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Pharmaceutical Research Feb 2016Nanostructured Lipid Carriers (NLCs) loading oxaprozin were developed to address an effective drug packaging and targeted delivery, improving the drug pharmacokinetics...
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.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Caco-2 Cells; Cell Line; Drug Carriers; Folic Acid; Humans; Mice; Nanoparticles; Oxaprozin; Permeability; Phosphatidylethanolamines; Polyethylene Glycols; Propionates
PubMed: 26350105
DOI: 10.1007/s11095-015-1788-x -
British Journal of Pharmacology Jul 2014Non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to induce PG-independent anti-inflammatory actions. Here, we investigated the role of three different...
BACKGROUND AND PURPOSE
Non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to induce PG-independent anti-inflammatory actions. Here, we investigated the role of three different NSAIDs (naproxen, ibuprofen and oxaprozin) on neutrophil responses to CXCL8 and C5a.
EXPERIMENTAL APPROACH
Human neutrophils were isolated from healthy volunteers by dextran and Ficoll-Hypaque density gradients. Neutrophils were pre-incubated with different concentrations (1-100 µM) of NSAIDs or kinase inhibitors. Neutrophil degranulation into supernatants was tested by elisa and zymography. Neutrophil chemotaxis was determined using Boyden chambers. F-actin polymerization was determined by Alexa-Fluor 488-conjugated phalloidin fluorescent assay. Integrin expression was assessed by flow cytometry. The phosphorylation of intracellular kinases was studied by Western blot.
KEY RESULTS
Pretreatment with NSAIDs did not affect neutrophil degranulation, but inhibited neutrophil migration and polymerization of F-actin, in response to CXCL8 and C5a. Pretreatment with different NSAIDs prevented C5a-induced integrin (CD11b) up-regulation, while only ibuprofen reduced CXCL8-induced CD11b up-regulation. Pre-incubation with naproxen or oxaprozin, but not ibuprofen, inhibited the PI3K/Akt-dependent chemotactic pathways. Both endogenous (released in cell supernatants) or exogenous (added to cell cultures) PGE2 did not affect C5a- or CXCL8-induced activities. Short-term incubation with NSAIDs did not affect neutrophil PGE2 release.
CONCLUSION AND IMPLICATIONS
Treatment with NSAIDs reduced C5a- and CXCL8-induced neutrophil migration and F-actin polymerization via different mechanisms. Inhibition by ibuprofen was associated with integrin down-regulation, while naproxen and oxaprozin blocked the PI3K/Akt pathway. Both NSAID actions were independent of COX inhibition and PGE2 release.
Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Chemotaxis, Leukocyte; Complement C5a; Dose-Response Relationship, Drug; Healthy Volunteers; Humans; Interleukin-8; Middle Aged; Neutrophils; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Structure-Activity Relationship; Young Adult
PubMed: 24597536
DOI: 10.1111/bph.12670 -
European Journal of Pharmacology Dec 2013Nonsteroidal anti-inflammatory drugs (NSAIDs) may interfere with the anti-platelet activity of aspirin at the level of the platelet cyclooxygenase-1 (COX-1) enzyme. In...
