Adverse tumor events induced by ranitidine: an analysis based on the FAERS database.

BACKGROUND: Ranitidine induced tumor adverse events remains a contradictory clinical question, due to the limited evidence of tumor risk associated with ranitidine in the real world. The purpose of this study was to evaluate the association of ranitidine with all types of tumors through the FAERS database and to provide a reference for clinical use. RESEARCH DESIGN AND METHODS: Cancer cases associated with ranitidine in the FAERS database from the first quarter of 2004 to the fourth quarter of 2023 were extracted to analyze demographic characteristics, and a disproportion analysis was performed. RESULT: A total of 662,998 ranitidine-related cancer cases were screened, and the 50-59 and 60-69 groups accounted for the largest proportion. In PT signal detection, ranitidine was associated with 98 PT, including penal cancer stage II, gastric cancer stage II, et al. In terms of outcome events, adverse events were higher in men (20.65%) than in women (18.47%). CONCLUSIONS: Ranitidine may induce various tumor-related adverse reactions, especially in long-term users and elderly patients. For these patients, tumor screening should be strengthened, and long-term use of ranitidine should be avoided. Since this study cannot prove causality, further evidence is needed for prospective studies with a larger sample size.

Rapid Structure Determination of Ranitidine Hydrochloride API in Two Crystal Forms Using Microcrystal Electron Diffraction.

The solid-state properties of drug candidates play a crucial role in their selection. Quality control of active pharmaceutical ingredients (APIs) based on their structural information involves ensuring a consistent crystal form and controlling water and residual solvent contents. However, traditional crystallographic techniques have limitations and require high-quality single crystals for structural analysis. Microcrystal electron diffraction (microED) overcomes these challenges by analyzing difficult-to-crystallize or small-quantity samples, making it valuable for efficient drug development. In this study, microED analysis was able to rapidly determine the configuration of two crystal forms (Forms 1, 2) of the API ranitidine hydrochloride. The structures obtained with microED are consistent with previous structures determined by X-ray diffraction, indicating microED is a useful tool for rapidly analyzing molecular structures in drug development and materials science research.

Clinical efficacy of recombinant human basic fibroblast growth factor combined with ranitidine in the treatment of recurrent oral ulcer and its effect on serum TNF, IL-2 and T-lymphocyte subsets.

Objective: To evaluate the clinical efficacy of recombinant human basic fibroblast growth factor (rh-bFGF) combined with ranitidine in the treatment of recurrent oral ulcer and its effects on serum TNF, IL-2 and T-lymphocyte subsets. Methods: This was a retrospective study. Eighty patients with oral ulcers admitted to First Medical Center, Chinese PLA General Hospital from July 2021 to June 2022 were randomly divided into the control group and the experimental group (n=40). Patients in the control group were given topical treatment with rh-bFGF gel, while those in the experimental group were given oral treatment combined with ranitidine based on the control group, and both groups were treated continuously for 14 days. The therapeutic effect, pain relief time, ulcer healing time, as well as the differences in the levels of inflammatory factors and T-lymphocyte subsets were compared and analyzed between the two groups. Results: The overall response rate of the experimental group was 92.5%, while that of the control group was 75%, with a statistically significant difference(P=0.03). After treatment, inflammatory factors indexes in the experimental group were significantly lower than those in the control group, with statistically significant differences (P=0.00). The indexes of T-lymphocyte subsets in the experimental group were significantly higher than those in the control group after treatment, with statistically significant differences (P=0.00). Conclusion: Recombinant human basic fibroblast growth factor combined with ranitidine is effective in the treatment of recurrent oral ulcers, boasting various benefits such as effectively promoting ulcer healing, reducing pain and inflammatory response, and enhancing immune function.

Inhibitors of gastric acid secretion increase oxidative stress and matrix metalloproteinase-2 activity leading to vascular remodeling.

