Development and validation of high-performance liquid chromatography-Orbitrap mass spectrometric method for quantification of NDMA in ranitidine drug products and evaluation of antioxidants as inhibitors of classical nitrosation reaction.

RATIONALE: N-Nitroso dimethylamine (NDMA) is a mutagenic impurity detected in several ranitidine products. The amino functional group of ranitidine is a risk factor for classical nitrosation-induced NDMA formation in ranitidine drug products during storage conditions. The United States Food and Drug Administration (US FDA) recommended the use of antioxidants to control NDMA in drug products. Considering the need for sensitive analytics, a liquid chromatography/high-resolution mass spectrometry (LC-HRMS) method was developed and validated to detect NDMA in this pilot study to demonstrate the antioxidants as inhibitors of nitrosation reactions. METHODS: The method, utilizing an EC-C18 column and tuned to atmospheric pressure chemical ionization/selected ion monitoring (APCI/SIM) mode, separated NDMA (m/z: 75.0553; tR: 3.71 min) and ranitidine (m/z: 315.1485; tR: 8.61 min). APCI mode exhibited four times higher sensitivity to NDMA than electrospray ionization (ESI) mode. Classical nitrosation of the dimethyl amino group of ranitidine was studied with sodium nitrite in solid pellets. Antioxidants (alpha-tocopherol, ascorbic acid, and trolox) were evaluated as NDMA attenuators in ranitidine pellets under vulnerable storage conditions. The developed method quantified NDMA levels in samples, extracted with methanol through vortex shaking for 45 min. RESULTS: The method achieved a limit of detection (LOD) and limit of quantitation (LOQ) of 0.01 and 0.05 ng/mL, respectively, with linearity within 1-5000 ng/mL (R1: 0.9995). It demonstrated good intra-day and inter-day precision (% RSD [relative standard deviation]: <2) and accuracy (96.83%-101.72%). Nitrosation of ranitidine induced by nitrite was significant (p < 0.001; R2 = 0.9579) at various sodium nitrite levels. All antioxidants efficiently attenuated NDMA formation during ranitidine nitrosation. Ascorbic acid exhibited the highest NDMA attenuation (96.98%), followed by trolox (90.58%). This study recommends 1% ascorbic acid and trolox as potent NDMA attenuators in ranitidine drug products. CONCLUSIONS: This study compared the effectiveness of antioxidants as NDMA attenuators in ranitidine under storage conditions susceptible to NDMA generation. The study concluded that ascorbic acid and trolox are potent inhibitors of NDMA formation and nitrosation attenuators in ranitidine drug products.

Histamine H2-receptor antagonism improves conduit artery endothelial function and reduces plasma aldosterone level without lowering arterial blood pressure in angiotensin II-hypertensive mice.

Aldosterone through the mineralocorticoid receptor MR has detrimental effects on cardiovascular disease. It reduces the bioavailability of nitric oxide and impairs endothelium-dependent vasodilatation. In resistance arteries, aldosterone impairs the sensitivity of vascular smooth muscle cells to nitric oxide by promoting the local secretion of histamine which activates H2 receptors. The present experiments tested in vivo and ex vivo the hypothesis that systemic H2-receptor antagonism reduces arterial blood pressure and improves vasodilatation in angiotensin II-induced chronic hypertension. Hypertension was induced by intravenous infusion of angiotensin II (60 ng kg-1 min-1) in conscious, unrestrained mice infused concomitantly with the H2-receptor antagonist ranitidine (27.8 µg kg-1 min-1) or vehicle for 24 days. Heart rate and arterial blood pressure were recorded by indwelling arterial catheter. Resistance (mesenteric) and conductance (aortae) arteries were harvested for perfusion myography and isometric tension recordings by wire myography, respectively. Plasma was analyzed for aldosterone concentration. ANGII infusion resulted in elevated arterial blood pressure and while in vivo treatment with ranitidine reduced plasma aldosterone concentration, it did not reduce blood pressure. Ranitidine improved ex vivo endothelial function (acetylcholine 10-9 to 10-6 mol L-1) in mesenteric resistance arteries. This was abolished by ex vivo treatment with aldosterone (10-9 mol L-1, 1 h). In aortic segments, in vivo ranitidine treatment impaired relaxation. Activation of histamine H2 receptors promotes aldosterone secretion, does not affect arterial blood pressure, and protects endothelial function in conduit arteries but promotes endothelial dysfunction in resistance arteries during angiotensin II-mediated hypertension. Aldosterone contributes little to angiotensin II-induced hypertension in mice.

In Silico Prediction of N-Nitrosamine Formation Pathways of Pharmaceutical Products.

