Effects of H2-receptor antagonists upon physiological acid secretory states in animals

The results reported in this paper indicate that representative H2-receptor antagonists are capable of maximally inhibiting gastric acid secretion in animals under the two general circumstances in which it occurs physiologically. Interdigestive or basal secretion was examined in chronic gastric fistula rats and food-stimulated secretion in vagally innervated, lesser curvature pouch dogs. The H2 antagonists studied and omeprazole, an inhibitor of the proton pump H+, K+-adenosine triphosphatase, also decreased pepsin secretion in rats, although not to the same maximal degree as acid secretion. Gastric emptying was increased by each H2 antagonist but only at high acid inhibitory doses. Omeprazole, in contrast, did not alter gastric emptying at a similar antisecretory dosage level. In dogs, a representative H2-receptor antagonist markedly inhibited food-stimulated acid secretion. These data suggest that the predominant effect of omeprazole and H2-receptor antagonists upon gastric function is to inhibit acid secretion and that H2-receptor antagonists may be capable of maximally inhibiting endogenous acid secretion in humans, as does omeprazole, if given under proper conditions.     

Discovery and development of the proton pump inhibitor]

Gastric (H+/K+)-ATPase, the proton pump of the parietal cell, is responsible for the final step of acid secretion in the stomach. In 1981, picoprazole, a substituted benzimidazole, was found to inhibit (H+/K+)-ATPase. It was reported in 1983 that omeprazole has the most potent efficacy among the substituted benzimidazoles and today, omeprazole has been used for treatment of gastroduodenal disease. Recently, lansoprazole, similar to omeprazole in chemical structure, was developed in Japan, and several other compounds, such as pantoprazole, E-3810 and NC-1300-O-3, have also been reported to suppress acid secretion through inhibition of (H+/K+)-ATPase. In the present paper the background of the discovery of (H+/K+)-ATPase and development of proton pump inhibitors is reviewed.     

Substituted benzimidazoles--a new dimension in ulcer therapy?

Substituted benzimidazoles represent a new class of gastric secretory inhibitors, which suppress acid secretion via direct inhibition of the parietal cell H+/K+-ATPase. The most potent derivative so far is omeprazole, which inhibits basal acid secretion and prevents the stimulatory effect of all classical acid secretory stimulants. In man, a single dose of 80 mg leads to almost complete achlorhydria over 24 hours. The results of the first duodenal ulcer trial with omeprazole are encouraging. No definite side effects have been attributed to the drug so far. Omeprazole may possibly initiate a new era in the medical treatment of peptic ulcer disease.     

Inhibition of acid secretion in guinea pigs by tricyclic antidepressants: comparison with ranitidine and omeprazole

The antisecretory properties of imipramine on gastric secretion in guinea pig in comparison with other antisecretory agents was determined. In awake guinea pigs s.c. infusion of histamine (30 micrograms/kg/hr) increased acid and fluid secretion by 3- to 4-fold. When acid output peaked, a bolus administration of the tricyclic anti-depressant imipramine inhibited acid and fluid secretion. Imipramine and other agents, such as ranitidine and omeprazole, inhibited gastric secretion in a dose-dependent fashion. The most potent was the H2-antagonist ranitidine (IC50, 0.2-0.3 mumol/kg), followed by the gastric H-K-adenosine triphosphatase inhibitor, omeprazole (IC50, 0.5-0.6 mumol/kg). Imipramine (IC50 1-2 mumol/kg) was the least potent of the inhibitors. Both ranitidine and omeprazole could abolish acid secretion, but maximal inhibition with imipramine was 60% of initial. Promethazine (25 mumol/kg), an H1 antagonist, and atropine (12 mumol/kg), a muscarinic antagonist, inhibited gastric secretion by 40 to 50%. Imipramine and atropine also inhibited basal acid secretion. In dispersed gastric cells comparison between imipramine and omeprazole showed that imipramine was about 5-fold more potent than omeprazole in blocking histamine or dibutyryl cyclic AMP stimulation of aminopyrine accumulation. Imipramine probably acts as a protonophore by increasing the rate of proton-gradient dissipation rather than by interfering with the hydrogen-pump system because, in gastric membranes, imipramine was 20-fold less potent than omeprazole in inhibiting the gastric H-K-adenosine triphosphatase activity. These results suggest that imipramine administered s.c. in guinea pigs is a potent antisecretory drug. Its action may be due to a combination of anticholinergic and antihistamine H2 activities.     

