Effects of 5-acetylspiro[benzofuran-2(3H),1'-cyclopropan]-3-one, a new anti-ulcer agent, on experimental acute and chronic ulcers

The effects of 5-acetylspiro[benzofuran-2(3H),1'-cyclopropan]-3-one (AG 629), a newly synthesized compound, on various experimentally induced ulcers were investigated. Oral or intraduodenal administration of AG 629 in a dose range of 25-100 mg/kg inhibited water-immersion stress ulcer, exertion ulcer, Shay ulcer, indometacin- and acetylsalicylic acid (ASA)-induced gastric ulcer, and indomethacin-induced small intestinal ulcer in rats, histamine-induced gastric ulcer in guinea pigs, and ASA-induced gastric ulcer in dogs, though it was not effective against cysteamine-induced duodenal ulcer in rats. AG 629 in doses of 6.3-25 mg/kg p.o. twice a day significantly promoted the healing of acetic acid- or thermal-cortisone-induced gastric ulcers and acetic acid-induced duodenal ulcers in rats. AG 629 (25-100 mg/kg i.d.) inhibited the secretion of gastric acid and pepsin in pylorus-ligated rats and the acid secretion stimulated by distension of the rat stomach with air, whereas this compound did not affect acid secretion stimulated by histamine, pentagastrin, carbachol or 2-deoxy-D-glucose. This study shows that AG 629 has both prophylactic and curative effects on various ulcers. The anti-ulcer effect of this agent seems to be mediated primarily by increasing mucosal resistance and secondarily by an antisecretory activity.     

Effects of 4-(4-bromophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride on acute gastric lesions, acid secretion in rats and on some hemodynamic parameters in cats

The effectiveness of 4-(4-bromophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (AN12) on acute ulcer models and gastric acid secretion in rats was compared with the action of the histamine H2-receptor antagonist roxatidine (R). AN12 or R given orally, produced significant, dose-dependent decreases in stress- and indomethacin-induced ulcers. The ED50 value of AN12 and R were 0.40 (0.27-0.60) and 13.27 (9.13-19.29) mg/kg, respectively, for stress ulcers and 0.68 (0.17-2.61) and 25 mg/kg, respectively, for indomethacin ulcers. The length and number of ethanol-provoked gastric damages were significantly reduced by R (50 and 100 mg/kg p.o.) but not by AN12 (0.5-2 mg/kg p.o.). In pylorus-ligated rats, AN12 (2 mg/kg p.o.) and R (50 and 100 mg/kg p.o.) significantly inhibited basal gastric acid secretion, increased pH and decreased acidity. The influence of AN12 (2 mg/kg) on the volume of stomach juice was close to that of R (100 mg/kg), AN12 (0.1-1.0 mg/kg i.v.) did not significantly affect the hemodynamics of anesthesized cats. It is suggested that the influence of some CNS amine neurotransmitters may be included in part, in the effects of AN12.     

Effect of OPC-12759, a novel antiulcer agent, on chronic and acute experimental gastric ulcer, and gastric secretion in rats

The antiulcer effects of OPC-12759, a novel antiulcer agent were compared with those of cetraxate in various experimental ulcer models and on gastric secretion in rats. OPC-12759 (0.3-30 mg/kg, b.i.d., p.o.) significantly accelerated the healing rate of acetic acid-induced gastric ulcer in a dose-dependent manner, while cetraxate did not. When administered orally at 0.3-30 mg/kg, b.i.d., for 7 days, pretreatment with OPC-12759 (0.3-30 mg/kg, b.i.d., p.o.) prevented the formation of acute gastric ulcers, induced by: restraint water immersion stress, aspirin, indomethacin, histamine, serotonin, platelet activating factor (PAF) and DDC. Cetraxate showed antiulcer activity against a part of the OPC-12759-positive gastric ulcer models. Given intraperitoneally at the single dosing range of 10-100 mg/kg, OPC-12759 inhibited the formation of these acute gastric ulcer models. OPC-12759 administered orally at 0.3-30 mg/kg, b.i.d., for 7 days did not inhibit basal gastric secretion in pylorus ligated rats. The results indicated that OPC-12759 possesses wide spectrum antiulcer activity as compared with cetraxate.     

