Effects of the novel anti-ulcer agent 1-(5'-oxohexyl)-3-methyl-7-propyl xanthine on experimental ulcers and gastric secretion in rats

The effects of 1-(5'-oxohexyl)-3-methyl-7-propyl xanthine (HWA 285) on various experimentally induced ulcers and gastric acid secretion were investigated in rats. HWA 285 (10-50 mg/kg, p.o.) inhibited restraint and water-immersion-induced stress, ulcers, indometacin- and absolute ethanol-induced gastric ulcers and mepirizole-induced duodenal ulcers in rats in a dose-dependent manner. HWA 285 (10-25 mg/kg i.d.) had inhibitory effects on acetylsalicylic acid-induced ulcers. The healing of acetic acid-induced chronic ulcers was significantly accelerated by HWA 285 (25 mg/kg p.o.) when it was given twice daily for 7 consecutive days. When given orally (twice a day, 11 doses in total) before the induction of gastric ulcers by stress, cimetidine at 100 mg/kg aggravated the ulcers, whereas, HWA 285 at 25 mg/kg had not such an effect. In conscious pylorus-ligated rats, HWA 285 (10-100 mg/kg i.p.) showed a dose-dependent inhibition on basal and desglugastrin- and 2-deoxy-D-glucose (2-DG)-stimulated gastric acid secretion. In stomach-lumen perfused rats, HWA 285 (30 mg/kg i.v.) inhibited 2-DG-stimulated gastric acid secretion but not carbachol-stimulated gastric acid secretion. These results suggest that the anti-ulcer effects of HWA 285 are produced by cytoprotective and central anti-secretory activity without peripheral anti-cholinergic properties. Whether the central anti-secretory effects of HWA 285 play thereby the key role, have to be clarified in further investigation.     

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.     

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 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.     

Pharmacological properties of the novel antimuscarinic agent 4-[2-(1,2-benzisoxazol-3-yl)-2-(hexahydro-1H-azepin-1-yl)a cetoxy]-1-et hyl-1- methylpiperidinium iodide

Pharmacological properties of 4-[2-(1, 2-benzisoxazol-3-yl)-2-(hexahydro-1H-azepin-1-yl)acetoxy]-1- ethyl-1- methylpiperidinium iodide (SX-810) were investigated and the following results were obtained. 1. In isolated guinea-pig ileum, SX-810 showed a competitive antagonistic effect against acetylcholine with a pA2 value of 7.93. 2. SX-810 (10-50 mg/kg p.o. or 10-50 micrograms/kg i.v.) inhibited the gastroduodenal contractions induced by bethanechol and carbachol in anaesthetized rats. 3. SX-810 (10-100 mg/kg p.o.) inhibited spontaneous gastric motility in conscious rats and rabbits. 4. SX-810 (10-100 mg/kg p.o.) inhibited gastric secretion in pylorus-ligated rats. 5. SX-810 (20-200 mg/kg p.o. or 1-10 mg/kg s.c.) inhibited the ulceration induced by pylorus ligation or by exposure to restrained and water-immersed stress in rats. 6. When administered orally to rats, SX-810 had no mydriatic effect even at 3000 mg/kg, but subcutaneously administered SX-810 (0.5-10 mg/kg) exhibited such action. 7. When administered orally to rats, SX-810 (100-500 mg/kg) caused no significant inhibition of the salivation induced by pilocarpine, but subcutaneously administered SX-810 (0.5-10 mg/kg) exhibited an inhibition of the salivation. In rabbits, SX-810 (200-500 mg/kg p.o.) also caused no significant inhibition of the salivation except at an extremely high dose of 1000 mg/kg p.o. 8. SX-810 (100-500 mg/kg p.o.) caused no significant effect on urine and electrolyte excretion in rats. These results indicate that oral use of SX-810 exhibits marked spasmolytic and antiulcerative activities without exerting systemic antimuscarinic side effects.     

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.     

