Anticonvulsant activity of oxaprozin in a rat model of pentylenetetrazole-induced seizure by targeting oxidative stress and SIRT1/PGC1α signaling.

The effect of oxaprozin (OXP) on an experimental model of seizures in rats was investigated in this study. Seizures in Wistar rats (200-250 g) were induced by pentylenetetrazole (PTZ, 60 mg/kg). The anticonvulsant effect of OXP (100, 200, and 400 mg/kg, intraperitoneally) was evaluated in a seizure model. After behavioral tests, the animals underwent deep anesthesia and were put down painlessly. Animal serum was isolated for antioxidant assays (nitric oxide (NO) and glutathione (GSH)). The animals' brains were also isolated to gauge the relative expression of genes in the oxidative stress pathway (sirtuin 1 (Sirt1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Pgc1α)). Intraperitoneal injection of OXP increased the mean latency of myoclonic jerks and generalized tonic-clonic seizure (GTCS) and decreased the number of myoclonic jerks and GTCS duration compared with the PTZ group. Biochemical tests showed that pretreatment with OXP was able to restore GSH serum levels and reverse the augmented NO serum levels caused by PTZ induction to the normal level. The quantitative polymerase chain reaction results also revealed that OXP counteracts the negative effects of PTZ by affecting the expression of the Sirt1 and Pgc1α genes. Overall, this study suggests the potential neuroprotective effects of the nonsteroidal, anti-inflammatory OXP drug in a model of neural impairment caused by seizures via the mechanism of inhibition of the oxidative stress pathway.

Application of CO2 Supercritical Fluid to Optimize the Solubility of Oxaprozin: Development of Novel Machine Learning Predictive Models.

Over the last years, extensive motivation has emerged towards the application of supercritical carbon dioxide (SCCO2) for particle engineering. SCCO2 has great potential for application as a green and eco-friendly technique to reach small crystalline particles with narrow particle size distribution. In this paper, an artificial intelligence (AI) method has been used as an efficient and versatile tool to predict and consequently optimize the solubility of oxaprozin in SCCO2 systems. Three learning methods, including multi-layer perceptron (MLP), Kriging or Gaussian process regression (GPR), and k-nearest neighbors (KNN) are selected to make models on the tiny dataset. The dataset includes 32 data points with two input parameters (temperature and pressure) and one output (solubility). The optimized models were tested with standard metrics. MLP, GPR, and KNN have error rates of 2.079 × 10-8, 2.173 × 10-9, and 1.372 × 10-8, respectively, using MSE metrics. Additionally, in terms of R-squared, they have scores of 0.868, 0.997, and 0.999, respectively. The optimal inputs are the same as the maximum possible values and are paired with a solubility of 1.26 × 10-3 as an output.

A drug-drug interaction study of a novel, selective urate reabsorption inhibitor dotinurad and the non-steroidal anti-inflammatory drug oxaprozin in healthy adult males.

BACKGROUND: Dotinurad is a novel, selective urate reabsorption inhibitor, which reduces serum uric acid levels by inhibiting the urate transporter 1. The results of nonclinical studies indicated the possibility that the concomitant use of the non-steroidal anti-inflammatory drug oxaprozin affects the pharmacokinetics of dotinurad. We evaluated drug-drug interactions with respect to the pharmacokinetics and safety of dotinurad when co-administered with oxaprozin. METHODS: This was an open-label, two-period, add-on study in healthy adult males. For a single dose of 4 mg of dotinurad with and without oxaprozin, we compared its pharmacokinetic parameters and evaluated safety. RESULTS: This study enrolled 12 subjects, 11 of whom completed the study. The geometric mean ratio (90% confidence interval [CI]) of the urinary excretion rate of glucuronate conjugates of dotinurad after co-administration with oxaprozin compared to administration of dotinurad alone was 0.657 (0.624-0.692), while the geometric mean ratios (90% CIs) of the maximum plasma concentration and area under the plasma concentration-time curve from time zero to infinity (AUC0-inf) were 0.982 (0.945-1.021) and 1.165 (1.114-1.219), respectively. During the study, two adverse events occurred after administration of dotinurad alone and one occurred after administration of oxaprozin alone. CONCLUSIONS: In comparison with administration of dotinurad alone, co-administration with oxaprozin was associated with a 34.3% decrease in the urinary excretion rate of the glucuronate conjugates of dotinurad, and a 16.5% increase in AUC0-inf of dotinurad. However, no clinically meaningful drug-drug interactions were observed. Administration of dotinurad alone was similar safety to co-administration with oxaprozin. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03350386.

