Lithium remains a cornerstone in the treatment of bipolar I disorder because of its well-established efficacy in reducing mood episode recurrence and suicide risk. However, its narrow therapeutic index makes patients particularly susceptible to clinically significant toxicity, especially following medication changes or drug-drug interactions. Nonsteroidal anti-inflammatory drugs (NSAIDs) are recognized to increase serum lithium concentrations by reducing renal lithium clearance, although reports involving nabumetone remain limited. We report the case of a 50-year-old woman with bipolar I disorder who had remained psychiatrically stable on chronic lithium therapy for approximately seven years before developing severe lithium toxicity following recent escalation of both lithium and nabumetone dosages. The patient presented with progressive confusion, lethargy, recurrent falls, tremor, myoclonic jerks, gait instability, generalized weakness, and altered mental status. Initial serum lithium concentration exceeded 2.9 mmol/L despite preserved renal function. Lithium and nabumetone were discontinued, aggressive intravenous fluid administration was initiated, and serial lithium concentrations were monitored. Given preserved renal function, declining serum lithium concentrations, and rapid neurologic improvement with supportive management, hemodialysis was deferred. The patient experienced progressive clinical recovery with normalization of lithium concentrations and resolution of neurologic symptoms. Lithium was cautiously reintroduced at a reduced dosage without recurrence of toxicity. Application of the Naranjo Adverse Drug Reaction Probability Scale yielded a score of 9, supporting a definite adverse drug reaction. This case highlights that severe lithium toxicity may occur despite preserved renal function following concurrent escalation of lithium and nabumetone therapy. The report emphasizes the importance of comprehensive medication reconciliation, recognition of clinically significant drug-drug interactions, close serum lithium monitoring following medication changes, and early recognition of neurologic manifestations suggestive of lithium toxicity.

The chemically diverse group of nonsteroidal anti-inflammatory drugs (NSAIDs) is a significant source of aquatic pollution, inducing oxidative stress in algae. The aim of this study was to evaluate the antioxidant response of Chlamydomonas reinhardtii exposed to four NSAIDs differing in toxicity and structure: flufenamic acid (FFA), nabumetone (NBT), ibuprofen (IBU), and naproxen (NPX). This study demonstrated that all pharmaceuticals significantly increased H2O2 production, confirming redox imbalance in cells. The antioxidant defense also showed compartment- and compound-specific signatures depending on the NSAID toxicity level. Less toxic IBU and NPX induced coordinated SOD isoforms and catalase activation, while more toxic FFA and NBT triggered chloroplast-targeted H2O2 scavenging via APX pathways. Notably, MSD3 transcript levels increased in all treatments, indicating its potential as an NSAID stress biomarker. IBR analysis demonstrated that antioxidant efficiency decreased with increasing NSAID toxicity. These findings demonstrate that NSAID toxicity shapes compartment- and isoform-specific antioxidant strategies in C. reinhardtii. We believe that future studies with a broader range of NSAIDs would enable us to investigate subcellular redox dynamics using compartment-specific ROS reporters and to identify NSAID-sensitive biomarkers for aquatic ecotoxicology monitoring.

Drug-induced mitochondrial toxicity is a major contributing factor to cardiotoxicity, which can cause drug attrition and adverse cardiac events. To assess the toxicity of anti-inflammatory agents, we used adult human primary cardiomyocytes (hPCMs) to screen 18 clinically available anti-inflammatory drugs in a high-content manner, and revealed widespread mitochondrial dysfunction without affecting cell viability. Nabumetone, a representative nonsteroidal anti-inflammatory drug with profound mitochondrial toxicity, induced mitochondrial fission, inhibited mitophagy, and impaired both electrophysiological and metabolic functions in adult hPCMs. Mechanistically, we uncovered that nabumetone (Nab) exerted its toxic effects through the prostaglandin E2- E-type prostanoid receptor 4 (PGE2-EP4) pathway, which was essential for its anti-inflammatory functions. To find an alternative route to ameliorate mitochondrial damage, we identified SIRT3 as a downstream target of nabumetone. Its mRNA, protein, and activity levels were significantly reduced upon nabumetone treatment. SIRT3 activator honokiol exhibited protective potential against NSAID-induced mitochondrial toxicity both in hPCMs and in nabumetone-treated mice. Finally, through screening mitochondrial liability in various common cardiomyocyte models, we identified mitochondrial abundance as an important determinant of the sensitivity of cells towards mitochondrial toxicants. Our study demonstrates the vast presence of mitochondrial dysfunction in human adult cardiomyocytes imposed by clinically used anti-inflammatory drugs, and identified both toxicity and protective pathways that may serve future therapeutic purposes.