The use of inhibitors of gastric acid secretion (IGAS), especially proton pump inhibitors (PPI), has been associated with increased cardiovascular risk. While the mechanisms involved are not known, there is evidence supporting increased oxidative stress, a major activator of matrix metalloproteinases (MMP), as an important player in such effect. However, there is no study showing whether other IGAS such as histamine H2-receptor blockers (H2RB) cause similar effects. This study aimed at examining whether treatment with the H2RB ranitidine promotes oxidative stress resulting in vascular MMP activation and corresponding functional and structural alterations in the vasculature, as compared with those found with the PPI omeprazole. Male Wistar rats were treated (4 weeks) with vehicle (2% tween 20), omeprazole (10 mg/Kg/day; i.p.) or ranitidine (100 mg/Kg/day; gavage). Then the aorta was collected to perform functional, biochemical, and morphometric analysis. Both ranitidine and omeprazole increased gastric pH and oxidative stress assessed in situ with the fluorescent dye dihydroethidium (DHE) and with lucigenin chemiluminescence assay. Both IGAS augmented vascular activated MMP-2. These findings were associated with aortic remodeling (increased media/lumen ratio and number of cells/µm2). Both IGAS also impaired the endothelium-dependent relaxation induced by acetylcholine (isolated aortic ring preparation). This study provides evidence that the H2RB ranitidine induces vascular dysfunction, redox alterations, and remodeling similar to those found with the PPI omeprazole. These findings strongly suggest that IGAS increase oxidative stress and matrix metalloproteinase-2 activity leading to vascular remodeling, which helps to explain the increased cardiovascular risk associated with the use of those drugs.

In Vitro and Biological Evaluation of Oral Fast-Disintegrating Films Containing Ranitidine HCl and Syloid® 244FP-Based Ternary Solid Dispersion of Flurbiprofen.

Flurbiprofen (FBP), a nonsteroidal anti-inflammatory drug (NSAID), is commonly used to treat the pain of rheumatoid arthritis, but in prolonged use it causes gastric irritation and ulcer. To avoid these adverse events of NSAIDs, the simultaneous administration of H2 receptor antagonists such as ranitidine hydrochloride (RHCl) is obligatory. Here, we developed composite oral fast-disintegrating films (ODFs) containing FBP along with RHCl to provide a gastroprotective effect as well as to enhance the solubility and bioavailability of FBP. The ternary solid dispersion (TSD) of FBP was fabricated with Syloid® 244FP and poloxamer® 188 using the solvent evaporation technique. The synthesized FBP-TSD (coded as TSD) was loaded alone (S1) and in combination with plain RHCl (S2) in the composite ODFs based on hydroxypropyl methyl cellulose E5 (HPMC E5). The synthesized composite ODFs were evaluated by in vitro (thickness, folding endurance, tensile strength, disintegration, SEM, FTIR, XRD and release study) and in vivo (analgesic, anti-inflammatory activity, pro-inflammatory cytokines and gastroprotective assay) studies. The in vitro characterization revealed that TSD preserved its integrity and was effectively loaded in S1 and S2 with optimal compatibility. The films were durable and flexible with a disintegration time ≈15 s. The release profile at pH 6.8 showed that the solid dispersion of FBP improved the drug solubility and release when compared with pure FBP. After in vitro studies, it was observed that the analgesic and anti-inflammatory activity of S2 was higher than that of pure FBP and other synthesized formulations (TSD and S1). Similarly, the level of cytokines (TNF-α and IL-6) was also markedly reduced by S2. Furthermore, a gastroprotective assay confirmed that S2 has a higher safety profile in comparison to pure FBP and other synthesized formulations (TSD and S1). Thus, composite ODF (S2) can effectively enhance the FBP solubility and its therapeutic efficacy, along with its gastroprotective effect.

Decreased Penetration Mechanism of Ranitidine Due to Application of Sodium Sulfobutyl Ether-ß-Cyclodextrin.

Permeability has an important effect on drug absorption. In this study, the effect of different concentrations of sodium sulfobutyl ether-ß-cyclodextrin (SBE-ß-CD) on the absorption of ranitidine was investigated to examine the mechanism of permeability changes. The results of a parallel artificial membrane permeability assay (PAMPA) showed that increasing the concentration of sodium sulfobutyl ether-ß-cyclodextrin, 0, 0.12% (w/v), 0.36% (w/v) and 3.6% (w/v), respectively, caused the apparent permeability coefficient of ranitidine to decrease to 4.62 × 10-5, 4.5 × 10-5, 3.61 × 10-5 and 1.08 × 10-5 in Caco-2 cells, respectively. The same results were obtained from an oral pharmacokinetic study in rats. Further studies indicated that SBE-ß-CD significantly increased the zeta potential of ranitidine. SBE-ß-CD interacted with ranitidine charges to form a complex that reduced ranitidine permeability, and SBE-ß-CD should be chosen with caution for drugs with poor permeability.

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.

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

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

In Vitro and In Vivo Evaluation of Composite Oral Fast Disintegrating Film: An Innovative Strategy for the Codelivery of Ranitidine HCl and Flurbiprofen.