The Role of Extracellular Proteases in Tumor Progression and the Development of Innovative Metal Ion Chelators that Inhibit their Activity.

The crucial role of extracellular proteases in cancer progression is well-known, especially in relation to the promotion of cell invasion through extracellular matrix remodeling. This also occurs by the ability of extracellular proteases to induce the shedding of transmembrane proteins at the plasma membrane surface or within extracellular vesicles. This process results in the regulation of key signaling pathways by the modulation of kinases, e.g., the epidermal growth factor receptor (EGFR). Considering their regulatory roles in cancer, therapeutics targeting various extracellular proteases have been discovered. These include the metal-binding agents di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) and di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), which increase c-MET degradation by multiple mechanisms. Both the direct and indirect inhibition of protease expression and activity can be achieved through metal ion depletion. Considering direct mechanisms, chelators can bind zinc(II) that plays a catalytic role in enzyme activity. In terms of indirect mechanisms, Dp44mT and DpC potently suppress the expression of the kallikrein-related peptidase-a prostate-specific antigen-in prostate cancer cells. The mechanism of this activity involves promotion of the degradation of the androgen receptor. Additional suppressive mechanisms of Dp44mT and DpC on matrix metalloproteases (MMPs) relate to their ability to up-regulate the metastasis suppressors N-myc downstream regulated gene-1 (NDRG1) and NDRG2, which down-regulate MMPs that are crucial for cancer cell invasion.

Oxaprozin prodrug as safer nonsteroidal anti-inflammatory drug: Synthesis and pharmacological evaluation.

Oxaprozin is a popular non-steroidal anti-inflammatory drug (NSAID) and its chronic oral use is clinically restricted due to its gastrointestinal (GI) complications. In order to circumvent the GI complications, oxaprozin was amended as a prodrug in a one-pot reaction using N,N-carbonyldiimidazole as an activating agent. Dextran of average molecular weight (60,000-90,000 Da) was exploited as a carrier in the process of oxaprozin prodrug production by esterification. The structural profiles of the synthesized oxaprozin prodrug were characterized by FT-IR and NMR spectroscopy. The oxaprozin prodrug possessed optimal molecular weight, lipophilicity, partition coefficient, protein binding, and degree of substitution of 52.4%. The release of oxaprozin upon hydrolysis of the prodrug in both simulated gastric fluid and simulated intestinal fluid followed first-order kinetics with 55.2 min of half-life. Varied ADME properties of the prodrug resulted upon Schrodinger's QikProp tool application. Oxaprozin prodrug displayed significant analgesic, antipyretic, and anti-inflammatory activities, with a remarkable decrease in the ulcer index and being devoid of antigenicity in experimental animals. Thus, it is evident that oxaprozin prodrug is a safer oral NSAID without causing any ulcerations.

Oxaprozin-Loaded Lipid Nanoparticles towards Overcoming NSAIDs Side-Effects.

