Relafen (nabumetone) / GSK - LARVOL DELTA

Mercapto-NSAIDs generate a non-steroidal anti-inflammatory drug (NSAID) and hydrogen sulfide. (PubMed, Chem Sci) - "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...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."

Journal • Inflammation • Pain

Radiolytic Elimination of Nabumetone from Aqueous Solution: Degradation Efficiency, and Degradants' Toxicity. (PubMed, Molecules) - "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."

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Synthesis, nonlinear optical activity, solvents effect, β-cyclodextrin effect, and cytotoxic activity on skin fibroblast and breast cancer cell lines of a new chalcone derivative of nabumetone. (PubMed, Spectrochim Acta A Mol Biomol Spectrosc) - "Cell biocompatibility was evaluated after culturing skin fibroblasts and breast cancer cells with INM using the MTT assay and fluorescence microscopy of the live/dead cell assay. It was observed that INM exhibited good NIH/3T3 cell adhesion and proliferation and the weak inhibiting ability of MDA-MB231."

Journal • Preclinical • Breast Cancer • Oncology • Solid Tumor

Clinical Evolution Of Adults Diagnosed of Hypersensitivity Reactions To NSAIDs (EAACI 2024) - "Our aim was to evaluate the clinical evolution of adults diagnosed of NIUA in our unit Method A prospective study was carried out evaluating patients (>18 y.o) diagnosed of NIUA, all of them diagnosed by a positive initial drug provocation test(iDPT) with acetyl-salicylic acid(ASA), between 2009-2019...Concerning the culprit NSAID, ibuprofen was involved in 49%, naproxen in 13,3%, dexketoprofen in 8,8%, ASA in 8,8%, dipyrone in 8,8%, paracetamol in 4,4% and diclofenac, indomethacin and nabumetone in 2,2% respectively...Rechallenge should be considered in patients with NIUA in order to assess the persistence or not of hypersensitivity to NSAIDs. More studies are in progress in order to investigate this observation."

Clinical • Allergy • Atopic Dermatitis • Dermatitis • Immunology

Clinical Evolution Of Adults Diagnosed of Hypersensitivity Reactions To NSAIDs (EAACI 2024) - "Our aim was to evaluate the clinical evolution of adults diagnosed of NIUA in our unit Method A prospective study was carried out evaluating patients (>18 y.o) diagnosed of NIUA, all of them diagnosed by a positive initial drug provocation test(iDPT) with acetyl-salicylic acid(ASA), between 2009-2019...Concerning the culprit NSAID, ibuprofen was involved in 49%, naproxen in 13,3%, dexketoprofen in 8,8%, ASA in 8,8%, dipyrone in 8,8%, paracetamol in 4,4% and diclofenac, indomethacin and nabumetone in 2,2% respectively...Rechallenge should be considered in patients with NIUA in order to assess the persistence or not of hypersensitivity to NSAIDs. More studies are in progress in order to investigate this observation."

Clinical • Allergy • Atopic Dermatitis • Dermatitis • Immunology

Degradation behaviors of Nabumetone and its metabolite during UV/monochloramine process: Experimental and theoretical study. (PubMed, J Environ Sci (China)) - "The transformation products of both NMT and MNA exhibited higher mutagenicity than their parent compounds. This study provides a deep understanding of the mechanism of radical degradation of NMT and MNA in the treatment of UV/NH2Cl."

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Dissecting CYP1A2 Activation by Arylalkanoic Acid Prodrugs toward the Development of Anti-Inflammatory Agents. (PubMed, Int J Mol Sci) - "Of note, all the examined compounds proved capable of interacting with the enzyme active site in a manner similar to Nabumetone, thus confirming that a productive metabolic transformation is feasible. On the basis of these findings, it is possible to argue that subtle differences in the way CYP1A2 accommodates the ligands depend on the fine details of their molecular structures. Overall, these data suggest that compounds simply formed by an aromatic moiety bearing an appropriate alkane-derived chain could lead to innovative anti-inflammatory agents."

Journal • CYP1A2

Nabumetone and flufenamic acid pose a serious risk to aquatic plants: A study with Chlamydomonas reinhardtii as a model organism. (PubMed, Chemosphere) - "No significant alteration in the ultrastructure of treated cells could be seen, except for changes in starch grain number and autophagic vacuoles that appeared in FFA-treated cells. To the best of our knowledge, this is the first work reporting the toxic effects of NBT and FFA on unicellular green algae."