Here, we evaluate the feasibility of co-loading plain ranitidine hydrochloride (RHCl) and microencapsulated flurbiprofen (FBP) in a Lycoat® RS780-based oral fast disintegrating film (ODF). These films were developed by the solvent casting method to minimize the adverse effects of FBP and reduce the dosage form burden on patients. Optimized FBP microparticles (M3) with an average size of 21.2 ± 9.2 µm were loaded alone (F1) and in combination with plain RHCl (F2) in the composite ODF. All films were evaluated physicomechanically and physicochemically. These films were resilient, flexible, and disintegrated within thirty seconds. SEM images showed intact FBP microparticles in both formulations and, moreover, did not observe an interaction between the drug and film components. Microencapsulated FBP was released in a controlled manner over 48 h from the proposed formulations, while RHCl was released within 5 min from F2. After in vitro evaluation, formulations were also tested for in vivo anti-inflammatory activity, cytokine (TNF-α and IL-6) levels, and gastroprotective effects in rats. The anti-inflammatory activity and gastroprotective effect of F2 were markedly higher than pure FBP and other synthesized formulations (M3 and F1). The average score of gastric lesions was in the order of pure FBP (15.5 ± 1.32) > M3 (8 ± 2) > F1 (1 ± 0.5) > F2 (0.5 ± 0) > control (0). Additionally, F2 showed a sustained anti-inflammatory effect up to 10 h in the rat paw edema model. Furthermore, F2 also markedly reduced TNF-α and IL-6 levels. Conclusively, the Lycoat® RS780-based composite film could be a promising carrier for the co-loading of microencapsulated FBP with RHCl. In the future, an optimized formulation (F2) could be capable of countering the issues related to multiple drug administration in geriatric patients and evading the gastric irritation associated with FBP.

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.

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.

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.

Renal histaminergic system and acute effects of histamine receptor 2 blockade on renal damage in the Dahl salt-sensitive rat.

Histamine is involved in the regulation of immune response, vasodilation, neurotransmission, and gastric acid secretion. Although elevated histamine levels and increased expression of histamine metabolizing enzymes have been reported in renal disease, there is a gap in knowledge regarding the mechanisms of histamine-related pathways in the kidney. We report here that all four histamine receptors as well as enzymes responsible for the metabolism of histamine are expressed in human and rat kidney tissues. In this study, we hypothesized that the histaminergic system plays a role in salt-induced kidney damage in the Dahl salt-sensitive (DSS) rat, a model characterized with inflammation-driven renal lesions. To induce renal damage related to salt sensitivity, DSS rats were challenged with 21 days of a high-salt diet (4% NaCl); normal-salt diet (0.4% NaCl)-fed rats were used as a control. We observed lower histamine decarboxylase and higher histamine N-methyltransferase levels in high-salt diet-fed rats, indicative of a shift in histaminergic tone; metabolomics showed higher histamine and histidine levels in the kidneys of high-salt diet-fed rats, whereas plasma levels for both compounds were lower. Acute systemic inhibition of histamine receptor 2 in the DSS rat revealed that it lowered vasopressin receptor 2 in the kidney. In summary, we established here the existence of the local histaminergic system, revealed a shift in the renal histamine balance during salt-induced kidney damage, and provided evidence that blockage of histamine receptor 2 in the DSS rat affects water balance and urine concentrating mechanisms.NEW & NOTEWORTHY Histamine is a nitrogenous compound crucial for the inflammatory response. The knowledge regarding the renal effects of histamine is very limited. We showed that renal epithelia exhibit expression of the components of the histaminergic system. Furthermore, we revealed that there was a shift in the histaminergic tone in salt-sensitive rats when they were challenged with a high-salt diet. These data support the notion that histamine plays a role in renal epithelial physiological and pathophysiological functions.

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.

An update on the current status and prospects of nitrosation pathways and possible root causes of nitrosamine formation in various pharmaceuticals.

