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1.
Arq. bras. med. vet. zootec. (Online) ; 72(3): 915-920, May-June, 2020. tab, graf
Artigo em Inglês | LILACS, VETINDEX | ID: biblio-1129595

RESUMO

Nabumetone is used to reduce the pain and inflammation in rheumatoid arthritis. In the current study, immunomodulatory effect of Nabumetone is investigated in mice. The control group was administered normal saline orally as placebo. Nabumetone was administered orally via gavage in two treatment groups at 14mg/kg.b.w. doses and 28mg/kgb.w., respectively. Haemagglutination (HA) assay, Jerne hemolytic plaque and mice lethality assays were applied. In HA assay, the titer was significantly decreased in Nabumetone treatment groups (P< 0.001). In Jerne hemolytic plaque formation assay, there was a significant reduction (P< 0.001) in number of plaques in Nabumetone treated groups when compared with control. In mice lethality assay, there was a significant difference in mortality ratio of mice in control and Nabumetone treated groups (P< 0.001). Therefore, it is concluded that Nabumetone suppresses the humoral immune response in mice.(AU)


A nabumetona é usada na redução da dor e inflamação da artrite reumática. No presente estudo, o efeito imunomodulador é investigado em camundongos. O grupo de controle recebeu solução salina via oral como placebo. Nabumetona foi administrada oralmente via gavagem em dois grupos de tratamentos com doses de 14mg/kg.b.w. e 28mg/kgb.w., respectivamente. Foram realizados ensaios de hemaglutinação (HA), placa hemolítica de Jerne e letalidade dos camundongos. No ensaio HA, o grau foi significativamente menor nos grupos de tratamento com nabumetoma (P< 0.001). No ensaio de formação de placa hemolítica de Jerne houve redução significativa (P< 0.001) no número de placas em grupos tratados com nabumetoma comparado ao controle. No ensaio de letalidade dos camundongos houve diferença significativa no grau de mortalidade de camundongos no grupo de controle e grupos tratados com nabumetoma (P< 0.001). Portanto, conclui-se que a Nabumetoma suprime a resposta imune humoral em camundongos.(AU)


Assuntos
Animais , Camundongos , Imunidade Humoral/efeitos dos fármacos , Nabumetona/administração & dosagem , Fatores Imunológicos/análise , Artrite Reumatoide/veterinária , Solução Salina , Hemaglutinação
2.
Xenobiotica ; 50(7): 783-792, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31855101

RESUMO

The pathway for the transformation of the prodrug nabumetone, 4-(6-methoxynaphthalen-2-yl)butan-2-one, to the active metabolite 6-methoxy-2-naphthylacetic acid (6-MNA), a potent cyclooxygenase-2 inhibitor, has not yet been clarified in humans.To confirm the activation pathway, authentic standards of the nabumetone intermediates, 2-(6-methoxynaphthalen-2-yl)ethyl acetate (6-MNEA), 2-(6-methoxynaphthalen-2-yl)ethan-1-ol (6-MNE-ol) and 2-(6-methoxynaphthalen-2-yl)acetaldehyde (6-MN-CHO) were synthesized. High performance liquid-chromatography and gas chromatography-mass spectrometry on nabumetone oxidation revealed the generation of three metabolites.The formation of 6-MNA after a 60-min incubation of nabumetone was detected and 6-MNE-ol, an alcohol-related intermediate, was also generated by in cryopreserved hepatocytes. However, 6-MNA was below detection limit, but 4-(6-methoxynaphthalen-2-yl)butan-2-ol (MNBO) and 4-(6-hydroxynaphthalen-2-yl)butan-2-one (M3) peak were found in both the microsomes and S9 extracts with any cofactors.Nabumetone has recently been proposed as a typical substrate of flavin-containing monooxygenase isoform 5 (FMO5) and was shown to be efficiently oxidized in vitro to 6-MNEA. 6-MNA was detected in the extract obtained from a combined incubation of recombinant FMO5 and S9 fractions.The specificity of FMO5 towards catalyzing this Baeyer-Villiger oxidation (BVO) was demonstrated by the inhibition of the BVO substrate, 4-methoxyphenylacetone. Further in vitro inhibition studies demonstrated that multiple non-cytochrome P450 enzymes are involved in the formation of 6-MNA.