Nonsteroidal anti-inflammatory drugs (NSAIDs) may interfere with the anti-platelet activity of aspirin at the level of the platelet cyclooxygenase-1 (COX-1) enzyme. In order to examine the interference of common NSAIDs with the anti-platelet activity of aspirin the human platelet rich plasma from voluntary donors was used for arachidonic acid-induced aggregation and determination of thromboxane synthesis. Further, docking studies were used to explain the molecular basis of the NSAID/aspirin interaction. The experimental results showed that celecoxib, dipyrone (active metabolite), ibuprofen, flufenamic acid, naproxen, nimesulide, oxaprozin, and piroxicam significantly interfere with the anti-platelet activity of aspirin, while diclofenac, ketorolac and acetaminophen do not. Docking studies suggested that NSAIDs forming hydrogen bonds with Ser530, Arg120, Tyr385 and other amino acids of the COX-1 hydrophobic channel interfere with antiplatelet activity of aspirin while non interfering NSAIDs do not form relevant hydrogen bond interactions within the aspirin binding site. In conclusion, docking analysis of NSAID interactions at the COX-1 active site appears useful to predict their interference with the anti-platelet activity of aspirin. The results, demonstrate that some NSAIDs do not interfere with the antiplatelet action of aspirin while many others do and provide a basis for understanding the observed differences among individual non-aspirin NSAIDs.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Blood Platelets; Catalytic Domain; Cyclooxygenase 1; Drug Interactions; Humans; Molecular Docking Simulation; Platelet Aggregation Inhibitors; Platelet Function Tests
PubMed: 24075938
DOI: 10.1016/j.ejphar.2013.09.032 -
Journal of Pharmaceutical and... Jan 2014A simple and sensitive method was developed and validated here for the analysis of thirteen nonsteroidal anti-inflammatory drugs (NSAIDs) in human plasma samples by...
A simple and sensitive method was developed and validated here for the analysis of thirteen nonsteroidal anti-inflammatory drugs (NSAIDs) in human plasma samples by hydrophilic interaction liquid chromatography (HILIC)-tandem mass spectrometry (MS/MS). A small volume of plasma (20μL) spiked with compounds was diluted with 80μL of 10-mM ammonium acetate followed by a simple protein precipitation with 400μL of acetonitrile. After centrifugation, the clear supernatant extract was directly injected into the HILIC-MS/MS, without any solvent evaporation and reconstitution steps. The chromatographic separation of the NSAIDs was achieved on a Unison UK-Amino HILIC column (50mm×3mm i.d., particle size 3μm) with a linear gradient elution system composed of 10mM ammonium acetate (pH 6.8) and acetonitrile at a flow rate of 0.4mL/min. The mass spectra obtained by HILIC-MS showed base peak ions due to [M+H](+) for indomethacin, oxaprozin, ketoprofen, alminoprofen, zaltoprofen, tiaprofenic acid, pranoprofen, and ketoprofen-d3 and due to [M-H](-) for etodolac, ibuprofen, diclofenac, fenoprofen, loxoprofen, naproxen, and ibuprofen-d3. Recoveries of these thirteen NSAIDs in plasma were 34.8-113% and the lower limits of quantitation were 0.125-1.25μg/mL. The intra- and interday coefficient of variations for all drugs in plasma were less than 14.6%. The data obtained from actual plasma determinations of zaltoprofen, ibuprofen, and diclofenac are also presented.
Topics: Acetates; Acetonitriles; Administration, Oral; Adult; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Blood Chemical Analysis; Drug Monitoring; Humans; Hydrophobic and Hydrophilic Interactions; Male; Middle Aged; Quality Control; Regression Analysis; Reproducibility of Results; Solvents; Tandem Mass Spectrometry
PubMed: 24036363
DOI: 10.1016/j.jpba.2013.08.023 -
Sheng Wu Yi Xue Gong Cheng Xue Za Zhi =... Jun 2013The present research was aimed to develop a high performance liquid chromatography (HPLC) method to determine oxaprozin in plasma and to evaluate the bioavailability of... (Randomized Controlled Trial)
Randomized Controlled Trial
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.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Biological Availability; Chromatography, High Pressure Liquid; Cross-Over Studies; Humans; Oxaprozin; Propionates; Tablets, Enteric-Coated
PubMed: 23865335
DOI: No ID Found -
Chemical & Pharmaceutical Bulletin 2012A 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...
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.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Cell Line, Tumor; Cell Proliferation; Coordination Complexes; HCT116 Cells; Humans; Magnetics; Oxaprozin; Propionates; Transition Elements
PubMed: 22790819
DOI: 10.1248/cpb.c12-00185 -
European Journal of Pharmaceutics and... Aug 2011The effect of the combined use of randomly methylated β-cyclodextrin (RAMEB), chitosan (CS), and bile components (dehydrocholic (DHCA) or ursodeoxycholic (UDCA) acids...