Omeprazole: a new approach to gastric acid suppression

Omeprazole, one of a new group of antisecretory drugs, is a substituted benzimidazole that does not exhibit the anticholinergic or histamine H2 antagonistic properties of drugs such as cimetidine. This agent suppresses gastric acid secretion by inhibiting the proton pump mechanism, thereby blocking the final step of acid secretion. Omeprazole is significantly more effective than the histamine H2 receptor antagonists in eliminating acid secretion; thus, it may be beneficial in patients who are resistant to these agents. Omeprazole is indicated for severe erosive esophagitis, gastroesophageal reflux disease that does not respond to H2 receptor antagonists, and hypersecretory diseases such as Zollinger-Ellison syndrome and systemic mastocytosis. Because of the theoretic risk of carcinogenesis, short-term therapy is recommended, although long-term therapy is required for hypersecretory diseases.     

A study comparing the antisecretory effect of TAK-438, a novel potassium-competitive acid blocker, with lansoprazole in animals

Proton pump inhibitors (PPIs) are widely used for the treatment of acid-related diseases. However, several medical needs such as suppression of night-time acid secretion and rapid symptom relief remain unmet. In this study, we investigated the effects of 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate (TAK-438), a novel potassium-competitive acid blocker, on acid secretion in rats and dogs under various conditions, in comparison with the PPI lansoprazole [2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl] methyl]sulfinyl]-1H-benzimidazole], to characterize the antisecretory action of TAK-438. TAK-438 showed a more potent and longer-lasting inhibitory effect than lansoprazole on the histamine-stimulated gastric acid secretion in rats and dogs. A pharmacokinetic study in rats showed that TAK-438 accumulated and was retained in the gastric tissue for more than 24 h, unlike that in the plasma. TAK-438 showed significant antisecretory activity with or without cimetidine pretreatment, in contrast to lansoprazole, which did not show antisecretory activity after cimetidine pretreatment in rats. TAK-438 increased the pH of the gastric perfusate to 5.7 in an unstimulated condition, and this effect was maintained in the presence of subsequent histamine stimulation. On the other hand, lansoprazole also increased the pH in an unstimulated condition, but this effect diminished after histamine stimulation. These results indicated that TAK-438 exerted a more potent and longer-lasting antisecretory effect than lansoprazole through high accumulation and slow clearance from the gastric tissue. In addition, TAK-438 was unaffected by the gastric secretory state, unlike PPIs. Therefore, TAK-438 can provide a novel mechanism of action to improve the present PPI-based treatment of acid-related diseases.     

Clinical effect of proton pump inhibitors on reflux esophagitis]

The clinical efficacy of proton pump inhibitors (PPI, omeprazole 20 mg or lansoprazole 30 mg), once daily, after breakfast, was studied in patients with erosive/ulcerative reflux esophagitis. The following results were obtained. 1) Twenty-four hour esophageal pH monitoring was performed before treatment and on 7th day of PPI medications. Omeprazole reduced the percent time pH less than 4 from 29.1 to 1.2 and lansoprazole from 68.0 to 2.4. 2) The cumulative disappearance rate of overall symptom was 52% after 1 week and 62% after 2 weeks with omeprazole these were 66% and 91%, and with lansoprazole respectively 3) The endoscopic healing rate was 63% was after 2 weeks and 76% after 4 weeks with omeprazole medication, and 76% and 97% respectively with lansoprazole. These results indicate that PPI medication inhibits the acid reflux almost completely and is a more useful therapeutic agent for GERD than H2-antagonists.     

The proton-pump inhibitors: similarities and differences

OBJECTIVE: This paper examines the clinical pharmacology of the proton-pump inhibitors (PPIs) and briefly reviews some comparative studies of these agents. BACKGROUND: PPIs have emerged as the treatment of choice for acid-related diseases, including gastroesophageal reflux disease (GERD) and peptic ulcer disease. Although these drugs-omeprazole, lansoprazole, pantoprazole, and rabeprazole-share a common structure (all are substituted benzimidazoles) and mode of action (inhibition of H+,K+-adenosine triphosphatase [ATPase]), each differs somewhat in its clinical pharmacology. RESULTS: In comparative clinical trials found in MEDLINE, PPIs administered once daily produced endoscopic evidence of healing in >90% of patients with duodenal ulcer after 4 weeks of treatment, in >90% of those with gastric ulcer after 6 weeks of treatment, and in >90% of those with ulcerative or erosive GERD after 8 weeks of treatment. Maintenance therapy with daily doses of a PPI has been shown to be an effective means of preventing GERD relapse. PPIs also inhibit the growth of Helicobacter pylori, now recognized as an important factor in peptic ulcer disease, and, when administered in combination with antibiotics, provide the best treatment for eradication of the bacterium. Rabeprazole has a more rapid onset of H+,K+-ATPase inhibition than the other PPIs and, compared with omeprazole, a greater effect on intragastric pH after the first dose. Omeprazole and lansoprazole have a greater potential for drug-drug interactions than do pantoprazole and rabeprazole. CONCLUSION: Although the individual PPIs have similar efficacy in many cases, differences between them should be considered when choosing a treatment regimen.     