脑室注射催产素对大鼠胃和十二指肠溃疡的作用

INTRODUCTION Central neurons that synthesize oxytocin are locatedin the supraoptic(SON) and paraventricular nuclei(PVN) of the hypothalamus. Magnocellular neurons inboth nuclei project to the posterior pituitary gland,     

Effects of KT1-32 on acute gastric lesions and duodenal ulcers induced in rats

We studied the effects of KT1-32 (sodium guaiazulene 3-sulfonate) on development of various acute gastric lesions and duodenal ulcers induced in rats. Male Donryu or Sprague-Dawley rats (220-270 g), fasted (but allowed free access to water) for 24 or 48 hr before the experiments, were used. KT1-32 (dissolved in distilled water, 10-100 mg/kg), given p.o. or intraduodenally (i.d.), dose-dependently inhibited the development of gastric lesions induced by HCl X ethanol (60% ethanol in 150 mM HCl), HCl X aspirin (aspirin 100 mg/kg in 150 mM HCl) or aspirin (150 mg/kg in pylorus-ligated preparation) and Shay ulcers (14 hr pylorus ligation). KT1-32 (30 and 100 mg/kg), given p.o. twice (9.5 hr apart), significantly inhibited the development of duodenal ulcers induced by mepirizole (200 mg/kg, s.c.), but did not inhibit gastric lesions developed simultaneously. KT1-32 (30 and 100 mg/kg), given p.o. or i.d., significantly reduced gastric acid secretion when examined using pylorus ligation preparations. KT1-32 (100 mg/kg, i.d.) had no effect on basal and suppressed duodenal HCO3- secretion by mepirizole. These results suggest that KT1-32 is a promising drug for the treatment of gastritis and peptic ulcers.     

Anti-ulcer effect of tea catechin in rats

Oral administration of tea catechin dose-dependently prevented absolute ethanol-induced (50, 100, 200 mg/kg) or restraint plus water immersion stress-induced acute gastric mucosal injury (300, 400 mg/kg) in rats. When the effect of test compound was evaluated on the 15th day after acetic acid injection to rats, repeated oral administration of tea catechin (25, 50, 100 mg/kg twice daily) dose-dependently accelerated the healing of acetic acid-induced chronic gastric ulcers. Tea catechin (10(-5)-10(-1) g/100 ml) concentration-dependently scavenged superoxide anions in vitro. Tea catechin (100, 200 mg/kg orally) markedly inhibited the increase in thiobarbituric acid-reactive substances in the injured mucosa of rats treated with 50% ethanol. Tea catechin (50, 100 mg/kg twice orally, daily) markedly inhibited the increase in content of thiobarbituric acid-reactive substances in the ulcerated region of acetic acid-induced gastric ulcers on the 7th and 15th days. In addition, at 50, 100 and 200 mg/kg orally, it dose-dependently prevented the decrease in gastric mucosal hexosamine content induced by absolute ethanol, although it failed to inhibit the basal gastric acid secretion. These results suggest that tea catechin may primarily protect gastric mucosa from acute gastric mucosal injury and promote the healing of chronic gastric ulcers by its antioxidant activity and gastric mucus-increasing actions.     

Anti-ulcer effect of 3-[p-(trans-4-aminomethylcyclohexylcarbonyl) phenyl] propionic acid hydrochloride (TEI-5103)

The anti-ulcer effects of the newly synthesized compound 3-[p-(trans-4-aminomethylcyclohexylcarbonyl)-phenyl]propionic acid hydrochloride (TEI-5103) on experimentally induced ulcers in rats were studied. TEI-5103 at doses of 25 to 400 mg/kg p.o. prevented formation of ulcers induced by serotonin, indomethacin, acetylsalicylic acid or stress (acute ulcer models), its effect being greater against gastric ulcers induced by serotonin. On acetic acid ulcer (chronic ulcer model), TEI-5103 at a daily dose of 200 mg/kg p.o. accelerated the healing of ulcers. TEI-5103 at doses of 100 to 400 mg/kg i.d. did not inhibit gastric acid secretion in pylorus-ligated rats. It markedly increased gastric blood flow in anesthetized rats (at 10-20 mg/kg i.v., measured by the aminopyrine clearance method), and also increased gastric blood flow in anesthetized dogs (at 2.5-10 mg/kg i.v., measured by the cross thermocouple method). These results indicate that TEI-5103 is effective as an anti-ulcer agent increasing gastric mucosal blood flow and possibly promoting the healing process of peptic ulcers.     

