Proliferative Effects of Histamine on Primary Human Pterygium Fibroblasts.

Purpose. It has been confirmed that inflammatory cytokines are involved in the progression of pterygium. Histamine can enhance proliferation and migration of many cells. Therefore, we intend to investigate the proliferative and migratory effects of histamine on primary culture of human pterygium fibroblasts (HPFs). Methods. Pterygium and conjunctiva samples were obtained from surgery, and toluidine blue staining was used to identify mast cells. 3-[4, 5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) was performed to evaluate the proliferative rate of HPFs and human conjunctival fibroblasts (HCFs); ki67 expression was also measured by immunofluorescence analysis. Histamine receptor-1 (H1R) antagonist (Diphenhydramine Hydrochloride) and histamine receptor-2 (H2R) antagonist (Nizatidine) were added to figure out which receptor was involved. Wound healing model was used to evaluate the migratory ability of HPFs. Results. The numbers of total mast cells and degranulated mast cells were both higher in pterygium than in conjunctiva. Histamine had a proliferative effect on both HPFs and HCFs, the effective concentration (10 µmol/L) on HPFs was lower than on HCFs (100 µmol/L), and the effect could be blocked by H1R antagonist. Histamine showed no migratory effect on HPFs. Conclusion. Histamine may play an important role in the proliferation of HPFs and act through H1R.

Screening of alternative drugs to the tumor suppressor miR-375 in esophageal squamous cell carcinoma using the connectivity map.

OBJECTIVE: The aim of this study was to identify alternative compounds to the tumor suppressor miR-375 using the connectivity map (CMAP) and to validate the antitumor effects of the identified drugs in esophageal squamous cell carcinoma (ESCC). METHODS: Gene profiling of miR-375-treated TE2 and T.Tn cells was applied in order to search the CMAP database. Among the compounds identified using the CMAP, we focused on 8 drugs [(-)-epigallocatechin-3-gallate, metformin, rosiglitazone among others], excluding 2 drugs among the top 10 compounds. We evaluated whether these compounds possess tumor-suppressive functions in ESCC. RESULTS: A cytotoxicity assay showed that the sensitivity of TE2 and T.Tn cells treated with the 8 compounds was evaluated based on IC50 values of 42.9 µM to 3.8 mM. A cell cycle analysis revealed that the percentage of TE2 and T.Tn cells incubated with 6 compounds in the G0/G1 phase or the G2/M phase increased by approximately 40-80%. A TUNEL assay showed that the percentages of apoptotic cells treated with almost all compounds were significantly increased (p < 0.05) compared with the control cells. CONCLUSION: The CMAP database is a useful tool for identifying compounds affecting the same molecular pathways, particularly products that are difficult to apply via practical approaches, such as microRNAs.

Impact of sleep disorders in Japanese patients with functional dyspepsia (FD): nizatidine improves clinical symptoms, gastric emptying and sleep disorders in FD patients.

BACKGROUND AND AIMS: The association between functional dyspepsia (FD) and sleep disorders has yet to be studied in detail. The aim of this study is to evaluate the risk factors associated with sleep disorders and the clinical response to nizatidine therapy for sleep disorders in Rome III-based FD patients. METHODS: We enrolled 94 FD patients and 52 healthy volunteers. We used Rome III criteria to evaluate upper abdominal symptoms, and the Self-Rating Questionnaire for Depression scores to determine depression status. Sleep disorder was evaluated using Pittsburgh Sleep Quality Index (PSQI) scores, and degree of anxiety by the State-Trait Anxiety Inventory. Gastric motility was evaluated. Thirty-four FD patients were treated with nizatidine (300 mg/day) or placebo for 4 weeks in a crossover trial. The primary end point of this study was to determine whether nizatidine could improve clinical symptoms and sleep disorders in FD patients. RESULTS: The global PSQI score for FD patients was significantly (P < 0.001) higher compared with healthy volunteers. There were significant correlations between global PSQI scores and total Gastrointestinal Symptom Rating Scale and Self-Rating Questionnaire for Depression scores (P < 0.001, P < 0.0001, respectively) in FD patients than in healthy volunteers. We found significant relationships between subjective sleep quality and both Tmax and T1/2 values in FD patients. Nizatidine significantly improved certain clinical symptoms, gastric emptying, and global PSQI score compared with placebo treatment. CONCLUSION: Sleep disorders in FD patients correlated significantly with both clinical symptoms of dyspepsia and depression compared with healthy volunteers. Nizatidine significantly improved gastroesophageal reflux symptoms, gastric emptying, and sleep disorders in FD patients.

