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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 + , CLEC5A high , MARCO low 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., (© 2021. The Author(s).)

Nizatidine (NIZ), a histamine H 2 -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/cm 2 ), 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.

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  μ mol/L) on HPFs was lower than on HCFs (100  μ mol/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.

Nizatidine (NIZ), closely related to Cimetidine, is a histamine H2 receptor inverse agonist used primarily as an anti-acid drug. Recent studies showed that this class of compounds may also modulate immune responses. To evaluate adjuvant effects of NIZ on vaccine immune modulation, we formulated NIZ with a H5N1 killed viral antigen and tested in vitro and in vivo. NIZ activated DC maturation and stimulated Th1 and Th2 immune responses to H5N1 vaccine. As a result, it enhanced both antibody and T cell-mediated immune responses. We also observed that a single immunization into C57BL/6 mice blocked IL-10 upregulation and potentiated Th1/Th2 dual polarization. Importantly, the inoculation of H5N1 vaccine with NIZ significantly improved protection of animals from death after challenge and reduced virus loads in the lung tissues. Considering its water-soluble nature, compared with Cimetidine, Nizatidine may be a better choice to use as a vaccine adjuvant.

Background: A study in Japan has found that nizatidine (NIZ) is more effective than other histamine H2 receptor agonists (H2RAs) in treating reflux esophagitis (RE), although the NIZ group included a greater number of patients with severe RE. As there was no difference in the level of acid suppression among H2RAs, it is possible that NIZ has other effects on esophageal acid exposure (EAE) besides acid suppression. In this study, the effect of NIZ on transient lower esophageal sphincter relaxations (TLESRs) and acid reflux was evaluated in healthy subjects., Methods: In 10 healthy subjects, while in a sitting position, esophageal motility and a pH study were measured for 3 hours after a meal on 2 separate days at least 2 weeks apart. Participants received an oral dose of 150 mg of NIZ, 60 min before the meal on one day and a placebo on the other. Both studies were preceded by a week of treatment with either NIZ (150 mg, bid) or a placebo and the order of treatment was randomized., Results: Basal LES pressure in the NIZ group (14.1 mmHg, median) was significantly greater than that of the placebo group (8.5 mmHg). The rate of TLESRs in the NIZ group (22.0/3 h) for the postprandial 3-hour period was significantly less than that of the placebo group (16.5/3 h) and the rate of acid reflux during TLESRs (24.7%) and the EAE (0.2%) in the NIZ group for the postprandial 3-hour period was also significantly less than that of the placebo group (74.4% and 2.8%, respectively)., Conclusion: NIZ significantly reduces acid reflux by inhibiting both the rate of TLESRs and acid reflux during TLESRs.

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.

Although thrombocytopenia associated with the use of histamine H2 receptor (H2R) antagonists has been described, a drug-dependent, platelet-reactive antibody has not previously been identified in such cases. We studied serum from a patient who developed acute, severe thrombocytopenia after exposure to the H2 receptor antagonist, ranitidine, and identified an antibody that reacted with normal platelets in the presence of this drug at pharmacologic concentrations. In flow cytometric and immunoprecipitation studies, the antibody was shown to be specific for the glycoprotein Ib/IX complex (GPIb/IX). From the pattern of monoclonal antibody (MoAb) inhibition and the reactions of antibody with Chinese hamster ovary (CHO) cells transfected with GPIX and GPIbbeta, we found that the patient's antibody is specific for an epitope on GPIX close to, or identical with a site recognized by the MoAb SZ1 that is a common target for antibodies induced by quinine and quinidine, drugs structurally unrelated to ranitidine. These findings provide evidence that immune thrombocytopenia can be caused by sensitivity to an H2 R antagonist and suggest that the SZ1 binding site on GPIX may be a common target for drug-induced antibodies. Further studies of the epitope for which SZ1 is specific may provide clues to the mechanism(s) by which drugs promote tight binding of antibody to a membrane glycoprotein and cause platelet destruction in patients with drug sensitivity.