Assuntos
Anti-Inflamatórios não Esteroides/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Nabumetona/metabolismo , Ácidos Naftalenoacéticos/metabolismo , Humanos , Redes e Vias Metabólicas , Microssomos Hepáticos/metabolismo , Pró-Fármacos
3.
Mater Sci Eng C Mater Biol Appl ; 106: 110184, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31753394

RESUMO

There is an increasing attention on solid lipid nanoparticles (SLNs) due to their high biocompatibility and ability to enhance bioavailability for poorly water-soluble drugs. Preparation of SLNs that are capable of high drug loading and sustained drug release through hot melt sonication method is reported here. SLNs of palmitic acid and stearic acid loaded with poorly water-soluble drugs, viz. fenofibrate (FF) and nabumetone (NBT) having spherical morphology and average particle size below 200 nm were prepared. Poloxamer 407 and pluronic® F-127 were used as surfactants. Particle size and spherical morphology was confirmed by dynamic light scattering, field emission scanning electron microscopy, transmission electron microscopy, and atomic force microscopy. The chemical, crystal, and thermal properties of SLNs were studied by Fourier transform infrared spectroscopy, X-ray diffraction, and differential scanning calorimetry, respectively. The palmitic acid-poloxamer 407 SLNs could entrap upto 13.8% FF with 80% entrapment efficiency while the stearic acid-pluronic® F-127 SLNs entrapped 13.6% NBT with 89% entrapment efficiency. The drug loaded in SLNs showed controlled release up to 3 days as confirmed by in-vitro drug release profile. Moreover, the drug loaded SLNs did not show any toxicity on macrophage cell line proving the use of these formulations as control drug delivery vehicles for the studied drugs.


Assuntos
Fenofibrato/química , Lipídeos/química , Nabumetona/química , Nanopartículas/química , Varredura Diferencial de Calorimetria , Preparações de Ação Retardada/química , Portadores de Fármacos/química , Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Ácidos Esteáricos/química
4.
Xenobiotica ; 49(11): 1296-1302, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30794062

RESUMO

1. The underlying microbial metabolic activity toward xenobiotics is among the least explored factors contributing to the inter-individual variability in drug response. 2. Here, we analyzed the effect of microbiota on a non-steroidal anti-inflammatory drug nabumetone. 3. First, we cultivated the drug with the selected gut commensal and probiotic bacteria under both aerobic and anaerobic conditions and analyzed its metabolites by high-performance liquid chromatography (HPLC) with UV detection. To analyze the effect of microbiota on nabumetone pharmacokinetics in vivo, we administered a single oral dose of nabumetone to rodents with intentionally altered gut microbiome - either rats treated for three days with the antibiotic imipenem or to germ-free mice. Plasma levels of its main active metabolite 6 methoxy-2-naphthylacetic acid (6-MNA) were analyzed at pre-specified time intervals using HPLC with UV/fluorescence detection. 4. We found that nabumetone is metabolized by bacteria to its non-active metabolites and that this effect is stronger under anaerobic conditions. Although in vivo, none of the pharmacokinetic parameters of 6-MNA was significantly altered, there was a clear trend towards an increase of the AUC, Cmax and t1/2 in rats with reduced microbiota and germ-free mice.


Assuntos
Microbioma Gastrointestinal/efeitos dos fármacos , Nabumetona/farmacocinética , Anaerobiose , Animais , Antibacterianos/farmacologia , Anti-Inflamatórios não Esteroides/metabolismo , Anti-Inflamatórios não Esteroides/farmacocinética , Disponibilidade Biológica , Microbioma Gastrointestinal/fisiologia , Imipenem/farmacologia , Masculino , Camundongos Endogâmicos BALB C , Nabumetona/metabolismo , Ácidos Naftalenoacéticos/metabolismo , Ácidos Naftalenoacéticos/farmacocinética , Ratos Wistar , Organismos Livres de Patógenos Específicos
5.
Chem Pharm Bull (Tokyo) ; 67(1): 75-78, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30606953

RESUMO

The absolute configuration of (+)-4-(6-methoxy-2-naphthyl)butan-2-ol ((+)-MNBO), a nabumetone metabolite, was determined using 1-fluoroindan-1-carboxylic acid (FICA). Both enantiomers of the FICA methyl esters were derivatized to diastereomeric esters of (+)-MNBO by an ester exchange reaction. The results of 1H- and 19F-NMR spectroscopy of the diastereomeric FICA esters of (+)-MNBO confirmed the absolute configuration of (+)-MNBO was (S).