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Giant Bladder Stone in a Young Male: When Surgery Complements Medicine for Better Outcomes (KIDNEY WEEK 2023) - "Case Description A 68-year-old male with history of rheumatoid arthritis on adalimumab was re-admitted with altered mental status, poor oral intake and AKI after a recent hospitalization for lumbar osteomyelitis requiring long term intravenous (IV) cefepime...Hemodialysis was contemplated due to worsening renal function with creatinine at 8.4 mg/dl (reference range: 0.5 - 1 mg/dl), hyperkalemia and concern for uremic encephalopathy, but he responded to supportive care with IV fluids and IV piperacillin tazobactam. A thorough history revealed intake of nabumetone for several years at doses as high as 1.5 gm daily...AKI developed during hospitalization has high mortality. A thorough understanding of etiology, clinical course and having a low threshold for kidney biopsy aids in diagnosis of AKI with possibilities of better outcomes in the elderly population."

Surgery • Acute Kidney Injury • CNS Disorders • Immunology • Infectious Disease • Inflammation • Inflammatory Arthritis • Nephrology • Renal Disease • Rheumatoid Arthritis • Rheumatology

Application of TGA/c-DTA for Distinguishing between Two Forms of Naproxen in Pharmaceutical Preparations. (PubMed, Pharmaceutics) - "In addition, using nabumetone, a close structural analog of naproxen, the specificity of the TGA and c-DTA methods was assessed. Studies have shown that the thermal analyses used are effective and selective in distinguishing the form of naproxen in pharmaceutical preparations. This indicates the potential possibility of using TGA supported by c-DTA as an alternative method."

Journal • Inflammation • Pain

Knee Pain In A Recreational Runner (ACSM 2023) - "There was full range of motion bilaterally.DIFFERENTIAL DIAGNOSIS1.Patellar tendonitis 2.Meniscal injury3.Tibial stress fractures with loose bodyTEST AND RESULTSBilateral knee with flexion and patella radiographs: -Mild medial compartment osteoarthritis bilaterally -Osteochondral defect involving the right medial femoral condyle-Large loose fragment within the intercondylar notch on the right-Patellar enthesopathy bilaterallyBilateral knee MRI without contrast:-Stress fracture of the medial aspect of the proximal tibial metaphysis extending to the intercondylar eminence, left -Stress fracture at the medial aspect of the proximal tibial metaphysis, right-Large osteochondral defect of the medial femoral condyle with detached fragment, rightBone mineral density: -Hip: T-score -2.0; Z-score -1.3FINAL/ WORKING DIAGNOSISBilateral tibial stress fractures with right knee loose body from osteochondritis dissecans lesionTREATMENT AND OUTCOMES1.Pain control with ketorolac (in..."

Immunology • Musculoskeletal Diseases • Musculoskeletal Pain • Orthopedics • Osteoarthritis • Osteoporosis • Pain • Rheumatology

Identification of HSD17B12 as an enzyme catalyzing drug reduction reactions through investigation of nabumetone metabolism. (PubMed, Arch Biochem Biophys) - "In conclusion, our study demonstrated that HSD17B12 is responsible for the formation of MNBO from nabumetone. Together with the evidence for pentoxifylline and S-warfarin reduction, this is the first study to report that HSD17B12, which is known to metabolize endogenous compounds, such as estrone and 3-ketoacyl-CoA, plays a role as a drug-metabolizing enzyme."

Journal

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Identification of Gut Bacterial Enzymes for Keto-Reductive Metabolism of Xenobiotics. (PubMed, ACS Chem Biol) - "Through in vitro biochemical assays, we report the identification of enzymes encoded in the genome of Clostridium bolteae that can reduce the ketone groups of nabumetone, hydrocortisone, and tacrolimus. The selected enzymes display different levels of activities against additional chemicals such as two dietary compounds (i.e., raspberry ketone and zingerone), chemotherapeutic drug doxorubicin, and its aglycone metabolite doxorubicinone. Thus, our results expand the repertoire of enzymes that can reduce the ketone groups in small molecules and could serve as the basis for future personalized medicine approaches."