Over the last two years, global regulatory authorities have raised safety concerns on nitrosamine contamination in several drug classes, including angiotensin II receptor antagonists, histamine-2 receptor antagonists, antimicrobial agents, and antidiabetic drugs. To avoid carcinogenic and mutagenic effects in patients relying on these medications, authorities have established specific guidelines in risk assessment scenarios and proposed control limits for nitrosamine impurities in pharmaceuticals. In this review, nitrosation pathways and possible root causes of nitrosamine formation in pharmaceuticals are discussed. The control limits of nitrosamine impurities in pharmaceuticals proposed by national regulatory authorities are presented. Additionally, a practical and science-based strategy for implementing the well-established control limits is notably reviewed in terms of an alternative approach for drug product N-nitrosamines without published AI information from animal carcinogenicity testing. Finally, a novel risk evaluation strategy for predicting and investigating the possible nitrosation of amine precursors and amine pharmaceuticals as powerful prevention of nitrosamine contamination is addressed.

Ranitidine Alleviates Anxiety-like Behaviors and Improves the Density of Pyramidal Neurons upon Deactivation of Microglia in the CA3 Region of the Hippocampus in a Cysteamine HCl-Induced Mouse Model of Gastrointestinal Disorder.

Elevated levels of histamine cause over-secretion of gastric hydrochloric acid (HCl), leading to gastrointestinal (GI) disorders and anxiety. Ranitidine is an antihistamine drug widely used in the management of GI disorders, as it works by blocking the histamine-2 receptors in parietal cells, thereby reducing the production of HCl in the stomach. While some reports indicate the neuroprotective effects of ranitidine, its role against GI disorder-related anxiety remains unclear. Therefore, we investigated the effect of ranitidine against anxiety-related behaviors in association with changes in neuronal density in the hippocampal cornu ammonis (CA)-3 region of cysteamine hydrochloride-induced mouse model of GI disorder. Results obtained from the open field test (OFT), light and dark box test (LDBT), and elevated plus maze (EPM) test revealed that ranitidine treatment reduces anxiety-like behaviors in experimental animals. Nissl staining and immunohistochemical assessment of ionized calcium-binding adapter molecule (Iba)-1 positive microglia in cryosectioned brains indicated enhanced density of pyramidal neurons and reduced activation of microglia in the hippocampal CA-3 region of brains of ranitidine-treated experimental mice. Therefore, this study suggests that ranitidine mediates anxiolytic effects, which can be translated to establish a pharmacological regime to ameliorate anxiety-related symptoms in humans.

Clinical Use of Gastric Antisecretory Drugs in Hospitalized Pediatric Patients.

Antisecretory drugs are frequently used in the treatment of pediatric gastrointestinal disorders. This study was aimed to assess the prescribing patterns and the safety of ranitidine and proton pump inhibitors (PPIs) in a cohort of Italian pediatric patients. Children aged >1 month to <16 years that were admitted to our Pediatric Clinic between 2016 and 2018 were enrolled in this retrospective observational study. All data were obtained from medical records and a parent telephone questionnaire. The exclusion criteria included the use of antisecretory therapy at hospital admission, failure to collect the relevant clinical data, and failure to administer the questionnaire. This study included 461 subjects, who were divided into four age groups: <2 years, 2−5 years, 6−11 years, and ≥12 years. Ranitidine was prescribed in 396 (85.9%) patients, mainly for the acute treatment of gastrointestinal symptoms, and a PPI was given to 65 (14.1%) children to treat gastroesophageal reflux disease, gastritis/ulcer, or for gastroprotection. During the study period, the percentage of patients treated with ranitidine progressively increased, except in the 2−5-year age group. We observed eighty-seven adverse drug reactions (ADRs), 61 of which occurred in the ranitidine group and 26 in the PPI group. The most common ADR was constipation (n = 35), which occurred more frequently in children treated with PPIs and in the 6−11-year age group. Ranitidine was the most used antisecretory drug in all the age groups, especially for acute treatment. Conversely, PPIs were the drugs of choice for prolonged treatments. Further research should be focused on developing an effective and safer alternative to ranitidine.

Ranitidine: A Proposed Mechanistic Rationale for NDMA Formation and a Potential Control Strategy.

The formation of N-nitrosodimethylamine (NDMA) in ranitidine hydrochloride drug substance (DS) and drug products has attracted considerable attention over the last few years. The drug structure is unusual in that it contains a vinyl nitro moiety. Although a variety of studies have been carried out to understand how NDMA is formed in the DS solids, a mechanistic description of NDMA formation has remained elusive. A new mechanistic view of NDMA formation is detailed here. Autoxidation of ranitidine can rationalize nitrite ion and dimethylamine liberation from ranitidine. The subsequent nitrosation is argued to be due to conversion of nitrite ion to the gas phase nitrosating agent nitrosyl chloride, NOCl. Oxygen scavenging packaging systems should be able to stop the autoxidation, and thus shut down the nitrite release from ranitidine. Without nitrite release NDMA cannot form. This may provide a practical means to stabilize ranitidine DS and solid dosage formulations against NDMA formation.

