thiourea and Stomach-Ulcer

Metiamide greatly reduced pentagastrin-stimulated and overnight secretion of acid and pepsin in 11 patients with duodenal ulcer and virtually abolished gastric secretion in three patients with gastric ulcer. The drug was equally effective when infused intravenously or intraduodenally. A therapeutic trial of Metiamide is warranted in diseases caused or aggravated by excess gastric secretion of acid and pepsin.

Topics: Atropine; Depression, Chemical; Duodenal Ulcer; Duodenum; Gastric Juice; Humans; Infusions, Parenteral; Injections, Subcutaneous; Pentagastrin; Pepsin A; Perfusion; Secretory Rate; Stomach Ulcer; Thiourea

In the present study, we examined the protective effect of N,N'-dimethylthiourea (DMTU), a scavenger of hydroxyl radical (·OH), against water-immersion restraint stress (WIRS)-induced gastric mucosal lesions in rats. When male Wistar rats fasted for 24 h were exposed to WIRS for 3 h, gastric mucosal lesions occurred with increases in the levels of gastric mucosal myeloperoxidase (MPO), an index of tissue neutrophil infiltration, pro-inflammatory cytokines (tumor necrosis factor alpha and interleukin 1beta), lipid peroxide (LPO), and nitrite/nitrate (NOx), an index of nitric oxide synthesis, and decreases in the levels of gastric mucosal nonprotein SH and vitamin C and gastric adherent mucus. DMTU (1, 2.5, or 5 mmol/kg) administered orally at 0.5 h before the onset of WIRS reduced the severity of gastric mucosal lesions with attenuation of the changes in the levels of gastric mucosal MPO, pro-inflammatory cytokines, LPO, NOx, nonprotein SH, and vitamin C and gastric adherent mucus found at 3 h after the onset of WIRS in a dose-dependent manner. Serum levels of corticosterone and glucose, which are indices of stress responses, increased in rats exposed to WIRS for 3 h, but DMTU pre-administered at any dose had no effect on these increases. These results indicate that DMTU protects against WIRS-induced gastric mucosal lesions in rats by exerting its antioxidant action including ·OH scavenging and its anti-inflammatory action without affecting the stress response.

Topics: Animals; Antioxidants; Ascorbic Acid; Blood Glucose; Corticosterone; Cytokines; Gastric Mucosa; Lipid Peroxides; Male; Neutrophil Infiltration; Nitric Oxide; Peroxidase; Protective Agents; Rats; Rats, Wistar; Stomach Ulcer; Stress, Physiological; Thiourea

In the present study we examined whether histamine H(4) receptors (H(4)Rs) have a role in gastric ulcerogenesis using a mouse model of gastric damage.. The H(4)R antagonist JNJ7777120 and the H(4)R agonists VUF8430 and VUF10460 were investigated in fasted CD-1 mice against the ulcerogenic effect induced by co-administration of indomethacin(IND, 30 mg/kg s.c.) and bethanechol (BET, 5 mg/kg i.p.). Both macroscopic and histologic lesions were examined. Strain-related differences were investigated by testing JNJ7777120 also in NMRI, BALB/c and C57BL/6J mice.. Neither JNJ7777120 nor the H(4)R agonists displayed effects in the normal stomach at any dose tested (10 and 30 mg/kg s.c.). As expected, IND+BET provoked several lesions in the fundic mucosa, which were significantly reduced by JNJ7777120 (10 and 30 mg/kg s.c.). The gastroprotective effect of JNJ7777120 (10 and 30 mg/kg s.c.) was observed in CD-1, NMRI and BALB/c, but not in C57BL/6J, mice. In CD-1 mice, the H(4)R agonists VUF8430 and VUF10460 (both at 10 and 30 mg/kg s.c.) did not modify the damage induced by IND+BET, however VUF8430 (10 mg/kg s.c.) prevented the gastroprotection induced by JNJ7777120 (10 mg/kg s.c.).. Data obtained with selective ligands suggest that the H(4)R may have a role in mouse gastric ulcerogenesis. If confirmed in humans, these data would emphasize the potential advantage of H(4)R blockers as gastrosparing anti-inflammatory drugs. The lack of effects of JNJ7777120 in C57BL/6J mice has to be carefully considered in the pharmacological characterization of H(4)R functions and/or new selective ligands.

