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.

Formulation, optimization, and evaluation of raft-forming formulations containing Nizatidine.

OBJECTIVE: The main objective of this research is to formulate, optimize, and evaluate raft-forming chewable tablets of Nizatidine. Various raft-forming agents were used in preliminary screening. Sodium alginate showed maximum raft strength, so tablets were prepared using sodium alginate as the raft forming agent, along with calcium carbonate (CaCO3) as antacid and raft strengthening agent, and sodium bicarbonate (NaHCO3) as a gas generating agent. RESEARCH DESIGN AND METHODS: Raft forming chewable tablets containing Nizatidine were prepared by direct compression and wet granulation methods, and evaluated for drug content, acid neutralization capacity, raft strength, and in-vitro drug release in 0.1 N HCl. Box-Behnken design was used for optimization. RESULTS: Two optimized formulations were predicted from the design space. The first optimized recommended concentrations of the independent variables were predicted to be X1 = 275.92 mg, X2 = 28.60 mg, and X3 = 202.14 mg for direct compression technique and the second optimized recommended concentrations were predicted to be X1 = 253.62 mg, X2 = 24.60 mg, and X3 = 201.77 mg for wet granulation technique. Optimized formulations were stable at accelerated environmental testing for six months at 35 °C and 45 °C with 75% relative humidity. X-Ray showed that the raft floated immediately after ingestion and remained intact for ∼3 h. CONCLUSION: Raft was successfully formed and optimized. Upon chewing tablets, a raft is formed on stomach content. That results in rapid relief of acid burning symptoms and delivering the drug into systemic circulation with enhanced bioavailability.

Formulation and characterization of floating microballoons of nizatidine for effective treatment of gastric ulcers in murine model.

BACKGROUND: The purpose of the present study was to formulate and characterize Nizatidine-encapsulated microballoons for enhancing bioavailability and increasing the residence time of drug in the gastrointestinal tract. METHODS: Microballoons were prepared using emulsion solvent diffusion method using Eudragit S-100 and HPMC as the polymer. The formulation process was optimized for polymer ratio, drug: polymer ratio, emulsifier concentration, stirring speed, stirring time. Optimized formulation was subjected to scanning electron microscopy, drug entrapment, buoyancy studies, in-vitro drug release and in-vivo floating efficiency (X-ray) study. In-vivo antiulcer activity was assessed by ethanol-induced ulcer in murine model. RESULTS: The microballoons were smooth and spherical in shape and were porous in nature due to hollow core. A sustained release of drug was observed for 12 h. Examination of the sequential X-ray images taken during the study clearly indicated that the optimized formulation remained buoyant and uniformly distributed in the gastric contents for a period of 12 h. In ethanol-induced ulcer model, drug-loaded Microballoon-treated group showed significant (p < 0.01) ulcer protection index as compared to free drug-treated group. CONCLUSION: Nizatidine-loaded floating microballoons may serve as a useful drug delivery system for prolonging the gastric residence time and effective treatment of gastric ulcers.

Nizatidine, a small molecular compound, enhances killed H5N1 vaccine cell-mediated responses and protects mice from lethal viral challenge.

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.

The effects of nizatidine on transient lower esophageal sphincter relaxations (TLESRs) and acid reflux in healthy subjects.

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.

Multicenter, double-blind, placebo-controlled crossover study to assess the acute prokinetic efficacy of nizatidine-controlled release (150 and 300 mg) in patients with gastroesophageal reflux disease.

