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Histamine type 2 receptor antagonists (H2RAs)have been found to alter gastric motility. The aims ofthis study were to determine if H2RAs affect antralcontractility in vitro and the mechanism of this effect. Guinea pig antral muscle strips werepinned in an organ bath after removing the mucosa, andcircular muscle tension was measured using an isometricforce transducer. Gastric myocytes were isolated from guinea pig stomach using collagenasedigestion, and cell lengths were measured using an imageanalysis system. In muscle strips, ranitidine andnizatidine increased the amplitude of spontaneous phasic antral contractions in aconcentration-dependent fashion with thresholdconcentrations of 5 μM. The order of potency for theH2RAs was ranitidine = nizatidine ≫ cimetidine >famotidine. The contractile effects of ranitidine and nizatidine werereduced, but not abolished, by tetrodo- toxin andomega-conotoxin GVIA and nearly abolished by atropine.In isolated cells, ranitidine and nizatidine, but notfamotidine or cimetidine, induced concentration-dependentcell shortening, with maximal shortening at 10 μM.These contractile effects of ranitidine and nizatidinein isolated cells were inhibited by atropine. Ranitidine and nizatidine increase antral contractility;this effect appears to be mediated by an interactionbetween ranitidine and nizatidine on cholinergicpathways with both direct effects on smooth musclecholinergic receptors and indirect effects by increasingcholinergic neurotransmission.

Effect of nizatidine 300 mg at night and omeprazole 20 mg in the morning on 24-hour intragastric pH and bacterial overgrowth in patients with acute duodenal ulcer.Brummer RJ, Stockbrugger RW.Department of Gastroenterology, University Hospital Maastricht, The Netherlands.The study investigated the effect of either nocturnal acid suppression by the H2 antagonist nizatidine 300 mg at night or prolonged acid suppression by the proton- pump inhibitor omeprazole 20 mg in the morning, during four weeks, on intragastric pH profile, occurrence of bacterial growth in gastric fluid and biopsies, and healing rate in 23 patients with an acute duodenal ulcer. The endoscopic healing rate did not differ significantly between the two treatment modalities. The 24-hr acid secretion was significantly more reduced by omeprazole than nizatidine (P < 0.002). After treatment by nizatidine and omeprazole, respectively, median 24-hr intragastric pH increased from 1.5 to 1.8 (P < 0.01) and from 1.5 to 6.1 (P < 0.01), respectively. Nighttime acid inhibition did not differ significantly. The difference in gastric bacterial colonization after either omeprazole or nizatidine did not reach significance. However, median 24-hr pH and the fraction of the day with pH < 3 and pH < 4 were significantly correlated to bacterial colonization of the gastric fluid (P < 0.05).

Nizatidine, a new histamine-2-receptor antagonist, stimulates gastrointestinal motility in dogs and gastric emptying of liquids in rats. Effect of nizatidine on gastric emptying of a solid meal was investigated using a novel gastric emptying model in rats. Male Wistar rats (weighing 200-300 g) were supplied with powdered food containing 30 w/w% barium 14 hr before the beginning of the experiment and x-ray photography of rat stomach was taken under light ether anesthesia. Gastric emptying was assessed by percentage of a decrease in area 30 min after drug was injected intraperitoneally. There was a positive correlation between the area of the gastric outline and the weight of the gastric contents (r = 0.94, P < 0.01). Ether anesthesia itself did not affect gastric emptying. Nizatidine increased gastric emptying dose-dependently (emptied percentage; vehicle: 4.9 +/- 1.5%, 1 mg/kg: 7.2 +/- 0.4%, 3 mg/kg: 10.4 +/- 2.0%, 10 mg/kg: 16.7 +/- 4.9%, 30 mg/kg: 25.7 +/- 7.4%). N-Desmethyl nizatidine (NDM) also stimulated gastric emptying, but nizatidine S-oxide, cimetidine, an famotidine had no significant effects on gastric emptying. Nizatidine and neostigmine, but not NDM, at a subthreshold dose accelerated gastric emptying treated with a low dose of acetylcholine (0.1 mg/kg). Atropine (2 mg/kg, -30 min) did not modulate the gastroprokinetic action of nizatidine, but blocked that of NDM. These findings suggest that this noninvasive method may allow measurement of gastric emptying of solids accurately and that nizatidine and NDM facilitate gastric emptying probably mediated by a direct and/or an indirect (acetylcholinesterase inhibition) cholinergic mechanism.

