Acetamides; Analysis of Variance; Animals; Ethanol; Gastric Mucins; Gastric Mucosa; Histamine H2 Antagonists; Male; Piperidines; Premedication; Pyridines; Rats; Rats, Wistar; Stomach Ulcer

We examined the anti-ulcer effects of FRG-8813, a new type histamine H2-receptor antagonist, on various experimental gastric and duodenal lesions in rats. FRG-8813, administered orally, inhibited the formation of lesions dose-dependently in experimental models with the exception of the Shay ulcer model. The anti-ulcer potency of FRG-8813 was 4 approximately 10 times greater than that of cimetidine when the ED50 values of both compounds were compared. Famotidine and cimetidine inhibited lesion formation at higher doses than the anti-secretory doses. The anti-ulcer action of FRG-8813, however, appeared at even lower doses than those of anti-secretory action. These results suggest that FRG-8813 is able to prevent lesion formation with anti-secretory action plus other mechanisms unlike typical histamine H2-receptor antagonists.

Topics: Acetamides; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Duodenal Ulcer; Gastric Acid; Histamine H2 Antagonists; Male; Piperidines; Pyridines; Rats; Rats, Wistar; Stomach Ulcer

We examined the anti-ulcer effects of FRG-8813, a new-type histamine H2-receptor antagonist, in chronic ulcer models of rats and mice (W/WV). FRG-8813, given orally twice a day for 7 days, accelerated the healing of gastric or duodenal ulcer induced by acetic acid injection or application at the non-antisecretory doses (0.3 approximately 3 mg/kg). Administration of FRG-8813 to rats with ulcers increased the amounts of mucus in the gastric mucosa. These actions of FRG-8813 were more potent than those of famotidine or cimetidine. In W/WV mice, several ulcers spontaneously developed on gastric mucosa during the 8 weeks after the birth. The ulcers were aggravated by several unknown factors after the ulcer generation in W/WV mice. The aggravation of ulcers was inhibited by the 4-week administration of FRG-8813 with diet at the dose of 1 or 10 mg/kg/day, but was not inhibited by cimetidine at the dose of 100 mg/kg/day. From these results, we suggest that FRG-8813 is able to accelerate the healing of ulcers by antisecretory plus increasing actions on the integrity of the gastric mucosal defense mechanisms; therefore FRG-8813 is expected to be a useful drug for the treatment of gastric or duodenal ulcers in humans.

Topics: Acetamides; Animals; Chronic Disease; Disease Models, Animal; Duodenal Ulcer; Gastric Acid; Histamine H2 Antagonists; Male; Mice; Piperidines; Pyridines; Rats; Rats, Wistar; Stomach Ulcer