The recent discovery of N-nitrosodimethylamine (NDMA), a mutagenic N-nitrosamine, in pharmaceuticals has adversely impacted the global supply of relevant pharmaceutical products. Contamination by N-nitrosamines diverts resources and time from research and development or pharmaceutical production, representing a bottleneck in drug development. Therefore, predicting the risk of N-nitrosamine contamination is an important step in preventing pharmaceutical contamination by DNA-reactive impurities for the production of high-quality pharmaceuticals. In this study, we first predicted the degradation pathways and impurities of model pharmaceuticals, namely gliclazide and indapamide, in silico using an expert-knowledge software. Second, we verified the prediction results with a demonstration test, which confirmed that N-nitrosamines formed from the degradation of gliclazide and indapamide in the presence of hydrogen peroxide, especially under alkaline conditions. Furthermore, the pathways by which degradation products formed were determined using ranitidine, a compound previously demonstrated to generate NDMA. The prediction indicated that a ranitidine-related compound served as a potential source of nitroso groups for NDMA formation. In silico software is expected to be useful for developing methods to assess the risk of N-nitrosamine formation from pharmaceuticals.

Targeting NF-κB/COX-2 signaling by soyasaponin I alleviates diclofenac-induced gastric ulceration in male albino rats.

Gastric ulceration is a prevalent worldwide clinical presentation due to altered gastric defense mechanisms. Nonsteroidal anti-inflammatory drugs are one of the common causes of gastric ulcers mediated by the release of inflammatory mediators. The study aimed to investigate the potential protective effect of soyasaponin I (soya) against diclofenac (DIC)-induced gastric ulcer in rats and to highlight the underlying mechanisms. The experiment was conducted on 40 male Wistar albino rats, equally distributed into five groups: control, DIC-induced ulcer (9 mg/kg/d, orally, twice daily for 3 days), ulcer/soya-, ulcer/ranitidine-, and ulcer/soya/selective nuclear factor kappa B inhibitor (JSH-23)-treated groups. The doses of soya, ranitidine, and JSH were 20, 25, and 5 mg/kg/d, respectively, given orally. Gastric specimens were prepared for gene and histological study and for biochemical analysis of gastric prostaglandin E2 (PGE2), oxidative markers, and inflammatory cytokines. The gastric samples were formalin-fixed, paraffin-embedded, and subjected to hematoxylin and eosin (H&E), PAS staining, and immunohistochemical assay for identification of nuclear factor kappa B (NF-κB), cyclooxygenase-2 (COX-2), and proliferation marker (Ki67) expressions. The findings revealed decreased gastric PGE2 and altered inflammatory and oxidative markers in the ulcer model group. The H&E staining showed mucosal injury characterized by mucosal surface defects and inflammatory cell infiltrations. The polymerase chain reaction (PCR) and immunohistochemistry demonstrated an upregulation of NF-κB and COX-2 expression at gene/protein levels; meanwhile, Ki67 downregulation. The soya-treated group showed maintained biochemical, histological, and PCR findings comparable to the ranitidine-treated group. The JSH-23-treated group still showed partial gastric protection with biochemical and immunohistochemical changes. Soyasaponin I ameliorated DIC-induced gastric ulcers by targeting the COX-2 activity through modulation of NF-κB signaling.

Exclusion of Ranitidine From Premedication Regimens During Paclitaxel Treatment.

This cohort study conducted in the Netherlands uses electronic medical records to assess incidence of hypersensitivity reactions with and without H2-receptor antagonist premedication before paclitaxel administration.

Oxidation of amine-based pharmaceuticals with unactivated peroxymonosulfate: Kinetics, mechanisms, and elimination efficiency of NDMA formation.

Amine-based pharmaceuticals are a significant class of N-nitrosodimethylamine (NDMA) precursors. This study investigated the use of unactivated peroxymonosulfate (PMS) to control amine-based pharmaceuticals and their NDMA formation potential. Kinetic analysis and product identification revealed that sumatriptan and doxylamine primarily underwent reactions at their tertiary amine group, while ranitidine and nizatidine had both tertiary amine and thioether group as reaction sites. The NDMA formation from sumatriptan and doxylamine during post-chloramination was significantly reduced with the abatement of the parent contaminants, while the formation of NDMA remained high even if full abatement of ranitidine and nizatidine was achieved. Product formation kinetics and reference standard tests revealed the great contribution of transformation products to NDMA formation. Ranitidine could be oxidized to sulfoxide-type product ranitidine-SO and N-oxide type product ranitidine-NO. Ranitidine-SO exhibited a high NDMA yield comparable to that of ranitidine (>90%), while ranitidine-NO showed a low NDMA yield (2%). With further oxidation of ranitidine-SO at the tertiary amine group, NDMA formation was reduced by more than 90%. The underlying mechanism for the importance of the tertiary amine group in NDMA formation was demonstrated by quantum chemical calculation. These findings underscore the potential of PMS pre-oxidation on NDMA control.