Glutaraldehyde-crosslinked chitosan-polyethylene oxide nanofibers as a potential gastroretentive delivery system of nizatidine for augmented gastroprotective activity.

Nizatidine (NIZ), a histamine H2-receptor antagonist, is soluble and stable in the stomach, however, it exhibits a short half-life and a rapid clearance. Therefore, chitosan (CS) and polyethylene oxide (PEO) nanofibers (NFs) at different weight ratios were prepared by electrospinning and characterized. The selected uncrosslinked and glutaraldehyde-crosslinked NFs were investigated regarding floating, solid-state characteristics, in vitro release, and in vitro cytotoxicity. The cytoprotective activity against ethanol-induced gastric injury in rats was evaluated through macroscopical, histopathological, immunohistochemical, and oxidative stress examinations. NFs based on 8:2 CS:PEO exhibited the smallest diameter (119.17 ± 22.05 nm) and the greatest mucoadhesion (22.82 ± 3.21 g/cm2), so they were crosslinked with glutaraldehyde. Solid-state characterization indicated polymers interaction, a successful crosslinking, and NIZ dispersion in NFs. Crosslinking maintained swollen mats at pH 1.2 (swelling% = 29.47 ± 3.50% at 24 h), retarded their erosion at pH 6.8 (swelling%= 84.64 ± 4.91% vs. 25.40 ± 0.79% for the uncrosslinked NFs at 24 h), augmented the floating up to 24 h vs. 10 min for the uncrosslinked NFs at pH 1.2 and prolonged the drug release (%drug released ≥ 93% at 24 h vs. 4 and 5 h for the uncrosslinked NFs at pHs 1.2 and 6.8, respectively). The viability of Caco-2 cells ≥ 86.87 ± 6.86% revealed NFs biocompatibility and unreacted glutaraldehyde removal. Crosslinking of 8:2 CS:PEO NFs potentiated the antiulcer activity (38.98 vs. 8.67 for the uncrosslinked NFs) as well as it preserved the gastric wall architecture, COX-2 expression, and oxidative stress markers levels of the normal rats.

A human liver cell-based system modeling a clinical prognostic liver signature for therapeutic discovery.

Chronic liver disease and hepatocellular carcinoma (HCC) are life-threatening diseases with limited treatment options. The lack of clinically relevant/tractable experimental models hampers therapeutic discovery. Here, we develop a simple and robust human liver cell-based system modeling a clinical prognostic liver signature (PLS) predicting long-term liver disease progression toward HCC. Using the PLS as a readout, followed by validation in nonalcoholic steatohepatitis/fibrosis/HCC animal models and patient-derived liver spheroids, we identify nizatidine, a histamine receptor H2 (HRH2) blocker, for treatment of advanced liver disease and HCC chemoprevention. Moreover, perturbation studies combined with single cell RNA-Seq analyses of patient liver tissues uncover hepatocytes and HRH2+, CLEC5Ahigh, MARCOlow liver macrophages as potential nizatidine targets. The PLS model combined with single cell RNA-Seq of patient tissues enables discovery of urgently needed targets and therapeutics for treatment of advanced liver disease and cancer prevention.

Nizatidine enhances salivary secretion in patients with dry mouth.

