Effects of ranitidine and nizatidine on the risk of gastrointestinal cancer.

Purpose: Gastrointestinal (GI) cancer occurs in digestive organs such as the stomach, colon, liver, esophagus, and pancreas. About 83,034 cases occurred in Korea alone in 2020. Dietary factors, alcohol consumption, Helicobacter pylori (H. pylori), and lifestyle factors increase the incidence of diseases such as gastritis, peptic ulcer, pancreatitis, and gastroesophageal reflux disease (GERD), which can develop into GI cancer. However, in 2019, the US Food and Drug Administration announced that the drugs ranitidine and nizatidine, which are used for digestive disorders, contain carcinogens. In this study, we investigated the effects of ranitidine and nizatidine on the development of GI cancer. Materials and methods: In this study, using National Health Insurance Service-National Sample Cohort (NHIS-NSC) version 2.5 (updated from 2002 to 2019), subjects who developed GI cancer were enrolled in the case group, and those who were at risk of, but did not develop, cancer were enrolled in the control group. Thereafter, risk-set matching was performed (1:3 ratio) by sex and age at the time of diagnosis of cancer in the case group. Through this procedure, 22,931 cases and 68,793 controls were identified. The associations of ranitidine and/or nizatidine with GI cancer were confirmed by adjusted odds ratios (aORs) and 95% confidence intervals (CIs) calculated through conditional logistic regression analysis. Results: The aORs of ranitidine and/or nizatidine users were lower than those of nonusers in all average prescription days groups (< 30 days/year: aOR [95% CI] = 0.79 [0.75-0.82]; 30-59 days/year: aOR [95% CI] = 0.66 [0.59-0.73]; 60-89 days/year: aOR [95% CI] = 0.69 [0.59-0.81]; ≥ 90 days/year: aOR [95% CI] = 0.69 [0.59-0.79]). Sensitivity analyses were conducted with different lag periods for the onset of GI cancer after drug administration, and these analyses yielded consistent results. Additional analyses were also performed by dividing subjects into groups based on cancer types and CCI scores, and these analyses produced the same results. Conclusion: Our study, using nationwide retrospective cohort data, did not find evidence suggesting that ranitidine and nizatidine increase the risk of GI cancer. In fact, we observed that the incidence of GI cancer was lower in individuals who used the drugs compared to nonusers. These findings suggest a potential beneficial effect of these drugs on cancer risk, likely attributed to their ability to improve digestive function.

Enhanced degradation of emerging contaminants by percarbonate/Fe(II)-ZVI process: case study with nizatidine.

Pharmaceuticals have recently emerged as a significant environmental concern due to the growth of population, expansion of industry, and the shift in modern lifestyles. Herein, we present a Fe(II)/percarbonate (SPC) process with dramatically enhanced efficiency by the introduction of zerovalent iron (ZVI). After the addition of ZVI, the removal rate of nizatidine (NZTD) went up from 71.7 to 84.2%. The removal rate of NZTD decreases with rising pH and speeds up with increasing temperature. It was found that under the condition of pH = 7 and T = 25 °C, the molar ratio of the optimal concentration of NZTD degradation in the system was [NZTD]0:[SPC]0:[Fe(II)]0:[ZVI]0 = 1:8:24:16, with a degradation rate of 99.8%. At the same time, target pollutants can also be successfully eliminated from actual water bodies. Moreover, we test for toxicity using luminescent bacteria, and the results demonstrate that the system is capable of effectively decreasing the toxicity of NZTD. The research findings can contribute to the clarification of the migration and transformation law of NZTD in the oxidation process, thereby providing a scientific basis and technical support for the removal of NZTD in the tertiary water treatment for a water source.

Nizatidine interacts with ct-DNA causing genotoxicity and cytotoxicity: an assessment by in vitro, in vivo, and in silico studies.

