The effect of histamine H2 receptor blockers on reparative processes in the gastric mucosa of patients with gastric peptic ulcer

AIM: To investigate effects of histamine H2-receptor antagonists (cimetidine, famotidine) on proliferative activity of gastric mucosa of patients with acute gastric ulcer. MATERIALS AND METHODS: We treated 74 patients (54 men and 20 women) with acute benign mediogastric ulcer at the age of 28-56 years. Group 1 consisted of 24 patients who received antacid; group 2--of 26 patients on 1 g/day cimetidine; group 3--24 patients who received famotidine 40 mg qPM. We assessed clinical efficiency of three-week therapy, grade of ulcer healing, proliferative activity of antral and fundic gastric epithelium and ulcer margin epithelium using autoradiography with 3H-thymidine. RESULTS: Clinical efficiency of histamine H2-receptor antagonists was significantly higher than of antacid. Cimetidine and famotidine stimulate proliferative activity in the epithelium of ulcer margins. CONCLUSION: The ability to stimulate proliferative activity of gastric mucosa makes H2-receptor antagonists an effective modality in acute gastric ulcer with low acid secretion.     

Effects of cimetidine, a histamine H2-receptor antagonist, on various experimental gastric and duodenal ulcers.

The effects of cimetidine, a new histamine H2-receptor antagonist, on the development of experimental gastric and duodenal ulcers were studied. It was found that either by the oral, intraduodenal, or intraperitoneal route this agent had a marked inhibitory activity on stress-, aspirin-, indomethacin-, or histamine-induced gastric ulcers in rats and guinea pigs. The effects of cimetidine on stress-, aspirin-, and indomethacin-induced gastric ulcers were dose-dependent in many cases. Pylorus-ligation uclers, reserpine- or serotonin-induced gastric ulcers were little influenced by cimetidine. Duodenal ulcers induced by continuous infusion of carbachol-histamine were significantly inhibited by a simultaneous infusion of cimetidine. An analysis of gastric contents in pylorus-ligated rats after stressing indicated a decreased volume and acid output as the result of intraduodenal cimetidine treatment. In contrast, cimetidine exerted little influence on gastric secretion in rats treated with aspirin or in guinea pigs treated with histamine. Thus, the mechanism of action of cimetidine in preventing gastric or duodenal ulcers is likely to occur by suppression of gastric secretory function in a duodenal ulcer model but by suppression of other unknown ulcerogenic factors in gastric ulcer models.     

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.     

Effects of four H2 histamine antagonists on bethanechol-stimulated acid and pepsin secretion in the dog

In five gastric fistula dogs, each of four H2-receptor antagonists was given (at doses roughly equal to the dose inhibiting histamine stimulation at 50%) as background infusion to graded doses of i.v. bethanechol. We measured acid and pepsin secretion and gastrin release. All four compounds noncompetitively inhibited acid secretion, reducing maximum acid outputs by 50 to 70%. Two compounds, tiotidine and cimetidine, shifted the bethanechol dose-response for pepsin secretion about 30% to the right at midpoint without reducing maximum output significantly, whereas the other two, ranitidine and metiamide, did not alter the dose-response. Dose-dependent gastrin release was unaffected by cimetidine, an imidazole compound, and augmented by tiotidine and ranitidine, the two nonimidazole compounds. Actions on pepsin and gastrin are thus not related to H2-receptor effects. The uniform effect of the four antagonists on acid secretion indicates an essential interaction between cholinergic and histamine effects on the parietal cell, although we could not distinguish between prereceptor, receptor and postreceptor sites for such interaction.     

Effect of H2-receptor blockade on gastric mucus composition. A comparative study with ranitidine and famotidine

The effects on gastric mucus by two different H2-receptor antagonists, famotidine and ranitidine, have been investigated in 20 patients with duodenal ulcer. Before and after 4 weeks' treatment with either drug the quality of mucus secretion was assessed by means of a 'mucoprotective index'. A significant (P less than 0.01) decrease in the values of this index was observed in famotidine-treated subjects, whereas no changes were detected in those given ranitidine. The findings of this study with famotidine are in keeping with the results previously reported with cimetidine using the same method. It is suggested that blockade of gastric H2-receptors alters the composition of gastric mucus in man. This effect is not shared by ranitidine.     