Topics: Animals; Anti-Inflammatory Agents; Bethanechol; Disease Models, Animal; Guanidines; Histamine Agonists; Histamine Antagonists; Indoles; Indomethacin; Male; Mice; Mice, Inbred C57BL; Piperazines; Pyrimidines; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; Species Specificity; Stomach Ulcer; Thiourea

Local intra-arterial infusion of high doses of the nitric oxide (NO) donor, nitroprusside (10-40 micrograms kg-1 min-1 for 15 min) induced dose-dependent haemorrhagic injury to the rat gastric mucosa and reduced systemic arterial blood pressure, whereas intragastric nitroprusside (10-50 mg ml-1), which caused similar falls in blood pressure, failed to induce such injury. The mucosal damage induced by nitroprusside was reduced by local concurrent infusion of superoxide dismutase (500-4000 i.u. kg-1). Local superoxide dismutase also abolished the mucosal injury induced by local infusion of the NO donor, S-nitroso-N-acetyl-penicillamine (40 micrograms kg-1 min-1), but not that induced by local infusion of endothelin-1 (5 pmol kg-1 min-1) indicating specific actions. Intravenous infusion of the iron chelator and peroxyl scavenger, desferrioxamine (0.25-1 mg kg-1 min-1) or the hydroxyl radical scavenger, dimethylthiourea (20 mg kg-1 min-1) also reduced the mucosal damage induced by the local administration of the NO donors, but not that induced by endothelin-1. These findings implicate the involvement of superoxide and possibly other oxygen-derived free radicals in the injurious actions of high levels of nitric oxide generated from NO donors, and may reflect a role of the cytotoxic peroxynitrite moiety.

Topics: Animals; Blood Pressure; Catalase; Deferoxamine; Disease Models, Animal; Drug Overdose; Drug Synergism; Endothelins; Free Radical Scavengers; Gastric Mucosa; Infusions, Intra-Arterial; Infusions, Intravenous; Male; Nitrates; Nitric Oxide; Nitroprusside; Penicillamine; Rats; Rats, Wistar; Reactive Oxygen Species; S-Nitroso-N-Acetylpenicillamine; Stomach Ulcer; Superoxide Dismutase; Thiourea; Vasodilator Agents

Oxygen-derived radicals are implicated in the pathogenesis of tissue damage and ulcerogenesis. This study aimed to examine the effect of manganese, glycine, and carotene, oxygen radical scavengers, on ethanol-induced gastric lesions in the rat and on ethanol cytotoxicity in epithelial cell culture.. MnCl2 + glycine (12.5-50 mg/rat) were injected subcutaneously up to 6 h before oral administration of 1 ml of 96% ethanol, and 0.5 ml carrot juice or beta-carotene was given orally 30 min before the ethanol. Mucosal injury was evaluated 1 h later by gross and microscopic scoring. The effect of Mn2+ and carrot juice was also tested in monolayers of radiolabeled epithelial cells exposed to H2O2 + ethanol injury as expressed by the extent of the isotope leakage.. Mn2+ and glycine pretreatment dose-dependently reduced ethanol-induced gastric lesion formation. Protection was maximal when treatment was applied 4 h before the insult. Gross damage was also markedly prevented by pretreatment with carotenes and dimethylthiourea (DMTU, 75 mg/kg intraperitoneally) but not by allopurinol. Mixtures of subtoxic concentrations of ethanol and H2O2 were highly lethal for epithelial cell monolayers. In this model, cell death was markedly attenuated by catalase, DMTU, Mn2+, and carrot juice.. Ethanol-induced gastric mucosal damage may involve generation of oxygen-derived radicals, independent of the xanthine oxidase system. By acting as oxygen radical scavengers, Mn2+, glycine, and carotenes, like catalase and DMTU, provide significant gastroprotection.

Topics: Allopurinol; Animals; Antioxidants; Carotenoids; Cells, Cultured; Chlorocebus aethiops; Enzyme Inhibitors; Epithelium; Ethanol; Free Radical Scavengers; Gastric Mucosa; Glycine; Male; Manganese; Rats; Rats, Inbred Strains; Stomach Ulcer; Thiourea

Epidermal growth factor (EGF, 10 micrograms/kg po, ip, or sc, BID, and 20 micrograms/kg iv) had no protective activity in the indomethacin-induced intestinal lesion model (6 h model). In the ethanol-induced gastric lesion model, EGF (10 micrograms/kg sc) reduced lesions by 52% and reduced gastric acid secretion by 68% (5 micrograms/kg iv). In the 24 h indomethacin-induced intestinal lesion model, pretreatment with EGF (10 micrograms/kg sc, BID; 1 day before and during indomethacin treatment) had no beneficial effects. Therefore, EGF had no protective effects against non-steroidal antiinflammatory drug (NSAID)-induced intestinal lesions at doses that protect against the necrotizing action of ethanol and that inhibit gastric acid secretion in the rat.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Dimaprit; Epidermal Growth Factor; Ethanol; Gastric Acid; Histamine H2 Antagonists; Humans; Indomethacin; Intestinal Mucosa; Male; Rats; Rats, Inbred Strains; Recombinant Proteins; Stomach Ulcer; Thiourea