Drug Utilisation Patterns of Alternatives to Ranitidine-Containing Medicines in Patients Treated with Ranitidine: A Network Analysis of Data from Six European National Databases.

INTRODUCTION: Ranitidine, a histamine H2-receptor antagonist (H2RA), is indicated in the management of gastric acid-related disorders. In 2020, the European Medicines Agency (EMA) recommended suspension of all ranitidine-containing medicines in the European Union (EU) due to the presence of N-nitrosodimethylamine (NDMA) impurities, which were considered to be carcinogenic. The aim of this study was to investigate the impact of regulatory intervention on use patterns of ranitidine-containing medicines and their therapeutic alternatives. OBJECTIVES: The aim was to study drug utilisation patterns of ranitidine and report discernible trends in treatment discontinuation and switching to alternative medications. METHODS: This retrospective, population-based cohort study was conducted using primary care records from six European countries between 2017 and 2023. To explore drug utilisation patterns, we calculated (1) incident use of ranitidine, other H2RAs, and other alternative drugs for the treatment of gastric ulcer and/or gastric bleeding; (2) ranitidine discontinuation; and (3) switching from ranitidine to alternative drugs (H2RAs, proton-pump inhibitors [PPIs], and other medicinal products for acid-related disorders). RESULTS: During the study period, 385,273 new ranitidine users were observed, with most users being female and aged 18-74 years. Ranitidine was the most commonly prescribed H2RA in the pre-referral period (September 2017-August 2019), with incidence rates between 0.8 and 9.0/1000 person years (PY). A steep decline to 0.3-3.8/1000 PY was observed in the referral period (September 2019-March 2020), eventually dropping to 0.0-0.4/1000 PY in the post-referral period (April 2020-March 2022). Switching from ranitidine to alternative drugs increased in the post-referral period, with the majority of patients switching to PPIs. Discontinuation of ranitidine use ranged from 270 to 380/1000 users in 2017 and decreased over time. CONCLUSIONS: Ranitidine was commonly used prior to referral, but it was subsequently discontinued and replaced primarily with PPIs.

Ranitidine as an adjuvant regulates macrophage polarization and activates CTLs through the PI3K-Akt2 signaling pathway.

Adjuvants are an indispensable component of vaccines, but there are few adjuvants for human vaccines. H2 receptor blockers, inhibiting gastric acid secretion, have immune enhancement effects. Ranitidine (RAN) is a water-soluble H2 receptor blocker, and whether it has an immune-enhancing effect is still unknown. In this study, flow cytometry, western blotting, and immunofluorescence methods were used to analyze whether RAN could activate macrophage polarization to the M1 phenotype in vivo and in vitro. Here, we found that the M1 inflammatory cytokine levels and surface markers in RAW264.7 cells were upregulated by NF-κB activation, possibly through the PI3K-Akt2 signaling pathway, after RAN treatment. Endocytic function was also enhanced by feedback regulation of Akt2/GSK3ß/Dynmin1 signaling. Furthermore, to evaluate the adjuvant function of RAN, we used OVA plus RAN as a vaccine to inhibit the growth of B16-OVA tumors in mice. We also found that in the RAN adjuvant group, macrophage polarization to M1, Th1 cell differentiation, and cytotoxic T lymphocyte (CTL) activation were significantly upregulated. The tumor growth of mice was inhibited, and the survival rate of mice was significantly improved. This study provides new evidence for the mechanism by which RAN activates the immune response and is expected to provide a new strategy for the research and development of tumor vaccine adjuvants.

Co prescription of anti-acid therapy reduces the bioavailability of mycophenolate mofetil in systemic sclerosis patients: A crossover trial.

OBJECTIVE: Mycophenolate mofetil (MMF) is an effective treatment option for interstitial lung disease (ILD) in systemic sclerosis (SSc). Many patients require co-administration of proton pump inhibitors (PPI) or H2 receptor blockers (HRB) because of various gastrointestinal (GI) manifestations in SSc. Co-treatment with PPI or HRB have shown to reduce serum drug levels in post-transplant patients. We wanted to see if there is a similar phenomenon for Mycophenolate in SSc. METHODS: Twenty SSc patients, who were on a stable dose of MMF (1.5-3 g) underwent a sequential cross over study with MMF alone in the first month, followed by co-treatment with Ranitidine and then Esomeprazole in the second and third month respectively. Estimation of 12-hour area under curve (AUC) of Mycophenolic Acid (MPA) levels and total GI score were calculated at the end of each month and compared between the treatment arms. [Trial registration: CTRI/2020/06/025,939] RESULTS: Co-administration of esomeprazole was associated with 32.7% (mean difference = 22.28 µg h ml-1) reduction in mean AUC MPA, whereas ranitidine caused a reduction of 21.97% (mean difference = 14.93 µg h ml-1) in MPA AUC when compared to MMF without anti-acid therapies. The addition of ranitidine or esomeprazole resulted in significant reduction in the total GI score. CONCLUSION: Co-administration of PPI or HRB can significantly reduce the bioavailability of MMF in patients with SSc. To avoid therapeutic failure of MMF drug level monitoring is essential when these agents are co-prescribed with MMF.