Effect of histamine H1- and H2-receptor blockade on canine gastric acid secretion

In dogs with gastric fistulae and Heidenhain pouches, inhibition of histamine-stimulated gastric acid secretion by the histamine H2-receptor antagonist metiamide is not increased by the addition of a histamine H1-receptor antagonist (mepyramine maleate). Under the conditions of this study there is no evidence for the presence of histamine H1-receptor sites on the gastric parietal cell.     

Inhibition of nocturnal acid secretion in duodenal ulcer patients by an H-2 histamine antagonist-cimetidine. A controlled double-blind investigation.

A new H-2-receptor antagonist, cimetidine, was tested as to its ability to suppress overnight gastric acid secretion in 8 male duodenal ulcer patients. In a double-blind controlled investigation, each volunteer was studied during four consecutive nights. In randomized order they received either 100, 200, or 300 mg of cimetidine or a placebo. No untoward clinical orlaboratory effects of the drug were found. Single-dose oral administration of 300 mg cimetidine caused a significant (P less than 0.05) inhibition of overnight gastric acid secretion for an 8-hr period, with the intragastric pH staying between 3.5-6.0. Cimetidine, because of its potent gastric acid inhibitory effect, may become an important therapeutic agent in the management of peptic ulcer disease.     

RANITIDINE—PHARMACOLOGY AND CLINICAL USE

Ranitidine is a new histamine H₂-receptor antagonist which differs in chemical structure from both histamine and cimetidine. Animal studies have shown that it is a potent, specific competitive antagonist with a highly effective inhibitory action upon the release of acid and pepsin in gastric secretion invoked by a wide range of secretory stimulants. Similar pharmacological properties have been shown in man. It has no other measurable pharmacological effect resulting from blockade of histamine H₂-receptors, nor does it appear to exert any other biological effects in man. The gastric secretory inhibitory effects of ranitidine are qualitatively similar to those of cimetidine but are 4–9 times more potent on a weight-for-weight basis. The pharmacodynamics and pharmacokinetics are such that by administering ranitidine 150 mg morning and night, effective inhibition of intragastric acidity is achieved. Ranitidine has a greater selectivity of action than cimetidine so avoiding certain unwanted effects such as interference with enzymic degradation of a wide range of drugs metabolised by the liver mixed function oxygenase system, antiandrogenic effects and the propensity to cause confusion in the elderly. In short term treatment of duodenal ulceration, ranitidine 150 mg twice daily relieves symptoms and heals ulcers with an expected rate of approximately 80% over four weeks rising to over 90% during eight weeks of treatment, compared with placebo healing rates of around 30%. Similarly, the gastric ulcer healing rate of 60–70% at four weeks and 85% at three months was superior to placebo rates of 40–50%. In both duodenal and gastric ulcer, responses were similar to those previously reported with cimetidine. Nightly maintenance treatment with ranitidine 150 mg significantly reduces the rate of recurrence in patients with duodenal or gastric ulceration. In reflux oesophagitis, ranitidine 150 mg twice daily for six weeks reduces symptoms, and improves endoscopic appearances. Higher doses of ranitidine have been shown to control patients with the Zollinger-Ellison syndrome resistant to cimetidine. There are some reports of beneficial effects of ranitidine on acute upper gastrointestinal haemorrhage. Administered before anaesthesia, ranitidine decreases the volume and elevates the pH of gastric juice and may reduce morbidity and mortality arising from aspiration pneumonitis.     

