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1.
Ecotoxicol Environ Saf ; 203: 110997, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32684518

RESUMO

A novel study on biodegradation of 30 mg L-1 of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) mixture (celecoxib, diclofenac and ibuprofen) by two wood-rot fungi; Ganoderma applanatum (GA) and Laetiporus sulphureus (LS) was investigated for 72 h. The removal efficiency of celecoxib, diclofenac and ibuprofen were 98, 96 and 95% by the fungal consortium (GA + LS). Although, both GA and LS exhibited low removal efficiency (61 and 73% respectively) on NSAIDs. However, 99.5% degradation of the drug mixture (NSAIDs) was achieved on the addition of the fungal consortium (GA + LS) to the experimental set-up. Overall, LS exhibited higher degradation efficiency; 92, 87, 79% on celecoxib, diclofenac and ibuprofen than GA with 89, 80 and 66% respectively. Enzyme analyses revealed significant induction of 201, 180 and 135% in laccase (Lac), lignin peroxidase (LiP) and manganese peroxidase (MnP) by the fungal consortium during degradation of the NSAIDs respectively. The experimental data showed the best goodness of fit when subjected to Langmuir (R2 = 0.980) and Temkin (R2 = 0.979) isotherm models which suggests monolayer and heterogeneous nature exhibited by the mycelia during interactions with NSAIDs. The degradation mechanism followed pseudo-second-order kinetic model (R2 = 0.987) indicating the strong influence of fungal biomass in the degradation of NSAIDs. Furthermore, Gas Chromatography-Mass Spectrometry (GCMS) and High-Performance Liquid Chromatography (HPLC) analyses confirmed the degraded metabolic states of the NSAIDs after treatment with GA, LS and consortium (GA + LS). Hence, the complete removal of NSAIDs is best achieved in an economical and eco-friendly way with the use of fungi consortium.


Assuntos
Anti-Inflamatórios não Esteroides/análise , Poluentes Ambientais/análise , Ganoderma/enzimologia , Ganoderma/crescimento & desenvolvimento , Lignina/metabolismo , Madeira/microbiologia , Anti-Inflamatórios não Esteroides/metabolismo , Biodegradação Ambiental , Biomassa , Poluentes Ambientais/metabolismo , Indução Enzimática/efeitos dos fármacos , Cinética , Lacase/biossíntese , Modelos Biológicos , Peroxidases/biossíntese
2.
AAPS PharmSciTech ; 21(5): 172, 2020 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-32533366

RESUMO

Dissolution testing and solubility determinations in different biorelevant media have gained considerable interest in the pharmaceutical industry from early-stage development of new products to forecasting bioequivalence. Among all biorelevant fluids, the preparation of fed-state simulated gastric fluid (FeSSGF) and handling of samples from dissolution/solubility testing in FeSSGF is considered to be relatively challenging. Challenges include maintaining the stability of FeSSGF medium upon sampling, filtration, and mitigating analytical interference of excipients and milk components. To overcome these challenges, standard and uniform working practices are required that are not only helpful in preparation of stable FeSSGF but also serve as a harmonizing guide for the collection of dissolution/solubility samples and their subsequent processing (i.e., handling and assay). The optimization of sample preparation methodology is crucial to reduce method-related variance by ensuring specificity, robustness, and reproducibility with acceptable recovery of the analytes. The sample preparation methodology includes a combination of techniques including filtration, solvent treatment, and centrifugation to remove the interfering media-related components and excipients from the analyte. The analytes of interest were chromatographically separated from the interfering analytes to quantify the drug concentration using the new high-performance liquid chromatography methods with ultraviolet detection. The methods developed allow rapid sample preparation, acceptable specificity, reproducible recoveries (greater than 95% of label claim), and quantification of study drugs (ibuprofen and ketoconazole). The sample preparation technique and method considerations provided here for ibuprofen and ketoconazole can serve as a starting point for solubility and dissolution testing of other small molecules in FeSSGF.


