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1.
Mol Cell Biochem ; 444(1-2): 187-196, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29204817

RESUMO

Hepatocellular carcinoma (HCC) is the fifth leading cause of death and is generally typified by elevated liver enzyme biomarkers, antioxidants, and chronic inflammation of hepatocytes. Although currently available drugs have shown remarkable alleviation of the cancerous condition, but at the same time they present a more severe challenge of toxic effects due to chemotherapy. Therefore, in order to bring more patient-compliant therapy, we aimed to refurbish the use of a COX inhibitor, oxyphenbutazone (OPB), with low dose of methotrexate (MTX) to treat diethyl nitrosamine (DENA)-induced HCC in Wistar rats and in Hep3B cells. Hep3B cells were subjected to assays like in vitro cytotoxicity, DNA synthesis, and caspase activity. The combination index was also evaluated, succeeding the cytotoxicity assay, to analyze the possible synergism. For in vivo study, Wistar strain male rats were given single intraperitoneal dose of DENA (200 mg/kg) and were supplied with sodium phenobarbital (0.1% in tap water) for promoting tumorigenesis throughout the study. MTX (2.5 and 5.0 mg/kg/week, ip) and OPB (70 mg/kg/week, po in two divided doses) were administered to the treatment groups from 3rd week till the termination of study. Several biochemical parameters including biomarkers of liver function, antioxidant enzymes, and histopathological examination of liver cells were tested. Significant synergism was witnessed in the cytotoxicity assay when Hep3B cells received varied dose combination treatment of MTX (0.25, 0.5, or 1.0 µmol/L) and OPB (2.5, 5.0, or 7.5 µmol/L). MTX (0.5 and 1.0 µmol/L) in combination with OPB (5.0 or 7.5 µmol/L) inhibited the cell proliferation as BrdU incorporation was quite low in DNA synthesis analysis, as well as caspase-9/-3 cascade was activated which led to apoptosis of cancer cells. Co-treatment with MTX and OPB exerted potential anticancer activity in rats than either of the drugs alone. Administration of combination therapy harmonized the DENA-induced elevation of serum biochemical parameters, including but not limited to, α-fetoprotein (AFP), alanine- and aspartate-aminotransferase, alkaline phosphatase, vascular endothelial growth factor (VEGF), and antioxidant enzymes like superoxide dismutase (SOD), catalase (CAT), and lipid per oxidation (LPO). All these results were optimally substantiated by histopathological examination. As evident COX-2 catalyzes the synthesis of PGE2, needed in the activation of Wnt/ß-catenin pathway, which in turn is responsible for activating the transcriptional proteins required for higher degree of cell division and thence growth. Therefore, inhibition of COX-2 by our novel combination infers that even low doses of MTX can elucidate noticeable anticancer activity when paired with OPB.


Assuntos
Citotoxinas/farmacologia , Dinoprostona/metabolismo , Oxifenilbutazona/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/metabolismo , Animais , Linhagem Celular Tumoral , Humanos , Masculino , Ratos , Ratos Wistar
2.
Acta Pharmacol Sin ; 39(2): 302-310, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28858300

RESUMO

Aberrant activity of enhancer of zeste homolog 2 (EZH2) is associated with a wide range of human cancers. The interaction of EZH2 with embryonic ectoderm development (EED) is required for EZH2's catalytic activity. Inhibition of the EZH2-EED complex thus represents a novel strategy for interfering with the oncogenic potentials of EZH2 by targeting both its catalytic and non-catalytic functions. To date, there have been no reported high-throughput screening (HTS) assays for inhibitors acting at the EZH2-EED interface. In this study, we developed a fluorescence polarization (FP)-based HTS system for the discovery of EZH2-EED interaction inhibitors. The tracer peptide sequences, positions of fluorescein labeling, and a variety of physicochemical conditions were optimized. The high Z' factors (>0.9) at a variety of DMSO concentrations suggested that this system is robust and suitable for HTS. The minimal sequence requirement for the EZH2-EED interaction was determined by using this system. A pilot screening of an in-house compound library containing 1600 FDA-approved drugs identified four compounds (apomorphine hydrochloride, oxyphenbutazone, nifedipine and ergonovine maleate) as potential EZH2-EED interaction inhibitors.


Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Ensaios de Triagem em Larga Escala/métodos , Complexo Repressor Polycomb 2/antagonistas & inibidores , Complexo Repressor Polycomb 2/metabolismo , Multimerização Proteica/efeitos dos fármacos , Apomorfina/farmacologia , Proteína Potenciadora do Homólogo 2 de Zeste/síntese química , Ergonovina/farmacologia , Polarização de Fluorescência , Humanos , Concentração de Íons de Hidrogênio , Limite de Detecção , Nifedipino/farmacologia , Oxifenilbutazona/farmacologia , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/síntese química , Fragmentos de Peptídeos/metabolismo , Ligação Proteica/efeitos dos fármacos , Temperatura
3.
J AOAC Int ; 100(4): 1110-1122, 2017 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-28145218

RESUMO

This study reports the use of two validated LC with tandem MS (MS/MS) methods to study the residue depletion profile of phenylbutazone (PBZ) and its metabolite oxyphenbutazone (OXPBZ) from equine serum, urine, and muscle, kidney, and liver tissues. One LC-MS/MS method, with an LOQ of 1.0 ng/mL for PBZ and 2.0 ng/mL for OXPBZ, was used for the analysis of the two drugs in the biological fluids (equine urine and serum); the other LC-MS/MS method, with an LOQ of 0.5 ng/g for PBZ and OXPBZ, was used for the analysis of the drugs in the equine tissue samples. PBZ was administered intravenously to two horses dosed with 8.8 mg/kg PBZ once daily for 4 days and sacrificed humanely at a slaughter plant 7 days after the last drug administration. Urine, serum, and kidney, liver, and muscle tissues were collected from the two horses and shipped on ice to the laboratory and stored at -20°C until analysis. The concentrations of PBZ and OXPBZ residues in the biological fluid and tissue samples collected at slaughter were measured with the two validated LC-MS/MS methods using deuterated internal standards. The results demonstrate that the validated methods are fit for studying the depletion kinetics of PBZ residues in equine tissues and biological fluids.


Assuntos
Resíduos de Drogas/análise , Cavalos , Oxifenilbutazona/análise , Fenilbutazona/análise , Drogas Veterinárias/análise , Animais , Cromatografia Líquida , Rim , Fígado , Muscidae , Soro , Espectrometria de Massas em Tandem
4.
Drug Test Anal ; 8(5-6): 535-8, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27443208

RESUMO

Phenylbutazone (PBZ) is permitted to be used for the treatment of musculoskeletal pain and inflammation in race horses but it is not approved for use in horses destined for human consumption. In a recent study initiated in our laboratory to study the disposition of PBZ and its oxyphenbutazone (OXPBZ) metabolite in equine tissues, we compared the effect of an additional enzymatic hydrolysis step with ß-glucuronidase on the results of the analysis for PBZ without enzymatic hydrolysis. Incurred tissue samples obtained from a female horse dosed with PBZ at 8.8 mg/kg for 3 days and sacrificed 6 days following the last administration were used for this study. Liver, kidney, and muscle tissues were collected, extracted, cleaned up on a silica-based solid-phase extraction (SPE) preceded by a weak-anion exchange SPE and analyzed with our in-house validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for PBZ and OXPBZ. Addition of the hydrolysis step resulted in a significant increase in recovery of both PBZ and OXPBZ residues. © 2016 Her Majesty the Queen in Right of Canada. Drug Testing and Analysis © 2016 John Wiley & Sons, Ltd.


Assuntos
Anti-Inflamatórios não Esteroides/análise , Resíduos de Drogas/análise , Cavalos/metabolismo , Oxifenilbutazona/análise , Fenilbutazona/análise , Espectrometria de Massas em Tandem/métodos , Animais , Anti-Inflamatórios não Esteroides/metabolismo , Anti-Inflamatórios não Esteroides/farmacocinética , Cromatografia Líquida/métodos , Resíduos de Drogas/metabolismo , Resíduos de Drogas/farmacocinética , Feminino , Contaminação de Alimentos/análise , Análise de Perigos e Pontos Críticos de Controle/métodos , Humanos , Hidrólise , Rim/química , Rim/metabolismo , Fígado/química , Fígado/metabolismo , Músculos/química , Músculos/metabolismo , Oxifenilbutazona/metabolismo , Oxifenilbutazona/farmacocinética , Fenilbutazona/metabolismo , Fenilbutazona/farmacocinética , Extração em Fase Sólida/métodos , Distribuição Tecidual
5.
Proc Natl Acad Sci U S A ; 109(40): 16004-11, 2012 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-23012453