PURPOSE: Nanostructured Lipid Carriers (NLCs) loading oxaprozin were developed to address an effective drug packaging and targeted delivery, improving the drug pharmacokinetics and pharmacodynamics properties and avoiding the local gastric side-effects. Macrophages actively phagocyte particles with sizes larger than 200 nm and, when activated, over-express folate beta receptors - features that in the case of this work constitute the basis for passive and active targeting strategies. METHODS: Two formulations containing oxaprozin were developed: NLCs with and without folate functionalization. In order to target the macrophages folate receptors, a DSPE-PEG2000-FA conjugate was synthesized and added to the NLCs. RESULTS: These formulations presented a relatively low polydispersity index (approximately 0.2) with mean diameters greater than 200 nm and zeta potential inferior to -40 mV. The encapsulation efficiency of the particles was superior to 95% and the loading capacity was of 9%, approximately. The formulations retained the oxaprozin release in simulated gastric fluid (only around 10%) promoting its release on simulated intestinal fluid. MTT and LDH assays revealed that the formulations only presented cytotoxicity in Caco-2 cells for oxaprozin concentrations superior to 100 µM. Permeability studies in Caco-2 cells shown that oxaprozin encapsulation did not interfered with oxaprozin permeability (around 0.8 × 10(-5) cm/s in simulated intestinal fluid and about 1.45 × 10(-5) cm/s in PBS). Moreover, in RAW 264.7 cells NLCs functionalization promoted an increased uptake over time mainly mediated by a caveolae uptake mechanism. CONCLUSIONS: The developed nanoparticles enclose a great potential for oxaprozin oral administration with significant less gastric side-effects.

[Determination of oxaprozin in human plasma with high performance liquid chromatography (HPLC) and its application].

The present research was aimed to develop a high performance liquid chromatography (HPLC) method to determine oxaprozin in plasma and to evaluate the bioavailability of two oxaprozin enteric coated tablets. A C18 column was used to separate the plasma after protein precipitation and the mobile phase was methanol-12. 5mmol/L ammonium acetate buffer solution (pH=3.0)(71:29). The calibration curve was linear in the concentration range of 0. 50-70. 56 microg . mL-1, and the intra and inter-day RSDs were less than 12. 33% and 10. 42% respectively. A single dose of 0. 4 g reference preparation or test preparation of oxaprozin enteric coated tablets was administered to 20 healthy volunteers according to a randomized crossover study. AUC0-->264h were (4 917. 44 +/- 629. 57) microg . h . mL-1 and (4 604. 30+/-737. 83) microg . h . mL-1, respectively; Cmax were (52. 34+/-7. 68) microg . mL-1 and (48. 66+/-4. 87) microg . mL-1, respectively; Tmax were (18. 70+/-2.27) h and (19. 30+/-1. 63) h, respectively; The relative bioavailability of test preparation was 94.0% +/- 13. 7%. The method is simple, rapid and selective for oxaprozin determination. There is no significant difference in the main pharmacokinetic parameters between the test formulation and reference formulation and the two formulations are in bioequivalence.

Transition metal(II) complexes with the non-steroidal anti-inflammatory drug oxaprozin: Characterization and biological profile.

A series of copper(II), nickel(II) and cobalt(II) complexes with the non-steroidal anti-inflammatory drug oxaprozin (Hoxa) have been synthesized and characterized by diverse techniques. The crystal structures of two copper(II) complexes, namely the dinuclear complex [Cu2(oxa)4(DMF)2] (1) and the polymeric complex {[Cu2(oxa)4]·2MeOH·0.5MeOH}2 (12) were determined by single-crystal X-ray diffraction studies. In order to evaluate in vitro the antioxidant activity of the resultant complexes, their scavenging ability towards 1,1-diphenyl-picrylhydrazyl (DPPH), hydroxyl and 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radicals was investigated revealing their high effectiveness against these radicals. The binding of the complexes to bovine serum albumin and human serum albumin was examined and the corresponding determined albumin-binding constants showed a tight and reversible interaction. The interaction of the complexes with calf-thymus DNA was monitored by diverse techniques including UV-vis spectroscopy, cyclic voltammetry, DNA-viscosity measurements and competitive studies with ethidium bromide. Intercalation may be proposed as the most possible DNA-interaction mode of the complexes.

Synthesis, characterization and antiproliferative activity of transition metal complexes with 3-(4,5-diphenyl-1,3-oxazol-2-yl)propanoic acid (oxaprozin).