Prescription changes in patients with gastrointestinal disorders after withdrawal of ranitidine: a nationwide population-based cohort study.

OBJECTIVE: Ranitidine products contain unacceptable levels of N-nitrosodimethylamine. This study aimed to investigate changes in the treatment regimen and their influencing factors after the ranitidine recall. METHODS: This retrospective study used data from nationwide Korean claims from 2019. Patients with gastrointestinal disorders treated with ranitidine for at least a month on 25 September 2019, were selected for this study. Other histamine-2 receptor antagonists (H2RAs), proton pump inhibitors (PPIs), potassium-competitive acid blockers (PCABs), and prostaglandin E1 analogs were administered as alternatives to ranitidine. Kaplan-Meier survival and Cox proportional hazards regression analyses were performed to gauge the time until switching to alternative drugs and assess the influencing factors. RESULTS: In total, 7502 patients were included in this study, among which 5164 (68.8%) switched from ranitidine to an alternative drug. The most prescribed alternative drugs were H2RAs, followed by PPIs, PCABs, and prostaglandin E1 analogs. Increasing age; Medical Aid insurance (MedAid); and a history of hypertension, diabetes mellitus, asthma, and osteoarthritis were associated with a higher probability of switching treatments. Patients with concomitant gastroesophageal reflux disease and peptic ulcers were more likely to switch to alternative drugs than patients with gastritis. CONCLUSIONS: Approximately two-thirds of patients with gastrointestinal disorders switched from ranitidine to alternative drugs within 3 months after ranitidine withdrawal. The Cox regression analysis showed that age (>55 years); insurance type (MedAid); comorbidities, such as hypertension, diabetes mellitus, asthma, and osteoarthritis, and gastrointestinal disorder severity influenced the switch from ranitidine to alternative drugs.

H1 and H2 antihistamines pretreatment for attenuation of protamine reactions after cardiopulmonary bypass: a randomized-controlled study.

BACKGROUND: Protamine administration post-cardiopulmonary bypass (CPB) can potentially cause hemodynamic instability. Histamine released from mast cells is believed to be responsible for hypotension after protamine administration. The aim of this study was to examine the effects of pretreatment with H1 and H2 antihistamines on changes in systemic arterial pressure following protamine administration. METHODS: This study was a randomized, triple-blinded, placebo-controlled study, conducted at a university hospital. Forty adult patients undergoing elective coronary artery bypass grafting (CABG) or single valve surgery were included. The patients were randomly allocated (20 patients in each group) to receive a single dose of combined chlorpheniramine 10 mg and ranitidine 50 mg or normal saline intravenously immediately after separation from CPB prior to protamine administration. Trajectory changes in systolic blood pressure (SBP), mean arterial pressure (MAP), and vasoactive-inotropic score (VIS) from baseline until 35 minutes following protamine administration (24-time points) were compared between the two groups. Serial serum tryptase levels were also obtained at baseline, 30 and 60 minutes after protamine was given. RESULTS: Forty patients were included in the analysis. Demographic and baseline blood pressure were similar between the two groups. At 30 minutes after protamine administration, there were no significant differences in both crude SBP [mean difference: -7.1 mmHg, 95% confidence interval (CI), -1.1 to 15.3 mmHg, P=0.09] and SBP after adjustment for the European System for Cardiac Operative Risk Evaluation (EuroSCORE II), CPB time, and VIS (mean difference: -3.9 mmHg, 95% CI, -11.9 to 4.0 mmHg, P=0.33). There were also no significant differences in crude MAP (mean difference: -2.1 mmHg, 95% CI, -6.9 to 2.7 mmHg, P=0.39) and adjusted MAP (mean difference: -0.7 mmHg, -5.9 to 4.4 mmHg, P=0.78) between the two groups. None of the patients in both groups had a significant increase in serum tryptase from baseline. No differences in median serum tryptase levels at baseline, 30 and 60 minutes were demonstrated between the two groups. CONCLUSIONS: Pretreatment with H1 and H2 antihistamines does not attenuate blood pressure responses to protamine administration in patients after CPB. Mechanisms other than histamine release from mast cells might be responsible for protamine-induced cardiovascular changes. TRIAL REGISTRATION: ClinicalTrials.gov NCT03583567.