RESUMO

Existing drugs are slow to eradicate Mycobacterium tuberculosis (Mtb) in patients and have failed to control tuberculosis globally. One reason may be that host conditions impair Mtb's replication, reducing its sensitivity to most antiinfectives. We devised a high-throughput screen for compounds that kill Mtb when its replication has been halted by reactive nitrogen intermediates (RNIs), acid, hypoxia, and a fatty acid carbon source. At concentrations routinely achieved in human blood, oxyphenbutazone (OPB), an inexpensive anti-inflammatory drug, was selectively mycobactericidal to nonreplicating (NR) Mtb. Its cidal activity depended on mild acid and was augmented by RNIs and fatty acid. Acid and RNIs fostered OPB's 4-hydroxylation. The resultant 4-butyl-4-hydroxy-1-(4-hydroxyphenyl)-2-phenylpyrazolidine-3,5-dione (4-OH-OPB) killed both replicating and NR Mtb, including Mtb resistant to standard drugs. 4-OH-OPB depleted flavins and formed covalent adducts with N-acetyl-cysteine and mycothiol. 4-OH-OPB killed Mtb synergistically with oxidants and several antituberculosis drugs. Thus, conditions that block Mtb's replication modify OPB and enhance its cidal action. Modified OPB kills both replicating and NR Mtb and sensitizes both to host-derived and medicinal antimycobacterial agents.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Resistência Microbiana a Medicamentos/efeitos dos fármacos , Ensaios de Triagem em Larga Escala/métodos , Mycobacterium tuberculosis/efeitos dos fármacos , Oxifenilbutazona/farmacologia , Animais , Cromatografia Líquida de Alta Pressão , Resistência Microbiana a Medicamentos/fisiologia , Ácidos Graxos/metabolismo , Feminino , Hidroxilação , Espectroscopia de Ressonância Magnética , Camundongos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/fisiologia , Oxifenilbutazona/metabolismo , Oxifenilbutazona/farmacocinética , Espécies Reativas de Nitrogênio/metabolismo
6.
Artigo em Inglês | MEDLINE | ID: mdl-22503874

RESUMO

Infrared and Raman spectroscopic analyses were carried out on 4-butyl-1-(4-hydroxyphenyl)-2-phenyl-3,5-pyrazolidinedione. The interpretation of the spectra was aided by DFT calculation of the molecule. The vibrational wavenumbers were examined theoretically using the Gaussian03 set of quantum chemistry codes and the normal modes were assigned by potential energy distribution calculations. A computation of the first hyperpolarizability of the compound indicates that the compound may be a good candidate as a NLO material. Optimized geometrical parameters are in agreement with the reported XRD results. The RMS error of the observed Raman bands and IR bands are found to be 35.09 and 39.57 for HF method and 14.31 and 17.17 for DFT method. The predicted infrared intensities and Raman activities are reported.


Assuntos
Pirazóis/química , Conformação Molecular , Oxifenilbutazona , Espectroscopia de Infravermelho com Transformada de Fourier , Análise Espectral Raman
7.
Ocul Immunol Inflamm ; 19(2): 145-50, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21428758

RESUMO

PURPOSE: To compare the evidence base and systemic treatment strategies for sarcoidosis. METHODS: Medline and EMBASE literature search on "sarcoidosis AND treatment", "sarcoidosis AND uveitis AND treatment", and "sarcoidosis AND eye AND treatment". The search was limited to randomized controlled trials (RCTs) and meta-analyses. RESULTS: A total of 19 RCTs for the systemic treatment of extraocular sarcoidosis were identified. The majority were on corticosteroid-oral and inhaled. There were two meta-analyses on corticosteroid, including a Cochrane review. Only two RCTs were indentified for the treatment of intraocular sarcoidosis, one on etanercept, and the other from 1967 on prednisolone or oxyphenbutazone vs. placebo. There were no meta-analyses. Due to the paucity of RCTs other treatment studies were included but these were limited to only a few immunosuppressive agents and on small numbers of patients. CONCLUSION: Limited high-quality evidence exists for the systemic treatment of sarcoidosis, in particular intraocular disease.


