General pharmacology of IY-81149, a new proton pump inhibitor

IY-81149 (2-[(4-methoxy-3-methyl)-2-pyridinyl]methylsulfinyl -5-(1H-pyrrol-1-yl)-1H-benzimidazole, CAS 172152-36-2) is a new proton pump inhibitor and expected to be an antiulcer drug. Its general pharmacological effects were studied in this paper. The doses given were vehicle control, 0.3, 1, 3, 100, 300 and 1000 mg/kg and were administered orally. The animals used in this study were mouse, rat, guinea pig and beagle dog. IY-81149 decreased spontaneous locomotor activity at 1000 mg/kg and showed a weak effect in motor performance at 300 and 1000 mg/kg. IY-81149 prolonged the hexobarbital-induced sleeping time dose dependently at 100, 300 and 1000 mg/kg. Oral administration of IY-81149 caused a dose-dependent hypothermic effect up to 300 mg/kg and showed analgesic effect at 1000 mg/kg. IY-81149 produced an antisecretory effect in pylorus ligated rats. The total gastric volume and acidity were significantly decreased at doses ranging from 1 to 3 mg/kg. However, IY-81149 had no effects on general behavior, did not show anticonvulsant activity, and did not affect blood pressure and heart rate, LVP (left ventricular peak systolic pressure), LVEDP (left ventricular end diastolic pressure), LVDP (left ventricular developing pressure), DP (double product), HR (heart rate), CFR (coronary flow rate), smooth muscle contraction, respiration, intestinal transport and renal function. These findings demonstrate that IY-81149 possesses weak central nervous system action and inhibitory effects on microsomal enzymes and gastric secretion after single administration. The results suggest that IY-81149 does not exert any notable pharmacological effects on the cardiovascular system, autonomic nerve system or smooth muscle function at all doses tested.     

Comparison of IY81149 with omeprazole in rat reflux oesophagitis

1. This study was aimed at evaluating the effects of IY81149[2-[[(4methoxy-3-methyl)-2-pyridinyl]methylsulfinyl]-5-(1H-pyrrol-1-yl)-1H-benzimidazole], a new proton pump inhibitor, on the development of the surgically induced reflux oesophagitis, on gastric secretion and on lipid peroxidation which is a marker of oxidative stress. Omeprazole was used as a reference drug. We furthermore investigated the influence of quercetin and desferrioxamine (DFO) on the development of the surgically induced reflux oesophagitis in rats on gastric secretion and on lipid peroxidation. 2. IY81149 and omeprazole significantly prevented the development of reflux oesophagitis and gastric secretion in a dose-dependent manner. The ED50 values of IY81149 for inhibition of oesophagitis and volume of gastric secretion were lower than of omeprazole (5.7 vs. 14.2 micromol, 15.3 vs. 24.0 micromol, respectively). IY81149 was also more potent in the acid output inhibition with an ED50 of 6.8 micromol compared with 20.8 micromol of omeprazole. 3. Malonyldialdehyde (MDA) content, the end product of lipid peroxidation, increased significantly in the oesophageal mucosa after the induction of reflux oesophagitis. IY81149 and omeprazole significantly and dose-dependently prevented lipid peroxidation. Quercetin (200 mg kg-1, p.o.) and DFO (800 mg kg-1, i.d.) significantly prevented the development of reflux oesophagitis and inhibited the lipid peroxidation independent of their actions on gastric secretion. 4. This result suggests that IY81149 is comparable with omeprazole in the treatment of reflux oesophagitis.     

Effects of TU-199, a novel H+, K(+)-ATPase inhibitor, on gastric acid secretion and gastroduodenal ulcers in rats.

