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1.
J Med Chem ; 64(8): 5123-5136, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33793232

RESUMO

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.


Assuntos
Oxaprozina/análogos & derivados , Receptores X de Retinoides/agonistas , Animais , Sítios de Ligação , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Meia-Vida , Humanos , Ligantes , Camundongos , Microssomos/metabolismo , Simulação de Dinâmica Molecular , Oxaprozina/metabolismo , Oxaprozina/farmacologia , Isoformas de Proteínas/agonistas , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Pirazóis/química , Pirazóis/metabolismo , Pirazóis/farmacologia , Ratos , Receptores X de Retinoides/genética , Receptores X de Retinoides/metabolismo , Relação Estrutura-Atividade
2.
Int J Mol Sci ; 21(18)2020 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-32948029

RESUMO

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.


Assuntos
Antineoplásicos/uso terapêutico , Quelantes/uso terapêutico , Ferro , Proteínas de Neoplasias/fisiologia , Peptídeo Hidrolases/fisiologia , Inibidores de Proteases/uso terapêutico , Zinco , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Quelantes/farmacologia , Progressão da Doença , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Líquido Extracelular/enzimologia , Vesículas Extracelulares/enzimologia , Humanos , Ácidos Hidroxâmicos/farmacologia , Ácidos Hidroxâmicos/uso terapêutico , Quelantes de Ferro/farmacologia , Quelantes de Ferro/uso terapêutico , Calicreínas/antagonistas & inibidores , Calicreínas/fisiologia , Metaloproteinases da Matriz/fisiologia , Terapia de Alvo Molecular , Proteínas de Neoplasias/antagonistas & inibidores , Oxaprozina/farmacologia , Oxaprozina/uso terapêutico , Fenilalanina/análogos & derivados , Fenilalanina/farmacologia , Fenilalanina/uso terapêutico , Inibidores de Proteases/farmacologia , Proteínas Quinases/fisiologia , Piridinas/farmacologia , Piridinas/uso terapêutico , Tiofenos/farmacologia , Tiofenos/uso terapêutico , Tiossemicarbazonas/farmacologia , Tiossemicarbazonas/uso terapêutico
3.
Clin Exp Nephrol ; 24(Suppl 1): 36-43, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32076889

RESUMO

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.


Assuntos
Benzotiazóis/administração & dosagem , Oxaprozina/administração & dosagem , Uricosúricos/administração & dosagem , Adulto , Anti-Inflamatórios não Esteroides/administração & dosagem , Benzotiazóis/efeitos adversos , Benzotiazóis/farmacocinética , Interações Medicamentosas , Glucuronídeos/urina , Humanos , Japão , Masculino , Oxaprozina/efeitos adversos , Sulfatos/urina
4.
Drug Deliv Transl Res ; 10(1): 83-92, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31407271

RESUMO

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.


Assuntos
Azepinas/química , Oxaprozina/administração & dosagem , Administração Cutânea , Animais , Iontoforese , Masculino , Camundongos , Oxaprozina/química , Oxaprozina/farmacocinética , Permeabilidade , Absorção Cutânea , Análise Espectral Raman , Ultrassonografia
5.
J Inorg Biochem ; 203: 110906, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31707332

RESUMO

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.


Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Complexos de Coordenação/síntese química , Ácido Flufenâmico/análogos & derivados , Manganês/química , Compostos Organometálicos/síntese química , Oxaprozina/análogos & derivados , DNA/química , Ligação Proteica , Soroalbumina Bovina/química , Soroalbumina Bovina/metabolismo
6.
Rom J Morphol Embryol ; 61(2): 493-502, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33544801

RESUMO

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.