H2 receptor antagonists are the medication given for treating stomach ulcers, but lately, reports have shown their role in healing several malignant ulcers. The present work entails the interaction of H2 blocker nizatidine with calf thymus (ct)-DNA for determining the binding mode and energetics of the interaction. Multi-spectroscopic, calorimetric, viscometric and bioinformatic analysis revealed that nizatidine interacted with ct-DNA via groove-binding mode and is characterised by exothermic reaction. Moreover, assessment of genotoxic potential of nizatidine in vitro was carried out in peripheral human lymphocytes by alkaline comet assay. DNA damage occurred at high concentrations of nizatidine. Genotoxicity of nizatidine was also evaluated in vivo by assessing cytogenetic biomarkers viz. micronuclei formation and chromosomal aberration test. Nizatidine was able to induce micronuclei formation and chromosomal damage at high dose. Additionally, cytotoxic activity of nizatidine was determined in cancer cell lines, namely HeLa and HCT-116 and compared with the normal human cell line HEK-293 employing MTT assay. It was observed that nizatidine was more toxic towards HeLa and HCT-116 than HEK-293. Cell morphology analysis by compound inverted microscopy further strengthens the finding obtained through MTT assay.

Formulation of stomach-specific floating microparticles of nizatidine and their radiographic evaluation

Nizatidine is an anti-secretogogue and a gastroprotective drug with a half-life of 1-2 h and is well absorbed in the stomach. This study aimed to optimize the process and develop floating microparticles of nizatidine that are based on low methoxyl pectin. Oil-in-oil dispersion method and Taguchi orthogonal array design were employed, and the prolonged residence time of the microparticles in the stomach was demonstrated. The constraints for independent variables, viz. A-polymer, B-internal solvent volume, C-surfactant, D-stirring rate and E-stirring time were set to generate the experimental runs. Particle size, percentage yield, micromeritic properties, entrapment efficiency, in vitro buoyancy and in vitro release were characterized. Surface morphology, zeta potential, in vitro release kinetics and in vivo floating performance of the optimized formulation was examined. The microparticles were free-flowing, irregular in shape and had a mean particle size distribution of 73-187 µ. Low methoxyl pectin played a predominant role in achieving buoyancy and optimum gastric retention for the modified release of the drug, suggesting Korsmeyer-Peppas model as the possible release mechanism. In vivo radiographic study in rabbits revealed that the drug was retained in the stomach for a period of 6 h. These results indicate that nizatidine floating microparticulate system provides modified drug release for the effective treatment of gastric ulcer

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.

Elucidating the molecular interaction of serum albumin with nizatidine and the role of ß-cyclodextrin: multi-spectroscopic and computational approach.

Nizatidine is a histamine H2 receptor antagonist which act by inhibiting the production of stomach acid, thereby, finds its application in treating various diseases related to the gastrointestinal tract. Studying albumin-drug interaction is important for understanding the pharmacokinetics and pharmacodynamics of therapeutic candidates. In the present work, the interaction of nizatidine with BSA was investigated by employing multi-spectroscopic and computational studies. The formation of BSA-nizatidine complex was characterised by UV-visible and fluorescence based-spectroscopic studies. Steady-state fluorescence demonstrated the static mode of quenching of BSA by nizatidine. The interaction was spontaneous and nizatidine binds to BSA with a stoichiometry of 1:1. Forster resonance energy transfer calculations revealed that there was a high possibility of energy transfer between nizatidine and BSA. The resultant secondary structural change in BSA on the addition of nizatidine was studied by circular dichroism spectroscopy. Moreover, synchronous and three-dimensional fluorescence spectroscopy was used to determine the conformational changes occurred in the structure of albumin on the binding of nizatidine. Competitive-site marker experiments suggested that nizatidine binds in the Sudlow site II of BSA. Additionally, the effect of ß-cyclodextrin as an inclusion compound on the interaction was studied. Furthermore, molecular modelling and simulation studies were performed to corroborate the results obtained above.Communicated by Ramaswamy H. Sarma.

Estimation of nizatidine gastric nitrosatability and product toxicity via an integrated approach combining HILIC, in silico toxicology, and molecular docking.