Assuntos
Butanos/química , Ácidos Carboxílicos/química , Nabumetona/metabolismo , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Nabumetona/química , Estereoisomerismo
6.
Mol Pharm ; 15(7): 2714-2720, 2018 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-29924614

RESUMO

Amorphous solid dispersions containing a polymeric component often impart improved stability against crystallization for a small molecule relative to the pure amorphous form. However, the relationship between side chain functionalities on a polymer and the ability of a polymer to stabilize against crystallization is not well understood. To shed light on this relationship, a series of polymers were functionalized from a parent batch of poly(chloromethylstyrene- co-styrene) to investigate the effect of functionality on the stability in amorphous solid dispersions without altering the physical parameters of polymers, such as the average molecular weight or backbone chain chemistry. The kinetics of the crystallization of the nonsteroidal anti-inflammatory drug nabumetone from amorphous solid dispersions containing each functionalized polymer were interpreted on the basis of two interactions: hydrogen bonding between the drug and the polymer and the solubility of the polymer in the amorphous drug. It was found that hydrogen bonding between functionalized polymers and nabumetone can impart stability against crystallization, but only if the polymer shows significant solubility in amorphous nabumetone. Methylation of a protic functionality can improve the ability of a polymer to inhibit nabumetone crystallization by increasing the solubility in the drug, even when the resulting polymer lacks hydrogen bonding functionalities to interact with the pharmaceutical. Furthermore, factors, such as the glass transition temperature of pure polymers, were uncorrelated with isothermal nucleation rates. These findings inform a framework relating polymer functionality and stability deconvoluted from the polymer chain length or backbone chemistry with the potential to aid in the design of polymers to inhibit the crystallization of hydrophobic drugs from amorphous solid dispersions.


Assuntos
Anti-Inflamatórios não Esteroides/química , Portadores de Fármacos/química , Nabumetona/química , Polímeros/química , Química Farmacêutica , Cristalização , Estabilidade de Medicamentos , Interações Hidrofóbicas e Hidrofílicas , Solubilidade
7.
Recent Pat Drug Deliv Formul ; 12(2): 130-149, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29485013

RESUMO

BACKGROUND: Nabumetone is biopharmaceutics classification system (BCS) class II drug, widely used in the treatment of osteoarthritis and rheumatoid arthritis. The most frequently reported adverse reactions for the drug involve disturbance in gastrointestinal tract, diarrhea, dyspepsia and abdominal pain. Microemulgel has advantages of microemulsion for improving solubility for hydrophobic drug. Patent literature had shown that the work for drug has been carried on spray chilling, enteric coated tablet, and topical formulation which gave an idea for present research work for the development of transdermal delivery. OBJECTIVE: The objective of the present research work was to optimize transdermal microemulgel delivery for Nabumetone for the treatment of arthritis. METHODS: Oil, surfactant and co-surfactant were selected based on solubility study of the drug. Gelling agents used were Carbopol 934 and HPMC K100M. Optimization was carried out using 32 factorial design. Characterization and evaluation were carried out for microemulsion and microemulsion based gel. RESULTS: Field emission-scanning electron microscopy (FE-SEM) study of the microemulsion revealed globules of 50-200 nm size. Zeta potential -9.50 mV indicated good stability of microemulsion. Globule size measured by dynamic light scattering (zetasizer) was 160nm. Design expert gave optimized batch as F7 which contain 0.2% w/w drug, 4.3% w/w liquid paraffin, 0.71% w/w tween 80, 0.35% w/w propylene glycol, 0.124% w/w Carbopol 934, 0.187% w/w HPMC K100M and 11.68% w/w water. In-vitro diffusion study for F7 batch showed 99.16±2.10 % drug release through egg membrane and 99.15±2.73% drug release in ex-vivo study. CONCLUSION: Nabumetone microemulgel exhibiting good in-vitro and ex-vivo controlled drug release was optimized.


Assuntos
Artrite/tratamento farmacológico , Butanonas/administração & dosagem , Butanonas/uso terapêutico , Administração Cutânea , Animais , Butanonas/química , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Emulsões , Géis/administração & dosagem , Géis/química , Nabumetona , Óvulo/metabolismo , Tamanho da Partícula , Ratos , Absorção Cutânea , Propriedades de Superfície , Tensoativos/administração & dosagem , Tensoativos/química
8.
ACS Chem Biol ; 12(9): 2379-2387, 2017 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-28783300

RESUMO

Flavin-containing monooxygenases (FMOs) are emerging as effective players in oxidative drug metabolism. Until recently, the functions of the five human FMO isoforms were mostly linked to their capability of oxygenating molecules containing soft N- and S-nucleophiles. However, the human FMO isoform 5 was recently shown to feature an atypical activity as Baeyer-Villiger monooxygenase. With the aim of evaluating such an alternative entry point in the metabolism of active pharmaceutical ingredients, we selected and tested drug molecules bearing a carbonyl group on an aliphatic chain. Nabumetone and pentoxifylline, two widely used pharmaceuticals, were thereby demonstrated to be efficiently oxidized in vitro by FMO5 to the corresponding acetate esters with high selectivity. The proposed pathways explain the formation of a predominant plasma metabolite of pentoxifylline as well as the crucial transformation of the pro-drug nabumetone into the pharmacologically active compound. Using the recombinant enzyme, the ester derivatives of both drugs were obtained in milligram amounts, purified, and fully characterized. This protocol can potentially be extended to other FMO5 candidate substrates as it represents an effective and robust bench-ready platform applicable to API screening and metabolite synthesis.