Antiulcer effects of 3-[[[2-(3,4-dimethoxyphenyl)ethyl] carbamoyl]methyl]-amino-N-methylbenzamide in experimental gastric and duodenal ulcers

Effects of 3-[[[2-(3,4-dimethoxyphenyl)ethyl]carbamoyl] methyl]-amino-N-methylbenzamide (DQ-2511), a newly synthesized compound, were evaluated using various types of experimental gastric and duodenal ulcers in rats. Pretreatment with DQ-2511, over the dose range 30-300 mg/kg p.o., resulted in a dose-related inhibition of water-immersion stress-, serotonin-, acetylsalicylic acid (ASA)-, indometacin-, ethanol-, and 2-deoxy-D-glucose(2DG) plus indometacin-induced gastric ulcers as well as cysteamine-induced duodenal ulcers. The antiulcer potencies of DQ-2511 were equal to or greater than those of H2-receptor antagonist cimetidine in these ulcer models except for ASA- and 2DG plus indometacin-induced ulcers. The rate of healing of chronic gastric ulcers induced by acetic acid was significantly accelerated by DQ-2511 (100 and 300 mg/kg p.o.) but not by the same doses of cimetidine. DQ-2511, at doses of 30 mg/kg p.o. and above, produced a significant decrease in gastric acid and pepsin output in pylorus-ligated rats. In anesthetized rats with acute gastric fistulae, 30 mg/kg i.v. of DQ-2511 significantly inhibited gastric acid secretion stimulated by 2DG, whereas it did not affect gastric hyperacidity evoked by either carbachol, histamine or pentagastrin. At effective antiulcer doses, this compound produced a sustained increase in gastric mucosal blood flow in conscious, restrained rats. Based on these observations, DQ-2511 is characterized as a new antiulcer compound with beneficial effects on both gastric aggressive and defensive factors. Furthermore, these results indicate a possible superiority of DQ2511 over cimetidine in regard to its antiulcer potency and spectrum.     

Effects of a gastric antisecretory-cytoprotectant 2-methyl-8-(phenylmethoxy)imidazo[1,2-a]pyridine-3-acetonitrile (Sch 28 080) on cysteamine, reserpine and stress ulcers in rats

Prostaglandin E2 and carbenoxolone, putative cytoprotective agents, were tested in cysteamine, reserpine and stress ulcers in rats. In cysteamine-induced duodenal ulcer, PGE2 was inactive at 0.1 and 0.5 mg/kg p.o.; carbenoxolone at 100 mg/kg p.o. decreased the incidence but not the severity of the ulcer. PGE2 at 5.0 mg/kg p.o. and carbenoxolone at 300 mg/kg p.o. showed moderate effects, but the dosage also inhibited cysteamine-stimulated acid secretion. PGE2 (0.1 and 0.3 mg/kg p.o.) was inactive and carbenoxolone (100 and 300 mg/kg p.o.) further aggravated the gastric ulceration caused by reserpine or cold-restraint stress. In contrast, atropine (3 and 10 mg/kg p.o.) and cimetidine (30, 100 and 300 mg/kg p.o.) were active in all three ulcer models. But the results with cimetidine in stress ulcer were somewhat variable. 2-methyl-8-(phenylmethoxy) imidazo [1,2-a] pyridine-3-acetonitrile (Sch 28 080), a novel structure with both cytoprotective and antisecretory activity, was highly efficacious in cysteamine, reserpine and stress ulcers (1-30 mg/kg p.o.), which was presumably adequately accounted for by its potent antisecretory activity. It is concluded that cysteamine, reserpine and stress ulcers may not be appropriate models for testing the potential antiulcer effect of primarily cytoprotective compounds.     

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 cimetidine and atropine sulfate on gastric secretion and healing of gastric and duodenal ulcers in rats.