The inflammatory pathogenesis of chronic gastritis is well established, but the specific inflammatory factors that causally drive its progression to gastric cancer (GC) remain unclear. Here, we combined Mendelian randomisation (MR) with multi-omics analyses to identify key macromolecular mediators in this transition. Genome-wide association study datasets of chronic gastritis and GC were interrogated using two-sample MR for 91 inflammatory factors and 731 immune-cell traits, with inverse-variance-weighted MR as the primary method. Transcriptomic, proteomic and single-cell RNA sequencing data from The Cancer Genome Atlas, Gene Expression Omnibus and independent cohorts were integrated to delineate expression dynamics and immune-microenvironment remodelling across disease stages. Leukaemia inhibitory factor receptor (LIFR), hepatocyte growth factor (HGF) and serine protease inhibitor E1 (SERPINE1), interleukin-10 receptor subunit beta (IL10RB) emerged as core progression-associated macromolecules and were validated by quantitative reverse-transcription PCR, western blotting, immunohistochemistry and functional proliferation assays. Structure-based virtual screening and molecular docking identified three approved compounds with targeting potential: rofecoxib, used here as a chemical probe to validate LIFR rather than as a therapeutic candidate and predicted to functionally suppress HGF signalling; nabumetone, a putative SERPINE1 inhibitor; and N-acetyl-L-cysteine, which enhanced IL10RB expression. Collectively, these data define a molecular continuum from chronic gastritis to GC and highlight LIFR, IL10RB, SERPINE1 and HGF as pivotal biological macromolecules and candidate therapeutic targets. The repurposing potential of anti-inflammatory agents, particularly rofecoxib and nabumetone, suggests a feasible strategy to intercept the gastritis-carcinoma sequence.

Nabumetone is a long acting nonsteroidal antiinflammatory drug (NSAID) that is available by prescription only and is used in therapy of chronic arthritis. Nabumetone has been linked to rare instances of clinically apparent, idiosyncratic drug induced liver disease.

The complexation of nabumetone (NAB) and naproxen (NAP) with cucurbit[7]uril (CB7) was investigated in aqueous solution by isothermal titration microcalorimetry, mass spectrometry, NMR spectroscopy, and computation methods. High-resolution mass spectrometry was used for the determination of the binding stoichiometry and the gas-phase stability of the drug-CB7 complex. The doubly charged NH4+ or Na+ adducts of the 1:1 complex were observed in the mass spectra. The dissociation of complexes was monitored at different collision energies, (1-16) eV, leading to the neutral loss of NH3 and the drug, with charge retention observed on CB7. By performing ITC experiments, all the thermodynamic parameters were determined for the NAB-CB7 complex in water at 25 °C. The corresponding values amounted to the following: logK = 4.66 ± 0.01; ΔrG° = -26.7 ± 0.1 kJ/mol; ΔrH° = -20.2 ± 0.7 kJ/mol; TΔrS° = 6.4 ± 0.8 kJ/mol, i.e., the formation of the inclusion complex is enthalpy driven and has a favorable entropy. The inclusion phenomena were further confirmed by NMR spectroscopy (1H, ROESY, and DOSY), suggesting the encapsulation of the naphthalene ring of both drugs inside the CB7 cavity. The results of the DFT calculations and the IGMH analysis were in accordance with the experimental ones, suggesting that van der Waals interactions play a major role in drug-CB7 complexation.