Antiulcer activity of the calcium antagonist propyl-methylenedioxyindene--II. Effects on acid secretion and gastric emptying in rats

1. Propyl-methylenedioxyindene (pr-MDI) is an intracellularly acting calcium antagonist which protects against cold/restraint-induced stress ulcers in rats. The doses of pr-MDI which produce antiulcer activity (10-30 mg/kg i.p.) are significantly lower than those which exhibit cardiovascular effects. 2. Two potential mechanisms for the antiulcer action of pr-MDI were investigated in this study: the effects on hydrochloric acid secretion and on gastric motility (gastric emptying). 3. Bethanechol-induced hydrochloric acid secretion in acutely pylorus-ligated rats was significantly obtunded by pr-MDI (30 mg/kg i.p.), but the effect was significantly weaker than that produced by verapamil (16 mg/kg i.p.) or cimetidine (10 mg/kg i.p.). Since 30 mg/kg pr-MDI produces greater antiulcer activity than the very high dose of 16 mg/kg verapamil, it is unlikely that inhibition of acid secretion plays more than a contributory role in the antiulcer mechanism of action of pr-MDI. 4. pr-MDI (10-30 mg/kg i.p.) produced a dose-dependent slowing of gastric emptying in rats fed a methylcellulose/Phenol Red test meal, and this effect correlated well with the antiulcer action. Verapamil (16 mg/kg i.p.) did not affect gastric emptying. 5. The results indicate that a reduction of gastric motility plays a major role in the mechanism of the antiulcer action of pr-MDI.     

Effects of MCI-727, a new antiulcer agent, on various gastric and duodenal lesions in experimental animals

Effects of a new antiulcer drug, MCI-727, on gastric and duodenal lesions, gastric secretion and gastric motility were studied in comparison with cimetidine and teprenone. MCI-727 dose-dependently (3-100 mg/kg, p.o. or i.d.) inhibited the development of acute gastric or duodenal lesions such as pyrolus ligation-, water-immersion stress-, indomethacin-, HCl-, HCl-ethanol-induced gastric lesions and cysteamine-induced duodenal lesions in rats and histamine-induced duodenal lesions in guinea pigs. These antiulcer effects exceeded those of cimetidine or teprenone. Repeated administration of MCI-727 (0.3-3 mg/kg/day, p.o., for 10 days) significantly promoted the spontaneous healing of acetic acid-induced chronic gastric ulcers. Concerning gastric acid secretion, MCI-727 selectively inhibited tetragastrin-stimulated acid secretion without effecting basal acid secretion and acid secretion by other stimuli. Cimetidine and teprenone inhibited acid secretion in several cases. MCI-727 and teprenone had inhibitory effects on gastric motility, although cimetidine had no effect. These results suggest that MCI-727 has a wide spectrum of antiulcer activity, and its mode of antiulcer action is different from that of cimetidine or teprenone.     

Effects of 15(R)-15-methyl prostaglandin E2 (arbaprostil) on gastric secretion and various gastric lesions induced in rats

