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.

Drug-induced tumoral disease: A global pharmacovigilance database analysis.

INTRODUCTION: Cancer remains a worldwide threat, having caused almost 10 million deaths in 2020. The American Cancer Society has identified both known and probable carcinogens, including commonly used drugs. The aim of this study is to describe the drugs most frequently reported in the occurrence of cancer. METHODS: Among all individual case safety reports (ICSRs) in the global pharmacovigilance database VigiBase, we searched for the 50 most reported drugs with an adverse drug reaction term belonging to the query "Malignant or unspecified tumors" until June 30, 2023. Then, we extracted the disproportionality measurement data, information component (IC), and reporting odds ratio (ROR) in order to assess a disproportionality signal. RESULTS: Among all ICSRs in VigiBase, 871,925 contained an ADR belonging to the SMQ "Malignant or unspecified tumors". Ranitidine was the drug with the most reported ADRs related to cancer (n=106,484), followed by lenalidomide (n=13,466), and etanercept (n=8014). The drugs with the highest IC were ranitidine (IC=5.2, 95% confidence interval [95% CI]=5.2-5.2), pioglitazone (1353 ICSRs, IC=4.2, 95% CI=4.2-4.2), and regorafenib (1272 ICSRs, IC=2.8, 95% CI=2.8-2.8). DISCUSSION: Our results show that the main pharmacological mechanisms are associated with ranitidine (link with levels of N-nitrosodimethylamine in ranitidine-based drugs), gene-activating drugs (pioglitazone: link with agonist effects on PPAR-γ gene activation), various pharmacological families with immunosuppressive effects (protein kinase inhibitors, immunomodulators, azathioprine, etc.), certain types of protein kinase inhibitors whose oncogenic mechanisms remain unclear (regorafenib, sorafenib, imatinib, ibrutinib, etc.), and hormone antagonists (tamoxifen, letrozole). Special monitoring of patients exposed to these drugs may be required. Further studies are needed to assess the risk with certain drugs in this ranking.

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.

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.

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.

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%.

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.

Phytochemical Estimation and Therapeutic Amelioration of Aesculus hippocastanum L. Seeds Ethanolic Extract in Gastric Ulcer in Rats Possibly by Inhibiting Prostaglandin Synthesis.

OBJECTIVE: To quantify phytochemicals using liquid chromatography and mass spectroscopy (LCMS) analysis and explore the therapeutic effect of Aesculus hippocastanum L. (AH) seeds ethanolic extract against gastric ulcers in rats. METHODS: Preliminary phytochemical testing and LCMS analysis were performed according to standard methods. For treatment, the animals were divided into 7 groups including normal control, ulcer control, self-healing, AH seeds low and high doses, ranitidine and per se groups. Rats were orally administered with 10 mg/kg of indomethacin, excluding the normal control group (which received 1% carboxy methyl cellulose) and the per se group (received 200 mg/kg AH seeds extract). The test group rats were then given 2 doses of AH seeds extract (100 and 200 mg/kg, respectively), while the standard group was given ranitidine (50 mg/kg). On the 11th day, rats in all groups were sacrificed, and their stomach was isolated to calculate the ulcer index, and other parameters such as blood prostaglandin (PGE2), tissue superoxide dismutase (SOD), catalase (CAT), malonyldialdehyde (MDA), and glutathione (GSH). All isolated stomach tissues were analyzed for histopathological findings. RESULTS: The phytochemical examination shows that the AH seeds contain alkaloids, flavonoids, saponins, phenolic components, and glycosides. LCMS analysis confirms the presence of quercetin and rutin. The AH seeds extract showed significant improvement in gastric mucosa conditions after indomethacin-induced gastric lesions (P<0.01). Further marked improvement in blood PGE2 and antioxidant enzymes, SOD, CAT, MDA and GSH, were observed compared with self-healing and untreated ulcer-induced groups (P<0.01). Histopathology results confirmed that AH seeds extract improved the mucosal layer and gastric epithelial membrane in treated groups compared to untreated ulcer-induced groups. CONCLUSIONS: LCMS report confirms the presence of quercetin and rutin in AH seeds ethanolic extract. The therapeutic effect of AH seeds extract against indomethacin-induced ulcer in rat model indicated the regenerated membrane integrity, with improved cellular functions and mucus thickness. Further, improved antioxidant enzyme level would help to reduce PGE2 biosynthesis.