Assuntos
Desenvolvimento de Medicamentos/métodos , Ácido Gástrico/metabolismo , Ibuprofeno/metabolismo , Cetoconazol/metabolismo , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/metabolismo , Antifúngicos/química , Antifúngicos/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Ibuprofeno/química , Cetoconazol/química , Reprodutibilidade dos Testes , Solubilidade , Comprimidos
3.
AAPS PharmSciTech ; 21(4): 127, 2020 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-32390062

RESUMO

The aim of the present study was to evaluate the development of an intra-articular nonsteroidal anti-inflammatory drug gelatin microsphere formulation based on quality risk management and quality by design approaches. Specifically, after setting the quality target product profile and the critical quality attributes, risk assessment was performed by constructing Ishikawa fishbone diagrams based on preliminary hazard analysis. A Plackett-Burman screening experimental design was applied in order to identify the factors (previously classified by risk assessment analysis as having high risk of failure) having a statistically significant impact on the formation of gelatin microspheres. Particle size, polydispersity index, and drug loading were used as responses, while diclofenac sodium was selected as a model drug. All drug-loaded gelatin microspheres were prepared by emulsion-crosslinking process. Screening results showed that gelatin type, surfactant type and quantity, oil phase type, emulsification speed, and glutaraldehyde's concentration had a statistically significant impact on microsphere's final and intermediate critical quality attributes. A design space was then constructed based on central composite design overlaying contour plots, while verification experiments for the optimum suggested formulation (derived from a set control strategy) showed good agreement between the predicted and the experimentally observed results. In addition, the physicochemical characterization of the optimum formulation showed the formation of significant molecular interactions between the drug and the gelatin matrix, leading to the complete amorphization of diclofenac within the microsphere structure, while dissolution release experiments showed a biphasic release profile which extended the drug's release for up to 30 days, governed by a Fickian diffusion release mechanism.


Assuntos
Anti-Inflamatórios não Esteroides/química , Diclofenaco/química , Desenvolvimento de Medicamentos/normas , Gelatina/química , Microesferas , Pesquisa Qualitativa , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/metabolismo , Bovinos , Diclofenaco/administração & dosagem , Diclofenaco/metabolismo , Desenvolvimento de Medicamentos/métodos , Liberação Controlada de Fármacos , Gelatina/administração & dosagem , Gelatina/metabolismo , Injeções Intra-Articulares , Tamanho da Partícula , Gestão de Riscos , Suínos
4.
J Med Chem ; 63(13): 6847-6862, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32469516

RESUMO

Every day, hundreds of millions of people worldwide take nonsteroidal anti-inflammatory drugs (NSAIDs), often in conjunction with multiple other medications. In the bloodstream, NSAIDs are mostly bound to serum albumin (SA). We report the crystal structures of equine serum albumin complexed with four NSAIDs (ibuprofen, ketoprofen, etodolac, and nabumetone) and the active metabolite of nabumetone (6-methoxy-2-naphthylacetic acid, 6-MNA). These compounds bind to seven drug-binding sites on SA. These sites are generally well-conserved between equine and human SAs, but ibuprofen binds to both SAs in two drug-binding sites, only one of which is common. We also compare the binding of ketoprofen by equine SA to binding of it by bovine and leporine SAs. Our comparative analysis of known SA complexes with FDA-approved drugs clearly shows that multiple medications compete for the same binding sites, indicating possibilities for undesirable physiological effects caused by drug-drug displacement or competition with common metabolites. We discuss the consequences of NSAID binding to SA in a broader scientific and medical context, particularly regarding achieving desired therapeutic effects based on an individual's drug regimen.


Assuntos
Anti-Inflamatórios não Esteroides/metabolismo , Albumina Sérica/metabolismo , Animais , Anti-Inflamatórios não Esteroides/sangue , Sítios de Ligação , Transporte Biológico , Modelos Moleculares , Conformação Proteica , Albumina Sérica/química
5.
Biochem Pharmacol ; 175: 113924, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32217099