We studied the effects of 15(R)-15-methyl prostaglandin E2 (arbaprostil) on gastric secretion and various acute and chronic gastric lesions produced in rats. Arbaprostil significantly inhibited gastric secretion in 4 hr-pylorus-ligated preparations when given intraduodenally in a dose of 30 or 100 micrograms/kg. The agent, however, significantly stimulated gastric secretion of rats with either a ligated or intact pylorus when given orally in doses of 3-100 micrograms/kg. Orally administered arbaprostil dose-dependently prevented the development of HCI-ethanol-, histamine-, water-immersion stress-, or indomethacin-induced gastric erosions. Intraduodenally administered arbaprostil also dose-dependently prevented the development of aspirin-induced gastric erosions in pylorus-ligated rats. Arbaprostil, given orally in doses of 1-100 micrograms/kg twice daily for 2 weeks, had little or no effect on the healing of acetic acid-induced gastric ulcers. However, oral administration of the agent in a dose of 3 or 10 micrograms/kg twice daily for 4 weeks significantly accelerated the healing of acetic acid-induced gastric ulcers. The increase in doses up to 100 micrograms/kg twice daily for 4 weeks had no effect on ulcer healing. These results indicate that arbaprostil, at either antisecretory or even acid stimulating doses, is effective in preventing the development of acute gastric erosions and in accelerating the healing of chronic gastric ulcers.     

Effects of a proton pump inhibitor, AG-1749 (lansoprazole), on reflux esophagitis and experimental ulcers in rats

The effects of (+/-)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy-2- pyridyl]methyl]sulfinyl]-1H-benzimidazole (lansoprazole, AG-1749) and famotidine on various experimental ulcers in rats were compared. AG-1749 inhibited reflux esophagitis; gastric lesions induced by water-immersion stress, aspirin or ethanol; and duodenal ulcers induced by cysteamine or mepirizole in a dose-dependent manner: the ID50 values were 0.7, 2.4, 0.7, 8.5, 1.1 and 0.3 mg/kg, p.o. or i.d., respectively. Famotidine inhibited reflux esophagitis with an ID50 value of 12.9 mg/kg, but did not cause 50% inhibition of ethanol-induced gastric lesions even at 100 mg/kg, although it showed almost the same or a little stronger potency on other experimental ulcers: ID50 values were 0.3-1.4 mg/kg. Significant aggravation of ethanol- or water-immersion stress-induced lesions was observed in rats given famotidine at 30 mg/kg twice daily for 4 days, but not in rats given AG-1749 at 10 mg/kg twice daily. Administration of AG-1749 for 14 consecutive days markedly accelerated the healing of acetic acid-induced gastric and duodenal ulcers, and the healing effect was significant at 10 and 30 mg/kg/day, p.o. Famotidine also accelerated the healing of ulcers, but its potency was less than that of AG-1749. The results of this study indicate that although AG-1749 is slightly less potent than famotidine in inhibiting acutely induced gastroduodenal lesions, this agent is superior to famotidine in promoting the healing of ulcers and in inhibiting reflux esophagitis and ethanol-induced gastric lesions.     

Effects of the new anti-ulcer agent KB-5492 on experimental gastric mucosal lesions and gastric mucosal defensive factors, as compared to those of teprenone and cimetidine.

Effects of KB-5492, a new anti-ulcer agent, on various experimental gastric mucosal lesions and mucosal defensive factors in rats were compared with those of teprenone and cimetidine. KB-5492 administered orally at 12.5-200 mg/kg inhibited water-immersion stress- and indomethacin-induced gastric mucosal lesions in a dose-dependent manner with ED50 values of 46 and 27 mg/kg, respectively, indicating that KB-5492 was more potent than teprenone but less potent than cimetidine. KB-5492, administered orally at 12.5-100 mg/kg, also inhibited ethanol-induced gastric mucosal lesions in a dose-dependent manner with an ED50 of 23 mg/kg, so KB-5492 was 3 times more potent than teprenone, whereas cimetidine produced no obvious inhibition. In addition, KB-5492, administered orally at 25 and 50 mg/kg twice daily for 10 consecutive days, significantly accelerated the healing of acetic acid-induced gastric ulcers more potently than teprenone and cimetidine. KB-5492 at anti-ulcer doses significantly increased gastric mucosal blood flow in normal anesthetized rats and inhibited the reduction of gastric mucosal hexosamine content induced by aspirin, but did not affect gastric acid secretion in pylorus-ligated rats. These results indicate that KB-5492 has potent and broad anti-ulcer properties, which are probably exerted by its enhancement of gastric mucosal defensive factors through increasing gastric mucosal blood flow and/or retaining gastric mucus, and not by its inhibition of gastric acid secretion.     