Ranitidine Use and Incident Cancer in a Multinational Cohort.

Importance: Ranitidine, the most widely used histamine-2 receptor antagonist (H2RA), was withdrawn because of N-nitrosodimethylamine impurity in 2020. Given the worldwide exposure to this drug, the potential risk of cancer development associated with the intake of known carcinogens is an important epidemiological concern. Objective: To examine the comparative risk of cancer associated with the use of ranitidine vs other H2RAs. Design, Setting, and Participants: This new-user active comparator international network cohort study was conducted using 3 health claims and 9 electronic health record databases from the US, the United Kingdom, Germany, Spain, France, South Korea, and Taiwan. Large-scale propensity score (PS) matching was used to minimize confounding of the observed covariates with negative control outcomes. Empirical calibration was performed to account for unobserved confounding. All databases were mapped to a common data model. Database-specific estimates were combined using random-effects meta-analysis. Participants included individuals aged at least 20 years with no history of cancer who used H2RAs for more than 30 days from January 1986 to December 2020, with a 1-year washout period. Data were analyzed from April to September 2021. Exposure: The main exposure was use of ranitidine vs other H2RAs (famotidine, lafutidine, nizatidine, and roxatidine). Main Outcomes and Measures: The primary outcome was incidence of any cancer, except nonmelanoma skin cancer. Secondary outcomes included all cancer except thyroid cancer, 16 cancer subtypes, and all-cause mortality. Results: Among 1 183 999 individuals in 11 databases, 909 168 individuals (mean age, 56.1 years; 507 316 [55.8%] women) were identified as new users of ranitidine, and 274 831 individuals (mean age, 58.0 years; 145 935 [53.1%] women) were identified as new users of other H2RAs. Crude incidence rates of cancer were 14.30 events per 1000 person-years (PYs) in ranitidine users and 15.03 events per 1000 PYs among other H2RA users. After PS matching, cancer risk was similar in ranitidine compared with other H2RA users (incidence, 15.92 events per 1000 PYs vs 15.65 events per 1000 PYs; calibrated meta-analytic hazard ratio, 1.04; 95% CI, 0.97-1.12). No significant associations were found between ranitidine use and any secondary outcomes after calibration. Conclusions and Relevance: In this cohort study, ranitidine use was not associated with an increased risk of cancer compared with the use of other H2RAs. Further research is needed on the long-term association of ranitidine with cancer development.

Pharmacological treatment of gastro-oesophageal reflux in children.

