Since the 2018 valsartan recall, the genotoxic impurity N-nitrosodimethylamine (NDMA) has been frequently detected in various pharmaceuticals. Matrix variability often complicates routine testing, requiring customized analyses. We developed a universal LC-MS/MS method enabling consistent NDMA detection across diverse pharmaceuticals. Separation utilized a C30 column (150 mm × 4.6 mm I.D., 5 µm), offering superior retention and shape selectivity for polar nitrosamines compared to conventional reversed phases. Unlike C18 or pentafluorophenyl phases, which often exhibit limited retention for NDMA, the C30 phase provides exceptional shape selectivity and enhanced hydrophobic interactions. This structural advantage, supplemented by its resistance to phase dewetting under highly aqueous conditions further ensures robust resolution between NDMA and complex drug matrices. The mobile phase consisted of 0.1% v/v formic acid in water and methanol under gradient elution at 1.0 mL/min. Detection used atmospheric pressure chemical ionization in positive ion mode. The method demonstrated a linear range of 2.0-100.0 ng/mL (r2 > 0.999), with a limit of detection of 1.0 ng/mL and a limit of quantification of 2.0 ng/mL. Validation per International Council for Harmonisation (ICH) guidelines confirmed accuracy (87.7%-115.5%) and precision (coefficient of variation, CV ≤ 10.7%). Application to 30 diverse pharmaceutical products, including sartans and ranitidine, showed robust resolution (> 2.0) between the analyte and active pharmaceutical ingredients (APIs). Notably, NDMA was quantified in historical batches of ranitidine (164.83 ± 5.68 ng/mL), nizatidine (10.25 ± 0.52 ng/mL), and amitriptyline (2.28 ± 0.19 ng/mL). While the histamine type 2 receptor antagonists significantly exceeded the acceptable daily intake limit, the remaining 27 products showed no detectable NDMA. These findings highlight the method's effectiveness for real-world surveillance and the critical risk of post-manufacturing NDMA generation during prolonged storage. This universal C30-based method provides a practical, reliable tool for routine screening, facilitating regulatory compliance and improved patient safety without drugspecific method development.

Covalent organic frameworks (COFs) demonstrate great potential as photocatalysts for the remediation of organic pollutants; however, their efficiency is often limited by the factor of rapid electron-hole recombination. In response to this challenge, we anchor ultrasmall (∼2.5 nm) bimetallic Au-Ag nanoclusters within the porous architecture of a nitrogen-rich COFs scaffold. The nitrogenated frameworks not only provide a high surface area and abundant active sites but also facilitate electron transfer. Meanwhile, the ultrafine Au-Ag nanoclusters exhibit strong plasmonic coupling, serving as dual light-harvesting units and electron transfer mediators. This synergistic configuration enhances carrier separation, enabling plasmon-exciton co-driven catalysis. The optimized COF-Au-Ag achieves simultaneous degradation of nizatidine (NZTD) and production of hydrogen peroxide (H2O2) via a unified photocatalytic mechanism centered on efficient charge separation and directional migration. This photocatalyst illustrates excellent recyclability in five consecutive cycles of use, offering a novel approach for designing multifunctional COF-based photocatalytic systems.