Selenium, a trace element, in the form of sodium selenite has been studied for its ability to protect the gastric mucosa against the injuries caused by hypothermic restraint stress, aspirin, indomethacin, reserpine, dimaprit, and various other gastric mucosal-damaging (necrotizing) agents in rats. The results demonstrate that oral administration of sodium selenite produces a significant inhibition of the gastric mucosal damage induced by all the procedures used in this study. Selenium, in a nonantisecretory dose, produced a marked cytoprotective effect against all the necrotizing agents. The cytoprotective effect of selenium against the effects of 80% ethanol and 0.6 M HCl was significantly reversed by prior treatment with a dose of indomethacin that inhibits prostaglandin biosynthesis. These data indicate that sodium selenite inhibits the formation of these lesions by the mucosal generation of prostaglandins. The concentrations of nonprotein sulfhydryls (NP-SH) were significantly decreased in the gastric mucosa following the administration of necrotizing agents--80% ethanol and 0.6 M HCl. Treatment with sodium selenite, which significantly reduced the intensity of gastric lesions, did not replenish the reduced levels of gastric mucosal NP-SH, thus ruling out the mediation of its protective effect through sulfhydryls. The antisecretory effect of sodium selenite, which becomes evident only in the high dose of 20 mumol/kg, may be responsible for the inhibition of gastric lesions induced by aspirin, indomethacin, reserpine, and dimaprit. Our findings show that selenium possesses significant anti-ulcer and adaptive cytoprotective effects. However, further detailed studies are required to confirm these effects, to establish its mechanism(s) of action, and to determine its role in the prophylaxis and treatment of peptic ulcer disease.

Topics: Administration, Oral; Animals; Aspirin; Cimetidine; Dimaprit; Ethanol; Female; Gastric Acid; Gastric Mucosa; Indomethacin; Male; Rats; Rats, Inbred Strains; Reserpine; Selenious Acid; Selenium; Stomach Ulcer; Thiourea

The gastric antisecretory and antiulcer effects of a novel compound, [1-(2,-dimethylphenyl)-3-isobutoxyamidinourea]hydrochloride (WHR1582A), are described. WHR1582A was active in preclinical ulcer models induced by 18-hr pylorus ligation, aspirin, indomethacin, reserpine, stress or cysteamine. WHR1582A inhibited acid secretion in the pylorus-ligated rat and in the anesthetized, lumen-perfused rat. The antisecretory effects of WHR1582A were antagonized by yohimbine, RX781094A and phentolamine. Propranolol, prazosin, corynanthine, methysergide, sulpiride and pimozide were unable to block its activity. WHR1582A blocked acid secretion stimulated by 2-deoxy-D-glucose but was inactive against the direct parietal cell stimulants carbachol and dimaprit. WHR1582A also inhibited electrically stimulated contractions that were mediated via the vagus in the isolated rat stomach preparation. The antisecretory activity of WHR1582A was not due to a reduction in gastric mucosal blood flow. These results demonstrate that WHR1582A is an effective antiulcer-antisecretory agent that exerts its gastric effects through the activation of alpha-2 adrenoceptors located presynapitcally on the vagus.

Topics: Adrenergic alpha-Agonists; Animals; Anti-Ulcer Agents; Aspirin; Carbachol; Clonidine; Cysteamine; Dimaprit; Gastric Acid; Gastric Mucosa; Indomethacin; Ligation; Male; Muscle Contraction; Norepinephrine; Phenylurea Compounds; Rats; Rats, Inbred Strains; Reserpine; Stomach Ulcer; Stress, Physiological; Thiourea; Yohimbine

The new H2-receptor antagonist mifentidine (DA 4577) was tested for its antisecretory and gastric motor effects in comparison with cimetidine and ranitidine. The Shay rat preparation (5 h) was used for studying gastric secretion; the gastric emptying of a liquid meal was chosen for studying gastric motility. All the three compounds inhibited acid secretion in a dose-dependent fashion. Calculated ED50s were 2.3, 12.2 and 92.8 mg X kg-1 for mifentidine, ranitidine and cimetidine, respectively. Therefore, in this animal model, mifentidine was about 40 times more potent than cimetidine and 5 times more potent than ranitidine. As far as gastric emptying is concerned, the effect of equiactive antisecretory doses (i.e. the respective ED50s calculated from the previously established dose-response curves) of all the three antagonists was completely different. Cimetidine delayed emptying rate, whereas ranitidine accelerated it and mifentidine was completely ineffective. However, at higher doses, also this compound affected emptying rate by reducing it dose-dependently. Gastric and duodenal ulcers were induced in the rat by dimaprit (100 mg X kg-1 intravenously) and cysteamine (250 mg X kg-1 subcutaneously), respectively. As far as gastric ulcer is concerned, the ED50s (the effective dose which protected 50% of the animals from lesions) were 0.23, 4.40 and 9.70 mg X kg-1 for mifentidine, ranitidine and cimetidine, respectively. As regards duodenal ulcer, the ED50 was 4.48 for mifentidine and 150.00 mg X kg-1 for ranitidine. In this animal model, the efficacy of cimetidine was very low. Therefore an ED50 could not be determined. In conclusion, results of the present investigation demonstrated that mifentidine is a potent antisecretory compound and an effective anti-ulcer agent in the rat.