OBJECTIVE: It was reported that salivary secretion increased in 30 volunteers with administered nizatidine. The aim of the present study was to investigate whether or not nizatidine enhances salivary secretion and improves the function of salivary glands in patients with dry mouth. METHODS: Both basal and stimulated salivary secretions were measured before and after the administration of nizatidine for a month in 18 healthy adult volunteers and 38 patients with dry mouth. In 6/38 patients, salivary gland scintigraphy was performed. RESULTS: After the administration of nizatidine for a month, salivary secretions significantly increased in the control and dry mouth patient groups compared to the pretreatment baseline. In addition, 25 of 38 dry mouth patients showed subjective improvements of oral dryness. In 3/4 patients, the function of salivary glands was improved on salivary gland scintigraphy. CONCLUSION: Nizatidine may reactivate salivary gland cells and be useful in the treatment of patients with dry month.

The Effect of Nizatidine, a MATE2K Selective Inhibitor, on the Pharmacokinetics and Pharmacodynamics of Metformin in Healthy Volunteers.

BACKGROUND AND OBJECTIVES: In the proximal tubule, basic drugs are transported from the renal cells to the tubule lumen through the concerted action of the H(+)/organic cation antiporters, multidrug and toxin extrusion (MATE) 1 and MATE2K. Dual inhibitors of the MATE transporters have been shown to have a clinically relevant effect on the pharmacokinetics of concomitantly administered basic drugs. However, the clinical impact of selective renal organic cation transport inhibition on the pharmacokinetics and pharmacodynamics of basic drugs, such as metformin, is unknown. This study sought to identify a selective MATE2K inhibitor in vitro and to determine its clinical impact on the pharmacokinetics and pharmacodynamics of metformin in healthy subjects. METHODS: Strategic cell-based screening of 71 US Food and Drug Administration (FDA)-approved medications was conducted to identify selective inhibitors of renal organic cation transporters that are capable of inhibiting at clinically relevant concentrations. From this screen, nizatidine was identified and predicted to be a clinically potent and selective inhibitor of MATE2K-mediated transport. The effect of nizatidine on the pharmacokinetics and pharmacodynamics of metformin was evaluated in 12 healthy volunteers in an open-label, randomized, two-phase crossover drug-drug interaction (DDI) study. RESULTS: In healthy volunteers, the MATE2K-selective inhibitor nizatidine significantly increased the apparent volume of distribution, half-life, and hypoglycemic activity of metformin. However, despite achieving unbound maximum concentrations greater than the in vitro inhibition potency (concentration of drug producing 50% inhibition [IC50]) of MATE2K-mediated transport, nizatidine did not affect the renal clearance (CLR) or net secretory clearance of metformin. CONCLUSION: This study demonstrates that a selective inhibition of MATE2K by nizatidine affected the apparent volume of distribution, tissue concentrations, and peripheral effects of metformin. However, nizatidine did not alter systemic concentrations or the CLR of metformin, suggesting that specific MATE2K inhibition may not be sufficient to cause renal DDIs with metformin.

H(2) antagonist nizatidine may control olanzapine-associated weight gain in schizophrenic patients.

BACKGROUND: Olanzapine is temporally associated, in a number of patients with schizophrenia, with weight gain. H(2) antagonists, like nizatidine, have been shown to control appetite in overweight patients. METHODS: A patient with olanzapine temporally associated weight gain was treated with nizatidine as "add-on" therapy. RESULTS: Nizatidine treatment was associated with good control and subsequent reduction of weight after 4 to 5 weeks of therapy in a patient with repetitive episodes of weight gain during olanzapine treatment. Olanzapine was otherwise well tolerated and effective in controlling psychopathology. CONCLUSIONS: H(2) antagonist treatment with olanzapine may be a valid medical strategy in preventing and/or reducing weight gain in patients with schizophrenia. Controlled studies are recommended to confirm this observation.

Anti-oxidant properties of H2-receptor antagonists. Effects on myeloperoxidase-catalysed reactions and hydroxyl radical generation in a ferrous-hydrogen peroxide system.

