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Journal of Enzyme Inhibition and... Dec 2021Novel tolmetin derivatives to were designed, synthesised, and evaluated for antiproliferative activity by NCI (USA) against a panel of 60 tumour cell lines. The...
Novel tolmetin derivatives to were designed, synthesised, and evaluated for antiproliferative activity by NCI (USA) against a panel of 60 tumour cell lines. The cytotoxic activity of the most active tolmetin derivatives and was examined against HL-60, HCT-15, and UO-31 tumour cell lines. Compound was found to be the most potent derivative against HL-60, HCT-15, and UO-31 cell lines with IC values of 10.32 ± 0.55, 6.62 ± 0.35, and 7.69 ± 0.41 µM, respectively. Molecular modelling studies of derivative towards the VEGFR-2 active site were performed. Compound displayed high inhibitory activity against VEGFR-2 (IC = 0.20 µM). It extremely reduced the HUVECs migration potential exhibiting deeply reduced wound healing patterns after 72 h. It induced apoptosis in HCT-15 cells (52.72-fold). This evidence was supported by an increase in the level of apoptotic caspases-3, -8, and -9 by 7.808-, 1.867-, and 7.622-fold, respectively. Compound arrested the cell cycle in the G0/G1 phase. Furthermore, the ADME studies showed that compound possessed promising pharmacokinetic properties.
Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Humans; Models, Molecular; Molecular Structure; Protein Kinase Inhibitors; Structure-Activity Relationship; Tolmetin; Vascular Endothelial Growth Factor Receptor-2
PubMed: 33896327
DOI: 10.1080/14756366.2021.1901089 -
Scientific Reports Nov 2020Tolmetin is a non-steroidal anti-inflammatory drug being used to decrease the level of hormones which are the reasons for pain, swelling, tiredness, and stiffness for...
Tolmetin is a non-steroidal anti-inflammatory drug being used to decrease the level of hormones which are the reasons for pain, swelling, tiredness, and stiffness for osteoarthritis and rheumatoid arthritis cases. We evaluated its solubility in supercritical carbon dioxide (SC-CO) with the aim of drug nanonization, considering temperature and pressure variations between 120 and 400 bar and 308-338 K, in the experiments. In this way, a PVT solubility cell based on static solubility approach coupled with a simple gravimetric procedure was utilized to evaluate the solubility of tolmetin. The solubility values between 5.00 × 10 and 2.59 × 10 mol fraction were obtained for tolmetin depending on the pressure and temperature of the cell. The measured data demonstrated a direct correlation between pressure and solubility of tolmetin, while the effect of temperature was a dual effect depending on the crossover pressure (160 bar). The calculated solubility data were modeled using several semi-empirical correlations, and the fitting parameters were calculated using the experimental data via appropriate optimization method. The correlated solubility data revealed that the KJ model was the most accurate one with an average absolute relative deviation percent (AARD%) of 6.9. Moreover, the carried out self-consistency analysis utilizing these correlations illustrated great potential of these models to extrapolate the solubility of tolmetin beyond the measured conditions.
PubMed: 33177600
DOI: 10.1038/s41598-020-76330-9 -
Pharmaceutics Apr 2022Tolmetin sodium (TLM) is a non-steroidal anti-inflammatory drug (NSAIDs). TLM is used to treat inflammation, skeletal muscle injuries, and discomfort associated with...
Tolmetin sodium (TLM) is a non-steroidal anti-inflammatory drug (NSAIDs). TLM is used to treat inflammation, skeletal muscle injuries, and discomfort associated with bone disorders. Because of the delayed absorption from the gastro intestinal tract (GIT), the currently available TLM dosage forms have a rather protracted start to the effect, according to pharmacokinetic studies. The aim of this study was to create a combination for TLM fast dissolving tablets (TLM-FDT) that would boost the drug's bioavailability by increasing pre-gastric absorption. The TLM-FDTs were developed using a Box-Behnken experimental design with varied doses of crospovidone (CP), croscarmellose sodium (CCS) as super-disintegrants, and camphor as a sublimating agent. In addition, the current study used response surface approach to explore the influence of various formulation and process factors on tablet qualities in order to verify an optimized TLM-FDTs formulation. The optimized TLM-FDTs formula was subsequently evaluated for its in vivo anti-inflammatory activity. TLM-FDTs have good friability, disintegration time, drug release, and wetting time, as well as fast disintegration and dissolution behavior. Significant increase in drug bioavailability and reliable anti-inflammatory efficacy were also observed, as evidenced by considerable reductions in paw thickness in rats following carrageenan-induced rat paw edema. For optimizing and analyzing the effect of super-disintegrants and sublimating agents in the TLM-FDTs formula, the three-factor, three-level full factorial design is a suitable tool. TLM-FDTs are a possible drug delivery system for enhancing TLM bioavailability and could be used to treat rheumatoid arthritis.