Topics: Animals; Bethanechol; Bethanechol Compounds; Cimetidine; Cysteamine; Dimaprit; Duodenal Ulcer; Female; Gastric Juice; Gastrointestinal Motility; Histamine H2 Antagonists; Imidazoles; Male; Ranitidine; Rats; Stomach Ulcer; Thiourea

The dual effects of clonidine on gastric experimental damage have been studied in the rat. At lower doses, clonidine prevents gastric lesions induced by oxotremorine plus neostigmine, probably through an alpha 2-agonist mechanism; at higher doses, the compound potentiates dimaprit-induced gastric damage, probably through an H2-agonist mechanism.

Topics: Animals; Anti-Ulcer Agents; Atropine; Clonidine; Dimaprit; Female; Ranitidine; Rats; Rats, Inbred Strains; Receptors, Muscarinic; Stomach Ulcer; Thiourea

The protective effect of cimetidine, ranitidine and a newer H2-receptor antagonist, mifentidine (proposed INN), on models of gastric and duodenal damage, caused by activation of H2 receptors, was studied. Gastric erosions were induced in rats by intravenous dimaprit (100 mg/kg) while duodenal damage was investigated in guinea pigs following subcutaneous administration of dimaprit (2 mg/kg, 6 doses). All the compounds reduced or abolished gastric and duodenal damage in rats and guinea pigs, mifentidine being more potent than both cimetidine and ranitidine. The antiulcer effect of the H2-receptor antagonists was related to the dose and to their ability to inhibit dimaprit-induced gastric acid secretion. The duration of action proved to be different for the three compounds. According to the two dosing schedules adopted to evaluate the duration of action, mifentidine, compared to cimetidine and ranitidine, required considerably lower oral dosages to display its protective effect.

Topics: Animals; Cimetidine; Dimaprit; Disease Models, Animal; Duodenal Ulcer; Female; Guinea Pigs; Histamine H2 Antagonists; Imidazoles; Ranitidine; Rats; Rats, Inbred Strains; Receptors, Histamine H2; Stomach Ulcer; Thiourea

Four experiments were conducted to evaluate the effect of diet and the administration of H2-antagonists in feed on gastric ulcer formation and performance of growing-finishing swine. Pigs receiving a finely ground diet (less than lmm) grew faster (.73 vs .68 kg/d, P less than .01) and had better feed utilization (3.47 vs 3.76, P less than .01) than pigs receiving a cracked corn-based diet. Incidence of ulcers in the esophageal region of the stomach of pigs fed the finely ground diet was greater (P less than .01) than in pigs fed cracked corn. The average daily gain of pigs receiving the finely ground diet was inversely related to ulcer incidence (r = .403, P less than .01, df = 59). The addition of 5, 10, 20 or 100 ppm of the H2-antagonist, metiamide, or 6, 18 or 54 ppm of SK&F 93479 to the finely ground diet did not improve pig performance or affect the incidence of gastric ulceration. The addition of 2, 6 and 18 ppm of SK&F 93479 to a corn-soy diet containing 4.5% alfalfa meal caused a reduction in gastric ulceration (P less than .05) and improved feed utilization by 3.2% (P less than .05). These data suggest that finely ground diets improve the performance of growing-finishing swine, but increase the incidence of ulcers in the esophageal region of the stomach. Severe gastric ulceration adversely affects swine performance. Feeding H2-antagonists does not reduce the ulcerogenic properties of finely ground diets, suggesting factors other than gastric acid secretion are involved in ulcerogenesis. The use of H2-antagonists in corn-soy diets improves feed utilization and reduces ulceration.