INTRODUCTION: The aim of the study is to test whether nizatidine delivered via a unique bimodal pulsatile-controlled release system, nizatidine controlled release (CR), accelerates gastric emptying in patients with gastroesophageal reflux disease (GERD). METHODS: Combined data were analyzed on 39 patients with delayed gastric emptying (DGE) from 2 studies (n = 84) assessing the prokinetic effect of nizatidine CR. A single-blind placebo baseline was followed by double-blind nizatidine CR (150 and 300 mg) in randomized sequence, 2 to 5 days apart. Each dose was followed 1 hour later by an egg-beater meal, labeled with Tc99m. Gamma camera images were obtained at meal completion, 1-, 2-, 3- and 4-hour postmeal. All the 84 patients were classified at baseline with DGE (gastric retention >6.3% at 4 hours) or normal gastric emptying. RESULTS: In the 39 patients identified with DGE, change from placebo baseline (CFB) for percent gastric retention at 4-hour postmeal with nizatidine CR (150 and 300 mg) was each improved and statistically significant (P < 0.05). In a subgroup of diabetic patients with DGE (n = 10), the CFB with nizatidine CR (300 mg) was significant (P < 0.05) at 3- and 4-hour postmeal. CONCLUSIONS: Nizatidine CR (150 and 300 mg) significantly enhanced gastric emptying of a standard meal in patients with GERD with DGE.

Onset of relief of symptoms of gastroesophageal reflux disease: post hoc analysis of two previously published studies comparing pantoprazole 20 mg once daily with nizatidine or ranitidine 150 mg twice daily.

BACKGROUND: Systematic assessments of the onset of symptom relief in the treatment of gastroesophageal reflux disease (GERD) are lacking. OBJECTIVE: This work evaluated the time interval until complete symptom relief from heartburn (including both daytime and nighttime heartburn) and acid regurgitation in patients with GERD or endoscopy-negative GERD (NERD) during the first 7 days of treatment with pantoprazole, nizatidine, or ranitidine. METHODS: This was a post hoc reanalysis of data from 2 previously published, multicenter, randomized, double-blind, active-controlled, parallel-group studies. Male and female patients aged >or=18 years with endoscopically proven GERD or NERD (Hetzel-Dent grade >or= [trial 1] or Savary-Miller grade 0 or 1 [trial 2]) were enrolled. Patients were required to have had reflux symptoms for the previous >or=3 months, with >or=1 symptom (ie, daytime heartburn, nighttime heartburn, or acid regurgitation) for >or=4 of the past 7 days in trial 1 or >or=1 symptom (ie, heartburn, acid eructation, or painful swallowing) of at least moderate intensity for the past 3 days in trial 2. The treatments were pantoprazole 20 mg once daily in both trials, nizatidine 150 mg BID in trial 1, or ranitidine 150 mg BID in trial 2. Presence and severity of symptoms were recorded on daily diary cards using a 4-point Likert-type scale. RESULTS: In total, 114 patients from trial 1 and 307 patients from trial 2 were evaluable for heartburn, and 58 patients from trial l and 271 patients from trial 2 were evaluable for acid regurgitation. In both studies, there were no significant differences in baseline characteristics between pantoprazole recipients and nizatidine or ranitidine recipients, with the exception of more men than women in trial 1 compared with trial 2 (P < 0.001). On day 2 of trial 1, 23 (39.0%) and 8 (14.5%) of pantoprazole and nizatidine recipients, respectively, experienced complete relief from heartburn (P < 0.01). The differences between groups remained statistically significant through day 7, when 28 (47.5%) and 8 (14.5 %) of pantoprazole and nizatidine recipients had no heartburn (P < 0.001). There were no differences in control of acid regurgitation over 7 days with pantoprazole compared with nizatidine or ranitidine, except at days 2 and 4 of trial 1, when significantly more patients receiving pantoprazole experienced relief from acid regurgitation than those receiving nizatidine (day 2: 60.6% [n = 20] vs 20.0% [n = 5], P < 0.01; day 4: 48.5% [n =16] vs 24.0% [n = 6], P < 0.05). CONCLUSION: In this post hoc reanalysis of data from 2 previously published clinical trials, use of pantoprazole 20 mg once daily was associated with effective early relief from heartburn and acid regurgitation among these patients with GERD and NERD; relief occurred as fast as and, in some cases, even faster than that seen with nizatidine or ranitidine.

Predictors and correlates for weight changes in patients co-treated with olanzapine and weight mitigating agents; a post-hoc analysis.