We studied the effects of TU-199, a novel H+, K(+)-ATPase inhibitor, on gastric acid secretion and gastroduodenal lesions in rats in comparison with those of omeprazole. TU-199 inhibited hog gastric H+, K(+)-ATPase activity and its potency was almost equal to that of omeprazole (IC50 = 6.2 and 4.2 microM, respectively). In vivo, TU-199 inhibited basal gastric acid secretion in pylorus-ligated rats in a dose-dependent manner (ED50 = 4.2 mg/kg p.o.). In gastric fistula rats. TU-199 (2.5 and 5 mg/kg i.d.) also inhibited gastric acid secretion stimulated by histamine, carbachol or tetragastrin. Furthermore, TU-199 prevented the formation of water-immersion restraint stress-, pylorus ligation- and indomethacin-induced gastric lesions, and mepirizole-induced duodenal ulcer in rats. These antisecretory and antiulcer effects of TU-199 were 2-4 times more potent than those of omeprazole. The results demonstrate that TU-199 potently inhibits the acid secretion and formation of ulcers in various experimental rat models via an inhibition of H+, K(+)-ATPase. These findings suggest that TU-199 may have a beneficial effect against peptic ulcer disease in humans.     

FR145715, a novel histamine H2 receptor antagonist, with specific anti-Helicobacter pylori activities.

The pharmacological profile of N-[3-[2-[N'-(2-methoxyethyl)guanidino]thiazol-4yl]benzyl-ace tamide (FR145715), a novel histamine H2 receptor antagonist, was examined in both in vitro and in vivo models using experimental animals in comparison with ranitidine. In isolated guinea-pig atria, FR145715 antagonized the effect of histamine on heart rate with approximately three times more potent activity than ranitidine. In in vivo experiments, intraduodenal FR145715 dose-dependently inhibited spontaneous gastric acid secretion in rats (Shay's rats), with a ED50 value of 18.4 mg/kg, which was comparable to that of ranitidine (30.5 mg/kg). FR145715 also inhibited histamine-stimulated acid secretion in stomach-perfused anaesthetized rats (Schild's rats), when given intravenously and intraduodenally with ED50 values of 0.59 and 2.72 mg/kg, respectively. Ranitidine displayed more potent activity having respective ED50 values of 0.10 and 0.17 mg/kg. In Heidenhain pouch dogs, intravenous and oral FR145715 dose-dependently inhibited gastrin-stimulated acid secretion with respective ED50 values of 0.12 and 0.32 mg/kg, which were similar to those of ranitidine (0.09 and 0.33 mg/kg). In gastric ulcer models, FR145715 dose-dependently inhibited water immersion restraint stress- and acidified aspirin-induced gastric lesions with ED50 values of 3.2 and 15.1 mg/kg (p.o.), respectively. The comparative compound, ranitidine, also showed beneficial effects on stress-induced gastric ulcers with an ED50 value of 1.5 mg/kg (p.o.). However, it failed to inhibit acidified aspirin-induced gastric ulcers. FR145715 inhibited HCl-induced gastric lesions in rats, while pre-treatment with indomethacin abolished its beneficial effects, suggesting that FR145715 has a so-called cytoprotective effect which is dependent on endogenous prostaglandin production. In addition to its atypical profile as a histamine H2 receptor antagonist, FR145715 exhibited strong anti-microbial activities against strains of Helicobacter pylori (H. pylori) with a mean minimal inhibitory concentration value of 0.32 microg/ml. Moreover, FR145715 showed no anti-microbial effects on 25 other bacteria examined. In addition, in vivo experiments using gnotobiotic piglets infected with H. pylori, FR145715 (16 mg/kg, t.i.d.) completely eliminated the organism with reduced intensity of inflammation, when treated orally for 10 days. These data demonstrate that FR145715 is a novel histamine H2 receptor antagonist having potent and selective anti-H. pylori activities as well as cytoprotective properties. The present data suggest that FR145715 might be useful for the patients suffering from ulcer relapse, since the drug might be able to eradicate H. pylori in the stomach, which is considered a key factor to cause ulcer recurrence in humans.     

