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1.
Probl Radiac Med Radiobiol ; 25: 309-320, 2020 Dec.
Artigo em Inglês, Ucraniano | MEDLINE | ID: mdl-33361843

RESUMO

The high level of nuclear radiation threats in the modern world determines the need to find new means of pharmacological protection of the health of military personnel and civilians from the effects of ionizing radiation. Of particular scientific interest in this aspect are natural polyphenols as a promising basis for the development of newdrugs, radiomodifiers. OBJECTIVE: Justification of the prospects of creating radioprotective agents based on compositions of plantpolyphenolic substances (PPS) and polysaccharides. MATERIAL AND METHODS: The experiments were performed on 130 laboratory white rats-male of Wistar line sexually mature weighting 180-240 g. Animals once received a total X-ray dose equivalent to 4.25 Gy. The effects ofquercetin and patulaten to the processes of reparative regeneration under conditions of X-ray irradiation andagainst the background of butadione suppression were investigated. Indicators in the study groups were compared using the Student's t-test for independent samples; the differences were considered statistically significantat p < 0.05. RESULTS: The various biological properties of quercetin, in particular, the ability to bind hydroxyl radicals, is thepotential for developing radioprotective agents based on it. At the first stage of the study, the effect of PPS andtheir compositions with polysaccharides on reparative regeneration was studied against the background of its suppression in intact and irradiated animals. With the oral administration of PPS and their compositions with pectin towhite rats, 30 minutes before the administration of butadion, an increase in the processes of reparative regeneration in the cells of the covering epitheliumof the esophagus was observed. At the same time, quercetin granulescaused the most expressive effect, which increased the statistically significant value of the mitotic index by 78.5 %in relation to the group of animals injected with butadion. At the second stage of the study, the effect of polyphenolic substances and their compositions with pectin on the processes of reparative regeneration in intact and irradiated white rats was studied on a model of linear skin wounds. The prophylactic administration of quercetin granules and the treatment of wounds with 20 % sterile quercetin gel significantly accelerated the healing process.Experimental data indicate that quercetin granules have the ability to stimulate the processes of reparative regeneration, quercetin showed the greatest efficiency with simultaneous use inside and topically. CONCLUSIONS: The research results indicate the promise of developing radioprotective drugs that can stimulatereparative regeneration processes based on compositions of plant polyphenolic substances and polysaccharides invarious qualitative and quantitative ratios.


Assuntos
Cromonas/farmacologia , Pectinas/farmacologia , Polifenóis/farmacologia , Quercetina/farmacologia , Lesões Experimentais por Radiação/tratamento farmacológico , Protetores contra Radiação/farmacologia , Cicatrização/efeitos dos fármacos , Animais , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Células Epiteliais/efeitos da radiação , Esôfago/efeitos dos fármacos , Esôfago/patologia , Esôfago/efeitos da radiação , Masculino , Índice Mitótico , Fenilbutazona/farmacologia , Lesões Experimentais por Radiação/etiologia , Lesões Experimentais por Radiação/patologia , Ratos , Ratos Wistar , Pele/efeitos dos fármacos , Pele/patologia , Pele/efeitos da radiação , Cicatrização/fisiologia , Raios X/efeitos adversos
2.
J Sep Sci ; 43(22): 4225-4233, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32966669

RESUMO

The effective concentration of a drug in the blood, i.e. the concentration of a free drug in the blood, is influenced by the strength of drug binding onto plasma proteins. Besides its efficacy, these interactions subsequently influence the liberation, absorption, distribution, metabolism, excretion, and toxicological properties of the drug. It is important to not only determine the binding strength and stoichiometry, but also the binding site of a drug on the plasma protein molecule, because the co-administration of drugs with the same binding site can affect the above-mentioned concentration and as a result the pharmacological behavior of the drugs and lead to side effects caused by the change in free drug concentration, its toxicity. In this study, the binding characteristics of six drugs with human serum albumin, the most abundant protein in human plasma, were determined by capillary electrophoresis-frontal analysis, and the obtained values of binding parameters were compared with the literature data. The effect of several drugs and site markers on the binding of l-tryptophan and lidocaine to human serum albumin was investigated in subsequent displacement studies which thus demonstrated the usability of capillary electrophoresis as an automated high-throughput screening method for drug-protein binding studies.