Ulcerogenesis of the gastroduodenal mucosa is caused by the digestive action of gastric juice and initially involves an inflammatory reaction with infiltration of phagocytes. The anti-inflammatory activity of many drugs have been attributed to the inhibition of the leukocyte enzyme, myeloperoxidase (MPO). In this study, the H2-antagonists in clinical use were found to be potent inhibitors of MPO-catalysed reactions (IC50 < 3 microM) under conditions resembling those in experiments with intact neutrophils. Since peak plasma concentrations of cimetidine, ranitidine and nizatidine are well within the micromolar range, after oral therapeutic dosing, our results may be of clinical relevance. The inhibitory actions of cimetidine and nizatidine were largely due to scavenging of hypochlorous acid (HOCl), a powerful chlorinating oxidant produced in the MPO-H2O2-Cl- system. In contrast to famotidine, ranitidine was also a potent scavenger of HOCl, while both drugs inhibited MPO reversibly by converting it to compound II, which is inactive in the oxidation of Cl-. The HOCl scavenging potencies of ranitidine and nizatidine were about three times higher than that of the anti-rheumatic drug, penicillamine, which had a potency similar to that of cimetidine. The rapid HOCl scavenging ability of penicillamine is thought to contribute to its anti-inflammatory effects. Using riboflavin as a probe, the H2-antagonists were found to be inhibitors of hydroxyl radical (.OH) generated in a Fe(2+)-H2O2 reaction mixture. Spectral analyses of the interaction of iron ions with the drugs and studies with chelators, suggest that the drugs were efficient chelators of Fe2+, in addition to their .OH scavenging abilities. Since the gastrointestinal tract can contain potentially reactive iron, the simultaneous presence of H2-antagonists may help to suppress iron-driven steps in tissue damage.

Tolerance during 29 days of conventional dosing with cimetidine, nizatidine, famotidine or ranitidine.

Twenty-four-hour intragastric acidity and 24-h plasma gastrin concentration were measured on four occasions in six groups of eight healthy male subjects. Each group was studied before dosing, and on days 1, 15 and 29 of dosing with a standard regimen of an H2-receptor antagonist (cimetidine 800 mg nocte, nizatidine 300 mg nocte, famotidine 40 mg nocte, ranitidine 150 mg nocte, ranitidine 150 mg b.d., or ranitidine 300 mg nocte). On the first day of dosing, each regimen using an H2-antagonist caused a significant decrease of intragastric acidity and a significant rise of plasma gastrin concentration. Continued dosing with each H2-antagonist resulted in a significant attenuation of the effect on intragastric acidity, which was most noticeable overnight, but no significant change of plasma gastrin concentration. When grouped together, median integrated nocturnal acidity for the 48 subjects was 485, 35, 67 and 117 mmol.h/L for days 0, 1, 15 and 29, respectively, associated with a median nocturnal integrated plasma gastrin concentration of 46, 72, 79 and 73 pmol.h/L. The study demonstrates that a degree of tolerance develops during continued dosing with all available H2-receptor antagonists, and that this phenomenon occurs during sustained elevation of plasma gastrin concentration.

Early evening nizatidine intake with a meal optimizes the antisecretory effect.

The importance of the temporal relationship between meal and nizatidine intake was studied in a six-armed, double-blind, placebo-controlled trial. Eleven healthy volunteers received early (18.00 hours) or late (21.00 hours) supper, with either placebo, early (18.00 hours) nizatidine, or late (21.00 hours) 300 mg nizatidine. Ambulatory 21-hour gastric pH-metry was performed and plasma nizatidine concentrations were determined by high pressure liquid chromatography. Early-nizatidine/early-supper (median pH 2.50), but not late-nizatidine/late supper (median pH 2.30), produced significantly higher median 21-hour pH values than did early-nizatidine/late-supper (median pH 1.90). Concomitant food delayed the absorption of nizatidine but did not change the drug's bioavailability. Oral nizatidine should be taken with food, preferably early in the evening, to optimize its anti-secretory effect.

