Risk of Cancer in Association with Ranitidine and Nizatidine vs Other H2 Blockers: Analysis of the Japan Medical Data Center Claims Database 2005-2018.

INTRODUCTION: In September 2019, ranitidine and nizatidine were suggested to contain N-nitrosodimethylamine, a carcinogenic substance. People have since been concerned about the potential impact of ranitidine/nizatidine use on the risk of cancer. OBJECTIVE: The objective of this study was to investigate the risk of cancer among people receiving ranitidine or nizatidine compared with other histamine 2 receptor antagonists (H2 blockers) [cimetidine, famotidine, roxatidine, and lafutidine]. METHODS: In the Japan Medical Data Center claims database (comprising people aged < 75 years) from 2005 to 2018, we identified new adult users of H2 blockers and classified them into ranitidine/nizatidine users and other H2 blocker users. We estimated the incidence of cancer diagnosis in each group and conducted a multivariable Cox regression analysis. RESULTS: We identified 113,745 new users of ranitidine/nizatidine (median age 41.2 years [interquartile range 31.7-51.1]; 49.1% men; median follow-up 2.4 years [1.1-4.5]) and 503,982 new users of other H2 blockers (median age 40.9 years [31.1-51.2]; 51.0% men; median follow-up 2.3 years [0.9-4.2]). The incidence rate of cancer diagnosis was 6.39 (95% confidence interval 6.13-6.66) cases per 1000 person-years (top three sites: breast 14.8%; colorectal 14.6%; and stomach 11.5%) in the ranitidine/nizatidine group and 6.17 (6.05-6.30) cases per 1000 person-years (colorectal 14.7%; breast 13.5%; and stomach 11.2%) in the other H2 blockers group. The adjusted hazard ratio (ranitidine/nizatidine users vs other H2 blocker users) was 1.02 (0.98-1.07). The results were similar by follow-up length, by cancer site, and when ranitidine and nizatidine users were separately compared with the other H2 blockers group. By cumulative dose, the adjusted hazard ratio (95% confidence interval) was 1.03 (0.98-1.08) from 1 to 180 defined daily doses (DDDs), 1.00 (0.73-1.39) from 181 to 365 DDDs, 0.95 (0.61-1.48) from 366 to 730 DDDs, and 0.83 (0.45-1.55) at > 730 DDDs. CONCLUSIONS: We found no evidence that ranitidine/nizatidine is associated with an increased risk of cancer, although further studies with more accurate measurement of exposure, inclusion of older people, and longer follow-up may be needed.

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.

[Safety of proton pump inhibitors]. / Seguridad de la utilización de los inhibidores de la bomba de protones.

The significant inhibitory capacity of gastric acid secretion of PPIs makes them the drugs of choice for treating acid-related diseases. The considerable prevalence of these diseases and the need for maintaining the administration of the drug during considerably long periods results in this therapeutic group being one of the most widely used. However, in spite of their extensive use, there continue to emerge concerns about their potential toxicity; concerns surrounding the specificity of their mechanism of action and a consequential suspicion that something so potent must involve harmful effects. PPIs act selectively on the final stage of the process of gastric acid secretion, namely the H+/K+-ATPase or proton pump. This enzyme represents an essential step in the process of secretion of H+, and PPIs exert a very specific action on the parietal cell, as they need an environment with very low pH levels, which only exist in this cell. In the present article, the adverse effects of PPIs are reviewed, with special emphasis on those related to their continued administration and on the special circumstances of patients, as in the case of the elderly, those with liver failure, pregnant and breastfeeding mothers and children. All the PPIs on the market share a common chemical basis and there are no great differences in their potential adverse effects, the possibility of them promoting opportunist infections or their capacity to generate pharmacokinetic interactions with other drugs, which, if occur, are generally insignificant. After two decades of use, PPIs have proved to be very effective and safe drugs.

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.

Extrapyramidal symptoms related to adjunctive nizatidine therapy in an adolescent receiving quetiapine and paroxetine.

Weight gain is a serious problem with recently introduced atypical antipsychotic agents. Nizatidine, a histamine2 (H2)-receptor antagonist, may help reduce this weight gain. To our knowledge, no adverse effects have been reported when nizatidine is given at recommended doses with atypical antipyschotic agents. We describe, however, an adolescent who was receiving quetiapine and paroxetine for schizophrenia and depression, and developed extrapyramidal symptoms (EPS; parkinsonism and akathisia) after taking nizatidine for weight loss. Based on a report of another patient who developed EPS after taking higher-than-recommended doses of nizatidine, we reviewed the literature on treatment with H2-receptor antagonists for weight gain and on central nervous system adverse effects of nizatidine. Nizatidine may be effective for reducing weight gain associated with both medical and psychiatric conditions. Its safety profile is usually benign, although some patients may develop serious adverse effects, such as EPS and delirium. Therefore, the drug is recommended for short-term management of weight gain associated with atypical antipsychotic agents. Patients receiving nizatidine therapy should be monitored closely for development of EPS, particularly when high doses are prescribed.