BACKGROUND: This study focuses on exploring the relationship between changes in appetite or eating behaviors and subsequent weight change for adult patients with schizophrenia or bipolar disorder treated with olanzapine and adjunctive potential weight mitigating pharmacotherapy. The aim is not to compare different weight mitigating agents, but to evaluate patients' characteristics and changes in their eating behaviors during treatment. Identification of patient subgroups with different degrees of susceptibility to the effect of weight mitigating agents during olanzapine treatment may aid clinicians in treatment decisions. METHODS: Data were obtained from 3 randomized, double-blind, placebo-controlled, 16-week clinical trials. Included were 158 patients with schizophrenia or bipolar disorder and a body mass index (BMI) > or = 25 kg/m2 who had received olanzapine treatment in combination with nizatidine (n = 68), sibutramine (n = 42), or amantadine (n = 48). Individual patients were analyzed for categorical weight loss > or= 2 kg and weight gain > or = 1 kg. Variables that were evaluated as potential predictors of weight outcomes included baseline patient characteristics, factors of the Eating Inventory, individual items of the Eating Behavior Assessment, and the Visual Analog Scale. RESULTS: Predictors/correlates of weight loss > or = 2 kg included: high baseline BMI, low baseline interest in food, and a decrease from baseline to endpoint in appetite, hunger, or cravings for carbohydrates. Reduced cognitive restraint, increase in hunger, and increased overeating were associated with a higher probability of weight gain > or = 1 kg. CONCLUSION: The association between weight gain and lack of cognitive restraint in the presence of increased appetite suggests potential benefit of psychoeducational counseling in conjunction with adjunctive pharmacotherapeutic agents in limiting weight gain during antipsychotic drug therapy. TRIAL REGISTRATION: This analysis was not a clinical trial and did not involve any medical intervention.

Effects of antisecretory agents on angiogenesis during healing of gastric ulcers.

BACKGROUND: We studied the effects of a proton pump inhibitor (PPI) and an H2-receptor antagonist (H2-blocker) on angiogenesis during gastric ulcer healing, by examining stromal cell-derived factor (SDF-1) and CXC chemokine receptor 4 (CXCR4) expression in the gastric mucosa. METHODS: Patients with gastric ulcers were allocated to an untreated control group, consisting of patients with active ulcers (GA), healing ulcers (GH), and ulcer scars (GS) or a PPI group (P; given rabeprazole at 20 mg/day), or an H2-blocker group (H; given nizatidine at 800 mg/day). Frozen sections of biopsy specimens were examined by reverse transcription-polymerase chain reaction (RT-PCR) to analyze SDF-1 and CXCR4 mRNA. RESULTS: CXCR4 mRNA levels were elevated in the control (GH and GS patients) group and the H2-blocker group. CXCR4 was significantly elevated in the P-GA subgroup of the PPI group (P<0.01), but its level decreased with time. CONCLUSIONS: In the PPI group, CXCR4 levels were increased in the early phase of ulcer healing and returned to a level similar to that in the control group during the scar phase. These results suggest that PPIs increase the expression of CXCR4 mRNA and thus promote vessel regeneration and maturation, facilitating ulcer healing.

Nizatidine for the treatment of pediatric gastroesophageal reflux symptoms: an open-label, multiple-dose, randomized, multicenter clinical trial in 210 children.