The aryl hydrocarbon receptor (AhR) was shown to be an important regulator of inflammatory processes at epithelial barriers, and is thus considered a therapeutic target for several chronic inflammatory diseases, such as inflammatory bowel disease. We aimed to identify and validate new AhR agonists that sustainably attenuate intestinal inflammation. Using a high-throughput luciferase reporter gene assay, 90 AhR ligands were identified out of 7448 approved and investigational drugs. Out of these, 15 AhR ligands were selected based on substance class, half maximal effective concentration, known toxicity and pharmacokinetic/pharmacodynamic profiles, and preclinical/clinical evaluation status for other indications. While Febuxostat, Nitazoxanide, Rabeprazole, 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester, 3-Indolepropionic acid, and Indirubin, were already known as AhR agonists, Nabumetone, Teriflunomide, Timapiprant/OC000459, and Caffeic acid phenylethyl ester have not yet been directly described in this context. Six compounds (Daidzein/Equol, as well as compounds no. 19, 22, 49, and 64, not yet disclosed due to pending patent applications) were newly described as AhR agonists. Hit compounds were studied in silico for their molecular interactions with AhR and in vitro for potential immunotoxicity and their ability to induce interleukin (IL)-10 and/or to suppress IL-1β in murine macrophages without significant cytochrome P450 1A1 induction in Caco-2 cells. Five compounds that met these criteria were functionally tested using organoid-based Transwell®-like models derived from gut biopsies. Five candidates restored the epithelial barrier, as evidenced by increased transepithelial electrical resistance and induction of the tight junction proteins claudin-1/-2 and occludin, while exhibiting anti-inflammatory effects, i.e., decreased expression of toll-like receptor 4. Out of these, one compound was selected for future in vivo preclinical studies.

Because no information is available on the use of nabumetone during breastfeeding, other agents may be preferred, especially while nursing a newborn or preterm infant.

Orthodontic treatment is commonly associated with pain, leading to reduced patient compliance and treatment adherence. Non-steroidal anti-inflammatory drugs (NSAIDs) are effective in reducing this pain by inhibiting prostaglandin synthesis. However, this mechanism may also interfere with orthodontic tooth movement (OTM) by affecting bone remodeling. This narrative review investigates the existing literature published between 2004 and 2024 to assess the impact of various NSAIDs on OTM and identify those that balance pain relief with minimal impact on tooth movement. Evidence shows that NSAIDs such as aspirin, ketorolac, diclofenac, and nimesulide significantly reduce OTM. The results for ibuprofen, meloxicam, and celecoxib were inconsistent with both no influence or a reduction in OTM, depending on dosage, mode, and duration of administration. Conversely, tenoxicam, nabumetone, etoricoxib, and parecoxib appear to have no effect on OTM. Among these, etoricoxib appears particularly promising due to its favorable gastrointestinal profile, high COX-2 selectivity, and negligible influence on OTM in clinical doses. However, the limited number of human trials highlights the need for further research to develop evidence-based guidelines for pain management that preserve treatment efficiency in orthodontics.

Organic chemistry in pharmaceutical education is indispensable for drug discovery and the understanding of biological phenomena and plays an important role in the identity formation of pharmacists. In the Model Core Curriculum for Pharmacy Education (2022 revision), organic chemistry is one of the most fundamental subjects in basic pharmaceutical sciences and plays an important role in the study of other fields. Based on basic pharmacy, the academic goal of pharmacological research is to develop problem-finding skills and foster the problem-solving abilities necessary for research that contributes to the development of pharmacy and medicine. The author devised ways for students to become interested in their research topics and to work on them independently. Specifically, the author adopted a teaching method that respects students' independence in scheduling and selecting synthetic routes. For example, in research to determine the absolute configuration of metabolites of the antibiotic nabumetone, students managed their own schedules and became able to conduct research with a sense of conviction and responsibility. In addition, in research on the synthesis of thiophene derivatives, presenting multiple synthetic routes and allowing students to choose one enabled them to propose the direction of the experiment based on their own opinions. Therefore, it is necessary to devise and support research procedures tailored to individual students.