BACKGROUND: Gastro-oesophageal reflux (GOR) is characterised by the regurgitation of gastric contents into the oesophagus. GOR is a common presentation in infancy, both in primary and secondary care, affecting approximately 50% of infants under three months old. The natural history of GOR in infancy is generally of a self-limiting condition that improves with age, but older children and children with co-existing medical conditions can have more protracted symptoms. The distinction between gastro-oesophageal reflux disease (GORD) and GOR is debated. Current National Institute of Health and Care Excellence (NICE) guidelines define GORD as GOR causing symptoms severe enough to merit treatment. This is an update of a review first published in 2014. OBJECTIVES: To assess the effects of pharmacological treatments for GOR in infants and children. SEARCH METHODS: For this update, we searched CENTRAL, MEDLINE, Embase, and Web of Science up to 17 September 2022. We also searched for ongoing trials in clinical trials registries, contacted experts in the field, and searched the reference lists of trials and reviews for any additional trials. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared any currently-available pharmacological treatment for GOR in children with placebo or another medication. We excluded studies assessing dietary management of GORD and studies of thickened feeds. We included studies in infants and children up to 16 years old. DATA COLLECTION AND ANALYSIS: We used standard methodology expected by Cochrane. MAIN RESULTS: We included 36 RCTs involving 2251 children and infants. We were able to extract summary data from 14 RCTs; the remaining trials had insufficient data for extraction. We were unable to pool results in a meta-analysis due to methodological differences in the included studies (including heterogeneous outcomes, study populations, and study design). We present the results in two groups by age: infants up to 12 months old, and children aged 12 months to 16 years old. Infants Omeprazole versus placebo: there is no clear effect on symptoms from omeprazole. One study (30 infants; very low-certainty evidence) showed cry/fuss time in infants aged three to 12 months had altered from 246 ± 105 minutes/day at baseline (mean +/- standard deviation (SD)) to 191 ± 120 minutes/day in the omeprazole group and from 287 ± 132 minutes/day to 201 ± 100 minutes/day in the placebo group (mean difference (MD) 10 minutes/day lower (95% confidence interval (CI) -89.1 to 69.1)). The reflux index changed in the omeprazole group from 9.9 ± 5.8% in 24 hours to 1.0 ± 1.3% and in the placebo group from 7.2 ± 6.0% to 5.3 ± 4.9% in 24 hours (MD 7% lower, 95% CI -4.7 to -9.3). Omeprazole versus ranitidine: one study (76 infants; very low-certainty evidence) showed omeprazole may or may not provide symptomatic benefit equivalent to ranitidine. Symptom scores in the omeprazole group changed from 51.9 ± 5.4 to 2.4 ± 1.2, and in the ranitidine group from 47 ± 5.6 to 2.5 ± 0.6 after two weeks: MD -4.97 (95% CI -7.33 to -2.61). Esomeprazole versus placebo: esomeprazole appeared to show no additional reduction in the number of GORD symptoms compared to placebo (1 study, 52 neonates; very low-certainty evidence): both the esomeprazole group (184.7 ± 78.5 to 156.7 ± 75.1) and placebo group (183.1 ± 77.5 to 158.3 ± 75.9) improved: MD -3.2 (95% CI -4.6 to -1.8). Children Proton pump inhibitors (PPIs) at different doses may provide little to no symptomatic and endoscopic benefit. Rabeprazole given at different doses (0.5 mg/kg and 1 mg/kg) may provide similar symptom improvement (127 children in total; very low-certainty evidence). In the lower-dose group (0.5 mg/kg), symptom scores improved in both a low-weight group of children (< 15 kg) (mean -10.6 ± SD 11.13) and a high-weight group of children (> 15 kg) (mean -13.6 ± 13.1). In the higher-dose groups (1 mg/kg), scores improved in the low-weight (-9 ± 11.2) and higher-weight groups (-8.3 ± 9.2). For the higher-weight group, symptom score mean difference between the two different dosing regimens was 2.3 (95% CI -2 to 6.6), and for the lower-weight group, symptom score MD was 4.6 (95% CI -2.9 to 12). Pantoprazole: pantoprazole may or may not improve symptom scores at 0.3 mg/kg, 0.6 mg/kg, and 1.2 mg/kg pantoprazole in children aged one to five years by week eight, with no difference between 0.3 mg/kg and 1.2 mg/kg dosing (0.3 mg/kg mean -2.4 ± 1.7; 1.2 mg/kg -1.7 ± 1.2: MD 0.7 (95% CI -0.4 to 1.8)) (one study, 60 children; very low-certainty evidence). There were insufficient summary data to assess other medications. AUTHORS' CONCLUSIONS: There is very low-certainty evidence about symptom improvements and changes in pH indices for infants. There are no summary data for endoscopic changes. Medications may or may not provide a benefit (based on very low-certainty evidence) for infants whose symptoms remain bothersome, despite nonmedical interventions or parental reassurance. If a medication is required, there is no clear evidence based on summary data for omeprazole, esomeprazole (in neonates), H2antagonists, and alginates for symptom improvements (very low-certainty evidence). Further studies with longer follow-up are needed. In older children with GORD, in studies with summary data extracted, there is very low-certainty evidence that PPIs (rabeprazole and pantoprazole) may or may not improve GORD outcomes. No robust data exist for other medications. Further RCT evidence is required in all areas, including subgroups (preterm babies and children with neurodisabilities).

Simultaneous interaction, degradation, and kinetic study of sparfloxacin with H2 receptor antagonist.

Sparfloxacin is a quinolone carboxylic acid derivative that shows activity as an antimicrobial agent, against a wide range of Gram-negative and Gram-positive organisms. It is clinically useful for the treatment of urinary tract infections, respiratory tract infections and gynecological infections. In this study in vitro drug-drug interaction of sparfloxacin has been carried out with famotidine and ranitidine. For these studies a two-component spectrophotometric process has been developed for sparfloxacin assay in the presence of famotidine or ranitidine. The reproducibility of the method is within ±5%. The technique has been applied to the development of sparfloxacin in methanol. The interaction studies of sparfloxacin with ranitidine and famotidine were carried out in methanol and methanol: Water mixtures (30:70, v/v; 50:50, v/v) and the kinetics of sparfloxacin degradation were evaluated in the presence and absence of famotidine and ranitidine. The decrease in the rate of degradation of sparfloxacin in the presence of famotidine or ranitidine, compared to that of sparfloxacin alone, indicated the possibility of interaction between the sparfloxacin and famotidine or ranitidine. The Thin layer chromatography (TLC) of the degraded solution showed the presence of a degradation product of sparfloxacin. The studies show that complexation with famotidine or ranitidine may affect the bioavailability of sparfloxacin.