BACKGROUND: Gastroesophageal reflux disease (GERD), which is reflux that produces damage or troubling symptoms, afflicts approximately 7% of infants and children to the extent that administration of physician-directed pharmacotherapy is warranted. OBJECTIVE: This study was designed in conjunction with the US Food and Drug Administration (FDA) to assess the tolerability and effectiveness of nizatidine, in different doses and formulations, including a newly formulated premade oral solution, for pediatric GERD. METHODS: Children aged 5 days through 18 years were recruited to this 8-week, open-label, multiple-dose, randomized, parallel-group, multicenter study. The original study design specified that patients aged 5 days through 12 years at study start be given a nizatidine capsule dissolved in infant formula or apple juice depending on patient age ("extemporaneous solution"). Children 13 through 18 years old were to be given the "adult dose" of nizatidine capsules 150 mg BID regardless of body weight. All patients aged < 13 years were randomized in blocks of 4 between 2 dose levels (2.5 and 5 mg/kg per dose BID). A protocol amendment during the study added a newly formulated, more pediatric-appropriate, premade oral solution that was developed at the request of the FDA. This premade formulation ("oral solution") was to replace the extemporaneous solution mixed in infant formula or apple juice. Subsequently, an additional 44 children aged < 13 years old were enrolled in the study and randomized to receive the new nizatidine oral solution for 8 weeks at the same 2 dose levels as used for the extemporaneous solution. Outcome data at 4 and 8 weeks included adverse events (AEs) (severity, relation to study drug, and any relationship to study withdrawal) and effectiveness (investigators' assessment of changes in reflux symptoms and overall physical well-being, and parent/child assessment of change in antacid use). Formal statistical analyses were not planned, but post hoc chi-square analyses were performed. RESULTS: Of 214 children enrolled, 210 (98%) intent-to-treat (ITT) patients received > or = 1 dose; of these, 173 (82%) completed 8 weeks of study. At least 77% were compliant (ie, medicated on > or = 75% of days). Of the ITT patients, 37 did not complete 8 weeks due to insufficient response, AEs (regardless of relationship to study drug), or other reasons. Although 292 AEs occurred in 115 patients, 277 (95%) were mild to moderate and 15 (5%) were severe. Most of the AEs in these children studied during the winter were related to infectious illnesses. Only 4 serious AEs occurred; 3 were unrelated to study drug. The fourth AE--considered possibly related--was worsening sickle cell anemia 18 days after medication discontinuation. Approximately 30% of patients became asymptomatic after 8 weeks of treatment, regardless of dosing or formulation, and despite reduction of antacid use in half of the patients. No clear superiority of any dose or formulation was demonstrated. CONCLUSIONS: This large study, although limited by its open-label design and post hoc analyses, supports the tolerability and effectiveness of 8 weeks of treatment with nizatidine in children aged 5 days through 18 years. AE incidence and severity were as expected for children during the winter season. There was an overall improvement in symptoms and a decrease in antacid use. Formulation did not appear to alter tolerability or effectiveness assessments: the premade solution, extemporaneous solution, and capsule provided comparable symptomatic relief with no disproportionate adverse reactions.

Bioequivalence of two oral formulations of nizatidine capsules in healthy male volunteers.

PURPOSE: The purpose of this randomized, crossover study was to compare the bioavailability of a generic and an innovator formulation of nizatidine 300 mg capsules under fasting conditions. METHODS: Twenty blood samples per period were collected from 20 healthy, Arab male volunteers over 16 h, plasma nizatidine concentrations were determined by HPLC assay, and pharmacokinetic parameters were determined by the non-compartmental method. RESULTS: Mean+/-SD C(max), T(max), AUC(0-->t), AUC(0-->infinity), and t1/2 were 2.96+/-0.54 and 3.28+/-0.68 microg/ml, 1.31+/-0.70 and 0.93+/-0.38 h, 9.04+/-1.66 and 9.03+/-1.94 microg x h/ml, 9.17+/-1.64 and 9.12+/-1.94 microg x h/ml, and 1.64+/-0.21 and 1.58+/-0.22 h for the generic and innovator formulation, respectively. The parametric 90% confidence intervals on the mean of the difference between log-transformed values were 98.06% to 103.21%, 98.74% to 103.71%, and 83.37% to 101.34%, for AUC(0-->t), AUC(0-->infinity), and C(max), respectively. CONCLUSION: The results indicate that these two formulations are equivalent in the rate and extent of absorption.

Teprenone, but not H2-receptor blocker or sucralfate, suppresses corpus Helicobacter pylori colonization and gastritis in humans: teprenone inhibition of H. pylori-induced interleukin-8 in MKN28 gastric epithelial cell lines.