PubMed: 35456714
DOI: 10.3390/pharmaceutics14040880 -
Scientific Reports Jan 2022Understanding the drug solubility behavior is likely the first essential requirement for designing the supercritical technology for pharmaceutical processing. Therefore,...
Understanding the drug solubility behavior is likely the first essential requirement for designing the supercritical technology for pharmaceutical processing. Therefore, this study utilizes different machine learning scenarios to simulate the solubility of twelve non-steroidal anti-inflammatory drugs (NSAIDs) in the supercritical carbon dioxide (SCCO). The considered NSAIDs are Fenoprofen, Flurbiprofen, Ibuprofen, Ketoprofen, Loxoprofen, Nabumetone, Naproxen, Nimesulide, Phenylbutazone, Piroxicam, Salicylamide, and Tolmetin. Physical characteristics of the drugs (molecular weight and melting temperature), operating conditions (pressure and temperature), and solvent property (SCCO density) are effectively used to estimate the drug solubility. Monitoring and comparing the prediction accuracy of twelve intelligent paradigms from three categories (artificial neural networks, support vector regression, and hybrid neuro-fuzzy) approves that adaptive neuro-fuzzy inference is the best tool for the considered task. The hybrid optimization strategy adjusts the cluster radius of the subtractive clustering membership function to 0.6111. This model estimates 254 laboratory-measured solubility data with the AAPRE = 3.13%, MSE = 2.58 × 10, and R = 0.99919. The leverage technique confirms that outliers may poison less than four percent of the experimental data. In addition, the proposed hybrid paradigm is more reliable than the equations of state and available correlations in the literature. 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.
PubMed: 35058504
DOI: 10.1038/s41598-022-04942-4 -
Reactive & Functional Polymers Jan 2021Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used over-the-counter drugs and their uncontrolled disposal is a significant environmental concern. Although...
Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used over-the-counter drugs and their uncontrolled disposal is a significant environmental concern. Although their fluorescent sensing is a desirable method of detection for its sensitivity and simplicity, the structural similarity of the drugs makes the design of selective sensors highly challenging. A thiourea-based fluorescent functional monomer was identified in this work to enable highly efficient synthesis of molecularly imprinted nanoparticle (MINP) sensors for NSAIDs such as Indomethacin or Tolmetin. Micromolar binding affinities were obtained in aqueous solution, with binding selectivities comparable to those reported for polyclonal antibodies. The detection limit was ~50 ng/mL in aqueous solution, and common carboxylic acids such as acetic acid, benzoic acid, and citric acid showed negligible interference.
PubMed: 33716552
DOI: 10.1016/j.reactfunctpolym.2020.104759 -
Acta Crystallographica. Section E,... Feb 2021The asymmetric unit of the title compound, sodium 2-[1-methyl-5-(4-methyl-benzo-yl)-1-pyrrol-2-yl]acetate dihydrate, Na·CHNO ·2HO, contains two sodium cations, two...
The asymmetric unit of the title compound, sodium 2-[1-methyl-5-(4-methyl-benzo-yl)-1-pyrrol-2-yl]acetate dihydrate, Na·CHNO ·2HO, contains two sodium cations, two organic anions ( and ) and two water mol-ecules. The coordination geometry around the sodium cations corresponds to a distorted octa-hedron. Each pair of sodium cations (- or -) is chelated by two bridging anions coordinated by the O atoms of the deprotonated carb-oxy-lic groups, and each sodium atom is coordinated by an O atom of a third anion, which connects pairs of sodium atoms, and a water mol-ecule. As a result, a two-dimensional polymer is formed in the crystal. Hirshfeld surface analysis and two-dimensional fingerprint plots were used to analyze the inter-molecular contacts present in the crystal.
PubMed: 33614141
DOI: 10.1107/S2056989021000414 -
Angewandte Chemie (International Ed. in... Sep 2022H O -driven enzymes are of great interest for industrial biotransformations. Herein, we show for the first time that oxalate oxidase (OXO) is an efficient in situ source...
H O -driven enzymes are of great interest for industrial biotransformations. Herein, we show for the first time that oxalate oxidase (OXO) is an efficient in situ source of H O for one of these biocatalysts, which is known as unspecific peroxygenase (UPO). OXO is reasonably robust, produces only CO as a by-product and uses oxalate as a cheap sacrificial electron donor. UPO has significant potential as an industrial catalyst for selective C-H oxyfunctionalisations, as we confirm herein by testing a diverse drug panel using miniaturised high-throughput assays and mass spectrometry. 33 out of 64 drugs were converted in 5 μL-scale reactions by the UPO with OXO (conversion >70 % for 11 drugs). Furthermore, oxidation of the drug tolmetin was achieved on a 50 mg scale (TON 25 664) with 84 % yield, which was further improved via enzyme immobilization. This one-pot approach ensures adequate H O levels, enabling rapid access to industrially relevant molecules that are difficult to obtain by other routes.