Actions of nizatidine, a selective histamine H2-receptor antagonist, on gastric acid secretion in dogs, rats and frogs

Nizatidine (LY139037), a selective histamine H2-receptor antagonist, is a potent inhibitor of gastric acid secretion. It was 17.8 times as active as cimetidine on histamine (10(-5) M)-induced secretion from the isolated gastric mucosa of the bullfrog. Nizatidine was 8.9 times as active as cimetidine on basal acid secretion of the chronic gastric fistula rats after s.c. administration. Against acid secretion from the vagally innervated gastric fistula and Heidenhain pouch of dogs stimulated with submaximal doses of histamine, methacholine and gastrin, nizatidine was, respectively, 6.5, 5 and 4.7 times as active as cimetidine by i.v. administration. Nizatidine was very well absorbed from the gut and was 5 to 10 times as active as cimetidine on gastric acid secretion of dogs induced by submaximal and maximal doses of histamine when given p.o. Equal molar doses of nizatidine showed equal peak effects when given i.v., s.c. or i.m. Pharmacological data indicate that nizatidine is safe and effective as an agent for the control of excessive gastric acid secretion.     

The effect of an H2-receptor antagonist on food-stimjlated acid secretion, serum gastrin, and gastric emptying in patients with duodenal ulcers. Comparison with an anticholinergic drug.

The purpose of the present series of experiments was to measure and compare the effects of an anticholinergic drug (isopropamide) and an antagonist of the histamine H2 receptor (metiamide) on food-stimulated acid secretion. Patients with duodenal ulcers were stimulated by a steak meal, and acid secretion was measured by in vivo intragastric titration. The largest dose of isopropamide that can be taken clinically without producing intolerable side effects (maximum tolerated dose) suppressed food-stimulated acid secretion by 35%. By contrast, metiamide in a 400-mg dose produced no side effects and almost completely abolished food-stimulated acid secretion. A dose-response curve revealed that a 50-mg dose of metiamide was required to suppress food-stimulated acid secretion by 50%. Further studies showed that metiamide and isopropamide are additive in suppressing food-stimulated acid secretion, and that metiamide has no effect on serum gastrin concentration or on gastric emptying.     

Pharmacology of ORF 17578, a new histamine H2-receptor antagonist: comparison with cimetidine and ranitidine

This paper describes the pharmacology of ORF 17578, a new histamine H2-receptor antagonist, in comparison to the standard H2-blockers cimetidine and ranitidine. ORF 17578 inhibited betazole-stimulated gastric acid output in gastric fistula dogs and gastric acid secretion in pylorus-ligated rats. When administered enterally (p.o. or i.d.) ORF 17578 (ED50 = 0.21 mg/kg in dogs and 2.5 mg/kg in rats) was 10 to 11 times more potent than cimetidine and 1.8 to 2.1 time more potent than ranitidine in dogs and rats. In both species, duration of p.o. antisecretory activity was longer than with ranitidine. When administered parenterally ORF 17578 (ED50 = 0.15 mg/kg i.v. in dogs and 1.1 mg/kg i.p. in rats) was more potent than cimetidine and ranitidine in rats and similar in potency to ranitidine in dogs. Comparison of parenteral to enteral potencies suggests that ORF 17578 was well absorbed from the gastrointestinal tract of both species with a bioavailability profile similar to that of ranitidine. In rabbit isolated parietal cells (pA2 = 7.53) and guinea-pig isolated atria (pA2 = 7.26), ORF 17578 competitively antagonized the effects of histamine with a potency greater than cimetidine and similar to ranitidine. Results from several additional test systems indicated that ORF 17578 was specific for the histamine H2-receptor and did not exhibit the additional pharmacology often associated with cimetidine.     

Effect of omeprazole and cimetidine on healing of chronic gastric ulcers and gastric acid secretion in rats

The effect of omeprazole and cimetidine on healing of chronic gastric ulcers and gastric acid secretion was investigated in rats. The effect of three doses of omeprazole given orally once daily for 25 days was investigated. In controls median ulcer healing was 19.6% after 25 days. Omeprazole increased median ulcer healing from 36% at 145 mumole/kg/day to 80% at 580 mumole/kg/day. Basal and pentagastrin stimulated gastric acid secretion decreased dose-dependently by nearly 90% at a dose of 580 mumole/kg/day 22-24 hr after the last dose of omeprazole. Cimetidine given twice daily, in a dose that initially inhibits gastric acid secretion by 95%, reduced acid secretion by only 50% 11 hr after the last dose. Median ulcer healing after treatment with cimetidine for 25 days was 41%. This study demonstrates that omeprazole has a more long-acting inhibitory effect on gastric acid secretion compared to cimetidine and accelerates healing of chronic gastric ulcers dose-dependently in rats.     