The effect of the combined use of randomly methylated β-cyclodextrin (RAMEB), chitosan (CS), and bile components (dehydrocholic (DHCA) or ursodeoxycholic (UDCA) acids and their sodium salts) on solubility and permeability through Caco-2 cells of oxaprozin (a very poorly water-soluble non-steroidal anti-inflammatory drug) has been investigated. Addition of CS, bile acids, and their sodium salts increased the RAMEB solubilizing power of 4, 2, and 5 times, respectively. Drug-RAMEB-CS co-ground systems showed very higher dissolution rate than corresponding drug-RAMEB systems. Addition of bile components further improved drug dissolution rate. The CS presence enabled a significant increase in drug permeability through Caco-2 cells with respect to drug-RAMEB systems. Moreover, CS and NaDHC showed a synergistic enhancer effect, enabling a 1.4-fold permeability increase in comparison with systems without bile salt. However, unexpectedly, no significant differences were found between physical mixtures and co-ground products, indicating that drug permeation improvement was due to the intrinsic enhancer effect of the carriers and not to drug-carrier interactions brought about by co-grinding, as instead found in dissolution rate studies. The combined use of RAMEB, CS, and NaDHC could be exploited to develop effective oral dosage forms of oxaprozin, with increased drug solubility and permeability, and then improved bioavailability.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Bile; Caco-2 Cells; Chitosan; Cholagogues and Choleretics; Dehydrocholic Acid; Drug Carriers; Drug Compounding; Drug Delivery Systems; Drug Synergism; Excipients; Humans; L-Lactate Dehydrogenase; Oxaprozin; Permeability; Propionates; Solubility; Ursodeoxycholic Acid; beta-Cyclodextrins
PubMed: 21439375
DOI: 10.1016/j.ejpb.2011.03.012 -
Journal of Oral and Maxillofacial... May 2010In 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... (Comparative Study)
Comparative Study Randomized Controlled Trial
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.
Topics: Adolescent; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Cross-Over Studies; Double-Blind Method; Edema; Face; Female; Humans; Male; Mandible; Molar, Third; Naproxen; Oxaprozin; Pain, Postoperative; Placebos; Propionates; Prospective Studies; Range of Motion, Articular; Tooth, Impacted; Trismus; Young Adult
PubMed: 20206429
DOI: 10.1016/j.joms.2009.09.094 -
Spectrochimica Acta. Part A, Molecular... Apr 2010The molecular structure, linear and nonlinear optical properties, and electronic properties of 4,5-diphenyl-2-2 oxazole propionic acid (oxaprozin) as a monomer were...
The molecular structure, linear and nonlinear optical properties, and electronic properties of 4,5-diphenyl-2-2 oxazole propionic acid (oxaprozin) as a monomer were investigated by using Hartree-Fock (HF) and density functional theory (DFT) calculations that used 6-31G(d,p) basis set. The first-order hyperpolarizability of oxaprozin (OXA) was found to be 1.117 x 10(-30) esu. The structure of oxaprozin dimer with HF/6-31G(d) level caused by the shifts of O-H and CO bands in the vibrational spectra of oxaprozin were also studied. Moreover, these calculated frequencies of oxaprozin dimer were compared with the solid FT-IR and FT-Raman spectra. The theoretical frequencies and infrared intensities were showed a good agreement with experimental data.
Topics: Crystallography, X-Ray; Dimerization; Electrons; Molecular Conformation; Oxaprozin; Propionates; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis, Raman; Vibration
PubMed: 20167532
DOI: 10.1016/j.saa.2010.01.004 -
Journal of Microencapsulation 2010A combined approach based on drug cyclodextrin (CD) complexation and loading into PLGA nanoparticles (NP) has been developed to improve oxaprozin therapeutic efficiency....
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.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Cyclodextrins; Drug Carriers; Lactic Acid; Nanoparticles; Oxaprozin; Particle Size; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Propionates
PubMed: 20113170
DOI: 10.3109/02652040903515508