RESUMO

ATP-binding cassette (ABCG2) is an efflux transporter that extrudes xenotoxins from cells in liver, intestine, mammary gland, brain and other organs, affecting the pharmacokinetics, brain accumulation and secretion into milk of several compounds, including antitumoral, antimicrobial and anti-inflammatory drugs. The aim of this study was to investigate whether the widely used anti-inflammatory drug meloxicam is an Abcg2 sustrate, and how this transporter affects its systemic distribution. Using polarized ABCG2-transduced cell lines, we found that meloxicam is efficiently transported by murine Abcg2 and human ABCG2. After oral administration of meloxicam, the area under the plasma concentration-time curve in Abcg2-/- mice was 2-fold higher than in wild type mice (146.06 ± 10.57 µg·h/ml versus 73.80 ± 10.00 µg·h/ml). Differences in meloxicam distribution were reported for several tissues after oral and intravenous administration, with a 20-fold higher concentration in the brain of Abcg2-/- after oral administration. Meloxicam secretion into milk was also affected by the transporter, with a 2-fold higher milk-to-plasma ratio in wild-type compared with Abcg2-/- lactating female mice after oral and intravenous administration. We conclude that Abcg2 is an important determinant of the plasma and brain distribution of meloxicam and is clearly involved in its secretion into milk.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/deficiência , Anti-Inflamatórios não Esteroides/metabolismo , Meloxicam/metabolismo , Leite/metabolismo , Distribuição Tecidual/fisiologia , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Administração Intravenosa , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/sangue , Cães , Feminino , Humanos , Células Madin Darby de Rim Canino , Masculino , Meloxicam/administração & dosagem , Meloxicam/sangue , Camundongos , Camundongos Knockout , Leite/efeitos dos fármacos , Distribuição Tecidual/efeitos dos fármacos
6.
Artigo em Inglês | MEDLINE | ID: mdl-32145638

RESUMO

Berberidis cortex, the dry bark of Berberis L., is used to treat diabetes and contains at least three bioactive components: berberine (BBR), berbamine (BBM) and magnoflorine (MGF). BBR in turn is metabolized into berberrubine (BRB). Although it is possible to quantify each of these components individually in serum, there are currently no methods for simultaneously quantifying all four. Here, we developed a specific and rapid method for simultaneously quantifying BBR, BBM, MGF and BRB in mouse serum using ultra high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Samples were pretreated by protein precipitation, separated using an ACQUITY UPLC® BEH C18 column and detected by a triple quadrupole mass spectrometer with electrospray ionization. The compound [9,10-(OC2H3)2]-BBR (d6-BBR) was used as internal standard for BBR and BRB, boldine (BOL) for MGF and tetrandrine (TET) for BBM. The m/z transitions for precursor/product ion pairs were 336.1/320.2 for BBR, 305.2/566.3 for BBM, 342.0/297.1 for MGF, 322.1/307.2 for BRB, 342.2/294.3 for d6-BBR, 312.2/580.3 for TET and 328.1/265.2 for BOL. We validated our method in terms of selectivity, linearity and lower limit of quantification, accuracy, precision, matrix effect and recovery, dilution integrity and stability. This method showed good linearity from 0.1 to 40 ng/mL for BBR, 8 to 3200 ng/mL for BBM, 5 to 2000 ng/mL for MGF and 0.2 to 80 ng/mL for BRB. The chromatographic run time was 3.9 min, and sample preparation took approximately 15 min per batch. Finally, we used our method to measure BBR, BBM, MGF and BRB in serum from diabetic mice after gavage administration of BBR hydrochloride, BBM hydrochloride, and MGF. This method is precise, accurate and suitable for high-throughput sample analysis.


Assuntos
Anti-Inflamatórios não Esteroides/sangue , Aporfinas/sangue , Benzilisoquinolinas/sangue , Berberina/sangue , Animais , Anti-Inflamatórios não Esteroides/metabolismo , Aporfinas/análise , Aporfinas/metabolismo , Benzilisoquinolinas/análise , Benzilisoquinolinas/metabolismo , Berberina/análogos & derivados , Berberina/metabolismo , Cromatografia Líquida de Alta Pressão , Diabetes Mellitus Experimental , Limite de Detecção , Camundongos , Padrões de Referência , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espectrometria de Massas em Tandem
7.
Artigo em Inglês | MEDLINE | ID: mdl-32163902