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.

A Bioanalytical Method for Quantification of N-nitrosodimethylamine (NDMA) in Human Plasma and Urine with Different Meals and following Administration of Ranitidine.

Control of N-nitrosoamine impurities is important for ensuring the safety of drug products. Findings of nitrosamine impurities in some drug products led FDA to develop new guidance providing recommendations for manufacturers towards prevention and detection of nitrosamine impurities in pharmaceutical products. One of these products, ranitidine, also had a published in vivo study, which has since been retracted by its authors, suggesting a potential for in vivo conversion of ranitidine to the probable human carcinogen, N-nitrosodimethylamine (NDMA). FDA subsequently initiated a randomized, double-blind, placebo-controlled, crossover clinical investigation to assess the potential for in vivo conversion of ranitidine to NDMA with different meals. A bioanalytical method toward characterization of NDMA formation was needed as previously published methods did not address potential NDMA formation after biofluid collection. Therefore, a bioanalytical method was developed and validated as per FDA's Bioanalytical Method Validation guidance. An appropriate surrogate matrix for calibration standards and quality control sample preparation for both liquid matrices (human plasma and urine) was optimized to minimize the artifacts of assay measurements and monitor basal NDMA levels. Interconversion potential of ranitidine to NDMA was monitored during method validation by incorporating the appropriate quality control samples. The validated methods for NDMA were linear from 15.6 pg/mL to 2000 pg/mL. Low sample volumes (2 mL for urine and 1 mL for plasma) made this method suitable for clinical study samples and helped to evaluate the influence of ranitidine administration and meal types on urinary excretion of NDMA in human subjects.

MELANOMA AND DYSPLASTIC NEVI DEVELOPMENT AFTER RANITIDINE/RILMENIDINE/МOXONIDINE, LERCANIDIPINE, ROSUVASTATIN AND VERAPAMIL/TRANDOLAPRIL - NEW DATA/CASE SERIES. THE POTENTIAL ROLE OF NITROSAMINE/NDSRIS CONTAMINATION IN POLYMEDICATION AS SUBSTANTIAL SKIN CANCER TRIGGERING FACTOR.

The idea of drug-induced/exogenic Nitrosogenesis is driven by the possibility of prolonged exposure of the human body to the influence of nitrosamines within the drug intake - substances or contaminants that have been proven to be carcinogenic or mutagenic one.Until recently, there was a complete lack of data in the scientific literature on the relationship between cancer, polymedication and polycontamination with nitrosamines. In the last decade, melanoma has been described repeatedly in the medical literature as a possible side-effect within the intake of possibly with nitrosamines contaminated medications such as: Valsartan, Hydrochlorothiazide, Amlodipine, Nebivolol, Bisoprolol and Perindopril. However, the contribution of the currently presented new data (5 new patients) is also due to the establishment of the possible pathogenetic role (with respect to melanoma) of several completely new drugs, previously unknown to the scientific community (potentially/actually contaminated with carcinogens/nitrosamines), such as: Ranitidine, Rosuvastatin, Lercanidipine, Rilmenidine, Trandolapril, Moxonidine and Verapamil.The leading and connecting link in shared new and old drug combinations of heterogeneous drug classes (polymedication) and melanoma development and progression remains again one and the same: the possible availability of nitroso component in the frame of exogenous nitrosogenesis according to the official FDA lists of 2023.The number of drugs shared as contaminated with nitrosamines after whose intake melanomas occur is increasing. Nitrosogenesis remains a new beginning, a new understanding and new interpretation of the carcinogenesis concerning melanoma, but probably also of cancer in general. Its further elucidation looks more than promising and is yet to come. More than worrying at the moment remains the fact that the scientific community has to clarify if: 1) peak concentrations of nitrosamines or NDSRIs within the framework of monomedication or 2) normal concentrations within the polymedication (catalogued in the list of FDA/ 2023 as potentially contaminated with hypothetical carcinogens), could hide relatively short-term risk of the development of real tumors: cutaneous melanomas and/or their precursor lesions. The validation of the concept of Nitrosogenesis and its relationship to Сarcinogenesis, is achieved in practice on the basis of the following facts: that it is the occurrence of the same monomorphic clinical pattern (melanoma/dysplastic nevi), developing after the intake of drugs with different mechanism of action, contaminated with nitrosamines/NDSRIs. The unifying link between the intake of certain drugs and the development of certain tumours remains the presence of nitrosamines. Ingredients that are present in drug preparations, identified as availability and as carcinogenic potency, but not yet reflected in packaging or prescriptions. The question remains: why?