Aplastic anemia associated with initiation of nizatidine therapy in a hemodialysis patient.

We report on a hemodialysis (HD) patient in whom fatal aplastic anemia developed after the administration of nizatidine, a histamine 2 (H2)-receptor antagonist. The patient was a 55-year old Japanese woman and had been on HD for 2 years due to endstage diabetic nephropathy. The patient had a hemorrhagic duodenal ulcer and had been treated with lansoprazole, a proton pump inhibitor, for 2 months. After improvement, lansoprozole was discontinued and she was subsequently treated with nizatidine. Twelve days after initiation of nizatidine treatment, the patient developed a high-grade fever with symptoms suggestive of upper respiratory infection. Hematological tests showed severe pancytopenia, and drug-induced aplastic anemia was diagnosed. Nizatidine was suggested as the causal drug. Despite intensive therapies, the patient died on the 23rd hospital day from generalized fungal infections. Although hematological adverse events have been reported in HD patients receiving H2-receptor antagonists, few studies of fatal aplastic anemia associated with these drugs have been reported. This case emphasized that careful observation is required after the initiation of H2-receptor antagonist treatment in HD patients.

Comparison of the efficacy of pantoprazole vs. nizatidine in the treatment of erosive oesophagitis: a randomized, active-controlled, double-blind study.

BACKGROUND: Pantoprazole is a proton pump inhibitor approved for the treatment of erosive oesophagitis and gastro-oesophageal reflux disease. AIM: To compare the efficacy and safety of pantoprazole vs. nizatidine for the treatment of symptomatic gastro-oesophageal reflux disease and endoscopically documented erosive oesophagitis (grade > or = 2). METHODS: A multicentre, double-blind, randomized, active-controlled study (221 patients) was performed to compare 20 and 40 mg pantoprazole daily with nizatidine 150 mg b.d. (maximum, 8 weeks). The primary end-point was endoscopic healing of erosive oesophagitis (grade 1 or 0). The secondary end-point was symptomatic improvement. RESULTS: Healing averaged 61%, 64% and 22% for pantoprazole 20 mg, pantoprazole 40 mg and nizatidine 150 mg, respectively, at 4 weeks, and 79%, 83% and 41% at 8 weeks (P < 0.05, differences between groups at both points). Starting on day 1 of symptom assessment, significantly fewer pantoprazole-treated patients reported night-time heartburn and regurgitation compared with nizatidine-treated patients. Symptoms of gastro-oesophageal reflux disease were completely eliminated in 68% and 65% of patients in the pantoprazole 20-mg and 40-mg groups and in 28% of patients in the nizatidine group at study completion. The difference between each pantoprazole group and the nizatidine group was significant (P < 0.05). CONCLUSIONS: Pantoprazole, at single daily doses of 20 mg and 40 mg for up to 8 weeks, provides more rapid relief of symptoms and superior healing of erosive oesophagitis than nizatidine 150 mg b.d., and is well tolerated.

Options for pharmacological management of obesity in patients treated with atypical antipsychotics.

Obesity is associated with considerable morbidity and decreased life expectancy. Weight gain is a commonly encountered problem associated with antipsychotic treatment. We reviewed the literature regarding the mechanisms of weight gain in response to these agents and eight substances implicated as potential obesity prevention or treatment: orlistat, sibutramine, fluoxetine, topiramate, amantadine, nizatidine and cimetidine, and metformin. Weight gain in response to antipsychotic treatment may be mediated through serotonergic, dopaminergic, adrenergic, cholinergic, histaminergic and glutaminergic receptors. Sex hormone dysregulation and altered insulin sensitivity have also been implicated. Two compounds, orlistat and sibutramine, have been shown to help prevent weight gain following a hypocaloric diet, but orlistat requires compliance with a fat-reduced diet, and sibutramine is unsuitable for patients taking serotonergic agents. The weight reducing effect of fluoxetine, even in conjunction with a hypocaloric diet, is only transient. Topiramate, amantadine and metformin may have adverse side-effects potentially outweighing the weight reducing potential. The effectiveness of cimetidine and nizatedine remains unclear. The hazards of these agents in a psychiatric population are discussed. It is concluded that the current evidence does not support the general use of pharmacological interventions for overweight patients treated with antipsychotic medication, although individually selected patients may benefit.