RESUMO

The present study included the procedure of preparing porous titania thin film using a direct nanocrystalline cellulose templating (NCC) as a bio-template. The microextraction applicability of the porous film was investigated by thin film microextraction (TFME) of the nonsteroidal anti-inflammatory drugs (NSAIDs) including ketorolac, meloxicam, diclofenac and mefenamic acid from different types of urine sample. The extracted NSAIDs were analyzed by HPLC-UV. Under optimum conditions, the calibration curves were linear within the range of 1.0-500 µg L-1 (2.0-200 µg L-1 for ketorolac, 2.0-500 µg L-1 for meloxicam, 1.0-200 µg L-1 for diclofenac and 1.0-200 µg L-1 for mefenamic acid). The limit of detection was found to be between 0.2 and 0.5 µg L-1. The calculated intra- and inter-day relative standard deviations RSDs% (n = 3) at concentration level of 10 µg L-1 were less than 6.3% and 6.0%, respectively. Finally, the method was successfully applied to determine selected NSAIDs in urine samples from different human individuals.


Assuntos
Anti-Inflamatórios não Esteroides/urina , Celulose/química , Nanopartículas/química , Titânio/química , Adulto , Anti-Inflamatórios não Esteroides/metabolismo , Cromatografia Líquida de Alta Pressão , Diclofenaco/urina , Feminino , Humanos , Cetorolaco/urina , Limite de Detecção , Masculino , Ácido Mefenâmico/urina , Meloxicam/urina , Membranas Artificiais , Pessoa de Meia-Idade , Porosidade , Microextração em Fase Sólida
8.
Xenobiotica ; 50(8): 919-928, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32039641

RESUMO

To reveal putative bioactivation pathways of diclofenac, in vitro human liver materials such as microsomal fractions and hepatocytes were used to confirm metabolic activation of diclofenac by 35S-cysteine trapping assay and covalent binding assay. Candidate human liver proteins possibly targeted by 14C-diclofenac via bioactivation were investigated using two-dimensional gel electrophoresis followed by detection of remaining radioactivity on the modified proteins with bio-imaging analyzer.In the 35S-cysteine trapping assay, three and two adducts with 35S-cysteine were observed in NADPH-fortified and UDPGA-fortified human liver microsomes, respectively. In the covalent binding assay using 14C-diclofenac in human hepatocytes, the extent of covalent binding of diclofenac to human hepatic proteins increased time-dependently. Addition of glutathione attenuated the extent of covalent binding of 14C-diclofenac to human liver microsomal proteins.Fifty-nine proteins from human hepatocytes were proposed as the candidate proteins targeted by reactive metabolites of diclofenac. Proteins modified by cytochrome P450-mediated reactive metabolites were identified by using a cytochrome P450 inhibitor, 1-aminobenzyltriazole and seven of the nine radioactive protein spots were removed by 1-aminobenzyltriazole treatment.In contrast, the remaining two radioactive protein spots, mainly containing human serum albumin and heat shock proteins, were not affected by the addition of 1-aminobenzyltriazole, which suggested the involvement of the acyl glucuronide of diclofenac, formed via uridine diphosphate-glucuronosyl transferases, in the covalent modifications induced by diclofenac.


Assuntos
Diclofenaco/metabolismo , Hepatócitos/metabolismo , Anti-Inflamatórios não Esteroides/metabolismo , Humanos , Microssomos Hepáticos/metabolismo
9.
Dalton Trans ; 49(7): 2323-2330, 2020 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-32022053

RESUMO

A superoxide dismutase mimic (Mn1) was functionalized with three positively charged-peptides: RRRRRRRRR (Mn1-R9), RRWWWRRWRR (Mn1-RW9) or Fx-r-Fx-K (Mn1-MPP). Characterization of the physico-chemical properties of the complexes show that they share similar binding affinity for Mn2+, apparent reduction potential and intrinsic superoxide dismutase activity. However, their accumulation in cells is different (Mn1-R9 < Mn1-MPP < Mn1-RW9 < Mn1), as well as their subcellular distribution. In addition, the three functionalized-complexes display a better anti-inflammatory activity than Mn1 when assayed at 10 µM. This improvement is due to a combination of an anti-inflammatory effect of the peptidyl moiety itself, and of the SOD mimic for Mn1-RW9 and Mn1-MPP. In contrast, the enhanced anti-inflammatory activity of Mn1-R9 is solely due to the SOD mimic.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Peptídeos Penetradores de Células/farmacologia , Superóxido Dismutase/metabolismo , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/metabolismo , Peptídeos Penetradores de Células/química , Peptídeos Penetradores de Células/metabolismo , Células HT29 , Humanos , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Estrutura Molecular , Superóxido Dismutase/química , Termodinâmica
10.
Spectrochim Acta A Mol Biomol Spectrosc ; 229: 118014, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31923791