The liability of the H2-receptor antagonist nizatidine (NZ) to nitrosation in simulated gastric juice (SGJ) and under WHO-suggested conditions was investigated for the first time. For monitoring the nitrosatability of NZ, a hydrophilic interaction liquid chromatography (HILIC) method was optimized and validated according to FDA guidance. A Cosmosil HILIC® column and a mobile phase composed of acetonitrile: 0.04 M acetate buffer pH 6.0 (92:8, v/v) were used for the separation of NZ and its N-nitroso derivative (NZ-NO) within 6 min with LODs of 0.02 and 0.1 µg/mL, respectively. NZ was found highly susceptible to nitrosation in SGJ reaching 100% nitrosation in 10 min, while only 18% nitrosation was observed after 160 min under the WHO-suggested conditions. The chemical structure of NZ-NO was clarified by ESI+/MS. In silico toxicology study confirmed the mutagenicity and toxicity of NZ-NO. Experiments evidenced that ascorbic acid strongly suppresses the nitrosation of NZ suggesting their co-administration for protection from potential risks. In addition, the impacts of the HILIC method on safety, health, and environment were favorably evaluated by three green analytical chemistry metrics and it was proved that, unlike the popular impression, HILIC methods could be green to the environment.

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.

A case of nizatidine-induced immediate hypersensitivity

Nizatidine is a histamine H₂ receptor antagonist that inhibits stomach acid production and is commonly used in the treatment of peptic ulcer and gastroesophageal reflux. H₂ receptor antagonists are typically well tolerated, and hypersensitivity reactions are rare. A 19-year-old woman developed urticaria 30 minutes after taking a drug containing nizatidine. Allergic reactions to nizatidine were confirmed via skin prick test, which also revealed cross-reactions to ranitidine. We believe that this is the first case report on immediate hypersensitivity to nizatidine in Korea.

The inhibition of first-pass metabolism of ethanol by H2-receptor antagonists: a tabulated review.

INTRODUCTION: In the 1980s-1990s numerous studies were performed on H2-receptor antagonist inhibition of ethanol first-pass metabolism. Blood alcohol concentrations warranting possible driving under the influence citations in the United States have subsequently dropped from ≥100 mg/dL to 50 mg/dL (Utah in 2019) (30 mg/dL or zero tolerance in some parts of the world). A reexamination of these studies seemed important. AREAS COVERED: Papers were compiled that addressed the effect of cimetidine, ranitidine, famotidine, and nizatidine on ethanol metabolism first from a PubMed search and then from citations within these papers. Studies were tabulated for fasting versus fed, ethanol and H2-receptor antagonist dose and a summary of pharmacokinetic changes. EXPERT OPINION: At doses of 0.15-0.30 mg/kg in the postprandial state (primarily after breakfast), the H2-receptor antagonists: cimetidine, ranitidine, famotidine, and nizatidine have all been found to increase the first-pass metabolism of ethanol. With cimetidine, there were sufficient studies to suggest it might be inhibitory outside these restricted states. While the role of inhibition of alcohol dehydrogenase has not been clearly defined, there is circumstantial evidence to support this mechanism. Further studies are required to elucidate the ability of H2-receptor antagonists to inhibit first-pass metabolism of ethanol.

Radioiodination and biological evaluation of nizatidine as a new highly selective radiotracer for peptic ulcer disorder detection.

Nizatidine has been labeled using [125 I] with chloramine-T as oxidizing agent. Factors such as the amount of oxidizing agent, amount of substrate, pH, reaction temperature, and reaction time have been systematically studied to optimize the iodination. Biodistribution studies indicate the suitability of radioiodinated nizatidine as a novel tracer to image stomach ulcer. Radioiodinated nizatidine may be considered a highly selective radiotracer for peptic ulcer imaging.

Molecular mobility in the supercooled and glassy states of nizatidine and perphenazine.

The dielectric properties of two pharmaceuticals nizatidine and perphenazine were investigated in the supercooled liquid and glassy states by broadband dielectric spectroscopy. Two relaxation processes were observed in both the pharmaceuticals. The relaxation process observed above the glass transition temperature is the structural alpha relaxation and below the glass transition temperature is the gamma relaxation of intramolecular origin. The Johari-Goldstein beta relaxation coming from the motion of the entire molecule is found to be hidden under the structural relaxation peak in both the pharmaceuticals.