Topics: Animal Feed; Animals; Disease Models, Animal; Female; Food Additives; Histamine H2 Antagonists; Male; Metiamide; Particle Size; Pyrimidinones; Stomach Ulcer; Swine; Swine Diseases; Thiourea

Although the factors involved in the induction of gastric pathology have long been studied, the exact roles of the two histamine receptors in this process are still obscure. The aim of this study was to evaluate the consequences of the activation of histamine H1- and/or H2-receptors in the pathogenesis of gastric damage and antagonism of these pathological developments by specific antagonists. The following agents were used: histamine as H1- and H2H2-agonist; 2-pyridylethylamine (PEA) and mepyramine as H1-agonist and antagonist; dimaprit and ranitidine as H2-agonist and antagonist. Intravenous administration of the agonists caused definite gastric damage in rats. Both the antagonists inhibited histamine-induced gastric lesions, but the PEA and dimaprit-induced erosions could be prevented only by giving the specific H1- or H2-antagonist. In conclusion, activation of either H1- or H2-receptors can play a crucial role in the pathogenesis of histamine-induced gastric damage in rats.

Topics: Aminopyridines; Animals; Atropine; Dimaprit; Drug Interactions; Female; Histamine; Pyridines; Pyrilamine; Ranitidine; Rats; Rats, Inbred Strains; Receptors, Histamine; Receptors, Histamine H1; Receptors, Histamine H2; Stomach Ulcer; Thiourea

In an effort to develop new types of antiulcer agents, we synthesized a series of novel 2-[omega-(thioureido)alkyl]- and 2-[omega-(cyanoguanidino)alkyl]-3(2H)-pyridazinone derivatives. All target compounds were evaluated for gastric antisecretory activity in the pylorus-lygated rat by the method of Shay, and selected compounds were evaluated in the stress-induced ulcer test in rats. Structure-activity relationships were established. Two series of the compounds had significant activity in antisecretory and/or antiulcer tests. The molecular features essential for the activities are a thiourea group or a 2-cyanoguanidine group, a phenyl group in the C-6 position of the 3(2H)-pyridazinone ring, a four-carbon chain length between the 3(2H)-pyridazinone ring and the functional group, and a methyl group at the N-3 position of the functional group. Among them, the three thiourea derivatives (24, 26, and 38) and the six 2-cyanoguanidine derivatives (61, 62, 65, 75, 85, and 86) had the most potent antisecretory and/or antiulcer activities. These compounds are not histamine H2-receptor antagonists.

Topics: Acetylcholine; Animals; Gastric Mucosa; Guanidines; Guinea Pigs; Ileum; Male; Pyridazines; Rats; Rats, Inbred Strains; Stomach Ulcer; Stress, Physiological; Structure-Activity Relationship; Thiourea

The effect of metiamide on reserpine-induced gastric ulcers and on gastric secretion during 6 h after ip administration was investigated in conscious intact rats and in rats with chronic gastric fistula. Reserpine, 3 mg/kg ip increased substantially the concentration of gastric acid in the first 4 h. Metiamide given every 3 h in a low dose (0.01 mumol/kg) intensified reserpine-induced gastric ulcers and also significantly increased the reserpine-induced acid concentration and output. In larger doses, (50-100 mumol/kg) metiamide considerably diminished gastric ulcer development and decreased gastric acid concentration. Given every 2 h metiamide in doses of 50-100 mumol/kg almost completely abolished gastric ulcer formation and markedly reduced the secretion of gastric acid in reserpinized rats. Anti-ulcer effect of metiamide was stronger than its antisecretory action, suggesting also the antiulcer action of metiamide other than inhibition of acid secretion. The results suggest that in conscious rats histamine H2-receptors are involved in reserpine-induced gastric ulcer development and gastric acid secretion. The antiulcer effect of metiamide may in part depend on its antisecretory action.

Topics: Animals; Gastric Acid; Male; Metiamide; Pepsin A; Rats; Rats, Inbred Strains; Receptors, Histamine; Receptors, Histamine H2; Reserpine; Stomach Ulcer; Thiourea; Time Factors

Histamine is known to induce gastric ulcers in guinea pigs after intraperitoneal administration and duodenal ulcers after repeated intramuscular administrations. This study was undertaken to clarify further the differential role of H1 and H2 receptor sites in respect to gastric and duodenal ulcer in the guinea pig. Groups of guinea pigs were treated with histamine, intraperitoneal (1.81 mg/kg intraperitoneal) or intramuscular (0.09 mg/kg intramuscular X 8 doses); the selective H2 agonist dimaprit (0.09-0.18 mg/kg X 8 doses intramuscular or 1.81-3.62 mg/kg intraperitoneal); NaCl, 154 mM (control); and the selective H1 and H2 antagonists, diphenhydramine (125 mg/kg X 2 doses, intramuscular) or cimetidine (50 mg/kg X 3 doses, intramuscular). Gastric and duodenal lesions were evaluated and residual gastric contents were analyzed. The selective induction of gastric or duodenal ulceration by histamine was confirmed, and the H2 agonist, dimaprit, has been shown to be ulcerogenic to the guinea pig duodenum by intraperitoneal or intramuscular administration. Diphenhydramine produced considerably more protection against histamine-induced gastric ulceration (62% decrease in incidence), while cimetidine was particularly effective in the prevention of histamine-induced duodenal ulcer (64% decrease in incidence). A differential role of histamine in the pathogenesis of gastric as opposed to duodenal ulcer is suggested by the present findings.