RESUMO

Eu(III) 2-{4-[(2-oxocyclopentyl)methyl]phenyl}propanoic acid complex (Eu-LPF), a novel low-toxic luminescent material based on energy transfer between the LPF ligand and Eu3+ ion, was synthesized and characterized by means of elemental analysis, thermogravimetric analyses, and FT-IR spectra. The spectroscopic properties of Eu-LPF were studied using UV-vis absorption spectroscopy and steady/transient state luminescence spectroscopy. Furthermore, the cytotoxicity of Eu-LPF on MCF-7 cells was investigated by MTT assay and flow cytometry. Its biocompatibility and utilization for cell imaging were studied as well. The results showed that Eu-LPF exhibited favorable luminescence properties, low toxicity and good biocompatibility, which endowed Eu-LPF with a potential capability for bioimaging and optical detection.


Assuntos
Anti-Inflamatórios não Esteroides/metabolismo , Neoplasias da Mama/patologia , Európio/metabolismo , Luminescência , Substâncias Luminescentes/metabolismo , Imagem Molecular/métodos , Fenilpropionatos/metabolismo , Anti-Inflamatórios não Esteroides/química , Apoptose , Neoplasias da Mama/metabolismo , Ciclo Celular , Proliferação de Células , Európio/química , Feminino , Humanos , Ligantes , Substâncias Luminescentes/química , Fenilpropionatos/química , Espectroscopia de Infravermelho com Transformada de Fourier , Células Tumorais Cultivadas
11.
Appl Microbiol Biotechnol ; 104(5): 1849-1857, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31925484

RESUMO

This article summarizes the current knowledge about the presence of naproxen in the environment, its toxicity to nontarget organisms and the microbial degradation of this drug. Currently, naproxen has been detected in all types of water, including drinking water and groundwater. The concentrations that have been observed ranged from ng/L to µg/L. These concentrations, although low, may have a negative effect of long-term exposure on nontarget organisms, especially when naproxen is mixed with other drugs. The biological decomposition of naproxen is performed by fungi, algae and bacteria, but the only well-described pathway for its complete degradation is the degradation of naproxen by Bacillus thuringiensis B1(2015b). The key intermediates that appear during the degradation of naproxen by this strain are O-desmethylnaproxen and salicylate. This latter is then cleaved by 1,2-salicylate dioxygenase or is hydroxylated to gentisate or catechol. These intermediates can be cleaved by the appropriate dioxygenases, and the resulting products are incorporated into the central metabolism. KEY POINTS: •High consumption of naproxen is reflected in its presence in the environment. •Prolonged exposure of nontargeted organisms to naproxen can cause adverse effects. •Naproxen biodegradation occurs mainly through desmethylnaproxen as a key intermediate.


Assuntos
Exposição Ambiental/efeitos adversos , Naproxeno/metabolismo , Naproxeno/toxicidade , Poluentes Químicos da Água/metabolismo , Poluentes Químicos da Água/toxicidade , Anti-Inflamatórios não Esteroides/análise , Anti-Inflamatórios não Esteroides/metabolismo , Anti-Inflamatórios não Esteroides/toxicidade , Organismos Aquáticos/efeitos dos fármacos , Organismos Aquáticos/metabolismo , Bacillus thuringiensis/metabolismo , Proteínas de Bactérias/metabolismo , Biodegradação Ambiental , Redes e Vias Metabólicas/efeitos dos fármacos , Naproxeno/análogos & derivados , Naproxeno/análise , Poluentes Químicos da Água/análise
12.
Chemosphere ; 242: 125141, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31677505