Acotiamide improves stress-induced impaired gastric accommodation.

BACKGROUND: Gastric accommodation is a reflex reaction related to gastric reservoir function. Psychological stress, such as anxiety, inhibits gastric accommodation in humans. Acotiamide enhances the effect of acetylcholine in the enteric nervous system, enhances gastric contractility, and accelerates delayed gastric emptying. However, the effect of acotiamide on stress-induced impaired gastric accommodation remains unclear. Therefore, we examined the effect of acotiamide on gastric accommodation and stress-induced impaired gastric accommodation using a conscious guinea pig model. METHODS: A polyethylene bag was inserted through the distal region of the gastric body into the proximal stomach of 5-week-old male Hartley guinea pigs. Gastric accommodation was evaluated by measuring the intrabag pressure in the proximal stomach after oral administration of a liquid meal. In the stress model, animals were subjected to water-avoidance stress. Acotiamide (Z-338) or nizatidine was administered subcutaneously. Fecal output was determined as the number of fecal pellets. KEY RESULTS: Administration of the liquid meal significantly decreased intrabag pressure, indicating induction of gastric accommodation. Acotiamide treatment prolonged liquid meal-induced gastric accommodation and significantly increased the number of fecal pellets compared to controls. Water-avoidance stress significantly inhibited liquid meal-induced gastric accommodation. Pretreatment with acotiamide significantly improved stress-induced impaired gastric accommodation. The number of fecal pellets in the acotiamide group increased significantly compared to controls. Acotiamide, but not nizatidine, significantly decreased gastric emptying. CONCLUSIONS & INFERENCES: Acotiamide prolongs gastric accommodation and improves stress-induced impaired gastric accommodation, indicating a potential role for acotiamide in the treatment of functional dyspepsia through its effects on gastric accommodation reactions.

The Slow Relaxation Dynamics in the Amorphous Pharmaceutical Drugs Cimetidine, Nizatidine, and Famotidine.

The slow molecular mobility in the amorphous solid state of 3 active pharmaceutical drugs (cimetidine, nizatidine, and famotidine) has been studied using differential scanning calorimetry and the 2 dielectric-related techniques of dielectric relaxation spectroscopy and thermally stimulated depolarization currents. The glass-forming ability, the glass stability, and the tendency for crystallization from the equilibrium melt were investigated by differential scanning calorimetry, which also provided the characterization of the main relaxation of the 3 glass formers. The chemical instability of famotidine at the melting temperature and above it prevented the preparation of the amorphous for dielectric studies. In contrast, for cimetidine and nizatidine, the dielectric study yielded the main kinetic features of the α relaxation and of the secondary relaxations. According to the obtained results, nizatidine displays the higher fragility index of the 3 studied glass-forming drugs. The thermally stimulated depolarization current technique has proved useful to identify the Johari-Goldstein relaxation and to measure τßJG in the amorphous solid state, that is, in a frequency range which is not easily accessible by dielectric relaxation spectroscopy.

Rejection of pharmaceutically-based N-nitrosodimethylamine precursors using nanofiltration.

N-Nitrosodimethylamine (NDMA) is a disinfection by-product (DBP) with many known precursors such as amine-containing pharmaceuticals that can enter the environment via treated wastewater. Reverse osmosis and tight nanofiltration membranes (MW cutoff < 200 Da) are treatment technologies that demonstrate high removal of many compounds, but at relatively high energy costs. Looser membranes (>200 Da) may provide sufficient removal of a wide range of contaminants with lower energy costs. This study examined the rejection of pharmaceuticals that are known NDMA precursors (∼300 Da) using nanofiltration (MW cutoff ∼350 Da). MQ water was compared to two raw water sources, and results illustrated that NDMA precursors (as estimated by formation potential testing) were effectively rejected in all water matrices (>84%). Mixtures of pharmaceuticals vs. single-spiked compounds were found to have no impact on rejection from the membranes used. The use of MQ water vs. surface waters illustrated that natural organic matter, colloids, and inorganic ions present did not significantly impact the rejection of the amine-containing pharmaceuticals. This study illustrates that NDMA formation potential testing can be effectively used for assessing NDMA precursor rejection from more complex samples with multiple and/or unknown NDMA precursors present, such as wastewater matrices.