Journal • Gastrointestinal Disorder

Discovery and characterization of gut microbial enzymes involved in keto-reductive metabolism (ACS-Sp 2022) - "Here, we characterized an oxidoreductase from the human gut bacterium Clostridium bolteae capable of reducing the ketone groups residing in two drugs (i.e., nabumetone and hydrocortisone) and two ketone-bearing dietary chemicals (i.e., raspberry ketone and zingerone). In addition, we have also identified additional oxidoreductase homologues that have similar ketone-reducing activities from multiple human gut microbial species. Our results expand the gut bacterial enzymatic inventory for the ketone-reduction of pharmaceuticals and dietary chemicals, but it also serves as the basis for elucidating bacteria-chemical interactions and illuminating strategies for future personalized medicines and dietary plans."

A universal methodology for reliable predicting the non-steroidal anti-inflammatory drug solubility in supercritical carbon dioxide. (PubMed, Sci Rep) - "The considered NSAIDs are Fenoprofen, Flurbiprofen, Ibuprofen, Ketoprofen, Loxoprofen, Nabumetone, Naproxen, Nimesulide, Phenylbutazone, Piroxicam, Salicylamide, and Tolmetin. Experimental measurements, model predictions, and relevancy analyses justified that the drug solubility in SCCO increases by increasing temperature and pressure. The results show that Ibuprofen and Naproxen are the most soluble and insoluble drugs in SCCO, respectively."

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Precision Medicine in Patients with Differential Diabetic Phenotypes: Novel Opportunities from Network Medicine. (PubMed, Curr Diabetes Rev) - "The interactome [or protein-protein interactions (PPIs)] is a useful tool to identify subtle molecular differences between precise diabetic phenotypes and predict putative novel drugs. Despite being previously unappreciated as T2DM determinants, the growth factor receptor-bound protein 14 (GRB14), calmodulin 2 (CALM2), and protein kinase C-alpha (PRKCA) might have a relevant role in disease pathogenesis. Besides, in silico platforms have suggested that diflunisal, nabumetone, niflumic acid, and valdecoxib may be suitable for the treatment of T1DM; phenoxybenzamine and idazoxan for the treatment of T2DM by improving insulin secretion; and hydroxychloroquine reduce the risk of coronary heart disease (CHD) by counteracting inflammation. Network medicine has the potential to improve precision medicine in diabetes care and enhance personalized therapy. However, only randomized clinical trials will confirm the clinical utility of network-oriented biomarkers and drugs in the..."

Clinical • Journal • Cardiovascular • Coronary Artery Disease • Diabetes • Gestational Diabetes • Heart Failure • Immunology • Inflammation • Metabolic Disorders • Type 1 Diabetes Mellitus • Type 2 Diabetes Mellitus • CALM2 • PRKCA

Identification of potential inhibitory analogs of metastasis tumor antigens (MTAs) using bioactive compounds: revealing therapeutic option to prevent malignancy. (PubMed, Mol Divers) - "The results suggested that several structural analogs (e.g., tramadol, nabumetone, DGLA and hydrocortisone) may act as agonist to block the MTA proteins and inhibit cancer progression at early stage. The study could be useful to develop effective medications against cancer metastasis in future. Due to encouraging results, we highly recommend further in vitro and in vivo trials for the experimental validation of the findings."

Journal • Oncology

New horizons in the roles and associations of COX-2 and novel natural inhibitors in cardiovascular diseases. (PubMed, Mol Med) - "Coxibs, including celecoxib, valdecoxib, etoricoxib, parecoxib, lumiracoxib, and rofecoxib, are selective cyclooxygenase-2 (COX-2) inhibitors used to treat osteoarthritis and rheumatoid arthritis...Interestingly, nabumetone, flurbiprofen axetil, piketoprofen-amide, and nepafenac are ester prodrugs that inhibit COX-2. The combination of galangin-like flavonol compounds with these prodrug metabolites may lead to the development of novel COX-2 inhibitors. This review focuses on the most compelling evidence regarding the role and mechanism of COX-2 in cardiovascular diseases and demonstrates that quercetin-like compounds exert potential cardioprotective effects by serving as cofactors of COX-2."