Nizatidine and cisapride enhance salivary secretion in humans.

BACKGROUND: Salivation plays an important role in the defence of the oesophageal mucosa against gastric acidic reflux and can be evoked by cholinergic stimulation. Both nizatidine and cisapride have been reported to increase acetylcholine concentrations in the cholinergic system. AIM: To investigate the effect of nizatidine and cisapride on salivary secretion, salivary epidermal growth factor and bicarbonate output. METHODS: The salivary volume and concentration of salivary epidermal growth factor and bicarbonate were measured after the administration of nizatidine (150 mg), famotidine (20 mg) and cisapride (5 mg) in 30 male healthy volunteers. RESULTS: Basal and stimulated salivary secretions were found to be increased after the administration of nizatidine and cisapride. In contrast, salivary secretion was not increased by famotidine. Although epidermal growth factor content was not augmented, nizatidine and cisapride administration also increased the bicarbonate output in mastication-stimulated saliva. CONCLUSIONS: Increased salivary secretion and bicarbonate output induced by nizatidine may be useful for the treatment of patients with gastro-oesophageal reflux disease.

Rebound hypersecretion after H2-antagonist withdrawal--a comparative study with nizatidine, ranitidine and famotidine.

Our previous study demonstrated rebound nocturnal acid hypersecretion after a 4-week course of nizatidine. Nocturnal acid output was increased by 77% two days after discontinuing treatment compared with pretreatment values. To confirm this effect with other H2-blockers we assessed daytime intragastric pH, fasting and meal-stimulated plasma gastrin and nocturnal acid output in 9 duodenal ulcer patients in remission before, during and two days after treatment with three different drugs. Each patient received 4-week courses of 300 mg ranitidine, 40 mg famotidine or 300 mg nizatidine, taken at 20.00 hours in randomized order with a 'washout' period of 4 weeks between each course of drug. Median nocturnal acid output (mmol/10 h) decreased during treatment with ranitidine to 3 (range 0-17), famotidine to 4 (1-12) and nizatidine 6 (0-40) compared with the respective pre-treatment values, 49 (20-126; P less than 0.01), 52 (22-105; P less than 0.01) and 32 (23-114; P less than 0.01). Two days after discontinuing treatment nocturnal acid output was increased after ranitidine at 77 (28-237; P less than 0.04) and after nizatidine at 64 (17-130; P less than 0.05) compared with pre-treatment values. There was no significant change in nocturnal acid output after famotidine at 57 (27-107) compared with the pre-treatment value. There was no change in daytime intragastric pH with any drug during or after treatment compared with the pre-treatment values. Fasting and meal-stimulated plasma gastrin concentrations were increased on the final treatment day with ranitidine and famotidine but had returned to pretreatment levels two days after treatment. The rebound acid hypersecretion may contribute to the high ulcer relapse rate after discontinuation of H2-receptor antagonists.

H2-antagonists and alcohol. Do they interact?