A series of novel Mn(II), Co(II), Ni(II), Cu(II) and Zn(II) complexes with oxaprozin (Hoxa), a non-steroidal anti-inflammatory drug, has been synthesized. The drug and complexes have been characterized by elemental and thermogravimetric (TG) analysis, Fourier transform (FT)-IR, 1H-NMR, 13C-NMR, UV-Vis spectroscopy and magnetic susceptibility measurements. The (pseudo)octahedral geometry has been proposed for all complexes based on electronic spectra and magnetic moments. With exception of the Cu(II) complex, where bridging bidentate mode of COO groups has been found, FT-IR spectra confirmed chelately coordinated COO groups in the other complexes. The general formula of the complexes is [M(H2O)2(oxa)2 ·χH2O, with χ=2 for M=Mn, Co and Ni and χ=1.5 for Zn. The binuclear Cu(II) complex, [Cu2(H2O)2(OH)(oxa)3]·2H2O, has strong Cu-Cu interactions of antiferromagnetic type. The complexes and Hoxa did not exhibit the cytotoxic effect to peritoneal macrophages. For the first time these complexes have been tested for their in vitro antiproliferative activity against human colon and breast cancer cell lines, HCT-116 and MDA-231, respectively. For all investigated compounds significant antiproliferative effects have been observed. Ni(II) complex has been shown to be a promising antiproliferative agent exerting excellent activity against HCT-116 even in nanomolar concentrations.

Development a novel robust method to enhance the solubility of Oxaprozin as nonsteroidal anti-inflammatory drug based on machine-learning.

Accurate specification of the drugs' solubility is known as an important activity to appropriately manage the supercritical impregnation process. Over the last decades, the application of supercritical fluids (SCFs), mainly CO2, has found great interest as a promising solution to dominate the limitations of traditional methods including high toxicity, difficulty of control, high expense and low stability. Oxaprozin is an efficient off-patent nonsteroidal anti-inflammatory drug (NSAID), which is being extensively used for the pain management of patients suffering from chronic musculoskeletal disorders such as rheumatoid arthritis. In this paper, the prominent purpose of the authors is to predict and consequently optimize the solubility of Oxaprozin inside the CO2SCF. To do this, the authors employed two basic models and improved them with the Adaboost ensemble method. The base models include Gaussian process regression (GPR) and decision tree (DT). We optimized and evaluated the hyper-parameters of them using standard metrics. Boosted DT has an MAE error rate, an R2-score, and an MAPE of 6.806E-05, 0.980, and 4.511E-01, respectively. Also, boosted GPR has an R2-score of 0.998 and its MAPE error is 3.929E-02, and with MAE it has an error rate of 5.024E-06. So, boosted GPR was chosen as the best model, and the best values were: (T = 3.38E + 02, P = 4.0E + 02, Solubility = 0.001241).

Development and In vitro and In vivo Evaluations of a Microemulsion Formulation for the Oral Delivery of Oxaprozin.

BACKGROUND: Oxaprozin is labeled as a Class II drug in the biopharmaceutical classification system, and its poor solubility in the entire gastrointestinal tract may be the main reason for its insufficient oral absorption capacity. OBJECTIVE: The purpose of this study was to develop an oxaprozin formulation to enhance its oral absorption. METHODS: Oxaprozin-loaded microemulsions were prepared using the titration method and pseudoternary phase diagram. Characterization experiments were performed on microemulsion preparations, including pH, particle size, shape, zeta potential, and stability (thermodynamic, dilution, and differential scanning calorimetry). Then, the in vitro release of the microemulsion and in vivo pharmacokinetics in rats were evaluated. RESULTS: Several microemulsion formulations were prepared. The optimal formulation was 15% oleoyl macrogolglycerides, 35% Tween 20/isopropanol (Km=2), and 50% distilled water. Its particle size met the requirements, and it had a spherical shape with a negatively charged surface. This microemulsion-loaded drug was applied to in vitro release and in vivo pharmacokinetic experiments at 7.47 mg/mL. In vitro release of the oxaprozin-loaded microemulsion best fit the firstorder model, while the microemulsion preparation had a certain sustained-release effect. In vivo pharmacokinetic experiments indicated that the microemulsion formulation significantly delayed the peak time of the blood concentration and simultaneously prolonged the half-life of drug elimination. CONCLUSION: The obtained data revealed satisfactory results for this novel microemulsion of oxaprozin, which is very meaningful for clinical trials.

Design of predictive model to optimize the solubility of Oxaprozin as nonsteroidal anti-inflammatory drug.