Objective: To determine the effect, if any, of histamine type 2 receptor antagonists (H2RAs) on serum alcohol levels under various conditions including type of H2RA receptor antagonist, alcohol dose, and fed status of the subject., Study Design: Meta-analysis of the published literature., Data Sources: Studies were identified by MEDLINE (January 1982 through December 1997) using the key words H2 receptor antagonists and alcohol. Other studies were identified by reviewing bibliographies of retrieved articles and by discussion with colleagues., Study Selection: Studies were selected if they involved the coadministration of H2RAs and alcohol in healthy, human volunteers. Studies that may have addressed this goal but were performed in another context, for instance the measurement of ulcer healing, were excluded., Data Extraction: Data were extracted on the design, number of participants, participant characteristics, type and dose of H2RA administered, serum alcohol levels (measured as Cmax) along with standard deviations, dose of alcohol received, and fed or fasted status of participants. Alcohol dose was arbitrarily divided into low dose (< or = 0.5 g/kg body weight) versus high dose (> 0.5 g/kg body weight). In addition, studies involving ranitidine and cimetidine were stratified by sample size into small (n < or = 10) versus not small (n > 10)., Measurements and Main Results: Twenty-four trials met selection criteria. Small elevations in Cmax were noted when cimetidine (2.71 mg/DL; 95% confidence internal [CI] 1.60, 3.83) or ranitidine (6.95 mg/DL; 95% CI 5.83, 8.08) were coadministered with alcohol. No such differences were noted for famotidine (0.28 mg/DL; 95% CI -1.24, 1.80) or nizatidine (2.33 mg/DL;, 95% CI -0.06, 4.72). The elevation detected with cimetidine and ranitidine was most pronounced in smaller studies (n < 10). Separate analyses investigating the effect of alcohol dose and fed or fasted status of participants revealed no clinically important differences., Conclusions: Cimetidine and ranitidine, but not the other H2RAs, can cause small elevations of serum alcohol level when alcohol and drug are administered concurrently. Studies with larger numbers of participants were less likely to demonstrate this effect. Relative to accepted, legal definitions of intoxication, the effect of any H2RA on blood alcohol level is unlikely to be clinically relevant.

Background and Objectives: During laparoscopy, the increase of the carbon dioxide tension may increase the synthesis of hydrochloric acid in the parietal cells of the stomach; the source of the secreted hydrogen ions is carbonic acid derived from the hydration of carbon dioxide. The present report tests this hypothesis by correlating the changes of end-tidal PCO2 (ETCO2) with the pH of the gastric juice in patients undergoing laparoscopic cholecystectomy., Methods: 40 adult patients were investigated: 20 controls, and 20 patients receiving 100 mg nizatidine intravenously, prior to surgery. In both groups, the ETCO2 was measured by capnography and the pH of the gastric juice was monitored before carbon dioxide insufflation and at the end of laparoscopy prior to carbon dioxide deflation., Results: In the control group, the ETCO2 increased following carbon dioxide insufflation from a mean basal value of 30.2 (standard deviation [SD] 4.6) mm Hg to 41.1 (SD 9.5) mm Hg, while the mean pH of the gastric juice decreased significantly from 1.9 (SD 0.4) to 1.27 (SD 0.43). There was a significant negative correlation between the ETCO2 and pH of the gastric juice (r = -0.4). In the Nizatidine group, the ETCO2 also increased following carbon dioxide insufflation from a mean basal value of 30.9 (SD 3.0) mm Hg to 39.4 (SD 5.3) mm Hg. However, in contrast with the control group, the mean pH of the gastric juice did not decrease, but paradoxically increased from 1.68 (SD 0.36) to 3.6 (SD 1.02)., Conclusions: During laparoscopy, the pH of the gastric juice is significantly decreased. This decrease is inversely related to the increase of ETCO2. The preoperative administration of the selective H2-blocker nizatidine can prevent the increase in gastric acidity and can result in a paradoxical increase of pH of the gastric juice.

We have studied the effect of oral nizatidine 6 mg kg-1 in total on preoperative gastric fluid pH and volume in children. One hundred and four healthy children, aged 4-11 yr, were allocated randomly to four groups (n = 26): placebo administered at 21:00 and 06:30 the night before and on the day of surgery, respectively (placebo-placebo: control); nizatidine 6 mg kg-1 at 21:00 and placebo at 06:30 (nizatidine-placebo); placebo at 21:00 and nizatidine 6 mg kg-1 at 06:30 (placebo-nizatidine); and nizatidine 3 mg kg-1 at 21:00 and 06:30 (nizatidine-nizatidine). Each child ingested a large volume of apple juice 3 h before estimated induction of anaesthesia. After induction of anaesthesia, pH and volume of gastric fluid obtained via an orogastric tube were measured. Mean pH in the placebo-nizatidine and nizatidine-nizatidine groups was significantly higher than that in the placebo-placebo group (5.7 (SEM 0.3), 6.0 (0.3) vs 1.8 (0.2), respectively) (P < 0.05). Mean pH in the nizatidine-placebo group was similar to that in the control group (2.3 (0.3) vs 1.8 (0.2)). The number of children with pH < 2.5 and volume > 0.4 ml kg-1 in the nizatidine-nizatidine (0%) and placebo-nizatidine (4%) groups was reduced compared with the control (46%) or nizatidine-placebo (38%) group.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of omeprazole (40 mg orally per day) and nizatidine (300 mg orally per day) on the disposition of phenytoin (4.5 mg kg(-1) p.o. single dose) were studied in 18 healthy, young adult males. Total and unbound plasma concentrations of phenytoin were measured for 48 h after each dose of phenytoin. Neither treatment altered the disposition kinetics of phenytoin, the hydroxylation of which is mediated specifically by cytochromes P450 of the 2C subfamily.