RESUMO

Diclofenac (DCF), a non-steroidal anti-inflammatory drug, is widespread in aquatic environments and coexists with heavy metals to form combined pollution. However, the interactive effects of DCF and heavy metals on aquatic organisms remain unknown. This study aimed to investigate the interactive effects of DCF and copper (Cu) on the bioconcentration, oxidative stress status and detoxification-related gene expression in crucian carp (Carassius auratus). Fish were exposed to Cu (100 µg L-1) and DCF (1, 10, 100 and 1000 µg L-1) alone or in combination for 7 days. Results obtained showed that the treatment of Cu combined with high levels of DCF (100 and 1000 µg L-1) significantly decreased tissue concentrations of DCF and Cu compared to the correspondingly individual exposure. Concerning oxidative stress status, as reflected by the activities of antioxidant enzymes and malondialdehyde content, low exposure concentrations of DCF (1 and 10 µg L-1) seemed to mitigate the oxidative stress induced by Cu, whereas the co-exposure of Cu with the highest level of DCF (1000 µg L-1) led to stronger oxidative damage in fish liver than Cu exposure alone. With regarding to detoxification-related genes, in most cases, the expressions of cyp 1a, cyp 3a, gstα, gstπ, pxr and P-gp in crucian carp were significantly altered upon exposure to the compounds in combination compared to exposure to the compounds individually. Collectively, these findings indicate the capacity of each of these pollutants to alter bioconcentration potential, pro-oxidative effects and detoxification-related gene responses of the other when both co-occur at specific concentrations.


Assuntos
Anti-Inflamatórios não Esteroides/toxicidade , Carpas/fisiologia , Cobre/toxicidade , Diclofenaco/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Anti-Inflamatórios não Esteroides/metabolismo , Bioacumulação , Biomarcadores/metabolismo , Carpas/metabolismo , Cobre/metabolismo , Diclofenaco/metabolismo , Carpa Dourada/metabolismo , Inativação Metabólica/efeitos dos fármacos , Fígado/metabolismo , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Poluentes Químicos da Água/metabolismo
13.
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
14.
Chem Asian J ; 15(4): 503-510, 2020 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-31886623

RESUMO

A series of coordination polymers synthesized from a bis-pyridyl linker, namely 4,4'-azopyridine (L), selected non-steroidal-anti-inflammatory drugs (NSAIDs), namely diclofenac (Dic), ibuprofen (Ibu), flurbiprofen (Flu), mefenamic acid (Mefe), and naproxen (Nap), and Zn(NO3 )2 were characterized by single crystal X-ray diffraction. One of the coordination polymers, namely CP3 derived from Flu, was able to form metallovesicles in DMSO, DMSO/H2 O and DMSO/DMEM (biological media) as revealed by TEM, AFM and DLS. Metallovesicle formation by CP3 was further supported by loading a fluorescent dye, namely calcein, as well as an anti-cancer drug, doxorubicin hydrochloride (DOX), as revealed by UV-vis and emission spectra, and fluorescence microscopy. DOX-loaded metallovesicles of CP3 (DOX@CP3-vesicle) could be delivered in vitro to a highly aggressive human breast cancer cell line, namely MDA-MB-231, as revealed by MTT and cell migration assays, and also cell imaging performed under laser scanning confocal microscope (LSCM). Thus, a proof of concept for developing a multi-drug delivery system derived from a metallovesicle for delivering an anti-cancer drug to cancer cells is demonstrated for the first time.


Assuntos
Anti-Inflamatórios não Esteroides/química , Complexos de Coordenação/química , Portadores de Fármacos/química , Polímeros/química , Zinco/química , Anti-Inflamatórios não Esteroides/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Cristalografia por Raios X , Doxorrubicina/química , Doxorrubicina/metabolismo , Doxorrubicina/farmacologia , Humanos , Microscopia de Força Atômica , Microscopia Confocal , Polímeros/síntese química
15.
Enzyme Microb Technol ; 131: 109392, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31615678

RESUMO

Rosmarinic acid (RA), as a hydroxycinnamic acid ester of caffeic acid (CA) and 3,4-dihydroxyphenyllactic acid (3,4-DHPL), is a phenylpropanoid-derived plant natural product and has diverse biological activities. This work acts as a modular platform for microbial production using a two-cofactor (ATP and CoA) regeneration system to product RA based on a cell-free biosynthetic approach. Optimal activity of the reaction system was pH 8 and 30 °C. Total turnover number for ATP and CoA was 820.60 ±â€¯28.60 and 444.50 ±â€¯9.65, respectively. Based on the first hour data, the RA productivity reached 320.04 mg L-1 h-1 (0.889 mM L-1 h-1).