Optimization of ranitidine hydrochloride based on stability performance in directly compressible immediate and sustained release formulations.

Ranitidine hydrochloride (RTD), a moisture-sensitive drug, has issues of stability during shelf life especially when formulated through wet granulation method. In current study, RTD was blended with non-hygroscopic excipient like ethyl cellulose and compressed using direct compression method. The physical and physicochemical characteristics were evaluated including hardness, thickness, diameter, friability, weight variation, disintegration, dissolution and accelerated stability study to optimize findings. Subsequently, the optimized formulation was characterized for Fourier Transform Infrared (FTIR) analysis and in vitro drug release kinetics. The physical characterization was unaffected by polymer variation while the friability and weight variation were within the USP limits. In vitro drug release depicted that the release rate was sustained by increasing the amount of ethyl cellulose, with a 10% increase of ethyl cellulose 99.09% drug was released. FTIR analysis exhibited no interaction among the ingredients of the optimized formulation (E2). The optimized formulation followed Hixson-Crowell release kinetics. Formulation A5 displayed immediate release characters as plain uncoated formulation. Accelerated studies showed no significant change in the drug content. The RTD was successfully sustained to be released up to 6 h and accelerated stability showed that the optimized formulation (E2) containing 4% starch 1500 and 10% of ethyl cellulose, respectively, was stable up to 6 months.

Is ranitidine necessary as premedication for regimens containing paclitaxel? A non-inferiority study.

BACKGROUND: Histamine type-2-receptor antagonist drugs (H2-antagonists) have been used as standard treatment to prevent hypersensitivity reactions (HRs) in paclitaxel-containing regimens, however, their use has been strongly questioned. Ranitidine has been the most widely used H2-antagonist. Therefore, especially after its withdrawal from the market, the objective of this study is to determine the impact of its elimination from premedication on HR incidence. METHODS: A cohort, multicenter, observational, prospective, and non-inferiority study, including paclitaxel-naïve cancer patients, designed to determine the incidence of HRs of any grade associated with paclitaxel administration and analyze non-inferiority against the incidence estimated in the literature (20%), with 5% as the maximum difference (Δ). Patients with a solid neoplasm of any type/stage, who initiated treatment with paclitaxel without H2-antagonists in the premedication regimen were enrolled. RESULTS: A total of 441 patients were included, of whom 50 presented 54 HRs of any grade. The cumulative incidence was 11.3% (95%CI 8.5-14.7), thus fulfilling the hypothesis of non-inferiority. Of the overall HRs detected, 15 were grade ≥ 3 with a cumulative incidence of 3.4% (95%CI 1.9-5.5). CONCLUSIONS: This study demonstrates that the elimination of ranitidine from paclitaxel premedication schedules is non-inferior in the development of HRs of any grade compared to the administration of H2-antagonists.

GC Analysis of Metformin, Ranitidine and Famotidine from Pharmaceuticals and Human Serum.

A method has been designed based on gas chromatography with flame ionization detection (FID) for the separation and analyses of ranitidine, famotidine and metformin after pre-column derivatization with trifluoroacetylacetone and ethyl chloroformate. DB-1 (30 m × 0.32 mm id) column with film thickness 0.25 µm was used for the separation at an initial temperature of column was 100°C for 2 min, and ramping at 20°C/min up to 250°C, with a hold time of 3 min. The rate of nitrogen flow was 2.5 mL/min and FID was used for detection. Complete separation was obtained between all the three drugs including excess of derivatization reagents. Linear calibration curves and detection limits were obtained in the ranges 0.1-30 µg/mL and 0.011-0.015 µg/mL. The procedure was repeatable in terms of peak heights/peak areas and retention time (n = 5) for derivatization, quantitation and separation with relative standard deviations (RSDs) within 2.0-3.0%. The approach was examined for the analyses of drug products and serum after the intake of the drugs by healthy volunteers, and recoveries were obtained within 95-98% with RSDs 2.4-3.1%.

Silver nanoparticles synthesized from Quercus brantii ameliorated ethanol-induced gastric ulcers in rats by decreasing oxidative stress and improving antioxidant systems.