Association between ranitidine use with potential NDMA impurities and risk of cancer in Korea.

N-Nitrosodimethylamine (NDMA) detected above the acceptable level in ranitidine products has been a great global concern. To examine the risk of cancer among people treated with ranitidine, we conducted a cohort study using the National Health Insurance Service-National Sample Cohort data (2002-2015) of South Korea. Patients were aged 40 or above as of January 2004 and began receiving ranitidine or other histamine-2 receptor antagonist (H2RA), active comparator, without a history of H2RAs prescription during the prior 2-years. The lag time was designated up to 6 years. The outcomes were an overall incident cancer risk and the risk of major single cancers during the follow-up. The association between ranitidine use and cancer risk was examined by Cox regression model. After exclusion and propensity score matching, 25,360 patients were available for analysis. The use of ranitidine was not associated with the overall cancer risk and major individual cancers [overall cancer: incidence rate per 1000 person-years, 2.9 vs 3.0 among the ranitidine users and other H2RAs users, respectively; adjusted hazard ratio (HR) and 95% confidence interval (95% CI) for all cancers, 0.98 (0.81-1.20)]. The higher cumulative exposure to ranitidine did not increase the cancer risk. Given the insufficient follow-up period, these findings should be interpreted carefully.

Profilaxis para sangrado gastrointestinal en pacientes del servicio de medicina interna de un hospital universitario / Gastrointestinal bleeding prophylaxis in internal medicine patients of a univeristy hospital

Introducción: Los medicamentos antiulcerosos son utilizados frecuentemente en pacientes hospitalizados, sin embargo, a menudo este uso no está indicado. Objetivo: Describir la frecuencia de prescripción e indicación de medicamentos para prevenir el sangrado gastrointestinal en pacientes hospitalizados. Materiales y métodos: Estudio de corte trasversal, descriptivo, prospectivo del servicio de Medicina Interna de la Sociedad de Cirugía de Bogotá- Hospital de San José de Bogotá, Colombia. Se excluyeron pacientes con diagnóstico de sangrado gastrointestinal o antecedente de alergia a los medicamentos antiulcerosos. Se recolectaron datos demográficos, así como fármacos prescritos. Se determinó si la indicación del fármaco era adecuada y se identificó el tipo de error de prescripción. Resultados: Se incluyeron 179 pacientes, 102 (57%) mujeres. Promedio de edad de 61,3 años (±20,2). El principal diagnóstico de ingreso fue enfermedad infecciosa 76 (42,4%). Del total de pacientes, 165 (92,17%) recibieron medicamento para prevención del sangrado gastrointestinal. La indicación fue adecuada en 75 pacientes (41,89%). El error más frecuente fue el uso en pacientes de bajo riesgo de sangrado, 101 (97,1%). Conclusión: Un alto porcentaje de los pacientes recibió medicación para la prevención del sangrado gastrointestinal. En aproximadamente la mitad de estos no estaba indicada.