Recent studies have confirmed the significant potential of the histamine H2 receptor (H2R) as a therapeutic target for multiple diseases, creating an urgent demand for efficient drug screening methodologies. To address this need, we developed an innovative technique utilizing immobilized H2R for the rapid identification and characterization of bioactive compounds from complex matrices. Compared with the previous screening methods, this approach can detect the binding mode of ligands on the basis of screening. In this study, the prepared H2R chromatographic column was successfully applied for kinetic interaction analysis between two specific ligands and the receptor. The bioactive compound screened and collected via the H2R column was identified as liquiritin using high-performance liquid chromatography coupled with ion trap mass spectrometry (HPLC-IT-MS). Competitive displacement assays revealed that liquiritin competes with nizatidine and ranitidine for the same binding sites. Notably, as the concentration of famotidine in the mobile phase increased, an inverse shift in the retention time of liquiritin was observed. To elucidate this phenomenon, molecular docking simulations were performed. The results suggest that nizatidine and ranitidine compete with liquiritin for the same binding sites, reducing liquiritin-protein binding and increasing the proportion of free liquiritin, thereby causing a forward shift in the retention peak. In contrast, the acidic residues (ASP186, ASP98) of famotidine may reorganize the protein's surface charge through salt bridges or hydrogen bonds, altering the electrostatic interactions of liquiritin and leading to the observed peak shift. Additionally, at higher concentrations, famotidine may form multimolecular complexes that indirectly stabilize liquiritin-protein binding. Literature review revealed that, compared to nizatidine and ranitidine, famotidine exhibits a positive regulatory effect on β-arrestin-mediated receptor desensitization and internalization. These findings further demonstrate that the established H2R receptor chromatography model can effectively screen bioactive components and determine their binding modes. This study lays the foundation for screening bioactive compounds from traditional Chinese medicines using receptor chromatography and provides preliminary insights into their mechanisms of action.

Thalamic hemorrhage (TH), a critical subtype of intracerebral hemorrhage, often leads to central post-stroke pain (CPSP) and neurological deficits, yet its molecular mechanisms remain poorly understood. This study investigated the role of Rip3 in TH pathophysiology by constructing Rip3-knockout (KO) mice and integrating behavioral assessments, transcriptomic sequencing, and molecular experiments. Results demonstrated that TH induced motor dysfunction, mechanical pain hypersensitivity, working memory impairment, and anxiety-like behaviors in wild-type (WT) mice, while Rip3 knockout significantly alleviated pain sensitivity and anxiety and reduced hemorrhage volume. Transcriptomic analysis identified 956 Rip3-related candidate genes, among which Tac1, Gal, and Pdyn were validated as key downstream genes through protein-protein interaction networks and experimental assays. RT-qPCR and Western blot revealed significant upregulation of these genes in WT mice post-TH, with reduced expression in KO mice. Functional enrichment analysis implicated these genes in pathways such as NEUREXINS_AND_NEUROLIGINS and DOPAMINERGIC_NEUROGENESIS. Drug prediction identified potential therapeutic candidates, including Nizatidine, Ginger Allergenic Extract, Paregoric, and Estradiol 3-Benzoate, with the latter showing promise in modulating synaptic plasticity and pain signaling. Inhibition of Pdyn and Tac1 alleviated mechanical allodynia, while all three inhibitors, including Gal's, exhibited significant anxiolytic effects in the TH-induced CPSP model. This study reveals, for the first time, a correlative link between Rip3 and post-TH neurological injury and CPSP, potentially mediated via Tac1, Gal, and Pdyn regulation, providing novel targets for therapeutic intervention. Future research should validate direct Rip3-gene interactions and the efficacy of predicted drugs.

The piezo-photocatalysis enhanced by piezoelectric nanogenerators is considered one of the most effective methods for treating emerging contaminants (ECs) in environmental water. In this study, BiFeO3/ZnIn2S4/Ag (BFO/ZIS/Ag) with boosting piezo-photocatalytic performance was synthesized by modulating the interaction between the step-scheme (S-scheme) heterojunction and the Mott-Schottky barrier. The catalytic rate of the optimized BFO/ZIS/Ag-0.01 catalyst is 4.85 × 10[-2] min[-1] for the degradation of niazitidine (NZT) under both ultrasonic and visible light radiation, which is respectively 4.3 and 4.8 times higher than that of pure BFO and ZIS. Furthermore, the total organic carbon (TOC) test revealed that NZT degradation reached 98.4 % after 120 min of continuous reaction. This enhanced piezo-photocatalytic performance is mainly due to the synergistic effect of integrated heterojunction and piezoelectric field. DFT calculations revealed that the charge transfer enhancement at the heterogeneous interface resulted from directional electron transfer to ZIS via Zn-O and S-Ag channels, following the introduction of Ag nanoparticles, which shortened the carrier separation path. Additionally, BFO bent the band of the composite catalyst, promoting carrier separation. These resulted in the generation of abundant highly active [1]O2, which specifically targeted and disrupted stable NZT molecules. Moreover, BFO/ZIS/Ag-0.01 exhibited strong inhibitory and antibacterial effects against Escherichia coli and Staphylococcus aureus via electrostatic adsorption and ionization. This study offers new insights into the restoration of aquatic environments and bacterial disinfection through the use of piezoelectric catalytic materials.