There are conflicting data on the existence of significant first-pass metabolism of alcohol (ethanol) in the human stomach and its inhibition by histamine H2-receptor antagonists. Alcohol is predominantly metabolised in the liver by the microsomal alcohol oxidising system, alcohol dehydrogenase (ADH) and a catalase enzyme. Histochemical and kinetic studies have revealed several ADH isoenzymes in the gastric mucosa with different kinetic properties. After small oral doses of alcohol first-pass metabolism in the stomach occurs, as shown by reduced area under the plasma concentration-time curve (AUC) compared with intravenous or intraduodenal administration. The activity of gastric ADH is reduced in women, the elderly, Asian individuals, the fasting state, chronic alcoholism and after gastrectomy. The effect is only present with small (< or = 0.3 g/kg) alcohol doses and with a high alcohol concentration. In a number of studies, cimetidine in therapeutic doses over 7 days produced a significant increase in the AUC and in the peak plasma concentration after administration of alcohol 0.15 and 0.30 g/kg. This was related to an inhibition of gastric ADH activity, as shown by in vitro studies. Ranitidine inhibited gastric ADH to a similar extent on a molar basis, but its effect on alcohol levels in vivo was less constant in various studies. Nizatidine also reduced gastric alcohol first-pass metabolism, but famotidine and roxatidine did not show this effect. In other studies, H2-receptor antagonists did not change AUC and peak alcohol concentration. The controversy is not easy to resolve, since a number of the positive studies did not use a placebo-controlled, randomised, crossover design, while some of the negative studies did not exclude habitual alcohol consumers and included Oriental volunteers, although both groups have been shown to lack significant gastric ADH activity. In this case, when first-pass metabolism of alcohol does not exist, this by definition cannot be abolished by H2-antagonists. The inclusion of oral and intravenous dosage data of alcohol is mandatory to positively identify first-pass metabolism in any individuals. The significance of the effect of H2-antagonists on blood alcohol concentrations is minor. It only occurs in young, male, nonalcoholic, non-Asian individuals, and alcohol must be given in a small (social) dose, in a high concentration, and after meals. An increase in alcohol levels in predisposed patients during treatment with some H2-antagonists cannot be excluded, although the likelihood is small. Furthermore, carefully designed studies are needed to clarify fully the significance of this interaction.

Pharmacokinetics and pharmacodynamics of a novel nizatidine controlled-release formulation in healthy subjects.

The pharmacokinetics and intragastric pH effects of a novel nizatidine controlled-release (CR) formulation were compared to a currently marketed immediate-release (IR) nizatidine formulation (Axid). The bimodal pulsatile release characteristics of nizatidine CR decreased its Cmax by approximately 42% compared to nizatidine IR while maintaining 90% relative bioavailability; tmax was approximately 1.6 times longer with the CR formulation. These characteristics enabled controlled-release nizatidine to sustain effective plasma drug concentrations for a greater duration than immediate-release nizatidine over the dosing intervals. In multiple doses, the 24-hour AUC ratio for all comparisons of nizatidine CR 150 mg bid, nizatidine CR 300 mg daily, and nizatidine IR 150 mg bid was between 97% and 99%. Mean pH AUC values for nizatidine CR 150 mg bid and nizatidine IR 150 mg bid were similar overall during the 0- to 14-hour and 14- to 24-hour dosing intervals. For the 14- to 24-hour dosing interval, nizatidine CR 150 mg maintained gastric pH over 3.0 and 4.0 for 42% and 27% of the time compared to 39% and 23% for nizatidine IR, respectively. Nizatidine CR 300 mg, compared to the 150-mg CR and IR regimens, had a greater effect on increasing evening intragastric pH, thus providing support for the potential utility of nizatidine CR 300 mg dosed at night in alleviating nocturnal symptoms of gastroesophageal reflux disease.

Twenty-four-hour control of gastric acidity by twice-daily doses of placebo, nizatidine 150 mg, nizatidine 300 mg, and ranitidine 300 mg.

This study was carried out to assess the effects on gastric acidity of placebo twice daily (bid), nizatidine 150 mg bid, nizatidine 300 mg bid, and ranitidine 300 mg bid by means of continuous 24-hour intragastric pH monitoring. Twelve patients with duodenal ulcer in remission were randomized to receive in single-blind fashion the above medications on four separate occasions, at least 1 week apart. The three active regimens produced higher pH values (P < .001) and maintained gastric pH above 3.0 units for a longer period (P < .001) than placebo in all time intervals but evening. Nizatidine 150 mg bid caused a lower rise in pH than nizatidine 300 mg bid (P < .01) and ranitidine 300 mg bid (P < .05) during both the daytime and the whole 24 hours. In these time windows also the time spent above 3.0 pH units was significantly shorter for the former regimen than for 300 mg bid of both nizatidine (P < .01) and ranitidine (P < .05). There was no difference between the latter two dosing schedules in terms of both potency and duration of action in all the time intervals considered. It is concluded that twice daily doses of H2 blockers are more effective than placebo in reducing gastric acidity. Three hundred milligrams twice daily of both nizatidine and ranitidine produce a significantly greater and longer-lasting acid suppression than 150 mg bid of nizatidine. Our study also confirms the greater effectiveness of H2 antagonists during nighttime than during day-time.