Influence of a muscle relaxant, tizanidine, on gastric acid secretion and gastric ulcer in rats

Effects of tizanidine, a centrally acting muscle relaxant, on gastric acid secretion and gastric ulcers were studied in the rat. Tizanidine (5 mg/kg, s.c.) did not influence basal acid secretion, but inhibited the centrally stimulated acid secretion in anesthetized rats. Intraduodenal administration of tizanidine (10 mg/kg) also inhibited the centrally stimulated acid secretion. The compound potentiated bethanechol-induced acid secretion at 10 mg/kg, s.c. Clonidine was found to have similar effects to tizanidine at the lower dose. Both tizanidine and clonidine inhibited basal acid secretion at a relatively low dose in conscious rats. Tizanidine (5 mg/kg, s.c.) did not modify indomethacin- and stress-induced ulcers, but Shay ulcers were slightly inhibited by the drug. Indomethacin ulcers were significantly inhibited by 10 mg/kg, s.c., 10 mg/kg, p.o. or 20 mg/kg, p.o. of tizanidine. Clonidine also was found to be a strong inhibitory agent of indomethacin-, stress- and Shay-ulcers. These results suggest that similar to clonidine, a high dosage of tizanidine influences gastric acid secretion and gastric ulcers, although the activity is lower than that of clonidine.     

Effects of misoprostol, (+/-)-methyl (11 alpha, 13E)-11, 16-dihydroxy-16-methyl-9-oxoprost-13-en-l-oate, on various gastric and duodenal lesions in rats

Male Sprague-Dawley rats (230-280 g), either fasted for 15-24 hr or non-fasted prior to experiments, were used. Misoprostol (3-100 micrograms/kg, p.o.) dose-dependently inhibited the development of 150 mM HCl X aspirin (100 mg/kg)-, 150 mM HCl X 60% ethanol-, and aspirin (150 mg/kg)-induced gastric lesions. Misoprostol (30, 100 micrograms/kg, p.o.), given twice daily for 4 days, significantly inhibited prednisolone (50 mg/kg given once daily for 4 days)-induced gastric lesions. Misoprostol (30 or 2 X 300 micrograms/kg, p.o.) also significantly inhibited water-immersion stress (21 degrees C, 10 hr)-induced gastric lesions or mepirizole (200 mg/kg)-induced duodenal lesions, respectively. In contrast, misoprostol (30-300 micrograms/kg, p.o.) had no effects on indomethacin (25 mg/kg)- and mepirizole (200 mg/kg)-induced gastric lesions. Misoprostol (30 micrograms/kg, p.o.) had no effect on gastric secretion in pylorus-ligated preparations (4 hr), but it (100 or 300 micrograms/kg, p.o.) significantly increased the volume and pepsin output. Gastric motility, either normal or enhanced with indomethacin (25 mg/kg), was inhibited by misoprostol (30 or 300 micrograms/kg, p.o.). Misoprostol (30 micrograms/kg, i.d.) significantly stimulated duodenal HCO3- secretion. Mechanisms by which misoprostol inhibits various gastric lesions remain unknown. However, the stimulatory activity on duodenal HCO3- secretion appears to be involved in the preventive effect of misoprostol on the development of duodenal lesions. The effects of cimetidine and 16,16-dimethyl PGE2 were also studied and compared with those of misoprostol.     

Effects of IT-066, a new histamine H2-receptor antagonist, on gastric acid secretion and experimental gastric ulcers in rats and dogs