Since 2018, N-nitrosamine impurities have become a widespread concern in the global regulatory landscape of pharmaceutical products. This concern arises due to their potential for contamination, toxicity, carcinogenicity, and mutagenicity and their presence in many active pharmaceutical ingredients, drug products, and other matrices. N-Nitrosamine impurities in humans can lead to severe chemical toxicity effects. These include carcinogenic effects, metabolic disruptions, reproductive harm, liver diseases, obesity, DNA damage, cell death, chromosomal alterations, birth defects, and pregnancy loss. They are particularly known to cause cancer (tumors) in various organs and tissues such as the liver, lungs, nasal cavity, esophagus, pancreas, stomach, urinary bladder, colon, kidneys, and central nervous system. Additionally, N-nitrosamine impurities may contribute to the development of Alzheimer's and Parkinson's diseases and type-2 diabetes. Therefore, it is very important to control or avoid them by enhancing effective analytical methodologies using cutting-edge analytical techniques such as LC-MS, GC-MS, CE-MS, SFC, etc. Moreover, these analytical methods need to be sensitive and selective with suitable precision and accuracy, so that the actual amounts of N-nitrosamine impurities can be detected and quantified appropriately in drugs. Regulatory agencies such as the US FDA, EMA, ICH, WHO, etc. need to focus more on the hazards of N-nitrosamine impurities by providing guidance and regular updates to drug manufacturers and applicants. Similarly, drug manufacturers should be more vigilant to avoid nitrosating agents and secondary amines during the manufacturing processes. Numerous review articles have been published recently by various researchers, focusing on N-nitrosamine impurities found in previously notified products, including sartans, metformin, and ranitidine. These impurities have also been detected in a wide range of other products. Consequently, this review aims to concentrate on products recently reported to contain N-nitrosamine impurities. These products include rifampicin, champix, famotidine, nizatidine, atorvastatin, bumetanide, itraconazole, diovan, enalapril, propranolol, lisinopril, duloxetine, rivaroxaban, pioglitazones, glifizones, cilostazol, and sunitinib.

Nitrosamine compounds pose a significant concern as potential carcinogens, prompting heightened scrutiny from regulatory bodies, particularly regarding their presence in pharmaceuticals. The detection of unacceptable levels of N-nitrosodiethylamine (NDMA) in ranitidine has led to widespread recalls, driving interest in alternative medications such as nizatidine, which shares a similar pharmacological class and is used to treat various gastrointestinal conditions. Despite fewer reports on NDMA levels in nizatidine, its structural similarity to ranitidine, characterized by a tertiary amine, underscores the potential for NDMA formation. Addressing the analytical challenges associated with nitrosamine detection, this study focuses on developing and validating an ultra-high pressure liquid chromatography triple quadrupole mass spectrometry (UHPLC-MS/MS) method for quantifying NDMA in both nizatidine active pharmaceutical ingredients and tablet formulations. Method validation adheres to International Council for Harmonisation recommendations, with a demonstrated linear range of 0.25-100 ng/mL for NDMA, exhibiting excellent linearity (regression coefficient >0.999) and efficient recovery rates ranging from 95.98% to 109.57%. The method shows high sensitivity, with limits of detection and quantification of 0.25 and 0.5 ng/mL, respectively. The developed UHPLC-MS/MS method offers a simple, precise, accurate, and selective approach for monitoring NDMA levels in nizatidine formulations available in Australia, promising enhanced sensitivity and specificity with limits of quantification in the ppb and sub-ppb ranges.