Comparative investigation of the influence of nizatidine, ranitidine, and cimetidine on the steady-state pharmacokinetics of theophylline in COPD patients.

The influence of usual regimens of the H2 blocking drugs, cimetidine, ranitidine, and nizatidine on the steady-state plasma concentrations and pharmacokinetic characteristics of theophylline was studied in seventeen patients with chronic obstructive pulmonary disease (COPD). Patients were dosed to steady-state with an oral, sustained-release formulation of theophylline given in therapeutic doses twice daily for 2 weeks. Over the next 4 weeks, each patient received a week-long regimen of each H2 blocker concomitantly with theophylline, and a week-long regimen of theophylline alone (control). At the end of each of the latter 4 weeks the steady-state pharmacokinetics of theophylline were assessed. Neither ranitidine nor nizatidine treatment altered the steady-state pharmacokinetics of theophylline relative to the control phase (i.e. no H2 blocker treatment). Values for theophylline C(ave), Cssmax, AUC0-12, and CLoral were significantly different during cimetidine treatment compared with all other treatments (ranitidine, nizatidine, and control). Cimetidine increased theophylline Cssmax, AUC0-12 and Cave by approximately 32%, and decreased theophylline oral clearance by approximately 23%. The authors conclude that cimetidine alters the steady-state pharmacokinetics of theophylline in COPD patients, whereas ranitidine and nizatidine are without effect.

Bicarbonate stimulatory action of nizatidine, a histamine H(2)-receptor antagonist, in rat duodenums.

Nizatidine, a histamine H(2)-antagonist, is known to inhibit acetylcholinesterase (AChE) activity and is used clinically as a gastroprokinetic agent as well as the anti-ulcer agent. We examined whether or not nizatidine stimulates duodenal HCO(3)(-) secretion in rats through vagal-cholinergic mechanisms by inhibiting AChE activity. Under pentobarbital anesthesia, a proximal duodenal loop was perfused with saline, and the HCO(3)(-) secretion was measured at pH 7.0 using a pH-stat method and by adding 10 mM HCl. Nizatidine, neostigmine, carbachol, famotidine or ranitidine was administered i.v. as a single injection. Intravenous administration of nizatidine (3-30 mg/kg) dose-dependently increased the HCO(3)(-) secretion, and the effect at 10 mg/kg was equivalent to that obtained by carbachol at 0.01 mg/kg. The HCO(3)(-) stimulatory action of nizatidine was observed at the doses that inhibited the histamine-induced acid secretion and enhanced gastric motility. This effect was mimicked by neostigmine (0.03 mg/kg) and significantly attenuated by bilateral vagotomy and pretreatment with atropine but not indomethacin. The IC(50) of nizatidine for AChE of rat erythrocytes was 1.4 x 10(-6) M, about 12 times higher than that of neostigmine. Ranitidine showed the anti-AchE activity and increased duodenal HCO(3)(-) secretion, similar to nizatidine, whereas famotidine had any influence on neither AChE activity nor the HCO(3)(-) secretion. On the other hand, duodenal damage induced by acid perfusion (100 mM HCl for 4 h) in the presence of indomethacin was significantly prevented by nizatidine and neostigmine, at the doses that increased the HCO(3)(-) secretion. These results suggest that nizatidine increases HCO(3)(-) secretion in the rat duodenum, mediated by vagal-cholinergic mechanism, the action being associated with the anti-AChE activity of this agent.