Introduction: Anti-ulcer medications are frequently used in hospitalized patients, yet their use is not usually indicated. Objective: To describe the frequency of prescription and indication of medications to prevent gastrointestinal bleeding in hospitalized patients. Materials and methods: A cross-sectional, descriptive, prospective study was carried out in the Internal Medicine service of the Surgery Society of Bogota-San Jose Hospital of Bogota (Colombia). Excluded patients were those with either a gastrointestinal bleeding diagnosis or a history of allergy to anti-ulcer medications. Demographic data and information regarding prescribed medications were collected. It was determined whether the medicine indication was adequate and the type of prescription error was identified. Results: 179 patients were included in the study, 57% (102) of which were women. The average age was 61.3 (±20.2) years old. Infectious disease was the main admission diagnosis (76; 42.4%). A 92.17% (165) of the total number of patients received medications to prevent gastrointestinal bleeding. This indication was adequate for 75 (41.89%) patients. The most frequent error was their use in bleeding low-risk patients (101; 97.1%). Conclusion: A high percentage of patients received medication to prevent gastrointestinal bleeding. However, in about half of these patients it was not indicated.

Sex-specific effects of excipients on oral drug bioavailability.

The mechanism of action of excipients eliciting sex differences in drug bioavailability is poorly understood. In this study, the excipients Cremophor RH 40 (PEG 40 hydrogenated castor oil), Poloxamer 188 (2-methyloxirane) and Tween 80 (polyoxyethylene (80) sorbitan monooleate) were screened at 0.07 - 5% concentrations for their effect on ranitidine bioavailability in male and female Wistar rats. We show that all excipient concentrations significantly increased ranitidine bioavailability in male, but not female, rats. The effect of these excipients on the intestinal efflux transporters P-glycoprotein (P-gp), breast cancer resistant protein (BCRP) and multi-drug resistant protein 2 (MRP2) were also monitored. Measured by ELISA assay, in male rats, peak reductions in intestinal P-gp protein expression occurred in the presence of 1% Cremophor RH 40 and Poloxamer 188 and 0.5% Tween 80. In contrast, no distinct changes were observed in female intestinal P-gp expression. Unlike P-gp, all excipients had a positive effect on MRP2 protein expression - albeit only in males - in a concentration-dependent manner. The excipients did not modulate intestinal BCRP protein expression in either sex. Endogenous hormones and a nuclear receptor (testosterone, oestradiol and pregnane X receptor; PXR) that are purported to regulate intestinal efflux membrane transporter expression were also quantified. In the presence of all excipients, testosterone levels significantly elevated in males, although PXR levels reduced at similar rates in both sexes. No significant effects were identified in oestradiol levels in male and female rats. It is clear that excipients are not inert and their pathway for modulating drug response is multi-dimensional and specific between sexes. This study showed that excipients increased drug bioavailability of a P-gp drug substrate due to its reductive effect on intestinal P-gp expression; we propose that this link may be due to the excipients modulating fundamental testosterone levels. Understanding the implication of excipients on intestinal physiology and hormone levels can therefore improve pharmaceutical design, clinical efficacy and instigate next generation personalised, sex-specific formulations.

Pharmacoepidemiological Research on N-Nitrosodimethylamine-Contaminated Ranitidine Use and Long-Term Cancer Risk: A Population-Based Longitudinal Cohort Study.

N-Nitrosodimethylamine (NDMA), a carcinogenic chemical, has recently been identified in ranitidine. We conducted a population-based study to explore ranitidine use and cancer emergence over time. Using the Taiwan National Health Insurance Research Database, a population-based cohort study was conducted. A total of 55,110 eligible patients who received ranitidine between January 2000 and December 2018 were enrolled in the treated cohort. We conducted a 1:1 propensity-score-matching procedure to match the ranitidine-treated group with the ranitidine-untreated group and famotidine controls for a longitudinal study. The association of ranitidine exposure with cancer outcomes was assessed. A multivariable Cox regression analysis that compared cancer risk with the untreated groups revealed that ranitidine increased the risk of liver (hazard ratio (HR): 1.22, 95% confidence interval (CI): 1.09-1.36, p < 0.001), lung (HR: 1.17, CI: 1.05-1.31, p = 0.005), gastric (HR: 1.26, CI: 1.05-1.52, p = 0.012), and pancreatic cancers (HR 1.35, CI: 1.03-1.77, p = 0.030). Our real-world observational study strongly supports the pathogenic role of NDMA contamination, given that long-term ranitidine use is associated with a higher likelihood of liver cancer development in ranitidine users compared with the control groups of non-ranitidine users treated with famotidine or proton-pump inhibitors.