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the frontline treatments for inflammation and pain. Hydrogen sulfide (H2S) and related persulfide (RS-SH) are important mediators of antioxidant response and protect cells from oxidative stress. Hybrids of these pharmacological agents have shown promise in clinical trials and are superior to the parent NSAID. Here, we report a new class of NSAID-H2S hybrids, where a strategic placement of a sulfhydryl group adjacent to a carbonyl of a NSAID facilitates the enzymatic generation of H2S. We show that α-mercapto-nabumetone, a derivative of the clinical drug nabumetone, is a substrate for 3-mercaptopyruvate sulfurtransferase (3-MST), an enzyme involved in H2S biosynthesis. The key step of 3-MST catalysis is the cleavage of a C-S bond adjacent to a carbonyl group, which generates an enolate and 3-MST persulfide, which in turn is cleaved under reducing conditions to generate H2S. Guided by a molecular docking study with 3-MST, we prepared two mercapto-nabumetone derivatives, protected as their thioacetates. In the presence of 3-MST, both mercapto-nabumetone derivatives generated H2S and the NSAID in a nearly quantitative yield, produced glutathione persulfide (GS-SH), an important mediator of cellular antioxidant response, and permeated cells to generate H2S. Lastly, to gain insights into the scope of this strategy, we prepared mercapto-NSAID derivatives containing a carboxylic acid. We found that the propensity to generate H2S depended on the nature of the enol that is produced during the transformation of the mercapto-NSAID into the parent NSAID. This offers new insights into 3-MST catalysis and how reaction outcomes can be modulated by the keto-enol equilibrium. Taken together, the atom economical transformation of a clinical NSAID with one strategically placed sulfhydryl group to generate H2S presents new opportunities to enhance the properties of NSAIDs through participation in endogenous H2S biosynthesis.

Advanced oxidation processes (AOPs), including ionizing radiation treatment, are increasingly recognized as an effective method for the degradation of pharmaceutical pollutants, including non-steroidal anti-inflammatory drugs (NSAIDs). Nabumetone (NAB), a widely used NSAID prodrug, poses an environmental risk due to its persistence in aquatic ecosystems and its potential toxicity to non-target organisms. In this study, the radiolytic degradation of NAB was investigated under different experimental conditions (dose rate, radical scavenging, pH, matrix effect), and the toxicity of its degradation products was evaluated. NAB was rapidly degraded at 300 Gy with prolonged irradiation. Mineralization of about 88% of NAB solutions was observed based on the evaluation of total organic carbon (TOC). The most efficient degradation of NAB occurred under N2O conditions, while it was retarded in the presence of thiourea. The water matrix components had a significant influence on the efficiency of degradation. In addition, the main degradation products were identified by LC-HRMS. Toxicity studies on different bacteria showed no significant impact of the NAB degradation products, while in silico predictive methods revealed their slightly increased toxicity compared to the parent compound, but considerably lower toxicity in comparison to its main active form 6-methoxy-2-naphthylacetic acid (MNA). Additionally, significantly lower toxicities are predicted for degradation products in N2O saturated solution. These results underline the importance of optimizing irradiation parameters for effective degradation and minimizing the formation of harmful by-products. Understanding all aspects of the AOP processes and the toxicological effects of the degradation products ensures effective mitigation of potential environmental and health risks of water treatment processes.

Background: Nabumetone (NAB) is a poorly soluble nonsteroidal anti-inflammatory prodrug (BCS class II drug) whose solubility is significantly improved by complexation with cyclodextrins (CDs). Methods: The solid complexes, in a 1:1 molar ratio, were prepared by mechanochemical activation by grinding, using β-cyclodextrin (β-CD) and its derivatives, hydroxypropyl- and sulfobutylether-β-cyclodextrin (HP-β-CD and SBE-β-CD). The complexation was confirmed by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and attenuated total reflectance Fourier-transformed infrared spectroscopy (ATR-FTIR). Obtained products were further characterized regarding their solubility, in vitro dissolution, permeability and chemical stability. Results: Co-grinding with HP-β-CD and SBE-β-CD yielded products that showed in vitro dissolution profiles in hydrochloric acid medium (pH 1.2) that were substantially different from that of pure NAB, yielding dissolution efficiency enhancements of 34.86 ± 1.64 and 58.30 ± 0.28 times, respectively, for the optimized products. Their in vitro dissolution and gastrointestinal permeability were also studied in a low-volume environment at pH 6.8, corresponding to the intestinal environment. Both β-CD derivatives increased NAB dissolution rate and NAB mass transport across the biomimetic membrane. The effect of β-CD derivatives on NAB chemical stability was studied under the stress conditions by the developed and validated UHPLC-DAD-HRMS method. In acidic conditions, pure and complexed NAB was prone to hydrolytic degradation, yielding one degradation product-pharmacologically inactive NAB metabolite. However, under the oxidative conditions at elevated temperatures, 10 NAB degradation products were identified from co-ground samples. All systems were stable during photo- and long-term stability studies. Conclusions: NAB complexes with HP-β-CD and SBE-β-CD are promising candidates for pharmaceutical product development.