Effects of various histamine H2-receptor antagonists (H2-RA) on gastrointestinal motility and gastric emptying were investigated. Ranitidine, nizatidine and cimetidine dose dependently induced contractions over the entire gastrointestinal tract, and the order of their effects was ranitidine > nizatidine > cimetidine. Roxatidine or famotidine had no effects on motility of the gastrointestinal tract. Ranitidine and nizatidine also induced contractions during the postprandial period and facilitated gastric emptying, while cimetidine, roxatidine or famotidine did not influence gastric emptying. Since acid reduction is thought to be the most important element of the treatment of peptic ulcer and reflux esophagitis, it was inferred that administration of a H2-RA selected with consideration of its property of facilitating gastrointestinal motility is effective in the treatment of patients with abnormal gastrointestinal motility.

1. Twelve healthy subjects were treated in a randomised placebo-controlled crossover study with placebo, 150 mg, 300 mg, and 600 mg nizatidine, 100 mg pirenzepine, and 300 mg nizatidine plus 100 mg pirenzepine for 1 week each. 2. On the seventh treatment day, heart rate, blood pressure, systolic time intervals, impedance cardiographic and Doppler ultrasound variables were measured. 3. Stroke volume and blood pressure were not altered by nizatidine and/or pirenzepine. By contrast, heart rate and cardiac output significantly (P < 0.05) decreased in a dose-dependent manner 1.5 and 3 h after administration of 300 and 600 mg nizatidine. Treatment with 150 mg nizatidine led to similar though non-significant trends. 4. While a slightly insignificant rise in heart rate was detected with pirenzepine alone, heart rate and cardiac output remained unchanged upon combined nizatidine and pirenzepine treatment as compared with placebo and baseline values. 5. In conclusion, nizatidine reduced heart rate and cardiac output in a dose-dependent manner, whereas this negative chronotropic effect was counteracted by concurrent administration of the anti-cholinergic drug pirenzepine.

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.

The H2-receptor antagonists, cimetidine, ranitidine, famotidine and nizatidine, were tested for their effect on the isolated smooth muscle strips from the rabbit stomach fundus and sigmoid colon. These H2-receptor antagonists were found to possess a concentration-dependent contractile effect on the above smooth muscle preparations and the order of potency was: ranitidine = nizatidine > famotidine > cimetidine. In addition, the smooth muscle preparations from the sigmoid colon were significantly more sensitive to the above compounds than the smooth muscle preparations from the stomach fundus.

In a series of 24 hour studies, intragastric acidity and plasma gastrin concentration were measured simultaneously in 46 healthy subjects before, during, and 24 to 48 hours after abrupt withdrawal of a histamine H2 receptor antagonist regimen. For 34 days subjects were given either cimetidine 800 mg at night (n = 8), ranitidine 150 mg twice daily (n = 10), ranitidine 300 mg at night (n = 12), nizatidine 300 mg at night (n = 8), or famotidine 40 mg at night (n = 8). All subjects responded to H2 blockade by a decrease in 24 hour intragastric acidity. Withdrawal of H2 blockade resulted in a significant rise in median nocturnal integrated intragastric acidity in 42 of 46 subjects (+36%; 95% CI +19, +55%) compared with prestudy values, but this rise was not associated with a significant change in the median integrated plasma gastrin concentration (+1%; 95% CI -12, +13%). A statistically significant rise in nocturnal acidity was observed after all regimens, except after dosing with famotidine. After stopping, median daytime integrated acidity and plasma gastrin concentrations in the whole group were raised, but not significantly: values were +15% (95% CI +4, +34%) and +5% (95% CI -2, +12%), respectively. A statistically significant increase in daytime acidity was observed only after dosing with ranitidine. In conclusion, intragastric hyperacidity occurs in most subjects after abrupt withdrawal of a histamine H2 receptor blocker, but this phenomenon is not associated with hypergastrinaemia.

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.

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.