Assuntos
Sarcoidose/tratamento farmacológico , Administração por Inalação , Administração Oral , Corticosteroides/administração & dosagem , Esquema de Medicação , Etanercepte , Medicina Baseada em Evidências/métodos , Oftalmopatias/tratamento farmacológico , Glucocorticoides/uso terapêutico , Humanos , Imunoglobulina G/uso terapêutico , Metanálise como Assunto , Oxifenilbutazona/uso terapêutico , Prednisolona/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Receptores do Fator de Necrose Tumoral/uso terapêutico , Sarcoidose Pulmonar/tratamento farmacológico
8.
Anal Chim Acta ; 672(1-2): 85-92, 2010 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-20579495

RESUMO

A confirmatory method for the determination of residues of nine non-steroidal anti-inflammatory drugs and one metabolite in animal muscles has been developed. After enzymatic hydrolysis samples were extracted with acetonitrile and cleaned up using alumina and C(18) SPE cartridges. Liquid chromatography-tandem mass spectrometry was used for the separation and determination of analytes. The method was validated in bovine muscles, according to the Commission Decision 2002/657/EC criteria. Applicability of the method in the analysis of swine, horse and chicken muscles was checked by precision and recovery experiment. The influence of matrix effect on the quantification of non-steroidal anti-inflammatory drugs residues was investigated. The method was used for the confirmation of phenylbutazone and oxyphenbutazone in horse muscle sample.


Assuntos
Anti-Inflamatórios não Esteroides/análise , Resíduos de Drogas/análise , Músculo Esquelético/química , Animais , Bovinos , Galinhas , Cromatografia Líquida , Cavalos , Oxifenilbutazona/análise , Fenilbutazona/análise , Suínos , Espectrometria de Massas em Tandem
9.
Bioorg Med Chem Lett ; 20(8): 2546-8, 2010 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-20299217

RESUMO

Previous cancer chemoprevention studies have demonstrated that the non-steroidal anti-inflammatory drugs (NSAIDs) can be effective in suppressing the development of various human malignancies. Recently we identified the possible anti-tumor promoting potentials of 14 new NSAIDs in the Epstein-Barr virus early antigen activation assay induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). In this study we report the inhibition of 7,12-dimethylbenz (a) anthracene (DMBA) induced two-stage mouse skin carcinogenesis by etodolac (ETD), one of the most potent NSAIDs identified in our in vitro cancer chemopreventive screening of this group of drugs. Topical administration of ETD at a very low dose of 85 nmol showed a significant decrease in both tumor incidence and burden. This effect is also accompanied by a delay in the tumor latency period. Since ETD showed potent chemopreventive activity in both in vitro and in vivo studies, it warrants prompt consideration for trial in humans as a potential cancer chemopreventive agent. We also investigated oxyphenbutazone (OPB) another commonly used NSAID for its cancer chemopreventive effect on peroxynitrite (PN) induced-TPA promoted skin tumors in the mouse. Following tumor initiation with 390 nmol of PN, the skin tumor promotion with 1.7 nmol of TPA was significantly inhibited by oral administration of 0.0025% OPB. The results demonstrate that OPB is a potent cancer chemopreventive agent in the highly sensitive in vivo mouse test model we used.


Assuntos
Anticarcinógenos/farmacologia , Transformação Celular Neoplásica/efeitos dos fármacos , Etodolac/farmacologia , Oxifenilbutazona/farmacologia , Neoplasias Cutâneas/prevenção & controle , 9,10-Dimetil-1,2-benzantraceno/toxicidade , Animais , Carcinógenos/toxicidade , Transformação Celular Neoplásica/induzido quimicamente , Camundongos
10.
J Anal Toxicol ; 33(1): 41-50, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19161668

RESUMO

A sensitive liquid chromatographic-tandem mass spectrometric method was developed and validated for screening, quantification, and confirmation of phenylbutazone and oxyphenbutazone in equine plasma. Analytes were recovered from plasma by liquid-liquid extraction followed by separation in a reversed-phase column and identification by mass spectrometry with selected reaction monitoring in negative electrospray ionization mode. Extraction recovery for both analytes was >80%. Limits of detection, quantification, and confirmation for both analytes were 0.01 microg/mL (S/N>or= 3), 0.05 microg/mL, and 0.05 microg/mL, respectively. The assay with d9-labeled phenylbutazone as internal standard (IS) was linear over a range of 0.05-20 microg/mL (r2>0.995). Intra- and interday precision in terms of coefficient of variation was less than 15%. Intra- and interday accuracy (bias%) was within 80-120%. Hemolysis of red blood cells decreased analyte signal intensity but did not affect quantification results because an isotope-labeled IS was used. Analytes were stable in plasma for 24 h at room temperature, 9 days at 4 degrees C, and 45 days at -20 degrees C and -70 degrees C. The method was successfully used in screening, quantification, and confirmation of phenylbutazone in post-competition plasma samples obtained from racehorses. The method is simple, rapid, and reliably reproducible.