Assuntos
Analgésicos/uso terapêutico , Oxaprozina/uso terapêutico , Analgésicos/farmacologia , Animais , Feminino , Humanos , Camundongos , Oxaprozina/farmacologia
7.
J Inorg Biochem ; 195: 101-110, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30939377

RESUMO

Four novel zinc complexes, namely [Zn(oxa)2(MeOH)4] (1), [Zn(oxa)2(H2O)(bipy)]·MeOH·2.5H2O (2·MeOH·2.5H2O), [Zn(oxa)2(bipyam)]·1.25MeOH (3·1.25MeOH) and [Zn(oxa)2(phen)] (4), with the non-steroidal anti-inflammatory drug oxaprozin (Hoxa) and a N,N'-donor heterocyclic ligand, such as 2,2'­bipyridylamine (bipyam), 1,10­phenanthroline (phen) or 2,2'­bipyridine (bipy), were characterized with physicochemical techniques, various spectroscopies and single-crystal X-ray crystallography. In these coordination compounds, the oxaprozin ligands are coordinated to zinc ion in a monodentate or a bidentate chelating binding mode. The antioxidant activity of the complexes was evaluated via their ability to scavenge in vitro 1,1­diphenyl­2­picrylhydrazyl, hydroxyl and 2,2'­azinobis­(3­ethylbenzothiazoline­6­sulfonic acid) radicals. The complexes bind to calf-thymus DNA via intercalation as suggested via a series of studies employing UV-vis spectroscopy, DNA-viscosity measurements and competition with ethidium bromide. The complexes may bind to serum albumins tightly and reversibly in order to get transferred through the bloodstream.


Assuntos
Complexos de Coordenação/química , Sequestradores de Radicais Livres/química , Substâncias Intercalantes/química , Oxaprozina/análogos & derivados , Animais , Bovinos , Complexos de Coordenação/síntese química , Complexos de Coordenação/metabolismo , DNA/química , Sequestradores de Radicais Livres/síntese química , Sequestradores de Radicais Livres/metabolismo , Humanos , Substâncias Intercalantes/síntese química , Substâncias Intercalantes/metabolismo , Ligantes , Estrutura Molecular , Oxaprozina/metabolismo , Soroalbumina Bovina/metabolismo , Albumina Sérica Humana/metabolismo , Zinco/química
8.
Chem Biol Drug Des ; 93(5): 811-817, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30582279

RESUMO

Oxaprozin (4,5-diphenyl-2-oxazolepropionic acid) is a non-steroidal, analgesic and antipyretic propionic acid derivative, whose activity in treating inflammatory disorders is well known. The aim of this study was to investigate the ability of oxaprozin to modulate the activity of matrix metalloproteinase 9 (MMP-9), a zinc-dependent endopeptidase involved in a wide range of physiological and pathological events associated with extracellular matrix (ECM) remodelling. The interaction between oxaprozin and MMP-9 was firstly investigated in silico by molecular docking and analysis with LIGPLOT software. Subsequently, the potential inhibitory activity of oxaprozin against MMP-9 and the possible mechanism of the ligand-enzyme interaction were investigated in vitro. Taking into account the in silico findings, MMP-9 can be considered a potential target of oxaprozin, which seems to be able to chelate the catalytic zinc ion through the nitrogen of the oxazole ring and the carboxylate moiety. Moreover, one of the phenyl rings interact with the S1' inhibitor-binding pocket through hydrophobic interaction. Gelatin zymography and enzymatic inhibition assay confirmed the potential role of oxaprozin as a competitive inhibitor of MMP-9. These observations sound particularly interesting if we consider the pathological role of MMP-9, especially evident in inflammatory conditions and cancer. This work may represent a starting point to improve the understanding of the role of oxaprozin, as well as its structural analogues, in modulating the MMP-9 function.


Assuntos
Metaloproteinase 9 da Matriz/química , Oxaprozina/química , Sítios de Ligação , Humanos , Cinética , Ligantes , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Simulação de Acoplamento Molecular , Oxaprozina/metabolismo , Estrutura Terciária de Proteína , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Software
9.
Arch Pharm (Weinheim) ; 351(2)2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29283449

RESUMO

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.