Evaluation and optimization of a HS-SPME-assisted GC-MS/MS method for monitoring nitrosamine impurities in diverse pharmaceuticals.

The probable carcinogenic nitrosamine impurities, such as N-nitrosodiethylamine (NDEA) and N-nitrosodimethylamine (NDMA), have been detected from various pharmaceuticals in recent years. The sensitive chromatographic methods, including liquid chromatography (LC) and gas chromatography (GC), have been applied for analyzing nitrosamines in the pharmaceutical substrates, such as sartans, ranitidine and metformin. In comparison of LC, the efficacy of GC for analyzing multiple nitrosamines in diverse pharmaceuticals will be limited or attenuated owing to the chemical properties of target analytes or matrix hinderance of pharmaceutical substrates. To extend the applicability of GC analysis for multiple nitrosamines in pharmaceuticals, this study presented a gas chromatograph tandem mass (GC-MS/MS) method for monitoring 14 nitrosamines within 44 pharmaceuticals, whereas the headspace-solid phase microextraction (HS-SPME) sampling mode was introduced. Chromatographic separation was achieved on a DB-heavyWax column (30 m × 0.25 mm; i.d., 0.25 µm), whereas the HS-SPME sampling mode with a 50/30 µm DVB/CAR/PDMS extracting fiber was applied for comparison of the direct injection mode. Meanwhile, the HS-SPME conditions were optimized to evaluate the effects of the parameters on analyzing total nitrosamines in pharmaceuticals by GC-MS/MS. The optimal conditions of HS-SPME were as follows: extracting solution of 90% NaCl, HS incubation time 1 min, SPME adsorbing at 80 â„ƒ for 30 min, and desorbing at 250 â„ƒ for 5 min. The limit of quantification (LOQ) for 14 nitrosamines in pharmaceutical matrices under the optimal conditions was 0.05 µg/g for the optimal HS-SPME, whereas the value was 0.05-0.25 µg/g for direct injection.

Mast cells selectively target large cholangiocytes during biliary injury via H2HR-mediated cAMP/pERK1/2 signaling.

Bile ducts are heterogenous in structure and function, and primary sclerosing cholangitis (PSC) damages specific bile ducts leading to ductular reaction (DR), mast cell (MC) infiltration, increased histamine release, inflammation, and fibrosis. Bile duct ligation (BDL) induces large duct damage via cyclic adenosine monophosphate (cAMP)/extracellular signal-related protein kinase (ERK) signaling, and large cholangiocytes express H2 histamine receptor (H2HR). We evaluated how MCs interact with large cholangiocytes during cholestasis. Male wild-type (WT) and MC-deficient (KitW-sh ) mice 10-12 weeks of age were subjected to BDL for 7 days. Select KitW-sh mice were injected with MCs pretreated with control or H2HR antagonist (ranitidine, 25 µm, 48 h) via tail vein injection. In vitro, MC migration toward small mouse cholangiocytes (SMCCs) and large mouse cholangiocytes (LMCCs) treated with lipopolysaccharide or histamine (±ranitidine) was measured. LMCCs were stimulated with MC supernatants pretreated with control, α-methyl-dl-histidine (to block histamine release), or ranitidine. Liver damage, large duct DR/senescence, inflammation, fibrosis, and cAMP/ERK immunoreactivity increased in BDL WT and KitW-sh +MC mice but decreased in BDL KitW-sh and KitW-sh +MC-H2HR mice. In vitro, MCs migrate toward damaged LMCCs (but not SMCCs) blocked by inhibition of H2HR. Loss of MC histamine or MC-H2HR decreases LMCC proliferation, senescence, H2HR, and cAMP/ERK levels. Human PSC livers have increased MC number found near DR, senescent ducts, and H2HR-positive ducts. Conclusion: Infiltrating MCs preferentially interact with large ducts via H2HR signaling promoting biliary and liver damage. Mediation of MCs may be a therapeutic strategy for PSC.