BACKGROUND: The role of teprenone in Helicobacter pylori-associated gastritis has yet to be determined. To investigate the effect of teprenone on inflammatory cell infiltration, and on H. pylori colonization of the gastric mucosa in H. pylori-infected patients, we first compared the effect of teprenone with that of both histamine H2 receptor antagonists (H2-RA) and sucralfate on the histological scores of H. pylori gastritis. We then examined its in vitro effect on H. pylori-induced interleukin (IL)-8 production in MKN28 gastric epithelial cells. MATERIALS AND METHODS: A total of 68 patients were divided into three groups, each group undergoing a 3-month treatment with either teprenone (150 mg/day), H2-RA (nizatidine, 300 mg/day), or sucralfate (3 g/day). All subjects underwent endoscopic examination of the stomach before and after treatment. IL-8 production in MKN28 gastric epithelial cells was measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Following treatment, the teprenone group showed a significant decrease in both neutrophil infiltration and H. pylori density of the corpus (before vs. after: 2.49 +/- 0.22 vs. 2.15 +/- 0.23, p =.009; 2.36 +/- 0.25 vs. 2.00 +/- 0.24, p =.035, respectively), with no significant differences seen in either the sucralfate or H2-RA groups. Teprenone inhibited H. pylori-enhanced IL-8 production in MKN28 gastric epithelial cells in vitro, in a dose-dependent manner. CONCLUSIONS: Teprenone may modify corpus H. pylori-associated gastritis through its effect on neutrophil infiltration and H. pylori density, in part by its inhibition of IL-8 production in the gastric mucosa.

Influence of anti-ulcer drugs used in Japan on the result of (13)C-urea breath test for the diagnosis of Helicobacter pylori infection.

BACKGROUND: The (13)C-urea breath test (UBT) is a simple breath test for the diagnosis of Helicobacter pylori infection, but several factors have been reported to affect the results of this test. In this study, the effects of the antiulcer drugs used in Japan on the results of UBT were determined. METHODS: The subjects of the study were 64 adult volunteers who tested positive for H. pylori infection by the serum antibody method. Eight classes of anti-ulcer drugs used in Japan were administered at their usual doses to these subjects: lansoprazole, a proton pump inhibitor (PPI); nizatidine, an H(2)-receptor antagonist (H(2)RA); and polaprezinc, ecabet sodium, rebamipide, teprenone, cetraxate hydrochloride, and sucralfate, all mucoprotective agents. The study drugs were randomized for administration to the subjects, and each of the drugs was administered for 14 consecutive days. The UBT was performed on days 0, 14, and 21. RESULTS: The mean Delta(13)C per thousand in the lansoprazole group was significantly decreased on day 14, to below 10 per thousand, in 4 of 16 subjects, and in 1 of the 4 subjects, the test result was negative, with the Delta(13)C per thousand falling to 1.7 per thousand. The value returned to baseline 1 week after the discontinuation of lansoprazole. The other drugs administered had no significant effect on the result of the UBT, except that the mean Delta(13)C per thousand showed a tendency to decrease after the administration of ecabet sodium and rebamipide. CONCLUSIONS: Administration of a PPI may produce a false-negative UBT result, while other anti-ulcer drugs, for the most part, have little effect on the result of the UBT when used alone. The (13)C-urea breath test (UBT) is a simple test for the diagnosis of Helicobacter pylori infection, but several factors have been reported to affect the results of this test. In this study, the effects of the anti-ulcer drugs used in Japan on the results of the UBT were determined.

Effect of nizatidine on olanzapine-associated weight gain in schizophrenic patients in Korea: a pilot study.

A pilot study was conducted to evaluate the effect of nizatidine on olanzapine-associated weight gain (OAWG) in ten patients with schizophrenia and schizophreniform disorder in Korea. Psychometric ratings with positive and negative syndrome scale (PANSS) and brief psychiatric rating scale (BPRS) were measured at baseline, week 4 and week 8; as were weight and body mass index (BMI). A combination of nizatidine for 8 weeks resulted in significant reversal of weight gain without worsening the psychopathology (weight: 3.5% and BMI: 3.7%). In line with studies of Western populations, an add-on therapy of nizatidine could be an effective option for the control of weight gain in olanzapine-treated patients in Korea. Our findings call for further evaluation of the effect of this drug on OAWG, with randomized placebo-controlled studies, in Asian populations.

The bioequivalence of nizatidine (Axid) in two extemporaneously and one commercially prepared oral liquid formulations compared with capsule.