Assuntos
Analgésicos/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Antipiréticos/uso terapêutico , Edema/tratamento farmacológico , Pró-Fármacos/uso terapêutico , Propionatos/uso terapêutico , Analgésicos/administração & dosagem , Analgésicos/química , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/química , Antipiréticos/administração & dosagem , Antipiréticos/química , Carragenina , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Feminino , Hidrólise , Masculino , Estrutura Molecular , Peso Molecular , Oxaprozina , Pró-Fármacos/administração & dosagem , Pró-Fármacos/química , Propionatos/administração & dosagem , Propionatos/química , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Úlcera/tratamento farmacológico
10.
Int J Pharm ; 531(2): 640-649, 2017 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-28522425

RESUMO

Previous studies highlighted an increase of the randomly-methylated-ß-cyclodextrin (RAMEB) solubilizing power towards oxaprozin when used in combination with L-arginine (ARG) or sepiolite nanoclay (SV). Therefore, the aim of this work was to investigate the possibility of maximising the RAMEB solubilizing efficacy by a joined approach based on the entrapment in SV of the drug-RAMEB-ARG complex. The quaternary nanocomposite was prepared by different techniques and characterized for solid state and dissolution properties, compared to ternary drug combinations with RAMEB-ARG, RAMEB-SV or ARG-SV. The dissolution rank order was drug-RAMEB-ARG-SV>>drug-RAMEB-ARG≈drug-RAMEB-SV>>drug-ARG-SV. The new hybrid nanocomposite enabled an increase from 60 up to 90% of oxaprozin dissolution parameters compared to the ternary systems with RAMEB-ARG and RAMEB-SV. Moreover, the lowest solubilizing efficacy of ternary systems with ARG-SV evidenced the specific synergic effect of both ARG and SV with RAMEB in enhancing oxaprozin dissolution properties. The superior performance of the quaternary nanocomposite was maintained after incorporation in a tablet formulation. In vivo studies on rats proved that the developed fast-dissolving tablet formulation, containing oxaprozin as cofused system with RAMEB, ARG and SV was more effective than the marketed tablet in terms of faster and more intense pain relieving effect in the treatment of adjuvant-induced arthritis.


Assuntos
Portadores de Fármacos/química , Nanopartículas/química , Propionatos/administração & dosagem , beta-Ciclodextrinas/química , Silicatos de Alumínio , Animais , Argila , Oxaprozina , Ratos , Solubilidade , Comprimidos
11.
Int J Pharm ; 515(1-2): 684-691, 2016 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-27825863

RESUMO

The combined strategy of drug-cyclodextrin (CD) complexation and complex loading into nanocarriers (deformable liposomes or nanostructured lipid carriers (NLC)), was exploited to develop effective topical formulations for oxaprozin transdermal administration. Oxaprozin was loaded as ternary complex with randomly-methylated-ßCD and arginine, selected as the best system in improving drug solubility. The colloidal dispersions, characterized for particle size, zeta-potential and entrapment efficiency, were investigated for drug permeation properties in comparison with a plain drug aqueous suspension, a ternary complex aqueous solution and a plain drug liposomal or NLC dispersion. Experiments with artificial membranes showed that the joined use of CD and both liposomes or NLC enabled a marked increase of the drug permeability (16 and 8 times, respectively) and was significantly more effective (P<0.05) than the drug as ternary complex (3.2 times increase), and the corresponding liposomal or NLC dispersion of plain drug (5.6 and 4.3 times increase, respectively). Experiments with excised human skin confirmed the significantly (P<0.05) better performance of deformable liposomes than NLC in promoting drug permeation; moreover, they evidenced a more marked permeability increase compared to the plain drug (24 and 12 fold, respectively), attributed to a possible enhancer effect of the nanocarriers components and/or of the randomly-methylated-ßCD.