Journal • Review • Cardiovascular • Immunology • Osteoarthritis • Pain • Rheumatoid Arthritis • Rheumatology

Toward Multitasking Pharmacological COX-Targeting Agents: Non-Steroidal Anti-Inflammatory Prodrugs with Antiproliferative Effects. (PubMed, Molecules) - "In this work, a pilot docking study aimed at comparing the interaction of two prodrugs, nabumetone (NB) and its tricyclic analog 7-methoxy-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one (MC), and their common active metabolite 6-methoxy-2-naphthylacetic acid (MNA) with the COX binding site, was carried out. Cytotoxicity, cytofluorimetry, and protein expression assays on prodrugs were also performed to assess their potential as antiproliferative agents that could help hypothesize an effective use as anticancer therapeutics. Encouraging results suggest that the studied compounds could act not only as precursors of the anti-inflammatory metabolite, but also as direct antiproliferative agents."

Journal • Oncology

[VIRTUAL] In vitro Anti-Staphylococcal Effect of Anti-inflammatory Drugs (WMF 2021) - " In vitro antimicrobial activity of twelve anti-inflammatory drugs (acetylsalicylic acid, celecoxib, diacerein, diclofenac sodium, diflunisal, ethenzamide, felbinac, ibuprofen, mefenamic acid, nabumetone, sulindac sulfide and tolfenamic acid) were tested against S. aureus ATCC 29213, 25923, 33591,33592 and 43300 using the broth microdilution method. Celecoxib and diacerein showed the most potent anti-staphylococcal effect (MIC ≥ 64 μg/mL). Sulindac sulfide and tolfenamic acid were only active against certain strains of S. aureus with MIC values128 and 256 μg/mL, respectively. Researchers showed that celecoxib, diacerein, and sulindac sulfide demonstrated anti-staphylococcal and anti-helicobacter pylori activity [1, 3, 4]."

Preclinical • Infectious Disease • Musculoskeletal Diseases

Nabumetone induced photogenotoxicity mechanism mediated by ROS generation under environmental UV radiation in human keratinocytes (HaCaT) cell line. (PubMed, Toxicol Appl Pharmacol) - "We also observed that photosensitized NB upregulated inflammatory markers, such as COX-2 and TNFα. This study proposes that sunlight exposure should be avoided by patients using nabumetone and proper guidance should be provided by clinicians regarding photosensitivity of drugs for better safety and efficacy."

Journal • Preclinical • Immunology • Musculoskeletal Diseases • Osteoarthritis • Pain • Rheumatoid Arthritis • Rheumatology • TNFA

Dataset of the first report of pharmacogenomics profiling in an outpatient spine setting. (PubMed, Data Brief) - "These medications included both non-opioid analgesics (i.e., aspirin, diclofenac, nabumetone, indomethacin, meloxicam, piroxicam, tenoxicam, lornoxicam, celecoxib, ibuprofen, flurbiprofen, ketoprofen, fenoprofen, naproxen, and mefenamic acid) and opioid analgesics (i.e., morphine, codeine, dihydrocodeine, ethylmorphine, hydrocodone, hydromorphone, oxycodone, oxymorphone, alfentanil, fentanyl, sufentanil, meperidine, ketobemidone, dextropropoxyphene, levacetylmethadol, loperamide, methadone, buprenorphine, dextromethorphan, tramadol, tapentadol, and tilidine). In supplemental spreadsheets, the raw and analysed pharmacogenomics data for all 30 patients evaluated in the primary research article are additionally provided. Collectively, the presented data offer significant reuse potential in future investigations of pharmacogenomics for pain management."

Biomarker • Clinical • Journal • Back Pain • Musculoskeletal Pain • Orthopedics • Pain • CYP1A2 • CYP2C19 • CYP2C9 • CYP3A4 • CYP3A5

Presence or absence of microbiome modulates the response of mice organism to administered drug nabumetone. (PubMed, Physiol Res) - "In the GF mice, the expression of the DMEs (CYP1A) responsible for the formation of active form of the drug are significantly increased in the small intestine and liver after nabumetone application. These results highlight the importance of gut microbiome in processes involved in drug metabolism in the both gastrointestinal tract and in the liver with possible clinical relevance."

Journal • Gastrointestinal Disorder

Early exposure of pregnant women to non-steroidal anti-inflammatory drugs delivered outside hospitals and preterm birth risk: nationwide cohort study. (PubMed, BJOG) - "Overall, non-selective NSAID use (delivered outside hospitals) during the first 22WG was found to be associated with an increased risk of prematurity. However, the association differs among NSAIDs."

Clinical • Journal