Nizatidine (Axid) is an H2-receptor antagonist used for the treatment of acid-related gastrointestinal disorders. Given the frequency of these conditions in children and the potential for pediatric use of nizatidine, an oral liquid dosage formulation would provide an alternative treatment option for patients unable to swallow solid oral dosage forms. This study was designed as an open-label, single-dose, four-way crossover trial to investigate the bioequivalence of 150 mg nizatidine administered in three oral liquid formulations (a commercially prepared oral syrup, an extemporaneous solution in apple juice, and an extemporaneous suspension in infant formula) relative to the marketed capsule formulation. Twenty-four adult subjects (ages 31.2 +/- 7.5 years; weight 71.1 +/- 11.8 kg) were enrolled, and blood samples for determination of plasma nizatidine concentrations were collected prior to drug administration and at 19 discrete intervals over a 24-hour postdose interval. Nizatidine was quantitated from plasma using a validated HPLC-MS assay, and a noncompartmental approach was used to describe nizatidine biodisposition in all subjects. Significant treatment effects were observed for log-normalized Cmax, AUC0-n, and AUC0-infinity (p < 0.001). Further evaluation revealed that nizatidine prepared in apple juice was markedly less bioavailable than the reference capsule, with 90% confidence intervals (CIs) of 0.518-0.626, 0.682-0.751, and 0.696-0.763 for Cmax, AUC0-n, and AUC0-infinity, respectively. The remaining two oral formulations demonstrated 90% CI within the guidelines established by the Food and Drug Administration (e.g., 0.80-1.25). Thus, nizatidine in infant formula and the commercially prepared oral syrup can be considered bioequivalent to the reference capsule.

Single-dose pharmacokinetics of nizatidine (Axid) in children.

The pharmacokinetics of nizatidine following a single 5.0 mg/kg oral dose given as an extemporaneous liquid formulation in apple juice was examined in 12 healthy children (8.0 +/- 2.4 years, 30.7 +/- 8.4 kg). Nizatidine and N-desmethylnizatidine were quantitated by HPLC/MS from five post dose blood samples taken over a 12-hour period. The apparent terminal elimination rate constant for nizatidine in the pediatric subjects (0.58 +/- 0.8h(-1)) was virtually identical to that (0.54 +/- 0.13 h(-1)) previously reported from adult studies. When corrected for an estimated 30% reduction in nizatidine oral bioavailability observed in adults upon coingestion of the drug with other fruit/vegetable juices, nizatidine pharmacokinetic parameter estimates (e.g., Cmax, CL/F, Vss/F) in our pediatric subjects were similar to those previously reported in adults who were administered dimensionally similar (e.g., approximately 4 mg/kg) solid oral doses of the drug. Examination of the mean area under the curve (i.e., AUC0-infinity for nizatidine and N-desmethylnizatidine suggested an approximate 15% metabolic conversion of the parent drug. Finally, nizatidine plasma concentrations in pediatric patients following a single 5.0 mg/kg oral dose exceeded the EC50 value of the drug for gastric acid suppression determined from adult studies for approximately 6 hours.

Effect of preoperative oral use of erythromycin and nizatidine on gastric pH and volume.

This randomized controlled trial examined the effects of preoperative oral erythromycin or nizatidine on gastric pH and volume. Sixty patients, ASA 1 and 2 status scheduled for elective surgery were studied. All subjects received oral study medication with 10 ml of water 60 minutes prior to surgery. Patients in Group 1 (n=20) were given erythromycin 200 mg, in Group 2 (n=20) nizatidine 300 mg, and in Group 3 (n=20) placebo capsule. A nasogastric tube was inserted immediately after anaesthesia induction. Gastric content was aspirated, and volume and pH recorded. pH values determined in Group 1 were 5.6+/-1.87; in Group 2, 5.65+/-1.92 and in Group 3, 3.5+/-1.93. There was no statistical difference between Groups 1 and 2, but there was a statistically significant difference between Group 3 and Groups 1 and 2 (P<0.001). The volume of gastric content was 10.25+/-6.65 ml in Group 1, 10.3+/-6.29 ml in Group 2 and 20.25+/-16.72 ml in Group 3. Again, there was no statistical difference between Groups 1 and 2, but there was a statistically significant difference between Group 3 and Groups 1 and 2 (P<0.05). The proportion of patients considered "at risk" of significant lung injury should aspiration occur was 10% of Group 1, 5% of Group 2 and 20% of Group 3 (not statistically different). We conclude that oral erythromycin and nizatidine given one hour prior to surgery are effective in reducing gastric pH and volume.