We examined the effects of a new histamine H2-receptor antagonist, 3-amino-4-(4-[4-(1-piperidinomethyl)-2-pyridyloxy]-cis-2- butenylamino)-3- cyclobutene-1,2-dione hydrochloride (IT-066), on gastric acid secretion and the healing process of experimental ulcers in rats and dogs. Famotidine, a well-established H2-receptor antagonist, was used as the reference drug. Male Donryu rats (240-260 g) and Beagle dogs of both sexes (8-10 kg), having Heidenhain pouches, were used. IT-066 dose-dependently inhibited the basal gastric acid secretion of rats, and this inhibition significantly persisted for 12 hr. In addition, the agent significantly inhibited histamine-stimulated acid secretion in both normal rats and rats with acetic acid ulcers. IT-066, given p.o. twice daily for 2 and 3 weeks after ulceration, significantly accelerated both spontaneous and delayed healing (with indomethacin) of acetic acid-induced gastric ulcers in rats. The effects of IT-066 on acid secretion and ulcer healing were almost the same or slightly more potent than those observed with famotidine. IT-066, when given i.v. or p.o., dose-dependently inhibited the gastric acid secretion stimulated by histamine, pentagastrin, or carbachol in dogs. The antisecretory effects of the agent on histamine-stimulated acid secretion significantly persisted for more than 6 hr. These results indicate that IT-066 appears to be a promising antisecretory and anti-ulcer agent.     

Effects of 12-sulfodehydroabietic acid monosodium salt (TA-2711), a new anti-ulcer agent, on gastric secretion and experimental ulcers in rats

Effects of 12-sulfodehydroabietic acid monosodium salt (TA-2711), a new anti-ulcer agent, on gastric secretion and experimental ulcers were investigated in rats. Oral administration of TA-2711 at doses of 25 to 100 mg/kg immediately after pyloric ligation markedly reduced pepsin activity and slightly lowered acid concentration without affecting the volume of gastric juice. Addition of TA-2711 (0.25-16 mg/ml) directly to gastric juice also reduced pepsin activity in vitro. Oral TA-2711 dose-relatedly inhibited the formation of pylorus-ligated ulcers (50-200 mg/kg), aspirin-induced gastric erosions (25-100 mg/kg) and cysteamine-induced duodenal ulcers (100-800 mg/kg). In addition, this drug prevented both the formation of gastric lesions (6.3-100 mg/kg, p.o.) and the fall in gastric potential difference (100 mg/kg, p.o.) induced by ethanol. The preventive effect against ethanol-induced lesions was suppressed by pretreatment with indomethacin (10 mg/kg, s.c.). Intravenous dosing of TA-2711 (10-100 mg/kg) never produced such effects on ethanol-induced lesions and pepsin activity as observed by oral administration. These results indicate that TA-2711 exerts its anti-ulcer effect by a local action, and it is suggested that both reduction of pepsin activity and a mucosal prostaglandin-mediated process are involved in the anti-ulcer action of TA-2711.     

Preventive and curative effects of curcumin on the development of gastric inflammatory diseases in rats

Preventive and curative effects of curcumin on experimental acute and chronic gastric ulcers were investigated to validate its clinical application on a remedy for peptic ulcer. Intraduodenal administration of curcumin, 5–20 mg/kg, inhibited gastric acid secretion in pylorus-ligated rats, and oral administration prevented ethanol-induced acute gastric mucosal lesions. Curcumin (20–80 mg/kg, p.o.) dose-dependently prevented both serotonin-induced gastric mucosal lesions and compound 48/80-induced gastric mucosal lesions in rats. Furthermore, oral administration of curcumin, 10–80 mg/kg, twice daily for 10 days, significantly accelerated the healing of acetic acid-induced chronic gastric ulcer and promoted mucosal regeneration in the ulcerated portion in a dose-related manner. Cimetidine prevented the formation of ethanol-induced gastric mucosal lesions, but not of serotonin-induced and compound 48/80-induced gastric mucosal lesions. Consecutive administration of cimetidine showed a marked acceleration in the healing of acetic acid-induced ulcer. Aminoguanidine, an inducible nitric oxide synthase (iNOS) inhibitor, showed anti-ulcerogenic effects similar to those oberved for curcumin. The present results indicate that curcumin exhibits gastric cytoprotection in the acute lesion models and ulcer healing promotion in the chronic ulcer model. The preventive and curative effects of curcumin might be due to an increase in the mucosal defensive mechanism through its antioxidant property and inhibition of NO or cytokine-mediated inflammation.     