A comparison of some of the pharmacological properties of etintidine, a new histamine H2-receptor antagonist, with those of cimetidine, ranitidine and tiotidine

Etintidine is a competitive antagonist of histamine H2-receptors in the isolated spontaneously beating guinea-pig right atrium with a pA2 value of 6.6 relative to values of 6.2, 6.7 and 7.3 for cimetidine, ranitidine and tiotidine, respectively. Low affinities for histamine H1 (pA2 = 4.2), cholinergic (pA2 = 4.4) and beta adrenergic (pA2 = 3.8) receptors indicated that etintidine has a high degree of specificity for the H2-receptor. The other antagonists studied also exhibited low affinities for these receptors; however, relative to these compounds, etintidine demonstrated a somewhat greater affinity for cholinergic receptors. Etintidine also antagonized basal gastric acid secretion in the conscious gastric fistula rat and histamine, pentagastrin, carbachol, 2-deoxy-D-glucose and meal-stimulated gastric acid secretion in conscious gastric fistula and Heidenhain pouch dogs. After oral administration to conscious Heidenhain pouch dogs, ED50 values for the inhibition of near maximal gastric acid secretion stimulated by histamine were 7.1, 5.4, 0.74 and 0.69 mumol/kg for cimetidine, etintidine, ranitidine and tiotidine, respectively. Onset and duration of the gastric antisecretory activities of the four compounds were similar. The order of potency as histamine H2-receptor and gastric antisecretory antagonists was cimetidine less than etintidine less than ranitidine less than tiotidine. Based on the high degree of specificity for the H2-receptor and its potent gastric antisecretory activity, etintidine may prove to be a useful agent in the treatment of peptic ulcer disease.     

The effect of subchronic administration of 7-(4-fluorobenzyloxy)-2,3-dimethyl-1-{[(1S,2S)-2-methylcyclopropyl]methyl}-1H-pyrrolo[2,3-d]pyridazine (CS-526), a novel acid pump antagonist, on gastric acid secretion and gastrin levels in rats

In the present report, we evaluated the effect of the novel acid pump antagonist 7-(4-fluorobenzyloxy)-2,3-dimethyl-1-{[(1S,2S)-2-methylcyclopropyl]methyl}-1H-pyrrolo[2,3-d]pyridazine (CS-526) and 2-[3-methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-ylmethanesulfinyl]-1H-benzimidazole (lansoprazole) on rebound gastric acid secretion, using an intragastric dialysis membrane perfusion model and on the serum and antral gastrin level after a 14-day treatment in rats. The effect of CS-526 on gastric acid secretion was almost constant during the 14 days of treatment. After the 14-day treatment, gastric acid secretion had returned to pretreatment levels. However, CS-526 slightly increased and lansoprazole potently increased gastric acid secretion thereafter. In the posttreatment period, the influence on rebound gastric acid secretion by lansoprazole treatment was significant, but that by CS-526 was not. The serum gastrin concentration after the 14-day treatment with CS-526 did not increase significantly, even at 100 mg/kg/day. On the other hand, lansoprazole at 100 mg/kg/day significantly elevated the serum gastrin concentration. After the 14-day treatment with CS-526 at 100 mg/kg/day, the antral gastrin content significantly increased. Lansoprazole at the doses of 30 and 100 mg/kg/day also significantly increased the antral gastrin content after the 14-day treatment. The elevation of the serum gastrin level after the lansoprazole treatment was suppressed by the concomitant administration of CS-526. In conclusion, CS-526 has a potent antisecretory effect on gastric acid secretion without rebound gastric hypersecretion. Moreover, CS-526 had minimal effects on the serum and antral gastrin elevation. It is suggested that these effects on gastric acid secretion and serum gastrin after subchronic treatment with CS-526 would be beneficial in clinical use.     