Characterization of antisecretory and antiulcer activity of CR 2945, a new potent and selective gastrin/CCK(B) receptor antagonist

The antigastrinic, antisecretory and antiulcer activities of CR 2945, (R)-1-naphthalenepropanoic acid,beta-[2-[[2-(8-azaspiro[4.5]dec-8-yl-carbonyl)-4,6-dimethylph enyl] amino]-2-oxoethyl], were investigated in vitro and in vivo in rats and cats. Its activities were compared with those of two gastrin/CCK(B) receptor antagonists, L-365,260 (3R(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin -3-yl)-N'-(3-methylphenyl)urea and CAM-1028 (4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[[1,7,7-trimethylbicyclo [2.2.1]hept-2-yl)oxy]carbonyl]amino]propyl]amino]-1-phenylethyl]amino -4-oxo-[1S-1alpha,2beta[S'(S')4alpha]]-butanoate -N-methyl-D-glucamine), of the histamine H2 receptor antagonist, ranitidine, and the proton pump inhibitor, omeprazole. Cytosolic Ca2+ elevation in rabbit parietal cells induced by gastrin (50 nM) was blocked by CR 2945 with an IC50 value of 5.9 nM. CAM-1028 and L-365,260 showed similar activity. CR 2945 antagonized pentagastrin-stimulated gastric acid secretion in rats (ED50 = 1.3 mg kg(-1) i.v. and 2.7 mg kg(-1) i.d.) and cats (1.6 mg kg(-1) i.v.). CR 2945 was slightly less potent than the reference compounds after i.v. administration, whereas after intraduodenal (i.d.) administration, it was more potent than both ranitidine and omeprazole. In the rat, the gastrin antagonism exhibited by CR 2945 was reversible and competitive, with a pA2 value of 7.33. CR 2945 had specific antigastrin activity, as it was unable to antagonize the gastric acid secretion stimulated by histamine or carbachol in rats up to the dose of 30 mg kg(-1). CR 2945 was about as efficacious as ranitidine against the indomethacin- and ethanol-induced gastric ulcers and the cysteamine-induced duodenal ulcer in rats. On the contrary, L-365,260 was only slightly effective. These results suggest that CR 2945 might be a promising compound for the therapy of acid-related disorders, and that its clinical use could help clarify the therapeutic potential of gastrin/CCK(B) receptor antagonists in the gut.     

The stimulatory effect of forskolin on gastric acid secretion in rats

Adenylate cyclase is involved in the histamine pathway of the parietal cell. We therefore studied the effect of forskolin, a direct activator of the membrane-bound adenylate cyclase, on gastric acid secretion in anaesthetized rats. Forskolin in the range of 0.1-1 mg/kg i.v. caused a dose-dependent stimulation of acid secretion. Higher doses were not tolerated. The duration of action of the forskolin-induced acid secretion was also dose-related. The combined infusion of forskolin (0.3 mg/kg per h i.v.) and histamine at a low rate (0.5 mg/kg per h i.v.) produced a maximal stimulation of acid secretion which was comparable to that with a histamine infusion of 10 mg/kg per h i.v. without forskolin. Administration of desglugastrin at a low rate (10 micrograms/kg per h i.v.) plus forskolin by i.v. infusion produced similar results. In contrast, infusion of carbachol (3 micrograms/kg per h i.v.) together with forskolin caused only an additive effect on acid secretion. Including an isobutyl-methyl-xanthine (IBMX) i.v. injection of 3 mg/kg at the beginning of the forskolin infusion (0.3 mg/kg per h i.v.) produced an acid output after 60 min which was approximately 50% of the maximal stimulation during a histamine (10 mg/kg per h i.v.) infusion. The IBMX/forskolin-induced stimulation was completely inhibited by 0.5 mg/kg omeprazole i.v. while the equipotent antisecretory dose (during histamine stimulation) of cimetidine caused only a weak decrease in acid output.     

Gastric acid inhibitory profile of saviprazole (HOE 731) compared to omeprazole.