Assuntos
Anti-Inflamatórios não Esteroides/sangue , Doping nos Esportes , Oxifenilbutazona/sangue , Fenilbutazona/sangue , Espectrometria de Massas por Ionização por Electrospray/métodos , Detecção do Abuso de Substâncias/métodos , Espectrometria de Massas em Tandem/métodos , Animais , Cromatografia Líquida de Alta Pressão , Hemólise , Cavalos , Reprodutibilidade dos Testes
11.
J Pharm Sci ; 96(11): 3117-24, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17979211

RESUMO

In the process of drug development, preclinical testing using experimental animals is an important aspect, for verification of the efficacy and safety of a drug. Serum albumin is a major binding protein for endogenous and exogenous ligands and regulates their distribution in various tissues. In this study, the structural and drug-binding properties of albumins on a biomembrane surface were investigated using reverse micelles as a model membrane. In reverse micelles, the secondary structures of all albumins were found, to varying degrees, to be intermediate between the native and denatured states. The tertiary structures of human and bovine albumin were similar to those of the native and intermediate states, respectively, whereas those of the dog, rabbit, and rat were in a denatured state. Thus, bovine albumin is an appropriate model for studying structural changes in human albumin in a membrane-water phase. Binding studies also showed the presence of species difference in the change in binding capacity of albumins during their interaction with reverse micelles. Among the albumins, rat albumin appears to be a good model for the protein-mediated drug uptake of human albumin in a biomembrane environment. These findings are significant in terms of the appropriate extrapolation of pharmacokinetics and pharmacodynamics data in various animals to humans.


Assuntos
Micelas , Albumina Sérica/química , Albumina Sérica/metabolismo , Animais , Dicroísmo Circular , Compostos de Dansil/química , Compostos de Dansil/metabolismo , Cães , Humanos , Ligantes , Membranas/química , Membranas/metabolismo , Oxifenilbutazona/química , Oxifenilbutazona/metabolismo , Ligação Proteica , Coelhos , Ratos , Sarcosina/análogos & derivados , Sarcosina/química , Sarcosina/metabolismo , Especificidade da Espécie , Espectrometria de Fluorescência
12.
Eur Cytokine Netw ; 16(2): 144-51, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15941686

RESUMO

4-Hydroxy-oxyphenbutazone (4OH-OPB), is currently in phase II trials for its immunosuppressive effect in patients with rheumatoid arthritis. 4OH-OPB and other compounds related to phenylbutazone were tested for their effect on in vitro cytokine production by monocytes and lymphocytes present in peripheral mononuclear cells (PBMC) or whole blood (WB) cultures, and compared against phenylbutazone and oxyphenbutazone, two known anti-inflammatory drugs. In PBMC cultures, 4OH-OPB was by far the most potent inhibitor, and both monokines and Th1 and Th2 lymphokines were efficiently inhibited at low concentrations. In WB cultures, 4OH-OPB was less effective than in PBMC cultures, but was still the best inhibitor of lymphokine production and, furthermore, was the only inhibitor of monokine production. The increase in 4OH-OPB concentration needed to induce the same inhibition of cytokine production in WB as in PBMC culture could be mimicked by the addition of erythrocytes to the PBMC cultures. Experiments with radioactively-labeled 4OH-OPB suggest that 4OH-OPB is taken up very rapidly into erythrocytes and is secreted by the erythrocytes with much slower kinetics via a multidrug-resistance-associated protein. The secreted compound is most likely structurally different from 4OH-OPB, as in PBMC and WB cultures, the inhibition of cytokine production seems to be caused by a different mechanism. In PBMC cultures, the inhibition of cytokine production is accompanied by a loss of cell viability, while this is not the case when 4OH-OPB inhibits cytokine production in WB. Our data suggest that 4OH-OPB may be useful as an immunosuppressive drug for patients with inflammatory diseases.


Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Interleucina-6/antagonistas & inibidores , Oxifenilbutazona/análogos & derivados , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/biossíntese , Humanos , Técnicas In Vitro , Interleucina-6/biossíntese , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Oxifenilbutazona/farmacologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo
13.
Biochemistry ; 43(46): 14577-83, 2004 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-15544328

RESUMO

Phospholipase A(2) (PLA(2); EC 3.1.1.4) is a key enzyme involved in the production of proinflammatory mediators known as eicosanoids. The binding of the substrate to PLA(2) occurs through a well-formed hydrophobic channel. To determine the viability of PLA(2) as a target molecule for the structure-based drug design against inflammation, arthritis, and rheumatism, the crystal structure of the complex of PLA(2) with a known anti-inflammatory compound oxyphenbutazone (OPB), which has been determined at 1.6 A resolution. The structure has been refined to an R factor of 0.209. The structure contains 1 molecule each of PLA(2) and OPB with 2 sulfate ions and 111 water molecules. The binding studies using surface plasmon resonance show that OPB binds to PLA(2) with a dissociation constant of 6.4 x 10(-8) M. The structure determination has revealed the presence of an OPB molecule at the binding site of PLA(2). It fits well in the binding region, thus displaying a high level of complementarity. The structure also indicates that OPB works as a competitive inhibitor. A large number of hydrophobic interactions between the enzyme and the OPB molecule have been observed. The hydrophobic interactions involving residues Tyr(52) and Lys(69) with OPB are particularly noteworthy. Other residues of the hydrophobic channel such as Leu(3), Phe(5), Met(8), Ile(9), and Ala(18) are also interacting extensively with the inhibitor. The crystal structure clearly reveals that the binding of OPB to PLA(2) is specific in nature and possibly suggests that the basis of its anti-inflammatory effects may be due to its binding to PLA(2) as well.


Assuntos
Anti-Inflamatórios não Esteroides/química , Sistemas de Liberação de Medicamentos , Inibidores Enzimáticos/química , Oxifenilbutazona/química , Fosfolipases A/química , Animais , Anti-Inflamatórios não Esteroides/metabolismo , Sítios de Ligação , Cristalização , Cristalografia por Raios X , Inibidores Enzimáticos/metabolismo , Humanos , Modelos Moleculares , Oxifenilbutazona/metabolismo , Fosfolipases A/antagonistas & inibidores , Fosfolipases A/metabolismo , Fosfolipases A2 , Ligação Proteica , Venenos de Víboras/antagonistas & inibidores , Venenos de Víboras/enzimologia , Venenos de Víboras/metabolismo
14.
Res Commun Mol Pathol Pharmacol ; 115-116: 39-48, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-17564304

RESUMO

The antirheumatic effect of pirfenidone was compared with a positive control drug, oxyphenbutazone which is used in patients suffering from rheumatoid arthritis, in a double blind clinical trial in humans. The data collected in this pilot project revealed that pirfenidone was more effective (p < 0.025) than oxyphenbutazone in providing relief from arthritic pain. In addition, a greater number (p < 0.025) of patients reported favorable response to oral pirfenidone than oral oxyphenbutazone. However, there were no significant differences in the number of patients who dropped out from the trial and the number of patients who tolerated the drugs for 21 days of the trial between the pirfenidone and oxyphenbutazone groups. It was concluded from this pilot study that pirfenidone potentially offers a novel therapeutic modality for the management of rheumatoid arthritis with little or no adverse effects unlike steroidal and non-steroidal anti-inflammatory drugs which are frequently used for this chronic debilitating disease.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Piridonas/uso terapêutico , Adulto , Antirreumáticos/administração & dosagem , Antirreumáticos/efeitos adversos , Artrite Reumatoide/fisiopatologia , Distribuição de Qui-Quadrado , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oxifenilbutazona/administração & dosagem , Oxifenilbutazona/uso terapêutico , Pacientes Desistentes do Tratamento , Projetos Piloto , Piridonas/administração & dosagem , Piridonas/efeitos adversos , Resultado do Tratamento
15.
J Pharm Biomed Anal ; 31(2): 401-6, 2003 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-12609680