Clinico-pharmacological evaluation of omeprazole, as a proton pump inhibitor, compared with H2-blockers]

We evaluated the safety, tolerance, pharmacokinetics and pharmacodynamics of omeprazole, a new anti-ulcer agent chiefly on the basis of our studies in healthy male volunteers. The type and incidence of side effects of omeprazole have been reported to be similar to those of H2-antagonists, and in our studies too, omeprazole was estimated to be safe and tolerable. Following single doses, the increase in AUC was not proportional to the increase in dosage. In the multiple-dose study, the AUC was greater on day 7 than on day 1. This finding may be due to a partial saturation of first pass elimination. Repeated omeprazole treatment (20 mg once daily for 4 days) inhibited the basal and stimulated acid secretion. Though H2-blockers inhibit the basal and stimulated pepsin secretion, omeprazole inhibited the stimulated pepsin secretion only.     

Growth inhibition of Ureaplasma urealyticum by the proton pump inhibitor lansoprazole: direct attribution to inhibition by lansoprazole of urease activity and urea-induced ATP synthesis in U. urealyticum.

The proton pump inhibitors (PPIs) omeprazole and lansoprazole and the acid-activated analog of lansoprazole AG-2000, which potently inhibit the urease of Helicobacter pylori (K. Nagata, H. Satoh, T. Iwahi, T. Shimoyama, and T. Tamura, Antimicrob. Agents Chemother. 37:769-774, 1993), also inhibited the urease activities of cell-free extracts as well as intact cells of Ureaplasma urealyticum. The 50% inhibitory concentrations were between 1 and 25 microM. These compounds also inhibited the ATP synthesis induced by urea in ureaplasma cells. The 50% inhibitory concentrations for ATP synthesis were close to those for urease activity, but they were lower than those of urease inhibitors, such as acetohydroxamic acid, hydroxyurea, and thiourea. In addition, one of the metabolites of lansoprazole found in human urine, M-VI, also inhibited ureaplasmal urease activity and the ATP synthesis induced by urea at almost the same concentrations as those of lansoprazole. The inhibition of PPIs against ureaplasma urease was very similar to those against H. pylori urease, suggesting that the inhibitory mechanism against these ureases was due to the blockage of the SH residues on the cysteine of the enzyme. Omeprazole, lansoprazole, AG-2000, and M-VI inhibited the growth of U. urealyticum. Since ureaplasma urease is thought to be involved in the pathogenicity of this organism in the urogenital tract, PPIs and their analogs may be useful as chemotherapeutic agents against diseases caused by U. urealyticum.     

Effects of ORF 17583, other histamine H2-receptor antagonists and omeprazole on gastric acid secretory states in rats and dogs

ORF 17583, a histamine H2-receptor antagonist, inhibited gastric acid secretion in pylorus-ligated rats (ED50 = 4.9 mg/kg intraduodenal; 3.4 mg/kg p.o.; and 0.21 mg/kg i.p.) and in total gastric fistula or Heidenhain pouch dogs stimulated by betazole (ED50 = 0.12 mg/kg p.o. and 0.08 mg/kg i.v.), histamine, tetragastrin, bethanechol, 2-deoxy-D-glucose or a meal (ED50 values ranged from 0.11-0.26 mg/kg p.o.). The nonspecific inhibition of gastric acid by ORF 17583 supports the existence of interdependence between histamine and the gastrin and cholinergic receptors on the parietal cell surface. Antisecretory potency of ORF 17583 after intraduodenal administration in pylorus-ligated rats was 6.4 times greater than cimetidine, 1.8 times greater than ranitidine, equal to that of omeprazole and 8 times less than that of famotidine. Oral antisecretory potency of ORF 17583 in gastric fistula dogs was 31 times greater than cimetidine, 3.7 times greater than ranitidine and equal to that of omeprazole and famotidine. Studies using equieffective antisecretory doses of ORF 17583 and ranitidine in dogs suggested that ORF 17583 has a short duration of antisecretory activity similar to that of ranitidine.     

Potent inhibitory action of the gastric proton pump inhibitor lansoprazole against urease activity of Helicobacter pylori: unique action selective for H. pylori cells.