Assuntos
Butanonas/metabolismo , Inibidores de Ciclo-Oxigenase 2/metabolismo , Oxigenases/metabolismo , Pentoxifilina/metabolismo , Inibidores de Fosfodiesterase/metabolismo , Humanos , Peróxido de Hidrogênio/metabolismo , Nabumetona , Oxirredução , Preparações Farmacêuticas/metabolismo , Especificidade por Substrato
9.
Phytother Res ; 31(1): 75-80, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27714886

RESUMO

The aim of the study was to investigate the herb-drug interaction of Andrographis paniculata Nees (Acanthaceae) and Andrographolide (AN) with nabumetone (NAB) in wistar rats. Pharmacokinetic and pharmacodynamic interactions were studied after co-administration of APE and AN with NAB in Wistar rats. In pharmacokinetic studies, significant decrease in Cmax, AUC0-t and AUC0-∞ of 6-MNA after co-administration with pure AN and APE has been observed. Tmax of 6-MNA has been increased to 2 h from 1.5 h in AN + NAB treated group. Changes in mean residential time, clearance and volume of distribution of 6-MNA in APE + NAB treated group and AN + NAB treated group indicated interference of other components of APE other than AN. In pharmacodynamic study, significant decrease in antiarthritic activity of NAB on concomitant administration with APE and AN has been observed. The study concludes that NAB exhibits pharmacokinetic and pharmacodynamic interactions with APE and AN in rats thus alarms the concomitant use of herbal preparations containing APE and AN with NAB. Further study is needed to understand the mechanism and predict the herb-drug interaction in humans. Copyright © 2016 John Wiley & Sons, Ltd.


Assuntos
Andrographis/química , Butanonas/química , Diterpenos/química , Diterpenos/farmacocinética , Extratos Vegetais/química , Animais , Butanonas/farmacologia , Feminino , Interações Ervas-Drogas , Nabumetona , Extratos Vegetais/farmacologia , Ratos , Ratos Wistar
10.
Int J Pharm ; 514(2): 428-444, 2016 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-27693736

RESUMO

The ability of a range of hydrophilic nonionic cellulose ethers (CEs) (namely methylhydroxethylcellulose, hydroxypropylmethylcellulose, ethylhydroxyethylcellulose, hydroxyethylcellulose and hydroxypropylcellulose) to prepare stable nabumetone nanoparticles (<1000nm, as measured by laser diffraction) using wet-bead milling has been investigated. Due to the limited range of CE molecular weights commercially available, the CEs were degraded using ultrasonication for varying lengths of time to yield CEs of lower molecular weight. Of the CEs tested, only hydroxyethylcellulose was found not to stabilise the production of nabumetone nanoparticles at any of the molecular weights tested, namely viscosity average molecular weights (Mv) in the range of 236-33kg/mol. All other CEs successfully stabilised nabumetone nanoparticles, with the lower molecular weight/viscosity polymers within a series being more likely to result in nanoparticle production than their higher molecular weight counterparts. Unfortunately due to the nature of the ultrasonication process, it was not possible to compare the size of nabumetone particles produced using polymers of identical Mv. There was, however, enough similarity in the Mv of the various polymers to draw the general conclusion that there was no strong correlation between the Mv of the various polymers and their ability to produce nanoparticles. For example hydroxypropylcellulose of 112.2kg/mol or less successfully produced nanoparticles while only ethylhydroxyethylcellulose and hydroxypropylmethyl polymers of 52 and 38.8kg/mol or less produced nanoparticles. These results suggest that polymer molecular weight is not the only determinant of nanoparticle production and that structure of the polymer is at least as important as its molecular weight. In particular the hydrophobic nature of the CE was thought to be an important factor in the production of nabumetone nanoparticles: the more hydrophobic the polymer, the stronger its interaction with nabumetone and the greater its ability to produce nanoparticles. In this context HPC was the most hydrophobic polymer and HEC the least hydrophobic.