The treatment of gastroparesis, constipation and small intestinal bacterial overgrowth syndrome in patients with Parkinson's disease.

INTRODUCTION: Parkinson's disease (PD) affects the nerves of the entire gastrointestinal (GI) tract and may result in profound gastrointestinal (GI) dysfunction leading to poor patient outcomes. Common GI disturbances in patients with PD include gastroparesis (GP), constipation and small intestinal bacterial overgrowth syndrome (SIBO). In particular, GP is difficult to treat due to the limited options available and precautions, contraindications and adverse effects associated with the approved treatments. Moreover, some commonly used medications can worsen pre-existing PD. AREAS COVERED: Our review will focus on treatment options for GP and SIBO with motilin agonists, dopamine receptor antagonists, Ghrelin agonists muscarinic agonists, 5-HT4 receptor agonists, antibiotics, probiotics and herbal formulation such as iberogast. Constipation occurs in the majority of patients with PD and fortunately many treatments are now available. Our review is based on original papers or reviews selected from PUBMED search and Cochrane reviews. EXPERT OPINION: Motility disorders of the GI tract are found frequently in patients with PD and treating the underlying GI disorders caused by PD with various prokinetics and laxatives is paramount in achieving improvements in patient's motor function. Various prokinetics and laxatives are now available to provide some relief of the GI morbidity caused by PD leading even to better absorption of even the PD treatments.

Development and validation of a sensitive LC-MS/MS assay for the quantification of nizatidine in human plasma and urine and its application to pharmacokinetic study.

We developed and validated a high performance liquid chromatographic method coupled with triple quadrupole mass spectrometry for analysis of nizatidine in human plasma and urine. The biological samples were precipitated with methanol before separation on an Agilent Eclipse Plus C18 column (100mm×46mm, 5µm) with a mixture of methanol and water (95:5, plus 5mM ammonium formate) as the mobile phase at 0.5mL/min. Detection was performed using multiple reaction monitoring modes via electrospray ionization (ESI) at m/z 332.1→155.1 (for nizatidine) and m/z 335.1→155.1 (for [(2)H3]-nizatidine, the internal standard). The linear response range was 5-2000ng/mL and 0.5-80µg/mL for human plasma and urine, with the lower limits of quantification of 5ng/mL and 0.5µg/mL, respectively. The method was validated according to the biological method validation guidelines of the Food and Drug Administration and proved acceptable. This newly developed analytical method was successfully applied in a pharmacokinetic study following single oral administration of a 150mg nizatidine capsule in to 16 healthy Chinese subjects. Maximum and endpoint concentrations in plasma and urine were quantifiable, suggesting our method is appropriate for routine pharmacokinetic analysis.

Extraction of ranitidine and nizatidine with using imidazolium ionic liquids prior spectrophotometric and chromatographic detection.

A new extraction medium was proposed for liquid-liquid extraction of the histamine H2 receptor antagonists ranitidine (RNT) and nizatidine (NZT). The ionic liquids with low vapor pressure and favorable solvating properties for a range of compounds such as 1-butyl-3-methylimidazolium hexafluorophosphate [C4mim][PF6] and 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide [C4mim][Tf2N] were tested for isolation of analytes. The extraction parameters of RNT and NZT, namely, amount of ionic liquid, pH of sample solution, shaking and centrifugation time were optimized. The isolation processes were performed with 1 mL of the ionic liquids. The extracted samples (pH values near 4) were shaken at 1750 rpm. The influence of interfering substances on the efficiency of extraction process was also studied. Methods for the histamine H2 receptor antagonists (ranitidine and nizatidine) determination after their separation using imidazolium ionic liquids by high performance liquid chromatography (HPLC) combined with UV spectrophotometry were developed. The application of ionic liquids in extraction step allows for selective isolation of analytes from aqueous matrices and their preconcentration. The above methods were applied to the determination of RNT and NZT in environmental samples (river water and wastewater after treatment).