The gastric proton pump inhibitor lansoprazole, its active analog AG-2000, and omeprazole dose dependently inhibited urease activity extracted with distilled water from Helicobacter pylori cells; the 50% inhibitory concentrations were between 3.6 and 9.5 microM, which were more potent than those of urease inhibitors, such as acetohydroxamic acid, hydroxyurea, and thiourea. These compounds also inhibited urease activity in intact cells of H. pylori and Helicobacter mustelae but did not inhibit ureases from other bacteria, such as Proteus vulgaris, Proteus mirabilis, and Providencia rettgeri. The mechanism of urease inhibition was considered to be blockage of the SH groups of H. pylori urease, since SH residues in the enzyme decreased after preincubation with lansoprazole and glutathione or dithiothreitol completely abolished the inhibitory action. The SH-blocking reagents N-ethylmaleimide and idoacetamide were also examined for their inhibition of the urease activity; their 50% inhibitory concentrations were 100- to 1,000-fold higher than those of lansoprazole. These results suggest that lansoprazole and omeprazole can potently and selectively inhibit H. pylori urease and that inhibition may be related to earlier findings indicating that these compounds have selective activity against HP growth.     

Proton pump inhibitors: an update

Since their introduction in the late 1980s, proton pump inhibitors have demonstrated gastric acid suppression superior to that of histamine H2-receptor blockers. Proton pump inhibitors have enabled improved treatment of various acid-peptic disorders, including gastroesophageal reflux disease, peptic ulcer disease, and nonsteroidal antiinflammatory drug-induced gastropathy. Proton pump inhibitors have minimal side effects and few significant drug interactions, and they are generally considered safe for long-term treatment. The proton pump inhibitors omeprazole, lansoprazole, rabeprazole, and the recently approved esomeprazole appear to have similar efficacy.     

Effect of histamine H2-receptor antagonists on vitamin B12 absorption.

OBJECTIVE: To discuss the potential of histamine H2-receptor antagonists (H2RAs) to cause malabsorption of vitamin B12 (cyanocobalamin). DATA SOURCES: Pertinent literature was identified via a MEDLINE search. Journals and references cited in published articles also were used as data sources. STUDY SELECTION: Studies evaluating the effect of H2RAs on vitamin B12 absorption were reviewed. DATA SYNTHESIS: H2RAs decrease acid secretion by the gastric parietal cells. Gastric acid and pepsin produced by these cells are required for the cleavage of vitamin B12 from dietary sources. Intrinsic factor (IF), also produced by gastric parietal cells, is required for vitamin B12 absorption from the gastrointestinal tract. Although H2RAs have not conclusively been shown to decrease IF secretion, studies have demonstrated a significant reduction in food-bound vitamin B12 absorption secondary to decreased acid secretion in patients taking these drugs. CONCLUSIONS: H2RAs have the potential to cause vitamin B12 deficiency. This may be important in patients with inadequate stores of vitamin B12 (e.g., poor diet), particularly those receiving H2RA therapy continuously for more than two years. Healthcare providers should be aware of this potential adverse effect.     

Rabeprazole: the role of proton pump inhibitors in Helicobacter pylori eradication

Proton pump inhibitors have become one of the cornerstones in the treatment of Helicobacter pylori infection. Rabeprazole (Pariet) is a substituted benzimidazole proton pump inhibitor with potent gastric acid suppression properties. Its high acid-base dissociation constant allows activation over a broader pH range, resulting in quick, irreversible binding to the H+/K+-ATPase pump, and a more rapid onset of action compared with omeprazole, lansoprazole and pantoprazole. Unlike other proton pump inhibitors, the metabolism of rabeprazole is primarily via a nonenzymatic reduction to the thioether derivative, and the cytochrome P450 isoenzyme 2C19 is only partly involved in its metabolism. The effect of genetic polymorphism in cytochrome P450 isoenzyme 2C19 on the pharmacokinetics and pharmacodynamics of rabeprazole is therefore limited. In humans, once-daily dosing of 5-40 mg of rabeprazole inhibits gastric acid secretion in a dose-dependent manner. In vitro studies have shown that rabeprazole possesses more potent antibacterial properties against the growth of H. pylori than other proton pump inhibitors. Furthermore, its thioether derivative has more potent inhibitory in vitro activity against the growth and motility of clarithromycin-resistant H. pylori than other proton pump inhibitors or commonly used antimicrobials. Despite these inherent favorable characteristics of rabeprazole, randomized controlled trials have largely shown equivalence amongst proton pump inhibitors when used with two antibiotics in the eradication of H. pylori, with cure rates of 75-89% on an intent-to-treat basis. However, rabeprazole appears to consistently achieve such comparable eradication rates even when used at reduced doses (10 mg twice daily) as part of clarithromycin-based triple therapy.     