Assuntos
Butanonas/química , Celulose/análogos & derivados , Celulose/química , Peso Molecular , Nanopartículas/química , Viscosidade , Estabilidade de Medicamentos , Nabumetona , Nanopartículas/ultraestrutura , Tamanho da Partícula , Polímeros/química , Ultrassom
11.
Spectrochim Acta A Mol Biomol Spectrosc ; 167: 142-156, 2016 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-27284764

RESUMO

The structure and several spectroscopic features along with reactivity parameters of the compound 4-(6-methoxy-2-naphthyl)-2-butanone (Nabumetone) have been studied using experimental techniques and tools derived from quantum chemical calculations. Structure optimization is followed by force field calculations based on density functional theory (DFT) at the B3LYP/6-311++G(d,p) level of theory. The vibrational spectra have been interpreted with the aid of normal coordinate analysis. UV-visible spectrum and the effect of solvent have been discussed. The electronic properties such as HOMO and LUMO energies have been determined by TD-DFT approach. In order to understand various aspects of pharmacological sciences several new chemical reactivity descriptors - chemical potential, global hardness and electrophilicity have been evaluated. Local reactivity descriptors - Fukui functions and local softnesses have also been calculated to find out the reactive sites within molecule. Aqueous solubility and lipophilicity have been calculated which are crucial for estimating transport properties of organic molecules in drug development. Estimation of biological effects, toxic/side effects has been made on the basis of prediction of activity spectra for substances (PASS) prediction results and their analysis by Pharma Expert software. Using the THz-TDS technique, the frequency-dependent absorptions of NBM have been measured in the frequency range up to 3THz.


Assuntos
Anti-Inflamatórios não Esteroides/química , Butanonas/química , Anti-Inflamatórios não Esteroides/farmacologia , Butanonas/farmacologia , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Citocromo P-450 CYP1A2/metabolismo , Humanos , Modelos Moleculares , Conformação Molecular , Simulação de Acoplamento Molecular , Nabumetona , Ligação Proteica , Teoria Quântica , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier , Análise Espectral Raman , Termodinâmica
12.
Pancreatology ; 16(3): 353-7, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27029853

RESUMO

BACKGROUND: It remains unknown whether nabumetone increases or decreases acute pancreatitis risk. To investigate this, we conducted a population-based case-control study using the database from the Taiwan National Health Insurance Program. METHODS: We analysed 5384 cases aged 20-84 years who had their first attack of acute pancreatitis during 1998-2011 and 21,536 controls without acute pancreatitis, and matched them according to sex, age and year in which acute pancreatitis was diagnosed. Never use of nabumetone was defined as subjects who had never received a nabumetone prescription; active use as subjects receiving a minimum of one prescription for nabumetone within 7 days before acute pancreatitis diagnosis and non-active use of nabumetone as subjects who did not receive a prescription for nabumetone within 7 days before but received at least one prescription for nabumetone ≥8 days before. The odds ratio and 95% confidence interval (CI) were estimated to investigate the risk of acute pancreatitis associated with nabumetone use, using the multivariable unconditional logistic regression model. RESULTS: The adjusted odds ratio of acute pancreatitis was 3.69 (95%CI 1.69, 8.05) for subjects with active use of nabumetone compared with those with never use. The odds ratios decreased to 1.0 (95%CI 0.88, 1.12) for subjects with non-active use. CONCLUSIONS: Active use of nabumetone may increase the risk of acute pancreatitis.


Assuntos
Butanonas/efeitos adversos , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Pancreatite/induzido quimicamente , Doença Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Bases de Dados Factuais , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Nabumetona , Razão de Chances , Fatores de Risco , Taiwan
13.
Eur J Drug Metab Pharmacokinet ; 41(2): 179-86, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25537338

RESUMO

Flurbiprofen axetil (FPA) is an injection product and a prodrug of a non-steroidal anti-inflammatory drug (NSAID). After injection, it is rapidly hydrolyzed to the active form, flurbiprofen (FP). Since frequent injections of FPA can lead to abnormal physiology, an administration strategy is necessary to ensure there is enhancement of the analgesic efficiency of FP after a single dose and to reduce the total number of doses. FP strongly binds to site II of albumin, and thus the free (unbound) FP concentration is low. This study focused on 6-methoxy-2-naphthylacetic acid (6-MNA), the active metabolite of nabumetone (a prodrug of NSAID). We performed ultrafiltration experiments and pharmacokinetics analysis in rats to investigate whether the inhibitory effect of 6-MNA on FP binding to albumin increased the free FP concentration in vitro and in vivo. Results indicated that 6-MNA inhibited the binding of FP to albumin competitively. When 6-MNA was injected in rats, there was a significant increase in the free FP concentration and the area under concentration-time curve (AUC) calculated from the free FP concentration, while there was a significant decrease in the total (bound + free) FP concentration and the AUC calculated from the total FP concentration. These findings indicate that 6-MNA inhibits the protein binding of FP in vivo. This suggests that the frequency of FPA injections can be reduced when administered with nabumetone, as there is increase in the free FP concentration associated with pharmacological effect.