Effectiveness and safety of nizatidine, 75 mg, for the relief of episodic heartburn.

BACKGROUND: The most frequent cause of episodic heartburn is food and beverage ingestion. Nizatidine, an H2-receptor antagonist, is currently approved for non-prescription use in the prevention and relief of heartburn at a dose of 75 mg up to twice a day. METHODS: Two identical studies were carried out to evaluate the efficacy of nizatidine, 75 mg, compared with placebo in treating heartburn in an "at-home" setting. The studies were multicentre, multiple-dose, placebo-controlled, randomized, parallel group design. A total of 994 subjects were randomized to treatment. Adequate relief of heartburn was assessed at 15, 30 and 45 min and 1, 2 and 3 h following a treatment dose. A subject's responses with respect to time to relief and attainment of adequate relief were combined into a derived response profile, the sustained adequate relief score. Adverse experiences were noted throughout the study period. RESULTS: The individual and combined study results showed that nizatidine, 75 mg, relieved heartburn faster and/or more consistently than placebo. The mean sustained adequate relief score, calculated over a subject's first four episodes, was 2.43 in the nizatidine-treated group compared with 2.14 in the placebo group (P < 0.001). Nizatidine-treated subjects attained sustained adequate relief in a significantly (P < 0.001) larger percentage (75%) of their heartburn episodes than did subjects treated with placebo (66%). No serious adverse experiences were associated with nizatidine treatment. CONCLUSION: Nizatidine, 75 mg, is a safe and effective treatment for episodic heartburn. The results showed that subjects taking nizatidine had heartburn relief that was achieved faster and/or more reliably than did subjects taking placebo.

Effects of computerized physician order entry on prescribing practices.

BACKGROUND: Computerized order entry systems have the potential to prevent errors, to improve quality of care, and to reduce costs by providing feedback and suggestions to the physician as each order is entered. This study assesses the impact of an inpatient computerized physician order entry system on prescribing practices. METHODS: A time series analysis was performed at an urban academic medical center at which all adult inpatient orders are entered through a computerized system. When physicians enter drug orders, the computer displays drug use guidelines, offers relevant alternatives, and suggests appropriate doses and frequencies. RESULT: For medication selection, use of a computerized guideline resulted in a change in use of the recommended drug (nizatidine) from 15.6% of all histamine(2)-blocker orders to 81.3% (P<.001). Implementation of dose selection menus resulted in a decrease in the SD of drug doses by 11% (P<.001). The proportion of doses that exceeded the recommended maximum decreased from 2.1% before order entry to 0.6% afterward (P<.001). Display of a recommended frequency for ondansetron hydrochloride administration resulted in an increase in the use of the approved frequency from 6% of all ondansetron orders to 75% (P<.001). The use of subcutaneous heparin sodium to prevent thrombosis in patients at bed rest increased from 24% to 47% when the computer suggested this option (P<.001). All these changes persisted at 1- and 2-year follow-up analyses. CONCLUSION: Computerized physician order entry is a powerful and effective tool for improving physician prescribing practices.

[Maintenance therapy of mild form of GERD by H2 receptor antagonists].

Because of high relapse rate after the healing by proton pump inhibitor(PPI) or H2 receptor antagonist(H2RA), GERD usually needs long time maintenance therapy. PPI is superior to H2RA in the first line as well as maintenance therapy. PPI is necessary for severe cases of GERD. However, H2RA is sufficient for milder form of GERD patients. Among the H2RA using in Japan, nizatidine has known to stimulate gastric emptying and elevate LES pressure. Nizatidine may be superior to other H2RAs in the treatment of GERD. Recently, nocturnal acid breakthrough which night time acid is secreted even PPI is administered twice daily has been documented. H2RAs are stronger than PPI to inhibit nocturnal acid breakthrough and may be better than night time acid reflux.