Cimetidine, a new histamine H2-receptor antagonist (50 or 100 mg/kg) and atropine sulfate (15 mg/kg) given intraduodenally, markedly inhibited gastric secretion in pylorus-ligated rats. Cimetidine (100 or 200 mg/kg/day) given for 10 or 12 consecutive days orally in two divided doses, significantly promoted the healing rate of both gastric and duodenal ulcers induced in rats. Atropine (30 mg/kg/day) also significantly accelerated the healing of duodenal ulcers but failed to affect gastric ulcers.     

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.     

Healing promoting effect of azuletil sodium (KT1-32) on experimental chronic gastric ulcers and acceleration of healing in SPF environment

We examined the healing promoting effects of azuletil sodium on acetic acid and clamping cortisone-induced gastric ulcer in rats. For the experiments on clamping-cortisone gastric ulcer, we used not only conventional rats in conventional conditions but also specific pathogen free (SPF) rats on SPF environment in order to prevent infection. The following results were obtained. 1) In acetic acid ulcer, azuletil sodium (AZE) (greater than or equal to 90 mg/kg/day, p.o.) significantly decreased ulcer index. As estimated on the basis of stage analysis (Ulcer, Healing, Scar), AZE (greater than or equal to 30 mg/kg/day, p.o.) significantly promoted the healing of ulcers. 2) In clamping cortisone ulcer (conventional), AZE (100 mg/kg/day, p.o.) significantly promoted the regeneration of blood vessels. 3) In clamping cortisone ulcer (SPF), AZE at greater than or equal to 30 mg/kg/day and 100 mg/kg/day significantly increased the healing index and mucosal regeneration index, respectively. 4) In clamping cortisone ulcer (SPF), the infection that was observed in the conventional test was not seen at all and the acceleration of healing was observed. Furthermore, the extent of adhesion was also reduced, and the standard errors of various healing indices were smaller. From these results, it is concluded that AZE accelerated the healing of experimentally-induced gastric ulcers in rats.     

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.     

Stimulatory effect of N-[4-[2-(dimethylamino)-ethoxy] benzyl]-3,4-dimethoxybenzamide hydrochloride (HSR-803) on normal and delayed gastrointestinal propulsion

To estimate the effect of a new gastroprokinetic agent, N-[4-[2-(dimethylamino)ethoxy]benzyl]-3,4-dimethoxybenzamide hydrochloride (HSR-803), on non-ulcer dyspepsia, the influence of HSR-803 on gastrointestinal propulsion was assayed in dogs, rats and mice in comparison with some gastroprokinetic agents. HSR-803 (30 mg/kg, p.o.) significantly enhanced gastric emptying in dogs, and it significantly improved the delayed gastric emptying induced by dopamine (0.4 mg/kg, i.p.) and morphine (1 mg/kg, s.c.) in rats. Metoclopramide (30 mg/kg, p.o.) also significantly restored the dopamine-induced delay, but at a dose of 10 mg/kg, p.o., it enhanced the morphine-induced delay in gastric emptying in rats. HSR-803 (10-100 mg/kg, p.o.) increased small intestinal transit in mice in a dose-dependent manner, and the effect was abolished by atropine (0.3 mg/kg, i.p.). Metoclopramide also increased small intestinal transit, but domperidone and cisapride had no effect. In delayed small intestinal transit in mice, HSR-803 (10-100 mg/kg, p.o.) improved the morphine (0.3 mg/kg, s.c.)-induced delay in a dose-dependent manner. In conclusion, because of the promotion of normal and delayed gastrointestinal propulsion, HSR-803 seems to be a promising gastroprokinetic agent for the treatment of non-ulcer dyspepsia. The action of HSR-803 is likely to be exerted through cholinergic stimulation.     

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.     