Gastric ulcers are caused by an imbalance between aggressive and defensive factors. The green synthesis of silver nanoparticles is becoming a new and promising method in the treatment of gastrointestinal ulcers. This study was conducted to investigate the protective and antioxidant effects of silver nanoparticles synthesized from Quercus brantii extract (NSQBE) on gastric damage induced by alcohol in rats. In this study, silver nanoparticles were produced by the green synthesis method using oak extract. The structure and morphology of nanoparticles were confirmed by various techniques such as UV-Vis spectroscopy, fourier transforms infrared spectrometer (FTIR), scanning electron microscope (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), energy-dispersive X-ray analysis (EDX), and dynamic light scattering )DLS(. For the animal studies, 30 male Wistar rats weighing 200 ± 20 g were randomly selected and divided into five groups (the normal, ethanolic, NSQBE treatment (received doses of 20 and 5 mg/kg), and standard (received a dose of 50 mg/kg of ranitidine) groups. After the rats were euthanized, their stomach was removed. A part of the stomach tissue of rats was used for histopathological studies, and the other part was used to study biochemical parameters such as the level of reactive oxygen species (ROS), protein carbonyl oxidation (PCO), malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD) and reduced glutathione (GSH) as well as nitric oxide (NO). Our results showed that in the ethanol group, the levels of ROS, MDA, PCO, and serum NO were higher than in the normal group. In addition, reduced GSH, CAT, SOD, tissue NO, gastric mucus, and antioxidant potential were decreased. In rats pretreated with NSQBE and ranitidine, the levels of ROS, MDA, PCO, and serum NO decreased, and the levels of GSH, CAT, SOD, tissue NO, gastric mucus, and antioxidant potential were increased in comparison to the ethanol group. The results of this study showed that silver nanoparticles synthesized using Quercus brantii are a promising approach for the treatment of gastric ulcers.

Major Shifts in Acid Suppression Drug Utilization After the 2019 Ranitidine Recalls in Canada and United States.

BACKGROUND: Drug shortages are a complex global challenge, and few studies have analyzed quantitative data on their impacts. In September 2019, detection of a nitrosamine impurity in ranitidine led to recalls and shortages. AIMS: We investigated the extent of the ranitidine shortage and its impacts on acid suppression drug utilization in Canada and the United States (US). METHODS: We conducted an interrupted time series analysis of acid suppression drug purchases in Canada and the US from 2016 through 2021 using IQVIA's MIDAS database. We used autoregressive integrated moving average models to determine the impact of the shortage on purchasing rates for ranitidine, other histamine-2 receptor antagonists (H2RAs), and proton pump inhibitors (PPIs). RESULTS: Prior to the recalls, 20,439,915 ranitidine units were purchased monthly in Canada and 189,038,496 in the US on average. After the recalls started in September 2019, purchasing rates decreased for ranitidine (Canada p = 0.0048, US p < 0.0001) and increased for non-ranitidine H2RAs (Canada p = 0.0192, US p = 0.0534). One month into the recalls, purchasing rates dropped by 99% (Canada) and 53% (US) for ranitidine and increased by 128.3% (Canada) and 37.3% (US) for non-ranitidine H2RAs. PPI purchasing rates did not change significantly in either country. CONCLUSIONS: The ranitidine shortage led to immediate and sustained shifts in H2RA utilization in both countries, potentially affecting hundreds of thousands of patients. Our results emphasize the need for future studies of the clinical and financial implications of the shortage, and the importance of ongoing work to mitigate and prevent drug shortages.

Patient Preparation with Esomeprazole Is Comparable to Ranitidine in Meckel Diverticulum Scintigraphy.

To localize ectopic gastric mucosa in patients with unexplained gastrointestinal bleeding and diagnose a Meckel diverticulum, 99mTc-pertechnetate imaging is the standard procedure. H2 inhibitor pretreatment enhances the sensitivity of the scan by reducing washout of 99mTc activity from the intestinal lumen. We aim to provide evidence of the effectiveness of the proton pump inhibitor esomeprazole as an ideal substitute for ranitidine. Methods: The scan quality for 142 patients who underwent a Meckel scan during a period of 10 y was evaluated. The patients were pretreated with ranitidine orally or intravenously before a switch to a proton pump inhibitor after ranitidine was no longer available. Good scan quality was characterized by the absence of 99mTc-pertechnetate activity in the gastrointestinal lumen. The effectiveness of esomeprazole to diminish 99mTc-pertechnetate release was compared with the standard treatment using ranitidine. Results: Pretreatment with intravenous esomeprazole resulted in 48% of scans with no 99mTc-pertechnetate release, 17% with release either in the intestine or in the duodenum, and 35% with 99mTc-pertechnetate activity both in the intestine and in the duodenum. Evaluation of scans obtained after oral ranitidine and intravenous ranitidine showed absence of activity in both intestine and duodenum in 16% and 23% of the cases, respectively. The indicated time to administer esomeprazole before starting the scan procedure was 30 min, but a delay of 15 min did not negatively influence the scan quality. Conclusion: This study confirms that esomeprazole, 40 mg, when administered intravenously 30 min before a Meckel scan, enhances the scan quality comparably to ranitidine. This procedure can be incorporated into protocols.