Topics: Carbon Dioxide; Mixed Function Oxygenases; Oxalates; Oxidoreductases; Tolmetin
PubMed: 35916874
DOI: 10.1002/anie.202207831 -
Biomedicines Apr 2023Glioblastoma (GBM) is the most prevalent and aggressive adult brain tumor. Despite multi-modal therapies, GBM recurs, and patients have poor survival (~14 months)....
Glioblastoma (GBM) is the most prevalent and aggressive adult brain tumor. Despite multi-modal therapies, GBM recurs, and patients have poor survival (~14 months). Resistance to therapy may originate from a subpopulation of tumor cells identified as glioma-stem cells (GSC), and new treatments are urgently needed to target these. The biology underpinning GBM recurrence was investigated using whole transcriptome profiling of patient-matched initial and recurrent GBM (recGBM). Differential expression analysis identified 147 significant probes. In total, 24 genes were validated using expression data from four public cohorts and the literature. Functional analyses revealed that transcriptional changes to recGBM were dominated by angiogenesis and immune-related processes. The role of MHC class II proteins in antigen presentation and the differentiation, proliferation, and infiltration of immune cells was enriched. These results suggest recGBM would benefit from immunotherapies. The altered gene signature was further analyzed in a connectivity mapping analysis with QUADrATiC software to identify FDA-approved repurposing drugs. Top-ranking target compounds that may be effective against GSC and GBM recurrence were rosiglitazone, nizatidine, pantoprazole, and tolmetin. Our translational bioinformatics pipeline provides an approach to identify target compounds for repurposing that may add clinical benefit in addition to standard therapies against resistant cancers such as GBM.
PubMed: 37189838
DOI: 10.3390/biomedicines11041219 -
World Journal of Clinical Cases Apr 2024Various non-steroidal anti-inflammatory drugs (NSAIDs) have been used for juvenile idiopathic arthritis (JIA). However, the optimal method for JIA has not yet been...
BACKGROUND
Various non-steroidal anti-inflammatory drugs (NSAIDs) have been used for juvenile idiopathic arthritis (JIA). However, the optimal method for JIA has not yet been developed.
AIM
To perform a systematic review and network meta-analysis to determine the optimal instructions.
METHODS
We searched for randomized controlled trials (RCTs) from PubMed, EMBASE, Google Scholar, CNKI, and Wanfang without restriction for publication date or language at August, 2023. Any RCTs that comparing the effectiveness of NSAIDs with each other or placebo for JIA were included in this network meta-analysis. The surface under the cumulative ranking curve (SUCRA) analysis was used to rank the treatments. value less than 0.05 was identified as statistically significant.
RESULTS
We included 8 RCTs (1127 patients) comparing 8 different instructions including meloxicam (0.125 qd and 0.250 qd), Celecoxib (3 mg/kg bid and 6 mg/kg bid), piroxicam, Naproxen (5.0 mg/kg/d, 7.5 mg/kg/d and 12.5 mg/kg/d), inuprofen (30-40 mg/kg/d), Aspirin (60-80 mg/kg/d, 75 mg/kg/d, and 55 mg/kg/d), Tolmetin (15 mg/kg/d), Rofecoxib, and placebo. There were no significant differences between any two NSAIDs regarding ACR Pedi 30 response. The SUCRA shows that celecoxib (6 mg/kg bid) ranked first (SUCRA, 88.9%), rofecoxib ranked second (SUCRA, 68.1%), Celecoxib (3 mg/kg bid) ranked third (SUCRA, 51.0%). There were no significant differences between any two NSAIDs regarding adverse events. The SUCRA shows that placebo ranked first (SUCRA, 88.2%), piroxicam ranked second (SUCRA, 60.5%), rofecoxib (0.6 mg/kg qd) ranked third (SUCRA, 56.1%), meloxicam (0.125 mg/kg qd) ranked fourth (SUCRA, 56.1%), and rofecoxib (0.3 mg/kg qd) ranked fifth (SUCRA, 56.1%).
CONCLUSION
In summary, celecoxib (6 mg/kg bid) was found to be the most effective NSAID for treating JIA. Rofecoxib, piroxicam, and meloxicam may be safer options, but further research is needed to confirm these findings in larger trials with higher quality studies.
PubMed: 38680254
DOI: 10.12998/wjcc.v12.i12.2056