Cytoprotective activity of tiquizium bromide (HSR-902) and its mechanism

The effects of HSR-902, an antimuscarinic agent, on acute gastric mucosal lesions induced by various necrotizing agents, gastric mucus secretion and gastric HCO3- secretion in rats were compared with those of pirenzepine.2HCl (pirenzepine), an antiulcer agent. 1) HSR-902 (10-100 mg/kg), given orally, dose-dependently prevented the gastric mucosal lesions induced by ethanol-HCl (60% ethanol in 150 mM HCl), aspirin-HCl (150 mg/kg of aspirin in 150 mM HCl), 0.6 N HCl and 0.2 N NaOH; and the cytoprotective effects of HSR-902 were almost equal or somewhat more potent than those of pirenzepine. 2) HSR-902 (30 mg/kg, p.o.), like pirenzepine, increased the alcian blue binding to gastric mucosa and both hexosamine and N-acetylneuramic acid in gastric juice and reversed the decrease of alcian blue binding to gastric mucosa in water-immersion stress. 3) HSR-902 (30 mg/kg, p.o.), unlike pirenzepine and atropine sulfate, increased the gastric HCO3- secretion in the pylorus-ligated preparations. 4) The cytoprotective effect of HSR-902 (30 mg/kg, p.o.), when examined using gastric mucosal lesion induced by aspirin-HCl, was not abolished by the pretreatment with indomethacin (10 mg/kg, s.c.) or N-ethylmaleimide (10 mg/kg, s.c.). 5) HSR-902 (30 mg/kg, p.o.) did not influence the gastric mucosal potential difference. These results suggest that HSR-902 is a promising drug for the treatment of gastritis and peptic ulcers.     

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.     

Healing-promoting action of rhinax with dual action on chronic gastric and duodenal ulcers induced by acetic acid in rats

Healing promoting actions of Rhinax, a multiconstituent herbal preparation, was investigated in chronic gastric and duodenal ulcer models induced by acetic acid in rats and the effects were compared with those of famotidine by gross of histological evaluation. Rhinax markedly promoted the well balanced healing of gastric ulcer at oral does of 25-100 mg/kg x 2 /day, as evidenced by the reduction of ulcer, regeneration of mucosa and proliferation of connecitve tissue. Rhinax caused an increase in gastric mucosa secretion in all the regenerated mucosa around the gastric ulcers. Famotidine failed to promote the healing of gastric ulcers at 100 mg/kg x 2/ day p.o. Rhinax also significantly accelerated the healing of acetic acid -induced duodenal ulcers as well famotidine. These results indicate that Rhinax is characterised by a potent promoting action on the healing of chronic ulcers, suggesting that the increase in gastric mucus secretion might be associated with the antiulcer action of Rhinax in rats.     

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.     

Increasing action of teprenone, a new antiulcer agent, on high-molecular-weight glycoprotein in gastric mucus during the healing process of acetic acid-induced ulcer in rats

The effects of teprenone on quantitative changes in gastric mucus glycoprotein during the healing process of acetic acid-induced ulcer in rats were investigated in comparison to those of cimetidine and proglumide. When estimated on the 15th day after operation, teprenone (50 and 100 mg/kg X 2/day, p.o.) significantly decreased the ulcer index by approx. 30%. On the other hand, cimetidine (100 mg/kg X 2/day, p.o.) and proglumide (500 mg/kg X 2/day, p.o.) did not significantly affect it. The high-molecular-weight glycoprotein (HMG, molecular weight of 2 X 10(6) or more) concentration in the gastric mucus of the control group (non-medicated ulcer rats) was 48.7% lower than that of the normal group (non-medicated rats without ulcer). On the contrary, the lower-molecular-weight glycoprotein (LMG, molecular weight between 5 X 10(5) and 2 X 10(6)) concentration of the control group was 95.3% higher than that of the normal group. Teprenone (at both doses) remarkably increased the concentration and secretion of the HMG. In contrast, those of the LMG were decreased by this drug. Cimetidine significantly decreased both the concentration and secretion of the total glycoprotein (HMG + LMG). Proglumide showed only slight increases in the concentration and secretion of the HMG, although it pronouncedly increased the total glycoprotein secretion. These results indicate that teprenone may strengthen the defensive force of gastric mucosa by increasing the HMG with a polymeric structure. In contrast, cimetidine may weaken the mucosal defense.