Assuntos
Trifosfato de Adenosina/metabolismo , Anti-Inflamatórios não Esteroides/metabolismo , Cinamatos/metabolismo , Coenzima A/metabolismo , Depsídeos/metabolismo , Sistema Livre de Células , Concentração de Íons de Hidrogênio , Temperatura
17.
Yakugaku Zasshi ; 139(8): 1085-1091, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31366843

RESUMO

Better prescription assistance can be provided by applying basic pharmaceutical science concepts, and by considering evidence from clinical trials. For example, several drugs are currently used to treat ulcerative colitis (UC), a form of inflammatory bowel disease. In general, after a drug is administered, it is first absorbed into the upper part of the small intestine and then enters the bloodstream. However, 5-aminosalicylic acid (5-ASA), which is commonly used to treat UC, acts locally on the colonic mucosa; its absorption must be prevented in the upper gastrointestinal tract so that it can be delivered to the colorectal mucosa. Therefore, in this case, it is important to consider drug dissolution tests rather than pharmacokinetics. Currently, three types of 5-ASA formulations are available: a pH-dependent release formulation, a time-dependent release formulation, and a combination of the two at maximum dosages of 3600, 4000, and 4800 mg, respectively. Although it is often thought that selecting a high dose is better, the clinical effectiveness of 5-ASA is determined by the amount of drug actually delivered to the lesion. Therefore, rather than dosage, it is most important to understand differences in drug solubility. It is beneficial to provide prescription assistance for the treatment of UC by 5-ASA, because when 5-ASA fails, a steroid or expensive biological drug is administered. We will present a case study and discuss the future of prescription assistance using Academic Detailing.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/metabolismo , Biofarmácia , Medicina Baseada em Evidências , Mesalamina/administração & dosagem , Mesalamina/metabolismo , Prescrições , Adulto , Ensaios Clínicos como Assunto , Colite Ulcerativa/tratamento farmacológico , Composição de Medicamentos , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Feminino , Humanos , Mucosa Intestinal/metabolismo , Solubilidade
18.
Environ Sci Pollut Res Int ; 26(24): 25167-25177, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31256392

RESUMO

Cadmium (Cd) is a common environmental pollutant that threatens humans' and animals' health. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used drugs due to their wide therapeutic action; however, they have significant side effects. Since, under many circumstances, humans and animals may be co-exposed to Cd and NSAIDs, the current investigation was assigned to explore the intertwining relationship between Cd and NSAIDs. Four groups of male Wister rats were used: control group: rats received saline; Cd group: rats received cadmium (Cd, 2 mg/kg) orally; Px group: rats received a NSAID (piroxicam, Px, 7 mg/kg, i.p.); and Cd+Px group: rats received both Cd+Px. All treatments were given once a day for 28 consecutive days. Then, blood samples, stomach, liver, and kidney tissues were collected. The results indicated that Px provoked gastric ulcer indicated by high ulcer index, while Cd had no effect on the gastric mucosa. In addition, treatment with Cd or Px alone significantly induced liver and kidney injuries indicated by serum elevations of AST, ALT, ALP, ALB, total protein, creatinine, and urea along with histopathological alterations. Significant increases in malondialdehyde and reduction in GSH and CAT contents were reported along with up-regulated expression of Bax and Bcl-2 after Cd or Px exposure. However, when Cd and Px were given in a combination, Cd obviously potentiated the Px-inflicted cellular injury and death in the liver and kidney but not in the stomach when compared to their individual exposure. This study concluded that oxidative stress mechanisms were supposed to be the main modulator in promoting Cd and Px toxicities when given in combination.