Clinical experience with pantoprazole in gastroesophageal reflux disease

BACKGROUND: Pantoprazole is a new proton pump inhibitor indicated for the treatment of erosive esophagitis associated with gastroesophageal reflux disease (GERD) and is available in both oral and intravenous (IV) formulations. OBJECTIVE: This paper reviews the pharmacologic properties of pantoprazole and summarizes the findings from clinical studies of this drug. METHODS: This review was compiled from the published literature, abstracts from clinical trials, and data on file with the manufacturer of pantoprazole. RESULTS: Pantoprazole selectively accumulates in the acidic environment of gastric parietal cells and acts at the final step of acid secretion by binding 2 key cysteine residues of the proton pump involved in gastric acid production. The bioavailability of pantoprazole is not altered by concomitant administration of food or antacids or with repeated dosing. Both oral and IV formulations of pantoprazole exhibit linear pharmacokinetics. Several clinical trials have proved pantoprazole superior to histamine-2-receptor antagonists (H2RAs) in reducing acid secretion and elevating gastric pH levels. Pantoprazole has been shown to be more effective than ranitidine (P < 0.05), famotidine (P < 0.001), and nizatidine (P < 0.05), and at least as effective as omeprazole, in healing erosive esophagitis and relieving associated symptoms of GERD, including regurgitation. Pantoprazole is also more effective than the H2RA nizatidine for the treatment of nighttime heartburn (P < 0.05). Studies have shown pantoprazole to be well tolerated; adverse events, including headache, diarrhea, flatulence, abdominal pain, eructation, nausea, and rash, occurred in < or = 6% of patients. The oral and IV formulations of pantoprazole are equally potent in inhibiting gastric acid secretion; thus, switching between formulations requires no dosage adjustments. Special patient populations, including the elderly and patients with renal or mild to moderate hepatic impairment, can take pantoprazole without an adjustment in dosage. CONCLUSIONS: Because of its unique pharmacokinetic properties, mechanism of action, and reduced potential for producing cytochrome P-450-based drug interactions, pantoprazole in both oral and IV formulations is effective over a full 24 hours and is well tolerated in a variety of patient types.     

Antisecretory and antiulcer activities of a novel proton pump inhibitor AG-1749 in dogs and rats

The antisecretory and antiulcer activities of 2[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl] sulfinyl]-1H-benzimidazole (AG-1749) were investigated in dogs and rats. AG-1749 inhibited both the (H+ + K+)-adenosine triphosphatase activity in canine gastric microsomes and dibutyryl cyclic AMP-stimulated acid formation in isolated canine parietal cells and suppressed the acid secretion stimulated by histamine, pentagastrin, bethanechol or a peptone meal in Heidenhain pouch dogs; the ID50 values were between 0.2 and 0.7 mg/kg p.o. AG-1749 inhibited both the histamine-stimulated and the basal acid secretion in pylorusligated rats and prevented water immersion stress or aspirin-induced gastric lesions and mepirizole or cysteamine-induced duodenal ulcers in rats; the ID50 values were between 0.3 to 3.6 mg/kg p.o. or i.d. Furthermore, AG-1749 prevented gastric lesions induced by absolute ethanol or acidified aspirin, and accelerated the healing of acetic acid-induced gastric or duodenal ulcers in rats. The inhibitory potency of AG-1749 in dogs was much the same as that of omeprazole and about half that of ranitidine. However, it was about 2 to 10 times more potent than omeprazole and 4 to 34 times more potent than ranitidine in rats. These results suggest that AG-1749 exerts prominent antiulcer activities mainly by suppressing acid secretion via an inhibition of a proton pump in gastric parietal cells and partly by protecting the gastrointestinal mucosa against various ulcerative stimuli.     

Possible mechanisms for (H+ + K+)-ATPase inhibition by proton pump inhibitors, omeprazole, lansoprazole and SCH 28080]

Proton pump inhibitors are classified into two distinct types, and the mechanisms are reviewed. Substituted benzimidazole such as omeprazole and lansorrazole, inhibit (H+ + K+)-ATPase by reacting with SH groups of enzyme after the drugs are transformed into their active forms in the acidic environment of the intracellular canaliculi of parietal cells. This type of enzyme inhibition results in potent and long-lasting inhibition of gastric acid secretion. On the other hand, substituted imidazo pyridines, such as SCH 28080, inhibit (H+ + K+)-ATPase by competing with K+. This inhibition is reversible and the antisecretory effect is short-lived. Recent studies on DNA cloning and sequencing for (H+ + K+)-ATPase have led to a better understanding of enzyme structure and also the sites of action of the proton pump inhibitors.