MULTIPLE BCCS AND DYSPLASTIC NEVI AFTER ACE INHIBITORS (ENALAPRIL/PERINDOPRIL): THE ROLE OF NITROSAMINE CONTAMINATION/AVAILABILITY AS SUBSTANTIAL SKIN CANCER TRIGGERING FACTOR.

Nitrosamines as contaminants in a wide variety of drugs are also found to be one of the most likely causes of skin cancer. A detailed analysis of this contamination could in the near future solve to a large extent the puzzle of carcinogenesis concerning the keratinocytic forms of cancer and melanoma. But also, probably cancer in general. Over 80% of skin cancer is due to acquired mutations, and nitrosamines, which are contained as contamination in certain batches of the most commonly distributed drugs worldwide (such as sartans, ACE inhibitors, ranitidine, metformin, hydrochlorothiazide, rifampicin, and a number of others.) are considered among the most powerful external mutagens, carcinogens. Carcinogens that until 2021 were not supposed to be present in medicines and carcinogens for which it was subsequently decided to create a regulatory regime for permissible availability. Regardless of whether these contaminants are applied within the so-called daily acceptable intake dose or many times above it, the problem with the availability of nitrosamines continues to be present. It is also caused by the lack of reflection of the concentration of the corresponding nitrosamine in a certain drug. Thus, it is impossible to calculate the ˝permissible daily intake of the total number of mutagens and their concentration based on polymedication˝. In practice, drug manufacturers distribute nitrosamines in parallel with drugs, although they are not listed as a component of the product but are identified and allowed as contamination or substances with permissible availability by the EMA/FDA. From another point of view, the fact that is not commented on is also of interest, namely that not all batches are affected by this contamination. This suggests that the contamination may have been controlled, since in a manufacturing error the contamination should be widespread. The registration of the potential contamination of a heterogeneous type of medicinal products on the European market to the executive agencies for drug control in certain geographical areas has remained for years without any answer and opens a number of questions. The problem with ACE inhibitors is similar to that with sartans, hydrochlorothiazide, metformin, and ranitidine. The ˝special impression˝ of the clinicians is determined by the fact that the patterns of manifestation of the skin tumors during the administration of a heterogeneous class of medications are similar to completely identical. From this it could be concluded that the unifying factor between the pattern of occurrence could not be based on the action of the main substance of each drug class, since it remains to be radically different. The unifying link remains the sole and only contamination or the permissible already availability of a new ingredient known as nitrosamines. We present cases of multiple basal cell carcinomas and dysplastic nevi following enalapril and perindopril administration. The role of potential contamination of ACE inhibitors with nitrosamines for the development of skin cancer is discussed.

Ultrasmall nitrogen-doped Cu0·92Co2·08O4 nanocrystal-decorated cerium dioxide nanoparticles for fast and complete degradation of ranitidine via permonosulfate activation.

A simple and efficient coagulation method was used for the rapid preparation of nitrogen-doped copper-cobalt oxide (N-Cu0.92Co2·08O4) supported on cerium dioxide (CeO2), that is, N-Cu0.92Co2·08O4@CeO2. A low concentration of N-Cu0.92Co2·08O4@CeO2 (0.15 g L-1) was shown to rapidly activate permonosulfate (PMS) (0.15 g L-1) to achieve 100% degradation of ranitidine within 10 min. A 100% degradation of ranitidine enabled by the catalyst was achieved over a wide range of pH (5.5-9.0), which could be completed within 8 min in the presence of anionic H2PO4-. Moreover, the N-Cu0.92Co2·08O4@CeO2 catalyst enabled more than 90% degradation of various typical antibiotics within 30 min, including tetracycline, sulfaixoxazole, and chloramphenicol, with degradation rates of 100%, 93.51%, and 90.01%, respectively. Even after four catalytic cycles, N-Cu0.92Co2·08O4@CeO2 could be regenerated to achieve 100% degradation of ranitidine. Electrochemical analysis demonstrated that the combination of N-Cu0.92Co2·08O4@CeO2 and PMS immediately produced a strong current density, thereby rapidly producing reactive oxygen species (ROS) with high performance for the degradation of the target pollutant. Combined ion quenching and electron paramagnetic resonance analyses indicated that the main ROS was the non-free radical 1O2. Finally, a plausible ranitidine degradation pathway was deduced based on liquid chromatography-mass spectrometry (LC-MS) analysis, wherein the toxic substance N-nitrosodimethylamine was not produced during the degradation process. In short, this study provides a new perspective for preparing ternary metal catalysts for advanced oxidation processes with practical application significance.