Assuntos
Clorpropamida/análise , Diclofenaco/análise , Flurbiprofeno/análise , Ibuprofeno/análise , Fenilbutazona/análise , Tolbutamida/análise , Sítios de Ligação/efeitos dos fármacos , Clorpropamida/farmacologia , Diclofenaco/farmacologia , Eletroforese Capilar , Flurbiprofeno/farmacologia , Humanos , Ibuprofeno/farmacologia , Lidocaína/antagonistas & inibidores , Lidocaína/química , Fenilbutazona/farmacologia , Albumina Sérica Humana/química , Tolbutamida/farmacologia , Triptofano/antagonistas & inibidores , Triptofano/química
3.
Sci Rep ; 10(1): 2558, 2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-32054946

RESUMO

Muscleblind-like 1 (MBNL1) is a ubiquitously expressed RNA-binding protein, which is highly expressed in skeletal muscle. Abnormally expanded CUG-repeats in the DMPK gene cause myotonic dystrophy type 1 (DM1) by sequestration of MBNL1 to nuclear RNA foci and by upregulation of another RNA-binding protein, CUG-binding protein 1 (CUGBP1). We previously reported that a nonsteroidal anti-inflammatory drug (NSAID), phenylbutazone, upregulates MBNL1 expression in DM1 mouse model by demethylation of MeR2, an enhancer element in Mbnl1 intron 1. NSAIDs inhibit cyclooxygenase (COX), which is comprised of COX-1 and COX-2 isoforms. In this study, we screened 29 NSAIDs in C2C12 myoblasts, and found that 13 NSAIDs enhanced Mbnl1 expression, where COX-1-selective NSAIDs upregulated Mbnl1 more than COX-2-selective NSAIDs. Consistently, knockdown of COX-1, but not of COX-2, upregulated MBNL1 expression in C2C12 myoblasts and myotubes, as well as in myotubes differentiated from DM1 patient-derived induced pluripotent stem cells (iPSCs). Luciferase assay showed that COX-1-knockdown augmented the MeR2 enhancer activity. Furthermore, bisulfite sequencing analysis demonstrated that COX-1-knockdown suppressed methylation of MeR2. These results suggest that COX-1 inhibition upregulates Mbnl1 transcription through demethylation of the MeR2 enhancer. Taken together, our study provides new insights into the transcriptional regulation of Mbnl1 by the COX-1-mediated pathway.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Ciclo-Oxigenase 1/genética , Ciclo-Oxigenase 2/genética , Proteínas de Ligação a DNA/genética , Proteínas de Membrana/genética , Distrofia Miotônica/tratamento farmacológico , Proteínas de Ligação a RNA/genética , Animais , Anti-Inflamatórios não Esteroides/classificação , Proteínas CELF1/genética , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/metabolismo , Camundongos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/crescimento & desenvolvimento , Mioblastos/efeitos dos fármacos , Mioblastos/metabolismo , Distrofia Miotônica/genética , Distrofia Miotônica/patologia , Miotonina Proteína Quinase/genética , Fenilbutazona/farmacologia
4.
Molecules ; 24(1)2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30609687

RESUMO

A drug design for safer phenylbutazone was been explored by reactivity and docking studies involving single electron transfer mechanism, as well as toxicological predictions. Several approaches about its structural properties were performed through quantum chemistry calculations at the B3LYP level of theory, together with the 6-31+G(d,p) basis sets. Molecular orbital and ionization potential were associated to electron donation capacity. The spin densities contribution showed a preferential hydroxylation at the para-positions of phenyl ring when compared to other positions. In addition, on electron abstractions the aromatic hydroxylation has more impact than alkyl hydroxylation. Docking studies indicate that six structures 1, 7, 8 and 13⁻15 have potential for inhibiting human as well as murine COX-2, due to regions showing similar intermolecular interactions to the observed for the control compounds (indomethacin and refecoxib). Toxicity can be related to aromatic hydroxylation. In accordance to our calculations, the derivatives here proposed are potentially more active as well safer than phenylbutazone and only structures 8 and 13⁻15 were the most promising. Such results can explain the biological properties of phenylbutazone and support the design of potentially safer candidates.