Ranitidine and the incidence of hypersensitivity reactions to paclitaxel: A retrospective cohort study.

Paclitaxel is a commonly used chemotherapeutic agent. To minimize the risk of hypersensitivity reactions (HSRs), which occur in approximately 16-42% of patients, premedication with dexamethasone, clemastine, and ranitidine was standard of care. As of October 2019, ranitidine is no longer available. We compared the risk of HSRs to paclitaxel with and without premedication with ranitidine, hypothesizing that the incidence of HSRs to paclitaxel will be similar. In this retrospective cohort study, all first-time paclitaxel users in the Groene Hart Hospital were included from January 2019 to August 2020. The primary outcome was the incidence of HSRs, using a Student's t-test. One-hundred and eight patients who were first-time users of paclitaxel in the Groene Hart Hospital met the inclusion criteria. Most patients were treated for breast or ovarian cancer, followed by lung cancer. Analysis of all 836 paclitaxel administrations was performed. Following 349 administrations with ranitidine as premedication, eight HSRs occurred (2.3%), while following 487 administrations without ranitidine, 12 HSRs occurred (2.5%), p-value of 0.87. An additional analysis on the occurrence of HSRs per patient was performed: 45 patients received premedication in the form of ranitidine, of which eight patients (17.8%) had a HSR. Sixty-three patients did not receive premedication in the form of ranitidine, of whom 10 (15.8%) had a HSR, p-value of .80. In conclusion, we found no difference in the incidence of HSRs during paclitaxel infusions between patients who received ranitidine as premedication versus those who did not.

Evaluation of pharmacokinetic interactions of amoxicillin with ranitidine in healthy human volunteers of Karachi, Pakistan.

Polypharmacy may be considered as the customary practice to provide optimum care services to patients but inter resulted in augmented probability of multiple drug interaction. Keeping in view the importance of drug interaction possibility, this study was designed to evaluate the effect of ranitidine on pharmacokinetics of amoxicillin in the local population of Karachi, Pakistan. Amoxicillin and ranitidine are the most commonly prescribed drugs to treat duodenal ulcer caused by Helicobacter pylori. The current investigation was carried out as a single center, open label, two phase, single dose, randomized way in cross over manner to evaluate the potential of pharmacokinetic interaction among amoxicillin formulation and ranitidine in adult healthy male volunteers. Post dosing blood samples were collected at multiple time points that are 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 10 hours after administering amoxicillin 250mg capsule with and without ranitidine. For estimation of amoxicillin concentration in plasma, an HPLC method was developed and validated. The solvent system consisted of 0.025M phosphate buffer: acetonitrile (94:6 v/v). C18 column was employed with a flow rate of 1.0 ml/minute and at 230nm. A linear pattern with a correlation coefficient of 0.999 in the concentration ranges of 25µg/mL to 0.097µg/mL for amoxicillin and 25µg/mL to 0.048µg/mL for ranitidine was observed. Amoxicillin retention time was about 8 minutes and ranitidine retention time was around 12 minutes. Amoxicillin levels were computed and the concentrations were applied to calculate the pharmacokinetic parameters. Pharmacokinetic parameters were estimated by Kinetica TM 4.4.1 (Thermo Electron Corp. USA). The analysis of variance (two way) and t test (two one sided) were applied on log transformed pharmacokinetic parameters of amoxicillin. The Tmax was determined between amoxicillin alone and amoxicillin with ranitidine by Friedman test. The 90% confidence interval values for Cmax(calc) (0.687-0.743) and Tmax(calc) (1.148-1.742) for amoxicillin with or without ranitidine were not found within the FDA acceptable limits of 0.8-1.25. Study demonstrated the significant reduction in peak plasma levels of amoxicillin in presence of ranitidine. It is advisable to administer both drugs with time interval to avoid such interactions and increases in the bactericidal efficacy of amoxicillin.