Assuntos
Ciclodextrinas/química , Portadores de Fármacos/química , Lipídeos/química , Lipossomos/química , Nanopartículas/química , Propionatos/química , Administração Cutânea , Química Farmacêutica/métodos , Ciclodextrinas/administração & dosagem , Humanos , Nanoestruturas , Oxaprozina , Tamanho da Partícula , Permeabilidade/efeitos dos fármacos , Propionatos/administração & dosagem , Pele/metabolismo , Absorção Cutânea/efeitos dos fármacos , Solubilidade , beta-Ciclodextrinas/administração & dosagem , beta-Ciclodextrinas/química
12.
J Pharm Biomed Anal ; 129: 350-358, 2016 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-27454086

RESUMO

The influence of l-arginine on the complexing and solubilizing power of randomly-methylated-ß-cyclodextrin (RameßCD) towards oxaprozin, a very poorly soluble anti-inflammatory drug, was examined. The interactions between the components were investigated both in solution, by phase-solubility analysis, and in the solid state, by differential scanning calorimetry, FTIR and X-ray powder diffractometry. The morphology of the solid products was examined by Scanning Electron Microscopy. Results of phase-solubility studies indicated that addition of arginine enhanced the RameßCD complexing and solubilizing power of about 3.0 and 4.5 times, respectively, in comparison with the binary complex (both at pH≈6.8). The effect of arginine was not simply additive, but synergistic, being the ternary system solubility higher than the sum of those of the respective drug-CD and drug-arginine binary systems. Solid equimolar ternary systems were prepared by physical mixing, co-grinding, coevaporation and kneading techniques, to explore the effect of the preparation method on the physicochemical properties of the final products. The ternary co-ground product exhibited a dramatic increase in both drug dissolution efficiency and percent dissolved at 60min, whose values (83.6 and 97.1, respectively) were about 3 times higher than the sum of those given by the respective drug-CD and drug-aminoacid binary systems. Therefore, the ternary co-ground system with arginine and RameßCD appears as a very valuable product for the development of new more effective delivery systems of oxaprozin, with improved safety and bioavailability.


Assuntos
Arginina/química , Soluções Farmacêuticas/química , Propionatos/química , beta-Ciclodextrinas/química , Aminoácidos/química , Anti-Inflamatórios/química , Varredura Diferencial de Calorimetria/métodos , Fenômenos Químicos , Oxaprozina , Pós/química , Solubilidade , Difração de Raios X/métodos , Raios X
13.
Int J Pharm ; 509(1-2): 8-15, 2016 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-27188644

RESUMO

A combined approach based on drug complexation with cyclodextrins, and complex entrapment in nanoclays has been investigated, to join in a single delivery system the benefits of these carriers and potentiate their ability to improve the dissolution properties of oxaprozin (OXA), a poorly water-soluble anti-inflammatory drug. Based on previous studies, randomly methylated ß-cyclodextrin (RAMEB) was chosen as the most effective cyclodextrin for OXA complexation. Adsorption equilibrium studies performed on three different clays (sepiolite, attapulgite, bentonite) allowed selection of sepiolite (SV) for its greater adsorption power towards OXA. DSC and XRPD studies indicated drug amorphization in both binary OXA-RAMEB coground and OXA-SV cofused products, due to its complexation or very fine dispersion in the clay structure, respectively. The drug amorphous state was maintained also in the ternary OXA-RAMEB-SV cofused system. Dissolution studies evidenced a clear synergistic effect of RAMEB complexation and clay nanoencapsulation in improving the OXA dissolution properties, with an almost 100% increase in percent dissolved and dissolution efficiency compared to the OXA-RAMEB coground system. Therefore, the proposed combined approach represents an interesting tool for improving the therapeutic effectiveness of poorly soluble drugs, and reducing the CD amount necessary for obtaining the desired drug solubility and dissolution rate increase.