Topics: Animals; Cimetidine; Dimaprit; Diphenhydramine; Duodenal Ulcer; Guinea Pigs; Histamine; Histamine H1 Antagonists; Histamine H2 Antagonists; Injections, Intramuscular; Injections, Intraperitoneal; Male; Receptors, Histamine H1; Receptors, Histamine H2; Stomach Ulcer; Thiourea

Mild stress of restraint for 10 min at an ambient temperature of 18 degrees C increased serum corticosterone levels in rats considerably. Histamine given intravenously prior to restraint alone significantly further intensified the stress-induced elevation of serum corticosterone. Dimaprit and cimetidine failed to modify corticosterone responses to the mild stress. Severe stress of restraint and cold of 3 h duration increased serum corticosterone and free fatty acid levels considerably. Histamine given prior to stress exposure left the corticosterone and hyperlipaemic responses to severe stress unchanged. Dimaprit inhibited and cimetidine intensified the stress-induced hyperlipaemia. The most striking finding in the present experiment was a powerful inhibition of gastric stress ulcer generation by intraventricularly administered histamine. Dimaprit was similarly effective. This strong anti-ulcer effect of histamine was abolished by intraventricular pretreatment of rats with either H1- or H2-receptor antagonists, chloropyramine or cimetidine. The results may suggest that in the rat a mild stress does not fully activate central histaminergic pathways involved in corticosterone responses. During severe stress histamine considerably prevents gastric ulcer generation and both H1- and H2-receptors mediate this action of histamine.

Topics: Animals; Brain; Corticosterone; Dimaprit; Fatty Acids, Nonesterified; Histamine H1 Antagonists; Histamine H2 Antagonists; Immobilization; Male; Rats; Receptors, Histamine; Stomach Ulcer; Stress, Physiological; Thiourea

The ability of two types of gastric acid inhibitor to reverse established gastric mucosal barrier damage was studied in canine Heidenhain pouches. A model of established barrier damage was prepared and validated by perfusing Heidenhain pouches with an acid saline solution containing 20 mmoles of aspirin for 2 hours (damage period) and then perfusing with acid saline alone for a third hour (recovery period). Increases in gastric mucosal permeability to H+ and Na+ produced in the damage period still were present and were significant in the recovery period. In subsequent experiments the effect of topically applied prostaglandin E2 and 15-methyl prostaglandin E2 and intravenously administered prostaglandin E2, 15-methyl prostaglandin E2, and Metiamide on the recovery period permeability was studied. Topical application of the prostaglandins and intravenous Metiamide had no effect on the increased permeability. Intravenously administered prostaglandins returned the permeability to normal and therefore reversed established barrier damage. This effect may have important therapeutic implications in acute gastric mucosal lesions.

Topics: Administration, Topical; Animals; Aspirin; Cell Membrane Permeability; Disease Models, Animal; Dogs; Female; Gastric Juice; Gastric Mucosa; Histamine; Injections, Intravenous; Metiamide; Prostaglandins E, Synthetic; Regression Analysis; Secretory Rate; Stimulation, Chemical; Stomach Ulcer; Thiourea

Topics: Animals; Bile Acids and Salts; Dogs; Gastric Mucosa; Ischemia; Metiamide; Stomach Ulcer; Thiourea

Stress produced severe mucosal ulcers, increased mucosal microcirculation and lowered mast cell counts in the glandular wall of rat stomachs. Mepyramine i.m. or metiamide i.p. effectively prevented both ulceration and microcirculatory changes but not stress-reduced mast cell counts.