Saviprazole (HOE 731), a substituted thienoimidazole, caused a dose-dependent inhibition of gastric acid secretion in dogs and rats with ID50 values which were not significantly different from that of omeprazole indicating that both compounds are equally effective. The duration of action in dogs lasted for more than 24 h and was dependent on the state of stimulation. Measurement of serum concentrations of 1 mg/kg saviprazole after intravenous or intraduodenal administration revealed a bioavailability of about 60% in dogs. The elimination half-life was about 30 min following both routes of administration. In rats basal acid secretion was inhibited by saviprazole. In addition stimulation of acid secretion by histamine, desglugastrin, carbachol and isobutylmethylxanthine-forskolin was equally inhibited. This was in agreement with the known mechanism of action, inhibition of the gastric proton pump which is the last step of acid secretion within the parietal cell. Surprisingly, at high dose levels, saviprazole differed from omeprazole. After saviprazole, 1 mg/kg i.v. to dogs, acid output dropped to zero but recovered within 30 min to a level of 90%, whereas omeprazole depressed acid output completely over the whole observation period (4.5 h). Similar results were obtained in pylorus-ligated rats.     

The long-lasting effect of TU-199, a novel H+, K(+)-ATPase inhibitor, on gastric acid secretion in dogs.

We have used Heidenhain-pouch dogs to investigate the effects of (+/-)-5-methoxy-2-{[(4-methoxy-3,5-dimethylpyrid-2-yl)methyl]sulph inyl}-1H-imidazo[4,5-b]pyridine (TU-199), an imidazopyridine derivative, on gastric acid secretion stimulated by histamine, carbachol and tetragastrin. We have also investigated the duration of the antisecretory effect of TU-199 using a measurement of intragastric pH for 24 h in gastric fistula dogs whose gastric acid secretion was stimulated by histamine. Single oral administration of TU-199 (0.1, 0.2 and 0.4mgkg(-1)) dose-dependently suppressed gastric acid secretion stimulated by histamine infusion. Oral treatment with TU-199 (0.2, 0.4 and 0.8 mg kg(-1)) also dose-dependently inhibited acid secretion induced by carbachol and tetragastrin. The inhibitory effect of TU-199 on stimulated gastric acid secretion was more potent than that of omeprazole, a well-known H+,K(+)-ATPase inhibitor in dogs. Repeated oral treatment with TU-199 at a dose of 0.2 mg kg(-1) once a day for seven days markedly suppressed histamine-stimulated gastric acid secretion in dogs. This inhibitory effect of TU-199 reached a maximum level after three or four doses and was more pronounced than that of omeprazole or lansoprazole. In gastric fistula dogs, the duration of intragastric pH-elevation by administration of TU-199 (0.3 mg kg(-1)) was much longer than that of omeprazole (0.6mgkg(-1)) or lansoprazole (0.9mgkg(-1)). The IC50 values (doses resulting in 50% inhibition) of TU-199, omeprazole and lansoprazole with regard to H+,K(+)-ATPase activity in dog gastric mucosal microsomes were 8.6, 8.8 and 9.9 microM, respectively. These results indicate that TU-199 inhibits gastric acid secretion via suppression of a H+,K(+)-ATPase activity. Our findings also suggest that TU-199 might have potent and long-lasting effects on gastric acid secretion.     

Use of a cannula insert in erratic emptying Heidenhain pouch dogs: effect of single and cumulative doses of omeprazole

A novel cannula insert was used to correct erratic emptying in Heidenhain pouch dogs. The insert restored the recovery of histamine or pentagastrin stimulated gastric acid secretion to that obtained from normal emptying pouch dogs, probably by displacing obstructing tissue within the pouch. Use of the insert did not cause any discomfort to the animals, nor did it alter basal secretion. There was no significant difference between the antisecretory activity of single doses of omeprazole in erratic emptying animals fitted with the insert (ED50 = 0.21 mumol/kg) and in dogs with a normal pouch (ED(50) = 0.13 mumol/kg). Use of the insert achieved an earlier steady secretory response which allowed cumulative dosing to be performed in each animal. There was no significant difference between the effect of cumulative (ED50 = 0.24 mumol/kg) and single doses of omeprazole in erratic emptying dogs. Although there was a significant difference between cumulative dosing in erratic emptiers and single dosing in normal animals it should still be possible to use erratic emptiers with the insert for screening purposes.     