Assuntos
Fenilbutazona/química , Fenilbutazona/farmacologia , Descoberta de Drogas/métodos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Fenilbutazona/efeitos adversos , Fenilbutazona/toxicidade , Relação Estrutura-Atividade
5.
Vet Surg ; 47(6): 784-791, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30094858

RESUMO

OBJECTIVE: To determine whether a cyclooxygenase (COX)-2 selective nonsteroidal anti-inflammatory drug (NSAID) would reduce gastric ulceration and gastrointestinal (GI) inflammation compared with a non-COX selective NSAID. STUDY DESIGN: Randomized block design. ANIMALS: Twenty-five healthy adult horses. METHODS: Horses were randomly assigned to receive placebo (n = 5), phenylbutazone (n = 10), or firocoxib (n = 10) administered daily for 10 days. Gastroscopy was performed on days 0 and 10, and both squamous and glandular ulcers were scored according to established scoring criteria. Fecal samples were collected on days 0, 10, and 20 to test for fecal myeloperoxidase (MPO) concentration by enzyme-linked immunosorbent assay. RESULTS: Both classes of NSAID induced GI injury as determined by gastric ulceration scores and fecal MPO. Glandular gastric ulceration scores and fecal MPO concentrations were higher in horses treated with phenylbutazone at day 10 (P < .001 and P = .0018, respectively). Increases in fecal MPO were significantly decreased 10 days following cessation of treatment for firocoxib but remained greater than baseline for the phenylbutazone group. CONCLUSION: Although both classes of NSAID induced gastric ulceration, the COX-2 selective NSAID firocoxib induced less severe glandular ulceration. Although there were increases in fecal MPO in both groups after 10 days of treatment, this increase was significant only in horses receiving the nonselective COX inhibitor phenylbutazone. CLINICAL SIGNIFICANCE: These findings suggest that both classes of NSAID induce GI injury in horses; however, at the dosages used in this study, the COX-2 selective NSAID firocoxib resulted in less severe injury.


Assuntos
4-Butirolactona/análogos & derivados , Anti-Inflamatórios não Esteroides/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Doenças dos Cavalos/tratamento farmacológico , Inflamação/veterinária , Fenilbutazona/farmacologia , Úlcera Gástrica/veterinária , Sulfonas/farmacologia , 4-Butirolactona/farmacologia , Animais , Fezes/química , Gastroenteropatias/tratamento farmacológico , Gastroenteropatias/veterinária , Cavalos , Inflamação/tratamento farmacológico , Peroxidase/metabolismo , Distribuição Aleatória , Úlcera Gástrica/tratamento farmacológico
6.
PLoS One ; 12(1): e0168837, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28045944

RESUMO

At high internal doses, pharmaceuticals have the potential for inducing biological/pharmacological effects in fish. One particular concern for the environment is their potential to bioaccumulate and reach pharmacological levels; the study of these implications for environmental risk assessment has therefore gained increasing attention. To avoid unnecessary testing on animals, in vitro methods for assessment of xenobiotic metabolism could aid in the ecotoxicological evaluation. Here we report the use of a 3-D in vitro liver organoid culture system (spheroids) derived from rainbow trout to measure the metabolism of seven pharmaceuticals using a substrate depletion assay. Of the pharmaceuticals tested, propranolol, diclofenac and phenylbutazone were metabolised by trout liver spheroids; atenolol, metoprolol, diazepam and carbamazepine were not. Substrate depletion kinetics data was used to estimate intrinsic hepatic clearance by this spheroid model, which was similar for diclofenac and approximately 5 fold higher for propranolol when compared to trout liver microsomal fraction (S9) data. These results suggest that liver spheroids could be used as a relevant and metabolically competent in vitro model with which to measure the biotransformation of pharmaceuticals in fish; and propranolol acts as a reproducible positive control.