Assuntos
Flurbiprofeno/análogos & derivados , Ácidos Naftalenoacéticos/metabolismo , Ligação Proteica/efeitos dos fármacos , Albuminas/metabolismo , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/metabolismo , Área Sob a Curva , Butanonas/administração & dosagem , Butanonas/metabolismo , Flurbiprofeno/administração & dosagem , Flurbiprofeno/metabolismo , Humanos , Injeções , Masculino , Nabumetona , Pró-Fármacos/administração & dosagem , Pró-Fármacos/metabolismo , Ratos , Ratos Wistar
14.
Am J Ther ; 23(6): e1498-e1503, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-25393072

RESUMO

In this open-label, laboratory-blinded, 2-way single dose study in 24 volunteers of both sexes we found that (1) nabumetone reaches mean Cmax ± SD of 0.56 ± 0.20 mg·L at mean tmax of 8.63 ± 7.05 hours, and mean area under the curve (AUC)last of 18.07 ± 7.19 h·mg·L; (2) there are no statistically significant differences between both sexes in pharmacokinetics of nabumetone; (3) 6-methoxy-2-naphthylacetic acid (6-MNA) reaches higher AUClast in men compared with women (mean ± SD, 721.23 ± 185.53 h·mg·L and 545.27 ± 97.69 h·mg·L, respectively; P = 0.013); (4) there is lower 6-MNA clearance in men (0.65 ± 0.22 L·h) in comparison with women (0.88 ± 0.18 L·h, P = 0.019), (5) intersubject variability of nabumetone and 6-MNA is between 35%-45% and 10%-30% for all assessed pharmacokinetics parameters (AUClast, Cmax, partial AUC values); (6) intrasubject variability (ISCV) for AUClast is low, 15.59% and 6.40% for nabumetone and 6-MNA, respectively, (7) ISCV for Cmax is 13.66% and 5.42% for nabumetone and 6-MNA, respectively. Nabumetone thus belongs to compounds with low to moderate ISCV and therefore this product is expected to produce consistent effects in clinical practice.


Assuntos
Butanonas/farmacocinética , Inibidores de Ciclo-Oxigenase 2/farmacocinética , Ácidos Naftalenoacéticos/farmacocinética , Adulto , Área Sob a Curva , Butanonas/administração & dosagem , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Feminino , Humanos , Masculino , Nabumetona , Fatores Sexuais , Adulto Jovem
15.
J Chromatogr A ; 1425: 17-24, 2015 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-26627589

RESUMO

A novel, rapid, simple and green vortex-assisted surfactant-enhanced emulsification microextraction method based on solidification of floating organic drop was developed for simultaneous separation/preconcentration and determination of ultra trace amounts of naproxen and nabumetone with high performance liquid chromatography-fluorescence detection. Some parameters influencing the extraction efficiency of analytes such as type and volume of extractant, type and concentration of surfactant, sample pH, KCl concentration, sample volume, and vortex time were investigated and optimized. Under optimal conditions, the calibration graph exhibited linearity in the range of 3.0-300.0ngL(-1) for naproxen and 7.0-300.0ngL(-1) for nabumetone with a good coefficient of determination (R(2)>0.999). The limits of detection were 0.9 and 2.1ngL(-1). The relative standard deviations for inter- and intra-day assays were in the range of 5.8-10.1% and 3.8-6.1%, respectively. The method was applied to the determination of naproxen and nabumetone in urine, water, wastewater and milk samples and the accuracy was evaluated through recovery experiments.


Assuntos
Butanonas/análise , Emulsificantes/química , Microextração em Fase Líquida/métodos , Naproxeno/análise , Tensoativos/química , Animais , Butanonas/urina , Calibragem , Cromatografia Líquida de Alta Pressão/métodos , Limite de Detecção , Leite/química , Nabumetona , Naproxeno/urina , Águas Residuárias/química , Água/química
16.
Drug Metab Rev ; 47(4): 520-33, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26415702