Topics: Aminopyridines; Animals; Dose-Response Relationship, Drug; Gastric Mucosa; Humans; Male; Mast Cells; Metiamide; Microcirculation; Pyrilamine; Rats; Receptors, Histamine; Stomach Ulcer; Stress, Psychological; Thiourea

Topics: Animals; Feeding Behavior; Food Deprivation; Male; Metiamide; Rats; Stomach Ulcer; Thiourea; Time Factors; Water Deprivation

In rats under either mild stress (= controls) or severe stress (= restraint) gastric secretion (acid; pepsin, volume), mucosal blood flow, serum gastrin and ulcer formation were evaluated without and with additional infusion of a low dose (0.25 mg/kg.h) metiamide over an 8 h experimental period. Calculated constants of dose-response characteristics for acid output in this species are: Km = 1.41 +/- 0.36 mg/kg.h; Vmax = 94.4 +/- 11.0 per cent. Restraint depresses markedly secretion and microcirculation, but stimulates ulcer formation and raises serum gastrin. In controls, metiamide inhibits secretion and ulcer index significantly, but leaves mucosal blood flow and gastrin unaltered. In contrast, with restraint and metiamide, ulcer index was not improved, whereas mucosal blood flow was restored to almost control levels. Therefore, H2-receptor blockers, in addition to inhibition of secretion, may interfere with microcirculation either directly or by secondary release of yet unknown mediator substance(s), depending on the prevailing tissue environment.

Topics: Acids; Animals; Dose-Response Relationship, Drug; Gastric Mucosa; Male; Metiamide; Pepsin A; Rats; Regional Blood Flow; Restraint, Physical; Stomach Ulcer; Thiourea

Restrain stress in rats inhibits gastric secretion and microcirculation. Secretion is further inhibited by metiamide, but mucosal blood flow is restored to normal. During stress the ulcer incidence is high, lower with prophylactic administration of metiamide and least with the latter and preserved gastroduodenal acid transit. No therapeutic metiamide effect can be detected.

Topics: Aminopyrine; Animals; Gastric Juice; Gastric Mucosa; Male; Metiamide; Microcirculation; Pepsin A; Rats; Receptors, Histamine; Receptors, Histamine H2; Restraint, Physical; Stomach Ulcer; Stress, Physiological; Thiourea

A series of thioureas derived from 5,6,7,8-tetrahydroquinoline, 1,5-, 1,6-, and 1,8-naphthyridiness, pyrido[2,3-b]azepine, and 7-azaindoline has been prepared and tested for antisecretory activity in the pylorus-ligated rat and protective activity against gastric erosions caused by cold-restraint stress. The thioureas exhibit different structure-activity relationships from the corresponding 5,6,7,8-tetrahydroquinoline-8-thiocarboxamides and these relationships are discussed. The activity of the thioureas is less affected by structural differences than the corresponding thioamides although they probably have the same mode of action.

Topics: Animals; Anti-Ulcer Agents; Gastric Juice; Gastric Mucosa; Male; Quinolines; Rats; Stomach Ulcer; Structure-Activity Relationship; Thiourea

Prevention of acute gastric erosions with histamine H2-receptor blocking agents suggests that these drugs may improve the ability of the gastric mucosa to maintain electrical, ionic, and protein concentration gradients. In 5 awake mongrel dogs, transmural potential difference, ion fluxes, and protein loss were measured across Heidenhain pouches topically exposed to isotonic solutions containing either 80 mM HCl or 80 mM HCl plus 20 mM sodium taurocholate (BS). The dogs received an intravenous infusion of either saline (as a control) or the H2 antagonist metiamide, 10 mumoles per kg-hr. Metiamide increased the H+ clearance rate found after acid test solution exposure but had no significant effect on potential difference or ion fluxes. H2 antagonism decreased the protein loss but not the increase in cation permeability due to BS. Net H+ loss actually increased, which, along with a decrease in Cl- gain, suggests inhibition of acid secretion by metiamide in BS-exposed gastric mucosa. These effects of metiamide point to histamine as a likely mediator of the gastric mucosal damage due to BS.

Topics: Animals; Cell Membrane Permeability; Dogs; Gastric Acidity Determination; Gastric Mucosa; Hydrochloric Acid; Metiamide; Potassium; Sodium; Stomach Ulcer; Taurocholic Acid; Thiourea

Topics: Histamine H1 Antagonists; Humans; Metiamide; Stomach Ulcer; Thiourea

Topics: Antacids; Drug Evaluation; Guanidines; Humans; Imidazoles; Metiamide; Stomach Ulcer; Thiourea

Because of evidence that Metiamide, an H2-receptor antagonist, strongly inhibits gastric acid secretion, the present study was designed to test the hypothesis that Metiamide will prevent bile salt-induced stress ulcers during hemorrhagic shock. Forty dogs were bled and maintained for 4 1/2 hr at a mean blood pressure of 40 to 50 mm Hg. In group A, 10 dogs received 300 mg of Metiamide orally 45 min before bleeding and 10 dogs received normal saline. The pylorus was occluded before bleeding and 100 ml of 15 mM bile salt were instilled into the stomach and aspirated at the end of 4 1/2 hr. At the time the animal was killed after 48 hr, no ulcers were seen in the stomachs of dogs treated with Metiamide. Sixty per cent of the dogs in the untreated group developed multiple gross ulcers. In group B the effect of Metiamide on the disappearance rate of H+ ion was measured by instillation of 50 mM HCl + 15 mM bile acid. No difference was noted in the rate of H+ ion disappearance between Metiamide-treated and control dogs. Also, in 5 normotensive dogs the rate of H+ ion disappearance was measured before and after treatment with Metiamide, and the loss of H+ was identical for both periods. Metiamide was effective in preventing stress ulcer in this experimental model. The protective effect of Metiamide is probably due to its inhibitory effect of H+ ion secretion.