These days, many efforts have been made to increase and develop the solubility and bioavailability of novel therapeutic medicines. One of the most believable approaches is the operation of supercritical carbon dioxide fluid (SC-CO2). This operation has been used as a unique method in pharmacology due to the brilliant positive points such as colorless nature, cost-effectives, and environmentally friendly. This research project is aimed to mathematically calculate the solubility of Oxaprozin in SC-CO2 through artificial intelligence. Oxaprozin is a nonsteroidal anti-inflammatory drug which is useful in arthritis disease to improve swelling and pain. Oxaprozin is a type of BCS class II (Biopharmaceutical Classification) drug with low solubility and bioavailability. Here in order to optimize and improve the solubility of Oxaprozin, three ensemble decision tree-based models including random forest (RF), Extremely random trees (ET), and gradient boosting (GB) are considered. 32 data vectors are used for this modeling, moreover, temperature and pressure as inputs, and drug solubility as output. Using the MSE metric, ET, RF, and GB illustrated error rates of 6.29E-09, 9.71E-09, and 3.78E-11. Then, using the R-squared metric, they demonstrated results including 0.999, 0.984, and 0.999, respectively. GB is selected as the best fitted model with the optimal values including 33.15 (K) for the temperature, 380.4 (bar) for the pressure and 0.001242 (mole fraction) as optimized value for the solubility.

Two Binding Sites of SARS-CoV-2 Macrodomain 3 Probed by Oxaprozin and Meclomen.

Severe acute respiratory syndrome-coronavirus-1/2 (SARS-CoV-1/2) macrodomain 3 (Mac3) is critical for replication and transcription of the viral genome and is therefore a potential therapeutic target. Here, we solved the crystal structure of SARS-CoV-2 Mac3, which reveals a small-molecule binding pocket. Two low-molecular-weight drugs, oxaprozin and meclomen, induced different patterns of nuclear magnetic resonance (NMR) chemical shift perturbations (CSPs). Meclomen binds to site I of SARS-CoV-2 Mac3 with binding pose determined by NMR CSP and transferred paramagnetic relaxation enhancement, while oxaprozin binds to site II as revealed by the crystal structure. Interestingly, oxaprozin and meclomen both perturb residues in site I of SARS-CoV Mac3. Fluorescence polarization experiments further demonstrated that oxaprozin and meclomen inhibited the binding of DNA-G4s to SARS-CoV-2 Mac3. Our work identified two adjacent ligand-binding sites of SARS-CoV-2 Mac3 that shall facilitate structure-guided fragment linking of these compounds for more potent inhibitors.

Nonsteroidal Anti-inflammatory Drug Oxaprozin is Beneficial Against Seizure-induced Memory Impairment in an Experimental Model of Seizures in Rats: Impact On Oxidative Stress and Nrf2/HO-1 Signaling Pathway.

There is substantial evidence that anti-inflammatory agents and antioxidants have neuroprotective properties and may be useful in the treatment of neurodegenerative disorders. In this regard, the effects of oxaprozin (OXP) (a nonsteroidal anti-inflammatory drug) on the experimental model of seizure and memory impairment caused by seizures in rats were investigated in the present study. Seizures in male Wistar rats (200-250 g, 8 weeks) were induced by pentylenetetrazol (PTZ, 60 mg/kg). The anticonvulsant effects of OXP (100, 200, and 400 mg/kg, administered intraperitoneally) were evaluated in the seizure model. The effect on memory was assessed using the passive avoidance (PA) test. After behavioral tests, the animals underwent deep anesthesia and were euthanized painlessly. Animal serum was isolated for antioxidant assays (MDA and GPx). The animals' brains (hippocampus) were also isolated to gauge the relative expression of genes in the oxidative stress pathway (Nrf2/HO-1). Intraperitoneal injection of OXP decreased the mean score on the Racine scale compared to the PTZ group. Moreover, in the PA test, OXP caused a significant increase in retention latency (RL) and total time spent in the light compartment (TLC) compared to the PTZ group. Biochemical tests showed that OXP was able to significantly increase GPx serum levels and significantly reduce MDA serum levels compared to the PTZ group. Quantitative polymerase chain reaction (qPCR) results also revealed that OXP counteracted the negative effects of PTZ by significantly increasing the expression of the Nrf2 and Hmox1 genes. Overall, this study suggests the potential neuroprotective effects of the nonsteroidal anti-inflammatory drug OXP in a model of memory impairment caused by seizures via inhibition of the oxidative stress pathway.