RESUMO

Carbonyl reductase 1 (CBR1), an enzyme belonging to the short-chain dehydrogenases/reductases family, has been detected in all human tissues. CBR1 catalyzes the reduction of many xenobiotics, including important drugs (e.g. anthracyclines, nabumetone, bupropion, dolasetron) and harmful carbonyls and quinones. Moreover, it participates in the metabolism of a number of endogenous compounds and it may play a role in certain pathologies. Plant polyphenols are not only present in many human food sources, but are also a component of many popular dietary supplements and herbal medicines. Many studies reviewed herein have demonstrated the potency of certain flavonoids, stilbenes and curcuminoids in the inhibition of the activity of CBR1. Interactions of these polyphenols with transcriptional factors, which regulate CBR1 expression, have also been reported in several studies. As CBR1 plays an important role in drug metabolism as well as in the protection of the organism against potentially harmful carbonyls, the modulation of its expression/activity may have significant pharmacological and/or toxicological consequences. Some polyphenols (e.g. luteolin, apigenin and curcumin) have been shown to be very potent CBR1 inhibitors. The inhibition of CBR1 seems useful regarding the increased efficacy of anthracycline therapy, but it may cause the worse detoxification of reactive carbonyls. Nevertheless, all known information about the interactions of polyphenols with CBR1 have only been based on the results of in vitro studies. With respect to the high importance of CBR1 and the frequent consumption of polyphenols, in vivo studies would be very helpful for the evaluation of risks/benefits of polyphenol interactions with CBR1.


Assuntos
Oxirredutases do Álcool/antagonistas & inibidores , Oxirredutases do Álcool/metabolismo , Polifenóis/farmacologia , Oxirredutases do Álcool/biossíntese , Oxirredutases do Álcool/genética , Animais , Bupropiona/metabolismo , Butanonas/metabolismo , Butirofenonas/metabolismo , Daunorrubicina/metabolismo , Doxorrubicina/metabolismo , Regulação Enzimológica da Expressão Gênica , Haloperidol/metabolismo , Humanos , Indóis/metabolismo , Nabumetona , Neoplasias/enzimologia , Fenilpropionatos/metabolismo , Quinolizinas/metabolismo , Especificidade por Substrato , Xenobióticos/metabolismo
17.
Ugeskr Laeger ; 177(17)2015 Apr 20.
Artigo em Dinamarquês | MEDLINE | ID: mdl-25922166

RESUMO

Pseudoporphyria cutanea tarda is a well described bullous skin disorder which resembles porphyria cutanea tarda. However, the levels of porphyrins in plasma, urine and faeces are normal. We present three cases of patients with classical symptoms of pseudoporphyria. Two of the patients developed pseudoporphyria after the combination of intensive sunbathing and medications well known to cause pseudoporphyria. The third case received haemodialysis and furosemide.


Assuntos
Porfiria Cutânea Tardia , Dermatopatias Vesiculobolhosas , Adulto , Butanonas/efeitos adversos , Feminino , Furosemida/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Nabumetona , Porfiria Cutânea Tardia/induzido quimicamente , Porfiria Cutânea Tardia/etiologia , Porfirinas/análise , Diálise Renal/efeitos adversos , Dermatopatias Vesiculobolhosas/induzido quimicamente , Dermatopatias Vesiculobolhosas/etiologia , Banho de Sol , Tetraciclina/efeitos adversos , Raios Ultravioleta/efeitos adversos
18.
Eur J Drug Metab Pharmacokinet ; 40(2): 127-35, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24659525

RESUMO

The metabolic reduction of nabumetone was examined by inhibition and correlation studies using human liver microsomes and cytosol. This reduction was observed in both fractions, with the V(max) values for reduction activity being approximately fourfold higher, and the V(max)/K(m) values approximately three-fold higher, in the microsomes than in the cytosol. The reduction of nabumetone was inhibited by 18ß-glycyrrhetinic acid, an 11ß-hydroxysteroid dehydrogenase (11ß-HSD) inhibitor, in the microsomal fraction. The reduction activity was also inhibited by quercetin and menadione [carbonyl reductase (CBR) inhibitors], and by phenolphthalein and medroxyprogesterone acetate [potent inhibitors of aldo-keto reductase (AKR) 1C1, 1C2 and 1C4] in the cytosol. A good correlation (r² = 0.93) was observed between the reduction of nabumetone and of cortisone, as a marker of 11ß-HSD activity, in the microsomal fractions. There was also an excellent relationship between reduction of nabumetone and of the AKR1C substrates, acetohexamide, and ethacrynic acid (r 2 = 0.92 and 0.93, respectively), in the cytosol fractions. However, a poor correlation was observed between the formation of 4-(6-methoxy-2-naphthyl)-butan-2-ol (MNBO) from nabumetone and CBR activity (with 4-benzoyl pyridine reduction as a CBR substrate) in the cytosol fractions (r² = 0.24). These findings indicate that nabumetone may be metabolized by 11ß-HSD in human liver microsomes, and primarily by AKR1C4 in human liver cytosol, although multiple enzymes in the AKR1C subfamily may be involved. It cannot be completely denied that CBR is involved to some extent in the formation of MNBO from nabumetone in the cytosol fraction.