Topics: Administration, Oral; Animals; Dogs; Gastric Acidity Determination; Gastric Juice; Gastric Mucosa; Humans; Infusions, Parenteral; Metiamide; Shock, Hemorrhagic; Stomach Ulcer; Stress, Psychological; Thiourea

Topics: Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Gastric Juice; Gastric Mucosa; Ischemia; Male; Metiamide; Pepsinogens; Rats; Stomach Ulcer; Stress, Physiological; Thiourea

This study has examined the inhibition produced by metiamide on the gastric secretion of acid and pepsin in 13 patients with duodenal and three with gastric ulcer. The effect of metiamide on the response to a range of doses of pentagastrin in three normal individuals was determined, as was the interaction of metiamide and atropine on prolonged basal secretion. Metiamide inhibited the secretion of acid more than pepsin and the gastric secretion of patients with gastric ulcer more than duodenal ulcer. Metiamide inhibited both the maximal secretory response attainable with pentagastrin and decreased the sensitivity to pentagastrin. Atropine augmented and prolonged the action of metiamide.

Topics: Atropine; Dose-Response Relationship, Drug; Drug Synergism; Duodenal Ulcer; Gastric Juice; Humans; Metiamide; Pentagastrin; Pepsin A; Secretory Rate; Stomach; Stomach Ulcer; Thiourea

Metiamide was given to patients with peptic ulcer or oesophagitis in a pilot study to establish the therapeutic value of the drug. Administration of metiamide resulted in relief of pain within a week in the majority of patients. Healing of duodenal and gastric ulcers was observed.

Topics: Duodenal Ulcer; Esophagitis; Gastric Acidity Determination; Gastric Juice; Humans; Metiamide; Nausea; Pain; Pancreatitis; Secretory Rate; Stimulation, Chemical; Stomach Ulcer; Thiourea; Time Factors

Forty rats were housed in standard activity wheel cages and fed for only 1 hr per day. The animals were equally divided into 4 groups that received either saline, 12.5 mg/kg, 25.0 mg/kg or 50.0 mg/kg of metiamide, an H2 receptor antagonist, 3 times a day. All animals died within 11 days and all demonstrated significant gastric lesions in the glandular fundus of the stomach. The 50.0 mg/kg dosage group, however, demonstrated significantly fewer ulcers than the saline animals and the lesions that did occur were significantly smaller than those noted in the control animals. Several hypotheses were offered to explain these results which took into account metiamide's effects on gastric secretion and motor activity. It was suggested that secretion of acid may be an important contributing factor in the formation of gastric ulcers in animals subjected to the "activity-stress" procedure.

Topics: Animals; Disease Models, Animal; Food Deprivation; Gastric Juice; Male; Metiamide; Rats; Stomach Ulcer; Stress, Physiological; Thiourea

Topics: Animals; Dogs; Gastric Juice; Metiamide; Shock, Hemorrhagic; Stomach Ulcer; Stress, Physiological; Thiourea

Topics: Binding, Competitive; Gastric Juice; Histamine; Histamine H1 Antagonists; Humans; Imidazoles; Parasympatholytics; Receptors, Drug; Stomach; Stomach Ulcer; Sulfides; Thiourea

Metiamide, an antagonist of histamine H(2) receptors, was administered intravenously to normal subjects and to patients with a peptic ulcer during vagal stimulation with a constant infusion of insulin. In normal and peptic-ulcer subjects there were reductions of 70% and 71% respectively in gastric-acid output compared with control tests on the same subjects. The decreased acid output resulted from a reduction in both volume of secretion and acid concentration. Metiamide is therefore a potent inhibitor of vagally-induced gastric acid secretion.

Topics: Adult; Blood Glucose; Depression, Chemical; Duodenal Ulcer; Female; Gastric Juice; Histamine H1 Antagonists; Humans; Imidazoles; Male; Middle Aged; Receptors, Drug; Secretory Rate; Stomach Ulcer; Sulfides; Thiourea; Vagus Nerve