Assuntos
Silicatos de Alumínio/química , Ciclodextrinas/química , Nanopartículas/química , Propionatos/química , Anti-Inflamatórios/química , Bentonita/química , Argila , Compostos de Magnésio/química , Silicatos de Magnésio/química , Oxaprozina , Compostos de Silício/química , Solubilidade , beta-Ciclodextrinas/química
14.
Pharm Res ; 33(2): 301-14, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26350105

RESUMO

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.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/farmacocinética , Portadores de Fármacos/química , Nanopartículas/química , Fosfatidiletanolaminas/química , Polietilenoglicóis/química , Propionatos/administração & dosagem , Propionatos/farmacocinética , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Células CACO-2 , Linhagem Celular , Ácido Fólico/química , Humanos , Camundongos , Oxaprozina , Permeabilidade , Propionatos/efeitos adversos
15.
Sheng Wu Yi Xue Gong Cheng Xue Za Zhi ; 30(3): 646-50, 2013 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-23865335

RESUMO

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.


Assuntos
Cromatografia Líquida de Alta Pressão , Propionatos/sangue , Propionatos/farmacocinética , Anti-Inflamatórios não Esteroides/sangue , Anti-Inflamatórios não Esteroides/farmacocinética , Disponibilidade Biológica , Estudos Cross-Over , Humanos , Oxaprozina , Propionatos/administração & dosagem , Comprimidos com Revestimento Entérico
16.
Chem Pharm Bull (Tokyo) ; 60(7): 865-9, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22790819

RESUMO

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.


Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/síntese química , Propionatos/química , Elementos de Transição/química , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/toxicidade , Linhagem Celular Tumoral , Complexos de Coordenação/química , Complexos de Coordenação/toxicidade , Células HCT116 , Humanos , Magnetismo , Oxaprozina
17.
Eur J Pharm Biopharm ; 78(3): 385-93, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21439375

RESUMO

The effect of the combined use of randomly methylated ß-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.


Assuntos
Anti-Inflamatórios não Esteroides/química , Bile/química , Quitosana/química , Composição de Medicamentos/métodos , Propionatos/química , beta-Ciclodextrinas/química , Bile/metabolismo , Células CACO-2 , Colagogos e Coleréticos/química , Ácido Desidrocólico/química , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Sinergismo Farmacológico , Excipientes/química , Humanos , L-Lactato Desidrogenase/efeitos dos fármacos , Oxaprozina , Permeabilidade , Solubilidade , Ácido Ursodesoxicólico/química
18.
J Oral Maxillofac Surg ; 68(5): 1018-24, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20206429

RESUMO

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.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Dente Serotino/cirurgia , Naproxeno/uso terapêutico , Propionatos/uso terapêutico , Dente Impactado/cirurgia , Adolescente , Estudos Cross-Over , Método Duplo-Cego , Edema/prevenção & controle , Face , Feminino , Humanos , Masculino , Mandíbula/fisiopatologia , Oxaprozina , Dor Pós-Operatória/prevenção & controle , Placebos , Estudos Prospectivos , Amplitude de Movimento Articular/fisiologia , Trismo/prevenção & controle , Adulto Jovem
19.
Artigo em Inglês | MEDLINE | ID: mdl-20167532

RESUMO

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.


Assuntos
Propionatos/química , Vibração , Cristalografia por Raios X , Dimerização , Elétrons , Conformação Molecular , Oxaprozina , Espectroscopia de Infravermelho com Transformada de Fourier , Análise Espectral Raman
20.
J Microencapsul ; 27(6): 479-86, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20113170

RESUMO

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.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Ciclodextrinas/química , Portadores de Fármacos/química , Ácido Láctico/química , Nanopartículas/química , Ácido Poliglicólico/química , Propionatos/administração & dosagem , Nanopartículas/ultraestrutura , Oxaprozina , Tamanho da Partícula , Copolímero de Ácido Poliláctico e Ácido Poliglicólico
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