Assuntos
Anti-Inflamatórios não Esteroides/metabolismo , Cádmio/metabolismo , Piroxicam/metabolismo , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Creatinina/metabolismo , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar
19.
J Appl Microbiol ; 127(3): 724-738, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31173436

RESUMO

AIMS: We aimed to expand the microbial biocatalyst platform to generate essential oxyfunctionalized standards for pharmaceutical, toxicological and environmental research. In particular, we examined the production of oxyfunctionalized nonsteroidal anti-inflammatory drugs (NSAIDs) by filamentous-fungi. METHODS AND RESULTS: Four NSAIDs; diclofenac, ibuprofen, naproxen and mefenamic acid were used as substrates for oxyfunctionalization in a biocatalytic process involving three filamentous-fungi strains; Beauveria bassiana, Clitocybe nebularis and Mucor hiemalis. Oxyfunctionalized metabolites that are major degradation intermediates formed by Cytochrome P450 monooxygenases in human metabolism were produced in isolated yields of up to 99% using 1 g l-1 of substrate. In addition, a novel compound, 3',4'-dihydroxydiclofenac, was produced by B. bassiana. Proteomic analysis identified CYP548A5 that might be responsible for diclofenac oxyfunctionalization in B. bassiana. CONCLUSIONS: Efficient fungi catalysed oxyfunctionalization was achieved when using NSAIDs as substrates. High purities and isolated yields of the produced metabolites were achieved. SIGNIFICANCE AND IMPACT OF THE STUDY: The lack of current efficient synthetic strategies for oxyfunctionalization of NSAIDs is a bottleneck to perform pharmacokinetic, pharmacodynamic and toxicological analysis for the pharmaceutical industry. Additionally, oxyfunctionalized derivatives are needed for tracking the fate and impact of such metabolites in the environment. Herein, we described a fungi catalysed process that surpasses previously reported strategies in terms of efficiency, to synthesize oxyfunctionalized NSAIDs.


Assuntos
Anti-Inflamatórios não Esteroides/metabolismo , Fungos/metabolismo , Basidiomycota/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Diclofenaco/metabolismo , Ibuprofeno/metabolismo , Ácido Mefenâmico/metabolismo , Mucor/metabolismo , Naproxeno/metabolismo , Proteômica
20.
Neuropharmacology ; 155: 150-161, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31145906

RESUMO

Lysophosphatidic acid (LPA) is a bioactive lipid mediator of inflammation that binds to its specific cell surface G protein coupled receptors (LPA1-6). It is reported that LPA induced cell apoptosis by targeting LPA1, while LPA1 blockade eliminated LPS-induced production of peritoneal neutrophil chemokines and cytokines. Previous studies have shown that Saikosaponin-d (SSd) mitigated depressive-like behaviors in rats exposed to chronic unpredictable mild stress (CUMS), as well as corticosterone-induced apoptosis in PC12 cells. The present study explored the role of SSd during modulating LPA1 mediated neuronal apoptosis in LPS-stimulated mice. The phenomenon that SSd alleviated LPS-induced depressive-like behaviors were observed by open field test (OPT), forced swim test (FST) and tail suspension test (TST). SSd inhibited the protein expression of LPA1 both in the CA1 and CA3 region of the hippocampus. Moreover, SSd significantly decreased the levels of RhoA, ROCK2, p-p38, p-ERK, p-p65, p-IκBα in LPS-stimulated mice as well as in LPA-stimulated SH-SY5Y cells. Additionally, SSd significantly decreased the expression of LPA1 and the degree of neuronal apoptosis in SH-SY5Y cells which were co-cultured with LPS-stimulated BV2 microglia. These results suggested that SSd improved LPS-induced depressive-like behaviors in mice and suppressed neuronal apoptosis by regulating LPA1/RhoA/ROCK2 signaling pathway.


Assuntos
Anti-Inflamatórios não Esteroides/metabolismo , Apoptose/fisiologia , Depressão/metabolismo , Neurônios/metabolismo , Ácido Oleanólico/análogos & derivados , Receptores de Ácidos Lisofosfatídicos/metabolismo , Saponinas/metabolismo , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Técnicas de Cocultura , Depressão/induzido quimicamente , Depressão/tratamento farmacológico , Relação Dose-Resposta a Droga , Humanos , Lisofosfolipídeos/metabolismo , Lisofosfolipídeos/toxicidade , Camundongos , Camundongos Endogâmicos ICR , Neurônios/efeitos dos fármacos , Ácido Oleanólico/metabolismo , Ácido Oleanólico/farmacologia , Ácido Oleanólico/uso terapêutico , Distribuição Aleatória , Saponinas/farmacologia , Saponinas/uso terapêutico
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