Effects of ranitidine and of cimetidine on pentagastrin-stimulated gastric acid secretion

We compared the effect of oral and intravenous ranitidine, a new H2-receptor antagonist, with that of cimetidine on pentagastrin-stimulated gastric acid secretion in normal subjects. Ranitidine in intravenous doses of 20, 60, and 100 mg and oral doses of 100, 150, and 200 mg inhibited acid secretion. Only the 100 mg iv ranitidine dose was substantially more effective than cimetidine. Comparable dose-related decreases in gastric secretory volume were observed. Acid inhibition correlated strongly (r = 0.90) with plasma ranitidine concentration, with the estimated plasma concentration producing 50% inhibition (IC50) being 95 ng/ml. Maximal acid inhibition achieved was 87.3%. We conclude that ranitidine is a potent inhibitor of gastric acid secretion and should be a valuable addition to the medical treatment of acid-peptic disease.     

Identification and specific blockade of two receptors for histamine in the cardiovascular system.

Histamine caused a fall in blood pressure in anesthetized dogs and cats which was only partially attenuated by mepyramine (pyrilamine), a histamine type H1-receptor antagonist. Further treatment with burimide or metiamide, type H2-receptor antagonists, caused nearly complete attenuation of the response to histamine. Burimamide alone had no effect on vasodilatation produced by histamine in the dog gracilis muscle whereas mepyramine alone caused a partial attenuation. An H2-receptor agonist, 4-methylhistamine and an H1-receptor agonist, 2-(2-pyridyl)ethylamine, both produced vasodilatation which was blocked by metiamide and mepyramine, respectively. Constriction of the saphenous vein produced by histamine was found to involve interaction with H1-receptors only. In the intact dog, histamine increased heart rate and decreased left ventricular dp/dt through direct effects. Mepyramine prevented the increase in heart rate but did not affect the chronotropic actions of isoproterenol and glyceryl trinitrate. H1-receptor blockade did not alter inotropic effects whereas subsequent H2-receptor blockade prevented the negative inotropic effect of histamine. It is concluded that both peripheral vascular and cardiac responses to histamine are mediated through activation of H1- and H2-histamine receptors.     

The role of mucoprotective drugs in gastric ulcer treatment: with specifical reference to their effects on gastritis mucosa

A study group supported by Ministry of Health, Labor and Welfare recently reported the Japanese guideline for gastric ulcer treatment which suggests that gastric ulcer can be cured by either H. pylori eradication or acid suppression therapy by proton pump inhibitors(PPI) and H2-receptor antagonists(H2RA). It also suggests that all mucoprotective drugs except sucrafate, misoprostol and enprostil can't be recommended for gastric ulcer treatment. However, some mucoprotective drugs have been shown to possess anti-inflammatory action, leading to the inhibition of leucocyte infiltration in H. pylori gastritis, while long-term usage of PPI and H2RA might worsen gastritis. Thus, mucoprotective drugs should be investigated in terms of long-term effects on H. pylori-gastritis rather than the effects on gastric ulceration.     