Effects of a new histamine H2-receptor antagonist, ranitidine, on experimental acute gastric and duodenal ulcers (author's transl)

Ranitidine at 100 to 200 mg/kg (i.d. or p.o.) potently inhibited the development of Shay ulcers, indomethacin- or phenylbutazone-induced gastric ulcers and histamine-carbachol-induced duodenal ulcers in rats. Ranitidine at 100 mg/kg (p.o.) also inhibited the development of water-immersion stress-induced gastric ulcers in rats, histamine-induced gastric and duodenal ulcers in guinea pigs, even though the inhibition rate remained within 70%. At that time, the gastric acid output in guinea pigs was reduced with some doses of the drug. Cimetidine at 100 to 200 mg/kg (p.o.) also inhibited the development of indomethacin-, phenylbutazone-, and water-immersion stress-induced gastric ulcers in rats and histamine-induced gastric and duodenal ulcers in guinea pigs. Shay ulcers and histamine-carbachol-induced duodenal ulcers in rats were not affected by cimetidine. Both ranitidine and cimetidine inhibited the gastric acid output in pylorus-ligated rats (7 hr); the maximal inhibition being 79.6% and 50.7% respectively. The mechanism by which ranitidine inhibits various experimental ulcers might be mainly the inhibition of gastric secretion. Gefarnate at 300 mg/kg (p.o.) significantly inhibited phenylbutazone-induced gastric ulcers in rats but had no effect on other ulcer models.     

Effect of DS-4574, a novel peptidoleukotriene antagonist with mast cell stabilizing action, on acute gastric lesions and gastric secretion in rats.

DS-4574 is a peptidoleukotriene antagonist with mast cell stabilizing activity. In the present study, we studied the effects of this compound on gastric secretion and various acute gastric lesions in rats. Intraduodenal administration of DS-4574 at doses of 5 to 10 mg/kg significantly and dose-dependently inhibited gastric acid secretion in pylorus-ligated rats, but a further increase in the dose up to 50 mg/kg did not cause any further inhibition. Shay ulceration in response to pylorus ligation was dose-dependently prevented by DS-4574 (10-25 mg/kg, i.d.). Water-immersion restraint stress- and aspirin-induced gastric ulcers were also significantly prevented in a dose-related manner by oral pretreatment with DS-4574 (10-50 mg/kg). The lower doses of DS-4574 (1-10 mg/kg, p.o.) significantly and dose-dependently protected the gastric mucosa against the necrotizing action of either absolute ethanol or concentrated hydrochloric acid, indicating that this compound possesses a potent gastroprotective activity. These antiulcer and gastric protective effects of DS-4574 were more potent than those of cimetidine used as a reference drug. These findings suggest that DS-4574 is useful for peptic ulcer therapy, as well as for the therapy of various allergic diseases, including asthma.     

Fluoxetine and sertraline stimulate gastric acid secretion via a vagal pathway in anaesthetised rats.

The effect of the selective serotonin reuptake inhibitors, fluoxetine and sertraline on basal, secretagogues (histamine or bethanechol)- and distention-stimulated gastric acid secretion was investigated in the urethane-anaesthetised acute gastric fistula rat. Gastric acid secretion was measured by flushing of the gastric contents with saline every 15 min. Fluoxetine (10 or 20 mg kg(-1), i.p.) produced a dose-dependent increase in basal gastric acid secretion. These stimulatory effects were abolished by vagotomy. Intraperitoneally administered sertraline also stimulated gastric acid secretion. The stimulatory effect of lower doses (5 mg kg(-1)) of sertraline was similar to that of the higher (30 mg kg(-1)) doses. The gastric secretory response to i.p. sertraline was long lasting (greater than 60 min), and blocked by vagotomy. Intraperitoneally administered fluoxetine (10 or 20 mg kg(-1)) or sertraline (5 mg kg(-1)) also increased gastric secretion induced by histamine, bethanechol or distention. The fluoxetine or sertraline stimulatory effects of histamine-induced acid secretion were abolished by vagotomy. Data indicate a stimulatory effect for fluoxetine and sertraline mediated by vagal nerve on gastric acid secretion in urethane-anaesthetised rats.