Gastric antisecretory and anti-ulcer effect of ME3407, a new benzimidazole derivative, in rats

The effects of a new benzimidazole derivative, ME3407 (n-butyl-2-(thiazolo-[5,4-b]pyrid-2-yl) sulfinylacetate, CAS 133903-90-9), on gastric acid secretion and gastric and duodenal ulcers in rats were examined. ME3407, given orally, inhibited dose-dependently (0.3-30 mg/kg) the incidence of gastric lesions such as Shay ulcers, and water-immersion stress-, acetylsalicylic acid (ASA)- and histamine-induced erosions. In addition, ME3407 showed marked therapeutic effect on HCl- and ASA-induced lesions. In the lumen-perfused rats, oral administration of ME3407 inhibited dose-dependently (1-100 mg/kg) gastric acid secretion induced by histamine and tetragastrin with ED50 values of 3.02 and 3.37 mg/kg, respectively. Oral administration of ME3407 at a dose of 30 mg/kg also inhibited the elevation of serum gastrin level. The development of duodenal ulcers caused by mepirizole and systeamine was also potently inhibited by ME3407 at an oral dose of 0.1-30 mg/kg. However, when given at 30 mg/kg intraduodenally, subcutaneously or intravenously, ME3407 did not inhibit these acutely induced gastric elosion and acid output. ME3407 was not detected in the serum upon oral administration. These results indicated that ME3407 was active only by oral administration, and exerts direct action on the ulcers and acid secretion from the gastric membrane.     

Histamine-induced villous damage in the rat duodenum

A single s.c. administration of histamine dose-dependently (5-20 mg/kg) induced villous damage of the proximal duodenum in 24-hr fasting rats. Time course studies indicate that histamine (20 mg/kg) induced severe exfoliation of the epithelial cells at the villous tips of the duodenal mucosa 0.5 hr after administration. The damage, however, tended to heal with time, and recovery was nearly complete 8 hr later. This villous damage was significantly inhibited by pretreatment with sodium bicarbonate given orally or cimetidine, omeprazole and NC-1300 given subcutaneously. Histamine (20 mg/kg) significantly stimulated gastric acid secretion and lowered the intraduodenal pH for 1 hr. Gastric content was significantly greater than that in the control group for 1 hr after histamine administration, probably due to stimulated gastric secretion and delayed emptying. We conclude that a single administration of histamine induces microscopical duodenal damage by stimulation of gastric acid secretion, but the damage heals with time, probably as a result of the short periods of acid stimulation and delayed emptying.     

N,N-dimethyl-10-(3-quinuclidinyl)-2-phenothiazine sulfonamide (LM 24056): mode of action of its gastric antisecretory effect

The inhibitory effect on gastric secretion of a phenothiazine molecule, N,N-dimethyl-10-(3-quinuclidinyl)-2-phenothiazine sulfonamide (LM 24056), was studied in dogs equipped with gastric fistula (GF) and Heidenhain denervated pouch (HP). LM 24056 was infused intravenously before exogenous stimulations started: the gastric stimulation ws obtained either by gastrin, by combination of gastrin + bethanechol (subthreshold dose) or by histamine. 1. On gastrin-stimulated secretion, preliminary infusion of LM 24056 results in a weak and non-significant reduction on GF acid secretion, while on HP, the inhibition is significant with 1 and 2 micrograms x kg-1 x h-1 of gastrin. The LM 24056 concentrations which produced 50% inhibition (IC50) of acid secretion is close to 0.5 mg x min-1. 2. LM 24056 exerts a strong inhibitory effect on combination gastrin + bethanechol-stimulated acid and pepsin secretions on GH and HP. IC50 is close to 0.25 mg x min-1. 3. LM 24056 is able to delay the histamine-stimulated acid secretion. There are some differences in the gastric inhibitory effects in relation to the moment of LM 24056 administration regarding exogenous stimulant: LM 24056 seems to be able to compete gastrin and to delay the normal histamine stimulation. The most important inhibitory effect is exerted on combination gastrin + bethanechol. LM 24056 could act as an antigastrinic substance.     