Assuntos
Butanonas/metabolismo , Citosol/metabolismo , Microssomos Hepáticos/metabolismo , 11-beta-Hidroxiesteroide Desidrogenases/metabolismo , 20-Hidroxiesteroide Desidrogenases/metabolismo , Humanos , Nabumetona , Oxirredução
19.
Curr Top Med Chem ; 14(23): 2734-42, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25515745

RESUMO

The properties of triplet excited states are markedly medium-dependent, which turns this species into valuable tools for investigating the microenvironments existing in protein binding pockets. Monitoring of the triplet excited state behavior of drugs within transport proteins (serum albumins and α1-acid glycoproteins) by laser flash photolysis constitutes a valuable source of information on the strength of interaction, conformational freedom and protection from oxygen or other external quenchers. With proteins, formation of spatially confined triplet excited states is favored over competitive processes affording ionic species. Remarkably, under aerobic atmosphere, the triplet decay of drug@protein complexes is dramatically longer than in bulk solution. This offers a convenient dynamic range for assignment of different triplet populations or for stereochemical discrimination. In this review, selected examples of the application of the laser flash photolysis technique are described, including drug distribution between the bulk solution and the protein cavities, or between two types of proteins, detection of drug-drug interactions inside proteins, and enzyme-like activity processes mediated by proteins. Finally, protein encapsulation can also modify the photoreactivity of the guest. This is illustrated by presenting an example of retarded photooxidation.


Assuntos
Acetatos/química , Antracenos/química , Butanonas/química , Elétrons , Flurbiprofeno/química , Naftalenos/química , Albumina Sérica/química , Animais , Bovinos , Interações Medicamentosas , Humanos , Lasers , Nabumetona , Oxirredução , Fotólise , Ligação Proteica
20.
Niger J Clin Pract ; 17(5): 649-54, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25244280

RESUMO

BACKGROUND: The potential combination of diuretics- angiotensin-converting enzyme inhibitors- Non-steroidal anti-inflammatory drugs (diuretics-ACEIs-NSAIDs), the so-called 'triple whammy', to produce clinically significant nephrotoxicity in chronic kidney disease (CKD) is often unrecognized. In 2013, in the British Medical Journal, we described accelerated post-operative acute kidney injury (AKI) in CKD patients concurrently on 'triple whammy' medications, a new syndrome that we aptly named 'quadruple whammy'. MATERIALS AND METHODS: Two case reports. RESULTS: I. A 59-year-old Caucasian male, hypertensive CKD III, serum creatinine (SCr) 1.42 mg/dL, developed accelerated oliguric AKI after elective right nephrectomy. Outpatient medications included Lisinopril-Hydrochlorothiazide and Nabumetone (NSAID). SCr rapidly more than doubled with metabolic acidosis and hyperkalemia within 24 hours, peaking at 4.02 mg/dL. 'Triple whammy' medications were promptly stopped and the hypotension was corrected. SCr was 1.64 mg/dL and stable, after three months. II. A 46-year-old Caucasian male, hypertensive CKD II, SCr 1.21 mg/dL, developed accelerated AKI after elective right hip arthroplasty. Outpatient medications included Lisinopril and Hydrochlorothiazide. Celecoxib (200 mg) was given pre-operatively. Within 36 hours, SCr rapidly more than doubled to 2.58 mg/dL, with metabolic acidosis. 'Triple whammy' medications were promptly stopped and the hypotension was corrected. SCr was 0.99 mg/dL, and stable, after one month. CONCLUSION: We have described two cases of preventable accelerated AKI following post-operative hypotension in CKD patients concurrently on 'triple whammy' medications. We dubbed this new syndrome "Quadruple Whammy". It is not uncommon. 'Renoprevention', the pre-emptive withholding of (potentially nephrotoxic) medications, including 'triple whammy' medications, pre-operatively, in CKD patients, together with the simultaneous avoidance of peri-operative hypotension would help reduce, if not eliminate such AKI - a call for more pharmacovigilance.


Assuntos
Lesão Renal Aguda/etiologia , Anti-Hipertensivos/efeitos adversos , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Hidroclorotiazida/efeitos adversos , Lisinopril/efeitos adversos , Complicações Pós-Operatórias , Insuficiência Renal Crônica/complicações , Anti-Hipertensivos/administração & dosagem , Artroplastia de Quadril/efeitos adversos , Butanonas/administração & dosagem , Butanonas/efeitos adversos , Celecoxib , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Combinação de Medicamentos , Quimioterapia Combinada/efeitos adversos , Humanos , Hidroclorotiazida/administração & dosagem , Lisinopril/administração & dosagem , Masculino , Pessoa de Meia-Idade , Nabumetona , Nefrectomia/efeitos adversos , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Síndrome , Wisconsin
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