Oxaprozin Analogues as Selective RXR Agonists with Superior Properties and Pharmacokinetics.

The retinoid X receptors (RXR) are ligand-activated transcription factors involved in multiple regulatory networks as universal heterodimer partners for nuclear receptors. Despite their high therapeutic potential in many pathologies, targeting of RXR has only been exploited in cancer treatment as the currently available RXR agonists suffer from exceptional lipophilicity, poor pharmacokinetics (PK), and adverse effects. Aiming to overcome the limitations and to provide improved RXR ligands, we developed a new potent RXR ligand chemotype based on the nonsteroidal anti-inflammatory drug oxaprozin. Systematic structure-activity relationship analysis enabled structural optimization toward low nanomolar potency similar to the well-established rexinoids. Cocrystal structures of the most active derivatives demonstrated orthosteric binding, and in vivo profiling revealed superior PK properties compared to current RXR agonists. The optimized compounds were highly selective for RXR activation and induced RXR-regulated gene expression in native cellular and in vivo settings suggesting them as excellent chemical tools to further explore the therapeutic potential of RXR.

Analgesic and anti-inflammatory effects of oxaprozin and naproxen sodium after removal of impacted lower third molars: a randomized, double-blind, placebo-controlled crossover study.

PURPOSE: In this study, oxaprozin, a long-acting nonsteroidal anti-inflammatory drug, and naproxen sodium were compared in terms of their effects on edema, pain, and trismus after surgery for impacted mandibular third molars. MATERIALS AND METHODS: Thirty healthy patients with bilaterally impacted mandibular third molars were included in this randomized, cross-over, double-blind, placebo-controlled study. Patients were assigned randomly to 1 of 3 surgery groups and received postoperatively 1,200 mg oxaprozin, 550 mg naproxen sodium, or a placebo. Postoperative edema was measured with ultrasonography performed before and after surgery. Trismus was measured by comparison of preoperative and postoperative maximum interincisal mouth opening measurements by caliper. Pain was assessed by a visual analog scale (VAS) and by recording the number of rescue analgesic pills taken. RESULTS: After removal of impacted third molars, the patients administered oxaprozin and naproxen showed superior results over those given placebo in terms of pain parameters (P < .05), but these treatments had no statistically significant effect on facial swelling. Comparing the oxaprozin and naproxen groups, there were no differences in the mouth opening measurements, but naproxen showed a statistically superior effect over the placebo (P < .05). Although not statistically significant, oxaprozin showed a more pronounced effect in reducing trismus than did the placebo (P = .07). CONCLUSIONS: Administration of either oxaprozin or naproxen sodium during the postoperative period is effective and has similar effects in reducing pain but questionable benefit for the management of trismus. However, neither agent has clinical benefit in terms of reducing edema.

Development of a new delivery system consisting in 'drug-in cyclodextrin-in PLGA nanoparticles'.

A combined approach based on drug cyclodextrin (CD) complexation and loading into PLGA nanoparticles (NP) has been developed to improve oxaprozin therapeutic efficiency. This strategy exploits the solubilizing and stabilizing properties of CDs and the prolonged-release and targeting properties of PLGA NPs. Drug-loaded NPs, prepared by double-emulsion, were examined for dimensions, zeta-potential and entrapment efficiency. Solid-state studies demonstrated the absence of drug-polymer interactions and assessed the amorphous state of the drug-CD complex loaded into NPs. Drug release rate from NPs was strongly influenced by the presence and kind of CD used. The percentage released at 24 h varied from 16% (plain drug-loaded NPs) to 50% (drug-betaCD-loaded NPs) up to 100% (drug-methylbetaCD-loaded NPs). This result suggests the possibility of using CD complexation not only to promote, but also to regulate drug release rate from NPs, by selecting the proper type of CD or CD combination.