Proton pump inhibitors in the treatment of peptic ulcers resistant to H2-receptor antagonists]

The aim of this study is to evaluate the therapeutic effect of proton pump inhibitors on peptic ulcers resistant to H2-receptor antagonists. Patients with ulcers resistant to at least 3 months treatment with standard or greater doses of H2-receptor antagonists were treated with 20 mg of omeprazole or 30 mg of lansoprazole, once daily, for 2 to 8 weeks. Endoscopy was performed every 2 weeks to confirm ulcer healing. Eleven of 28 (39%) gastric ulcers healed within 4 weeks and 20 (71%) within 8 weeks with omeprazole. Eight of 19 (42%) gastric ulcers healed within 4 weeks and 14 (74%) within 8 weeks with lansoprazole. All of the duodenal ulcer healed within 6 weeks with omeprazole or lansoprazole. No adverse effects were observed in this study. These results suggest that proton pump inhibitors are highly effective in the treatment of peptic ulcer resistant to H2-receptor antagonists.     

Decreased oral warfarin clearance after ranitidine and cimetidine

Oxidative metabolism inhibition of a number of drugs by cimetidine has been attributed to its imidazole ring, a hypothesis that has been supported by reports that ranitidine does not affect drug metabolism despite being five times as potent as cimetidine as an H2-receptor antagonist. In five healthy subjects ranitidine at 150 mg twice daily induced a 27% fall in apparent oral warfarin clearance. In the same subjects cimetidine at 1 gm/day induced a 36% decrease in warfarin clearance. In two of the subjects the experiment was repeated after giving 750 mg ranitidine per day and in two other subjects after 200 mg cimetidine twice daily. In both instances there was a stepwise fall in warfarin clearance with increasing doses. The data indicate that interference with drug metabolism by H2-receptor antagonists is not confined to cimetidine but that on a molar basis ranitidine and cimetidine are roughly equivalent in inhibiting warfarin clearance and that the effects are related to dose.     

Effects of cimetidine upon gastric secretion and mucosal blood flow in the rat stressed by restraint

The effect of the histamine-H2-receptor blocking agent cimetidine (CT) on gastric secretion, mucosal blood flow (MBF), and gastric mucosal stress ulcer index was studied in rats (n = 96) during control conditions (3.9, 15.6, 62.4 microMol/kg/h CT i.p. over 8 h) with calculation of kinetic constants (Vmax; Km) for gastric secretion, MBF and ulcer index, it is shown that CT actions become considerably modified by severe stress. Under mild stress the reduction of MBF and acid secretion by increasing CT doses is parallel. Severe stress alone reduces MBF more than gastric acid (65 vs. 30%). This phenomenon is partly reversed by a dose of 62.4 microMol/kg/h (= 16 mg/kg/h), which is associated with the lowest ulcer index observed. There is no significant correlation between the latter and either acid concentration, acid output, or MBF. The concentrations of pepsin in gastric juice or of serum gastrin neither change with severe stress alone or with additional CT. It is concluded that CT has anti-stress ulcer properties coinciding with reduced acidity in the gastric lumen, but that in addition this beneficial effect may be mediated by factors other than acid reduction.     

Peptic ulcer disease: new developments

The wide array of medications aimed at all levels of acid secretion and at multiple levels of tissue function makes the choice of appropriate treatment for individual patients a challenge. The breakthrough development of cimetidine, followed by the rapid proliferation of new H2-receptor antagonists, new insights into parietal cell function, and the growth in our understanding of mucosal defense will make the treatment of peptic ulcer disease the challenge of the 1990s.     

Interactions between alcohol and gastric metabolizing enzymes: practical implications.

It has been demonstrated recently that some portion of ingested alcohol does not enter the systemic circulation and is not retained in the gastrointestinal tract; instead, gastric oxidation or first-pass metabolism of ethanol occurs in the stomach, catalyzed by gastric alcohol dehydrogenase. First-pass metabolism of ethanol is minimal in the fasting state; it is lower in women than in men, and in alcoholics than in nonalcoholics; and it is abolished in patients after subtotal gastrectomy. In addition, some drugs may affect first-pass ethanol metabolism. Studies of the effects of H2-receptor antagonists on blood ethanol levels are reviewed. It is concluded that some H2-receptor antagonists (cimetidine and nizatidine, in particular) can inhibit gastric ethanol oxidation and thus increase blood alcohol levels after drinking. The clinical and medicolegal implications of these findings are discussed.