Gastric antisecretory and antiulcer/cytoprotective effects of 2-cyano-3-(ethylthio-3-methylthio)-2-propenoic acid methyl ester

AY-28,200 (2-cyano-3-(ethylthio-3-methylthio)-2-propenoic acid methyl ester), a new gastric antisecretory/antiulcer agent, inhibited basal and pentagastrin-stimulated gastric acid secretion in the conscious rat (ED50 = 7.6 and 1.9 mg/kg i.g., respectively). For inhibition of basal secretion, peak activity was attained in 5 to 6 h after dosing and was maintained for more than 10 h, with no gastric antisecretory activity occurring at 24 h. The K+ stimulated H+-K+ ATPase activity from rabbit gastric microsomes was inhibited by AY-28,200 (IC50 = 22 mumol/l). AY-28,200 inhibited ethanol-induced gastric lesions, at 3 mg/kg p.o. AY-28,200's cytoprotective effects against ethanol lasted for more than 4 h. AY-28,200 blocked acetylsalicylic acid and stress-induced gastric ulcers but was inactive against indomethacin-induced gastric ulcers. These results suggest that AY-28,200 is a parietal cell proton pump inhibitor with cytoprotective properties, and may produce its cytoprotective effect by stimulating the formation of endogenous prostaglandins.     

L-365,260, a potent CCK-B/gastrin receptor antagonist, suppresses gastric acid secretion induced by histamine and bethanechol as well as pentagastrin in rats.

We evaluated the effects of a potent cholecystokinin (CCK)-B/gastrin receptor antagonist, L-365,260 (3R(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin - 3-yl)-N'-( 3-methylphenyl) urea); a selective CCK-A receptor antagonist, devazepide (L-364,718); and cimetidine on gastric acid secretion induced by pentagastrin, histamine and bethanechol in anesthetized rats. We also evaluated the effects of L-365,260 and cimetidine on acid secretion in pylorus-ligated rats. Intravenous administration of L-365,260, L-364,718 and cimetidine dose-dependently reduced acid secretion induced by pentagastrin (20 nmol/kg/hr), with ED50 values of 0.63, 19.1 and 2.5 mumol/kg, respectively. Of interest was the finding that L-365,260, like cimetidine, dose-dependently inhibited acid secretion induced by histamine (100 mumol/kg/hr) and bethanechol (5 mumol/kg/hr) with ED50 values of 5.9 and 4.3 mumol/kg, respectively. L-364,718, even at 30 mumol/kg, i.v., had only a slight effect on histamine- or bethanechol-induced acid secretion. Gastric acid secretion was suppressed by treatment with L-365,260 (3-100 mumol/kg, i.v.) and cimetidine (11.9-396.4 mumol/kg, i.v.) in pylorus-ligated rats, with ED50 values of 13.3 and 96.9 mumol/kg, respectively. These results indicate that L-365,260 suppresses acid secretion induced by histamine and bethanechol in rats and that the gastrin receptor plays an important role in acid secretion in pylorus-ligated rats.     