Nizatidine and omeprazole enhance the effect of metronidazole on Helicobacter pylori in vitro.

Treatment failures are common in patients infected with metronidazole-resistant Helicobacter pylori in the gastric mucosa when triple therapy including metronidazole is used. In patients with treatment failure and metronidazole-resistant H. pylori, a higher eradication rate for H. pylori was found after secondary treatment with bismuth/ranitidine in combination with antibiotics including metronidazole, compared with the same antibiotics combined with a standard dose of omeprazole. This agrees with our previous finding that bismuth was able to reduce the susceptibility of H. pylori to metronidazole. In this study, we have found that nizatidine, an H(2)-receptor antagonist, is also able to reduce the susceptibility of H. pylori to metronidazole in vitro, despite having no direct inhibitory effect on the growth of H. pylori. This agrees with earlier findings that compounds having the ability to reverse antibiotic resistance do not necessarily have an antibiotic or chemotherapeutic effect in the sense of growth inhibition. Therefore, it was decided to investigate the effect of nizatidine and omeprazole on the oxidative respiratory chain, as it is known that metronidazole is able to inhibit the activity of fumarate reductase of H. pylori. This enzyme is a key enzyme in the alternative respiratory chain under anaerobic conditions. Nizatidine was, in these preliminary experiments, found to inhibit fumarate reductase in a dose-dependent way, like metronidazole, whereas omeprazole had almost no effect on fumarate reductase. No other significant effects on the enzymes of the respiratory chain were found. The synergistic effect of nizatidine on metronidazole resistant H. pylori strains could be explained by the effect on fumarate reductase, whereas the effect of omeprazole is different and could be an inhibition of a proton pump in H. pylori. Reversal of antimicrobial resistance with the help of different non-antibiotics seems to be possible by using quite different compounds, and is therefore to be explained by different molecular mechanisms.

Lack of effect of nizatidine-induced elevation of gastric pH on the oral bioavailability of dapsone in healthy volunteers.

STUDY OBJECTIVE: To investigate the effect of histamine2 (H2)-receptor antagonist-induced elevation of gastric pH on oral bioavailability of a single dose of dapsone 100 mg. DESIGN: Prospective, randomized, crossover, open-label, single-dose pharmacokinetic study. SETTING: Teaching hospital. PATIENTS: Sixteen men were enrolled in the study; data from 11 subjects were evaluable. INTERVENTIONS: Participants received two treatments separated by at least 14 days. Treatment A consisted of a single dose of dapsone 100 mg. Treatment B consisted of a single dose of dapsone 100 mg plus two doses of oral nizatidine 300 mg administered 3-4 hours apart to maintain gastric pH above 6.0. Plasma samples collected before and up to 120 hours after dapsone administration were analyzed for dapsone and monoacetyldapsone (MADDS) by high-performance liquid chromatography. Pharmacokinetic parameters were determined by noncompartmental analysis. MEASUREMENTS AND MAIN RESULTS: Gastric pH in the first 6 hours after dapsone administration was above 6.0 for a mean +/- SD of 1.1% +/- 2.9% of the time in the absence of nizatidine and 69.5% +/- 18.0% of the time during nizatidine therapy. The geometric mean dapsone maximum plasma concentration (Cmax) declined by 13% (p<0.01), and median time to Cmax occurred 2 hours later (p<0.01) with nizatidine coadministration compared with dapsone alone. Inclusion of the 90% confidence interval for the mean Cmax ratio within the equivalence interval of 0.8-1.25 demonstrated the lack of clinical significance for this modest decrease in Cmax. Neither the area under the dapsone plasma concentration-time curve from zero to infinity nor the elimination half-life of dapsone were significantly altered by nizatidine. No clinically significant changes were observed in the pharmacokinetics of MADDS with regard to coadministration of nizatidine. CONCLUSION: Elevation of gastric pH by H2-receptor antagonists, such as nizatidine, does not result in clinically important changes in the rate or extent of oral dapsone absorption.