New 2-(4-(4-bromophenylsulfonyl)phenyl)-4-arylidene-oxazol-5(4H)-ones: analgesic activity and histopathological assessment.

This paper reports the synthesis, analgesic activity, acute toxicity and histopathological (HP) assessment of four new compounds from oxazol-5(4H)-ones class that contain in their molecule a diarylsulfone moiety. The new 2-(4-(4-bromophenylsulfonyl)phenyl)-4-arylidene-oxazol-5(4H)-ones were obtained by reaction of 2-(4-(4-bromophenyl-sulfonyl)benzamido)acetic acid intermediate with aromatic aldehydes (benzaldehyde, 4-methoxy, 4-nitro or 4-bromobenzaldehyde), in acetic anhydride and in the presence of anhydrous sodium acetate. The new compounds have been characterized by spectral techniques, such as: Fourier-transform infrared spectroscopy (FT-IR), mass spectrometry (MS), proton nuclear magnetic resonance (1H-NMR) and by elemental analysis. The acute toxicity of the new oxazol-5(4H)-ones in mice was assessed through "acute toxic class" method, according to Organization for Economic Co-operation and Development (OECD) Guidelines. The HP assessment of some preserved organs collected from mice has been performed. The analgesic activity of all new synthesized compounds was carried out with two pharmacological tests: the writhing test and the hot plate test. In order to predict the binding affinities of the synthesized oxazol-5(4H)-ones derivatives against molecular targets involved in pain and inflammation, molecular docking simulations were performed. The results of the writhing test indicated that the most active compound was the oxazolone that contains in the molecule a methoxy group. The acute oral toxicity study revealed no lethal effect of new compounds. The HP assessment of the preserved organs collected from mice did not indicate any cytohistopathological aspects that can be linked to any inflammatory, neoplastic or cytotoxic process, demonstrating the low toxicity of new compounds.

The study of ultrasound and iontophoresis on oxaprozin transdermal penetration using surface-enhanced Raman spectroscopy.

The potential for physicochemical driving forces facilitating topical transport of the lipid-soluble drug oxaprozin (OXA) was investigated using surface-enhanced Raman spectroscopy (SERS) in this study. Azone, iontophoresis (IP), and sonophoresis (SP) were combined and performed on mouse skin for the OXA transdermal penetration, and the synergistic effect was analyzed using Raman spectroscopy. The data of characteristic peak intensity were processed with overlapping peak resolving and standard normalization. The results showed that Azone promoted the transdermal penetration of OXA (5.9-fold greater than the OXA concentration of normal penetration); SP enhanced OXA transdermal penetration (5.5-fold); IP enhanced OXA transdermal penetration (4.2-fold); the combined application of Azone and SP (Azone+SP) and SP+IP can improve the enhancement coefficient of OXA transdermal penetration (8.4-fold and 6.1-fold, > 5.9, > 5.5, > 4.2), and their combined application has a synergistic effect; Azone+IP does not have a synergistic effect while the enhancement coefficient of Azone+IP (5.3-fold, < 5.9) and Azone+SP+IP (7.2-fold, < 8.4) was slightly reduced. As for the drug OXA, Azone+SP is an effective method of transdermal penetration.

Manganese(II) coordination compounds of carboxylate non-steroidal anti-inflammatory drugs.

Upon the interaction of MnCl2 with the non-steroidal anti-inflammatory drugs oxaprozin or flufenamic acid in the presence of the nitrogen-donors 2,2'-bipyridine or 1,10-phenanthroline as co-ligands, one dinuclear and two trinuclear Mn(II) complexes were isolated. The complexes were characterized by diverse techniques. The complexes were evaluated for their scavenging activity against free radicals such as hydroxyl, 1,1-diphenyl-2-picrylhydrazyl and 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid). The in vitro binding affinity of the complexes to calf-thymus (CT) DNA and serum albumins was also monitored. In total, we may suggest that the complexes present promising scavenging activity against the radicals tested, and they may bind to CT DNA via intercalation and reversibly to serum albumins.