The effect of hexamethonium on gastric acid secretion in the conscious rat

Evidence against a role for histamine in pentagastrin-stimulated acid secretion has been obtained previously using hexamethonium in gastric fistula rats. This possibility has been re-examined in conscious rats provided with gastric fistulae or Heidenhain pouches. Hexamethonium (20 mg/kg s.c.) inhibited basal acid secretion and acid secretion stimulated by histamine and pentagastrin in gastric fistula rats. The same dose of hexamethonium failed to produce a significant inhibition of acid secretion stimulated by bethanechol, pentagastrin or histamine in the presence of a low dose of bethanechol in Heidenhain pouch rats. These results provide no evidence to oppose the view that pentagastrin-stimulated acid secretion in the rat is mediated at least in part through the mobilization of gastric mucosal histamine. The inhibition of secretagogue induced acid secretion in the gastric fistula rat is mainly the result of a reduction in the basal acid output.     

Effect of somatostatin, secretin, and glucagon on secretagogue stimulated aminopyrine uptake in isolated canine parietal cells

Somatostatin, secretin, and glucagon have been shown to inhibit gastric acid secretion in vivo and thus have been postulated to act directly on the parietal cell. To test the hypothesis that these peptides directly influence the acid secretory cells, we studied the effect of the three gastrointestinal hormones using aminopyrine uptake as an index of acid production. The parietal cells were stimulated to increase aminopyrine uptake by submaximal concentrations of histamine (10(-6) mol/l), methacholine (10(-6) mol/l), and pentagastrin (10(-6) mol/l), but in no concentrations did these gastrointestinal hormones affect any of the secretagogues' response. Our data suggest that gastrointestinal peptides do not modulate acid secretion at the parietal cell level.     

Time course of inhibition of gastric acid secretion by omeprazole and ranitidine in gastric fistula rats

Basal, pentagastrin- and histamine-stimulated acid secretion were measured in gastric fistula rats treated with the H+/K(+)-ATPase inhibitor, omeprazole, and the H2-receptor antagonist, ranitidine. All doses of omeprazole (20, 30, 40, 80, 400 mumol/kg) and ranitidine (125, 187.5, 250, 375 mumol/kg) essentially abolished the basal acid output for various periods of time. Omeprazole, 80 mumol/kg, administered twice daily, reduced the 24-h basal acid secretion more effectively than did 400 mumol/kg given once daily. Four daily administrations of ranitidine reduced the 24-h basal acid output to a similar extent as omeprazole administered twice. Omeprazole (20, 80 mumol/kg) was more effective than ranitidine (125, 375 mumol/kg) in inhibiting acid secretion evoked by maximal doses of pentagastrin (650 nmol/kg per h) and histamine dihydrochloride (136 mumol/kg), whereas this difference was less pronounced for the inhibition of acid responses induced by a threshold dose (1.1 mumol/kg) of histamine. The inhibition evoked by omeprazole (80 mumol/kg x 2) and ranitidine (375 mumol/kg x 4) of basal and histamine (1.1 and 136 mumol/kg)-induced acid secretion was similar after 1 and 4 weeks of treatment. After the end of drug administration, the acid secretion induced by threshold doses of histamine was significantly elevated in the omeprazole-treated rats, whereas no significant hypersecretion of acid was seen during the recovery period in rats treated with ranitidine. Plasma gastrin concentrations were significantly elevated after 4 weeks of treatment with omeprazole but returned to pretreatment levels after 4 weeks of recovery.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of KB-5492, 1-(3,4,5-trimethoxybenzyl)-4-((4-methoxyphenyl)oxycarbonylmethyl) p iperazine monofumarate monohydrate, on gastric lesions and gastric secretion in rats

Effects of a newly synthesized compound, KB-5492, on gastric lesions and gastric secretion were studied in rats. Oral KB-5492 inhibited the lesions induced by HCl.ethanol, HCl.aspirin, water-immersion stress, indomethacin, histamine and prednisolone at 30-300 mg/kg. The ED50 values varied from about 35 to 98 mg/kg. KB-5492 had no effect on gastric acid secretion even at 300 mg/kg. KB-5492 appeared to have a much more potent protective effect than a known anti-ulcer drug, sofalcone, against acute gastric lesions.     