RESUMO

Adulterations with synthetic drugs are common problems with herbal medicine and this can potentially cause serious adverse effects. It is therefore important to determine the presence of synthetic drugs in herbal medicine to ensure patients' safety. The objective of this study was to develop sensitive and specific methods to analyse phenylbutazone, caffeine and oxyphenbutazone present in a traditional Indonesian herbal product. Liquid chromatography-mass spectrometry-mass spectrometry (LC-MS-MS) methods in the selected reaction-monitoring (SRM) mode were developed. It was found that the sample contained 0.53% w/w (n=3, RSD=7.56%) phenylbutazone and 0.04% w/w (n=3, RSD=8.39%) caffeine. This corresponded to 43.17 mg phenylbutazone and 3.23 mg caffeine in each sachet of powder. The methods were validated for linearity, precision, accuracy, LOD and LOQ. LOD and LOQ were found to be 3.69 and 12.29 ng/ml, respectively for phenylbutazone. For caffeine, the LOD and LOQ were 0.84 and 2.80 ng/ml, respectively. Oxyphenbutazone in the sample was found to be present at a level below the quantification level of 10.2 ng/ml. With better methods developed for analysis of adulterants in herbal medicine, the quality and safety of these medicines can be better controlled and regulated to ensure patients' safety.


Assuntos
Cromatografia Líquida/métodos , Contaminação de Medicamentos , Medicina Herbária , Espectrometria de Massas/métodos , Cafeína/análise , Oxifenilbutazona/análise , Fenilbutazona/análise , Sensibilidade e Especificidade
16.
J Pharm Biomed Anal ; 28(5): 973-82, 2002 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-12039640

RESUMO

The interactions between a nonsteroidal anti-inflammatory drugs, oxyphenbutazone (OPB), with two cyclodextrins, beta-cyclodextrin (beta-CD) and gamma-cyclodextrin (gamma-CD), have been studied in an aqueous medium and in the solid state. Differential scanning calorimetry, hot stage microscopy, thermogravimetric analysis and X-ray diffraction (XRD) powder have been the techniques used to characterize the interactions in the solid state. Although OPB forms inclusion compounds with beta- and gamma-CD in the aqueous medium, only the OPB/gamma-CD inclusion compound was obtained in the solid state by the kneading method. The XRD powder used at different temperatures has proven be a useful tool in characterizing the behaviour of these binary systems.


Assuntos
Anti-Inflamatórios não Esteroides/química , Ciclodextrinas/química , Oxifenilbutazona/química , Varredura Diferencial de Calorimetria , Solubilidade , Soluções , Termogravimetria , Difração de Raios X
17.
Am J Vet Res ; 62(5): 673-5, 2001 May.
Artigo em Inglês | MEDLINE | ID: mdl-11341383

RESUMO

OBJECTIVE: To describe the pharmacokinetics of phenylbutazone and oxyphenbutazone after IV administration in miniature donkeys. ANIMALS: 6 clinically normal miniature donkeys. PROCEDURE: Blood samples were collected before and 5, 10, 20, 30, 45, 60, 90, 120, 180, 240, 300, 360, and 480 minutes after IV administration of phenylbutazone (4.4 mg/kg of body weight). Serum was analyzed in triplicate by use of high-performance liquid chromatography for determination of phenylbutazone and oxyphenbutazone concentrations. The serum concentration-time curve for each donkey was analyzed separately to estimate model-independent pharmacokinetic variables. RESULTS: Serum concentrations decreased rapidly after IV administration of phenylbutazone, and they reached undetectable concentrations within 4 hours. Values for mean residence time ranged from 0.5 to 3.0 hours (median, 1.1 hour), whereas total body clearance ranged from 4.2 to 7.5 ml/kg/min (mean, 5.8 ml/kg/min). Oxyphenbutazone appeared rapidly in the serum; time to peak concentration ranged from 13 to 41 minutes (mean, 26.4 minutes), and peak concentration in serum ranged from 2.8 to 4.0 mg/ml (mean, 3.5 microg/ml). CONCLUSION AND CLINICAL RELEVANCE: Clearance of phenylbutazone in miniature donkeys after injection of a single dose (4.4 mg/kg, IV) is rapid. Compared with horses, miniature donkeys may require more frequent administration of phenylbutazone to achieve therapeutic efficacy.