In a randomized, multicenter trial, nizatidine 150 mg or 300 mg, or placebo, was administered twice daily for six weeks to 515 patients with gastroesophageal reflux disease (GERD). Gelusil antacid tablets were taken as needed for pain. Significantly superior rates of endoscopically proven complete healing (normal-appearing mucosa) versus placebo occurred after three weeks with nizatidine 150 mg, and after six weeks with nizatidine 300 mg. Six-week healing rates were 38.5% for nizatidine 300 mg, 41.1% for nizatidine 150 mg, and 25.8% for placebo. The nizatidine 150 mg treatment group had significantly greater improvement in daytime and nighttime heartburn severity after one day of therapy versus placebo. Twice-daily administration of nizatidine 150 mg or 300 mg provides prompt relief from the major symptom of GERD, heartburn, and complete healing of esophagitis is seen in many patients.

I have read with great interest the article by Sarosiek et al. [1] reporting a stimulatory effect of rabeprazole on esophageal mucin. The article describes a pharmacological property which may have a pivotal role in protecting the esophageal mucosa against gastro-esophageal reflux and which appears to be unique in comparison with other proton pump inhibitors (PPIs). As quoted by Sarosiek et al., if we take into consideration the influence of PPIs on gastric mucin, neither omeprazole nor lansoprazole were found to increase gastric mucus secretion in experimental studies. On the contrary, we already reported, in a double-blind placebo-controlled study, that, in humans, a 4-week treatment with omeprazole 20 mg significantly reduces the amount of total and neutral mucoproteins into the gastric juice, as well as the viscous and protective properties of gastric mucus as assessed by means of a ‘mucoprotective index’ [2]. Gastric mucus secretion reverts to normal only 2 weeks after the drug withdrawal. Similar results were observed with lansoprazole (Guslandi et al., unpublished data). Hence, the finding of a mucus-stimulating effect by rabeprazole suggests that this effect is unrelated to the inhibition of the gastric proton pump and may be due to its specific chemical structure. Similar discrepancies have been shown in our past studies with other acid-inhibiting agents, H2-receptor antagonists. While cimetidine and famotidine promote qualitative alterations in gastric mucus secretion, other H2-blockers such as ranitidine and nizatidine have no similar effects [3, 4]. The ability of rabeprazole to enhance gastric and esophageal mucus secretion represents an additional therapeutic effect of remarkable value in clinical practice.

Inhibition of gastric alcohol dehydrogenase (ADH) activity by cimetidine results in elevated blood levels of ethanol after moderate consumption. To search for alternative H2-blockers lacking such an effect, we compared cimetidine, ranitidine, nizatidine, and famotidine. They inhibited rat gastric ADH noncompetitively, with a Ki for ethanol oxidation of 0.68 mM for cimetidine, 0.5 mM for ranitidine, 1 mM for nizatidine, and 4.5 mM for famotidine. These concentrations are higher than therapeutic plasma levels, but intracellular concentrations in the gastric mucosa (assessed with [3H]cimetidine and [14C]famotidine) were at least 10- and 2-fold greater than in the blood, respectively. These results suggests that, given at therapeutic doses in vivo, the degree of inhibition by cimetidine and ranitidine should be significant and comparable, that by nizatidine should be smaller, and that by famotidine should be negligible. These drugs also exerted either mixed or competitive inhibition of rat hepatic ADH, but the effects of cimetidine and famotidine were observed at concentrations unlikely to occur in vivo. Thus, in alcoholics and in social drinkers who require treatment with H2-receptor antagonists, famotidine might be preferable to the other H2 blockers tested.