H2 histamine receptor blockade in the treatment of Alzheimer disease: a randomized, double-blind, placebo-controlled trial of nizatidine.

OBJECTIVES: To evaluate the efficacy of nizatidine, a histamine H2-blocking drug, in delaying the progression of cognitive impairment in older adults with Alzheimer disease (AD). DESIGN: A one-year, randomized, double-blind, placebo-controlled trial. PARTICIPANTS: Fifty-one older men and women aged 67 to 96 years with AD were recruited from the Cache County Study on Memory in Aging. METHODS: Patients were stratified by age and by the presence of one or more epsilon 4 alleles at the APOE locus, then randomized to receive nizatidine 75 mg (Axid ARTM, Whitehall Robins) or a matching placebo tablet twice daily. Cognitive outcomes were assessed at baseline, six, and twelve months after enrollment using tests from the CERAD battery and additional measures of visuospatial memory, verbal memory, and verbal fluency. RESULTS: Subjects showed significant declines in language, fluency, and praxis but most measures of memory had already "bottomed out." Intention-to-treat and compliance-based analyses showed no effect of nizatidine on any of the cognitive outcome measures over the one-year study interval. CONCLUSIONS: These results do not support claims for the efficacy of nizatidine in over-the-counter dosages as a means of preventing symptom progression in AD.

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.

Nizatidine in combination with amoxycillin and clarithromycin in the treatment of Helicobacter pylori infection.

BACKGROUND: The efficacy of H2-antagonists in combination with antibiotics in curing Helicobacter pylori infection remains controversial, and it is uncertain whether double dose H2-antagonist therapy is superior to standard dose. AIM: To determine the efficacy of two doses of nizatidine in combination with two antibiotics in the treatment of H. pylori. METHODS: A randomized controlled trial was conducted in 160 patients comparing nizatidine 150 mg with 300 mg b.d. (standard vs. double dose), in combination with clarithromycin (500 mg) and amoxycillin (1000 mg) b.d. for 14 days, in Australia and Taiwan. Compliance was based on a clinical assessment and pill count. H. pylori status was determined by histology (antrum and corpus) and CLO-test. RESULTS: Baseline clinical and endoscopic findings were similar in both arms of the study. Based on an intention-to-treat analysis, cure of H. pylori was achieved in 78% (95% CI: 70.4-85.4%) in the standard nizatidine dose arm and 70% (95% CI: 61.6-78.2%) in the double dose arm (P=0.2). Similar cure rates were observed in ulcer and non-ulcer patient groups. Compliance was excellent in the single and double dose arms (85 and 91%, respectively). CONCLUSIONS: The combination of nizatidine in standard or double dose with clarithromycin and amoxycillin is similarly efficacious in curing H. pylori infection.

Placebo-controlled trial of cisapride and nizatidine in unselected patients with functional dyspepsia.

OBJECTIVE: Patients in most trials of pharmacotherapy for nonorganic dyspepsia have been groups referred selectively for endoscopy, which could have led to a selection bias of nonresponders, explaining the negative outcome of most controlled treatment trials in nonorganic dyspepsia. The aim of this study was to evaluate the effects of cisapride and nizatidine in patients with nonorganic dyspepsia who were recruited directly from primary care settings, and to evaluate the therapeutic implications of dyspepsia subgrouping. METHODS: A consecutive series of patients who consulted their general practitioner with dyspepsia were invited to an interview and endoscopy. Before endoscopy, symptoms were classified as reflux-like, dysmotility-like, ulcer-like, or unclassifiable. A total of 330 patients with either minor or no abnormalities at endoscopy were randomized to double blind treatment with cisapride 10 mg t.i.d., nizatidine 300 mg at night, or placebo for 2 wk. RESULTS: A symptomatic response was found in 62% of patients on cisapride (therapeutic gain cisapride vs placebo: 0.1% [95% confidence interval -14% to 14%]) and in 54% of patients on nizatidine (therapeutic gain nizatidine vs placebo: -8% [95% confidence interval -22% to 7%]). Response to treatment was independent of symptom classification. CONCLUSIONS: The effects of a 2-wk course of cisapride or nizatidine in unselected patients with dyspepsia recruited from primary care were not superior to those of placebo. Symptom subgrouping was not predictive of response to therapy.

A man with palpable purpuric hand lesions.

A 75-year-old man with seronegative rheumatoid arthritis presented with a three-day history of low-grade fever, new arthralgias, mouth sores, and bilateral cutaneous hand lesions. He had not had hand trauma.