Assuntos
Anti-Inflamatórios não Esteroides/farmacocinética , Equidae/metabolismo , Oxifenilbutazona/farmacocinética , Fenilbutazona/farmacocinética , Animais , Anti-Inflamatórios não Esteroides/sangue , Área Sob a Curva , Equidae/fisiologia , Masculino , Oxifenilbutazona/sangue , Fenilbutazona/sangue
18.
J Chromatogr B Biomed Sci Appl ; 738(1): 17-25, 2000 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-10778922

RESUMO

Ethyl acetate extracts of equine serum, containing 0-5 microg/ml of hydrocortisone (HYD), dexamethasone (DEX), oxyphenbutazone (OPB), indomethacin (IND), phenylbutazone (PB) and probenecid as internal standard, were evaporated with nitrogen, resuspended in methanol and analyzed by HPLC, using a C-18 column equilibrated with 51:49 acetonitrile-water, 0.1% trifluoroacetic acid, at 1 ml/min. The eluate was monitored at 254 nm. The selectivity (inter-assay C.V.<4%), sensitivity (limits of quantitation of 0.25 microg/ml for HYD, DEX and IND, 0.5 microg/ml for PB and 1 microg/ml for OPB, despite the occurrence of significant degradation of OPB and PB during the analysis) and precision (intra-assay and inter-assay C.V.'s of about 3-6 and 9-15%, respectively) of the method appeared appropriate for anti-doping control of racehorses.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Dexametasona/sangue , Cavalos/sangue , Hidrocortisona/sangue , Indometacina/sangue , Fenilbutazona/sangue , Animais , Anti-Inflamatórios/sangue , Anti-Inflamatórios não Esteroides/sangue , Concentração de Íons de Hidrogênio , Oxifenilbutazona/sangue , Sensibilidade e Especificidade
19.
Equine Vet J ; 31(5): 411-6, 1999 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-10505957

RESUMO

Suxibuzone (SBZ), a nonsteroidal anti-inflammatory drug, was administered to 6 horses at a dose rate of 7.5 mg/kg bwt by intravenous (i.v.) route. Plasma and synovial fluid concentrations of suxibuzone and its main active metabolites, phenylbutazone (PBZ) and oxyphenbutazone (OPBZ), were measured simultaneously by a sensitive and specific high-performance liquid chromatographic method. The pharmacokinetic parameters were determined by noncompartmental analysis. Plasma SBZ concentrations rapidly decreased and were not detectable beyond 20 min after treatment. The parent drug was not detected in any synovial fluid samples. Average maximum plasma concentrations of PBZ (16.43 microg/ml) and OPBZ (2.37 microg/ml) were attained at 0.76 and 7.17 h, respectively. The mean residence time (MRT) of PBZ was 6.96 h in plasma. Oxyphenbutazone plasma concentrations were below those reached by phenylbutazone during the first 12 h after suxibuzone administration, even though its values were detectable for at least 24 h (MRT = 10.65 h). Plasma concentrations of PBZ and OPBZ exceeding EC50 and IC50 of TXB2 and PGE2 were reached by at least 12 h. Synovial fluid concentrations of PBZ and OPBZ were 2.87+/-0.37 microg/ml and 0.97+/-0.08 microg/ml at 9 h after suxibuzone administration and exceeded IC50 of PGE2 for at least this time. In the present study, suxibuzone was well tolerated following i.v. injection.


Assuntos
Anti-Inflamatórios não Esteroides/farmacocinética , Cavalos/metabolismo , Fenilbutazona/análogos & derivados , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/efeitos adversos , Área Sob a Curva , Contagem de Células Sanguíneas/veterinária , Cromatografia Líquida de Alta Pressão/veterinária , Hematócrito/veterinária , Cavalos/fisiologia , Indometacina/sangue , Indometacina/farmacocinética , Injeções Intravenosas/veterinária , Masculino , Oxifenilbutazona/sangue , Oxifenilbutazona/farmacocinética , Fenilbutazona/administração & dosagem , Fenilbutazona/efeitos adversos , Fenilbutazona/sangue , Fenilbutazona/farmacocinética , Líquido Sinovial/metabolismo
20.
Drug Dev Ind Pharm ; 25(9): 1051-6, 1999 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-10518246

RESUMO

Dissolution-dialysis studies of commercial tablets of oxyphenbutazone were carried out to establish the applicability of this technique for the in vitro evaluation of oxyphenbutazone dosage form. While disintegration time and dissolution rate studies did not give a true indication of bioavailability, an excellent correlation was obtained between the dialysis rate constant K and the pharmacokinetic parameters AUC and Cmax.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/farmacocinética , Oxifenilbutazona/administração & dosagem , Oxifenilbutazona/farmacocinética , Disponibilidade Biológica , Estudos Cross-Over , Diálise/métodos , Humanos , Técnicas In Vitro , Solubilidade , Comprimidos , Fatores de Tempo
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