In clinical practice, H2-receptor antagonists, including nizatidine, in addition to their use in the treatment of peptic ulcer and gastroesophageal reflux, are also useful in alleviating dyspeptic symptoms. Patients with functional dyspepsia show a tendency to delayed gastric emptying. Results of preliminary studies have demonstrated that nizatidine has a prokinetic effect due to its cholinergic properties. The aim of this study was to evaluate the effect of nizatidine on gastric emptying in patients with functional dyspepsia. Sixteen patients with dyspeptic symptoms referred for gastroscopy by primary care physicians were enrolled in this randomized, placebo-controlled, double-blind cross-over study. They received nizatidine 150 mg twice daily or placebo for 2 months. After a 1-month washout period, the 2-month treatment was repeated, with these patients acting as their own controls. Gastric emptying was measured by scintigraphy, and dyspeptic symptoms and quality of life were evaluated at the end of both treatment periods. Gastric emptying of solids during nizatidine therapy was prolonged (T1/2 110.1 +/- 76.7 vs. 65.6 +/- 23.2 min, P = 0.03), but nizatidine had no effect on gastric emptying of liquids. Nizatidine improved the symptom scores and seven of eight aspects of quality of life - but not significantly. In conclusion, nizatidine decreases the gastric emptying rate of solids without having a significant effect on symptoms or quality of life in functional dyspepsia.

Saliva is a neurally induced solution with buffering capacity against acidic solutions. Salivation therefore plays an important role in defending the esophageal mucosa against refluxed gastric acid and is evoked by cholinergic stimulation. Both nizatidine and cisapride are reported to increase acetylcholine concentrations in the postganglionic cholinergic synapses. We performed this study to clarify the effect of administration of nizatidine and cisapride on salivary secretion. Eight-week-old male Sprague–Dawley rats were used for the experiments. Histamine-stimulated gastric acid secretion was measured after intraduodenal administration of nizatidine or famotidine to determine the equipotent acid-suppressing doses. Salivary secretion was then measured for 3 hr after intraduodenal administration of nizatidine (30 mg/kg), famotidine (3 mg/kg), or cisapride (1 mg/kg). Both nizatidine and famotidine dose-dependently inhibited histamine-stimulated gastric acid secretion. Total salivary secretion was significantly increased by nizatidine (P = 0.02) and cisapride (P = 0.02) but not by famotidine (P = 0.50) compared with controls.

Histamine type 2 receptor antagonists (H2RAs) have been found to alter gastric motility. The aims of this study were to determine if H2RAs affect antral contractility in vitro and the mechanism of this effect. Guinea pig antral muscle strips were pinned in an organ bath after removing the mucosa, and circular muscle tension was measured using an isometric force transducer. Gastric myocytes were isolated from guinea pig stomach using collagenase digestion, and cell lengths were measured using an image analysis system. In muscle strips, ranitidine and nizatidine increased the amplitude of spontaneous phasic antral contractions in a concentration-dependent fashion with threshold concentrations of 5 microM. The order of potency for the H2RAs was ranitidine = nizatidinecimetidinefamotidine. The contractile effects of ranitidine and nizatidine were reduced, but not abolished, by tetrodotoxin and omega-conotoxin GVIA and nearly abolished by atropine. In isolated cells, ranitidine and nizatidine, but not famotidine or cimetidine, induced concentration-dependent cell shortening, with maximal shortening at 10 microM. These contractile effects of ranitidine and nizatidine in isolated cells were inhibited by atropine. Ranitidine and nizatidine increase antral contractility; this effect appears to be mediated by an interaction between ranitidine and nizatidine on cholinergic pathways with both direct effects on smooth muscle cholinergic receptors and indirect effects by increasing cholinergic neurotransmission.

In a randomized, multicenter trial, nizatidine 150 mg or 300 mg, or placebo, was administered twice daily for six weeks to 515 patients with gastroesophageal reflux disease (GERD). Gelusil antacid tablets were taken as needed for pain. Significantly superior rates of endoscopically proven complete healing (normal-appearing mucosa) versus placebo occurred after three weeks with nizatidine 150 mg, and after six weeks with nizatidine 300 mg. Six-week healing rates were 38.5% for nizatidine 300 mg, 41.1% for nizatidine 150 mg, and 25.8% for placebo. The nizatidine 150 mg treatment group had significantly greater improvement in daytime and nighttime heartburn severity after one day of therapy versus placebo. Twice-daily administration of nizatidine 150 mg or 300 mg provides prompt relief from the major symptom of GERD, heartburn, and complete healing of esophagitis is seen in many patients.