Pharmacological properties of the orally active leukotriene antagonist [[5-[[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propyl]thio]-1,3,4- thiadiazol-2-yl]thio]acetic acid

The anti-leukotriene effect of [[5-[[3-(4-acetyl-3-hydroxy -2- propylphenoxy)propyl] thio]-1,3,4-thiadiazol-2-yl] thio] acetic acid (YM-16638) was examined. In isolated guinea-pig ileum, YM-16638 antagonized the contractions induced by slow reacting substance of anaphylaxis (SRS-A) and leukotriene D4 (LTD4) with IC50 values of 6.0 x 10(-8) and 1.1 x 10(-7) mol/l, respectively. However, the compound at 10(-5) mol/l did not affect the contractions induced by histamine, acetylcholine, 5-hydroxytryptamine, prostaglandin (PG)E2 and PGF2 alpha. In isolated guinea-pig trachea, YM-16638 inhibited the contractions elicited by LTC4, LTD4 and LTE4 and its IC50 values were 5.7 x 10(-8), 1.6 x 10(-7) and 9.6 x 10(-8) mol/l, respectively. In isolated human bronchi, YM-16638 also antagonized the contractions induced by LTC4, LTD4 and LTE4 and its IC50 values were 6.0 x 10(-8), 1.2 x 10(-7) and 2.1 x 10(-8) mol/l, respectively. YM-16638 at the doses of 3 to 100 mg/kg p.o. inhibited the skin reaction induced by LTD4 in conscious guinea-pigs and its ED50 value was 17.9 mg/kg p.o. Successive oral administration of YM-16638 (50 mg/kg/d) for 10 days did not develop tolerance in its inhibitory effect against LTD4-induced skin reaction. Furthermore, the compound at the doses of 10 and 30 mg/kg p.o. significantly inhibited the antigen-induced bronchoconstriction in conscious guinea-pigs pretreated with mepyramine, propranolol and indomethacin. These results indicate that YM-16638 is a selective, potent and orally active leukotriene antagonist.     

YF476 is a new potent and selective gastrin/cholecystokinin-B receptor antagonist in vitro and in vivo

Background : We newly synthesized YF476 ((R)-1-[2,3-dihydro-2-oxo-1-pivaloylmethyl-5-(2'-pyridyl)-1H-1,4-benzodiazepin-3-yl]-3-(3-methylamino-phenyl)urea) as a gastrin/cholecystokinin-B (CCK-B) receptor antagonist. We investigated the pharmacological profile of YF476 in vitro and in vivo .
Methods : We examined the binding properties of YF476 to the rat brain, cloned canine and cloned human gastrin/CCK-B receptors, and the effect of YF476 on secretagogue-induced gastric acid secretion in rats and Heidenhain pouch dogs.
Results : YF476 replaced the specific binding of [¹²⁵I]CCK-8 to the rat brain, cloned canine and cloned human gastrin/CCK-B receptors, with K _i values of 0.068, 0.62 and 0.19 n M , respectively. The affinity of YF476 for rat brain gastrin/CCK-B receptor was 4100-fold higher than that for rat pancreatic CCK-A receptor. In anaesthetized rats, intravenous YF476 inhibited pentagastrin-induced acid secretion with an ED ₅₀ value of 0.0086 μmol/kg, but did not affect histamine- and bethanechol-induced acid secretion at a dose of 10 μmol/kg. In Heidenhain pouch dogs, intravenous and oral YF476 inhibited pentagastrin-stimulated gastric acid secretion in a dose-dependent manner with ED ₅₀ values of 0.018 and 0.020 μmol/kg, respectively, but did not affect histamine-induced acid secretion.
Conclusion : These results suggest that YF476 is an extremely potent and highly selective gastrin/CCK-B receptor antagonist, and that the gastrin/CCK-B receptor is not involved in histamine- or bethanechol-induced gastric acid secretion in dogs or rats.