Assuntos
Avaliação Pré-Clínica de Medicamentos , Fígado/efeitos dos fármacos , Oncorhynchus mykiss/metabolismo , Poluentes Químicos da Água/análise , Animais , Atenolol/farmacologia , Biotransformação , Carbamazepina/farmacologia , Diazepam/farmacologia , Diclofenaco/farmacologia , Feminino , Cinética , Fígado/metabolismo , Metoprolol/farmacologia , Modelos Animais , Fenilbutazona/farmacologia , Propranolol/farmacologia , Espectrometria de Massas em Tandem , Xenobióticos/farmacologia
7.
Chem Biol Drug Des ; 87(6): 936-45, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26808199

RESUMO

As a NPY-2 receptor agonist, PYY24-36- Leu31 is reported to suppress appetite and has a potential in obesity treatment, but its short half-life limits the clinical application. The use of chemical modification to improve interactions with human serum albumin (HSA) is an effective strategy for prolonging the half-lives of peptide analogues. So based on the characteristics that phenylbutazone has a good combination with HSA, we selected a proper linker to link with PYY24-36 -Leu31 to create long-acting and highly biologically active PYY24-36 -Leu31 conjugates, and successfully find a novel, long-acting PYY24-36 -Leu31 conjugate 8 that, when dosed every other day in diet induce obese (DIO) mice for 2 weeks, results in a significant reduction in food intake and body weight and improvement in blood parameter and hepatic steatosis.


Assuntos
Portadores de Fármacos , Fígado Gorduroso/tratamento farmacológico , Fenilbutazona , Receptores de Neuropeptídeo Y/agonistas , Albumina Sérica , Animais , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Fígado Gorduroso/sangue , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Camundongos Obesos , Fenilbutazona/química , Fenilbutazona/farmacocinética , Fenilbutazona/farmacologia , Receptores de Neuropeptídeo Y/metabolismo , Albumina Sérica/química , Albumina Sérica/farmacocinética , Albumina Sérica/farmacologia
8.
PLoS One ; 10(10): e0141419, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26512724

RESUMO

The following study evaluates the overt toxic potential of carprofen (CRP), flunixin (FXN) and phenylbutazone (PBZ) in Old world vultures in relation to historic toxicity data for diclofenac and ketoprofen, with the Cape vulture (Gyps coprotheres) being the indicator species. The toxic potential of a single oral dose of CRP (11.5 mg/kg), FXN (1 mg/kg),PBZ (1.7 mg/kg) or water was evaluated by means of a four-way parallel study (n = 2), as means of ascertaining if these drugs were as toxic as diclofenac in the vulture. No unscheduled deaths or pathological lesions were noted following exposure. Clinical signs of lethargy and depression were, however, noted in one CRP, two FXN and one PBZ treated birds. Mild reversible inhibition of UA excretion was evident in all three groups, although UA remained within the population reference interval in contrast to the effects previously described for diclofenac and ketoprofen. All treatment groups had a drug concentration responsive increase in alanine transferase activity. CRP, FXN and PBZ were characterised by a maximum plasma concentration (Cmax) of 1051.8 ± 620.7 ng/ml, 335.9 ± 36.3 ng/ml and 11150 ± 2474.9 ng/ml at 4 ± 4.3, 0.45 ± 0.02 and 5.3 ± 5.2 hours (Tmax) respectively and a half-life of elimination of 13.3 ±5, 1.8±1 and 18.7 ±11.4 hours respectively. While we could not demonstrate a lethal effect of the tested substances, the presence of toxic clinical signs, clinical pathological changes and/or long half-lives of elimination suggests that all three drugs have a potential for toxicity in a larger population or on repeat administration. In conclusion while the studied substances were not as overtly toxic as diclofenac, they are of safety concern.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Carbazóis/farmacologia , Clonixina/análogos & derivados , Falconiformes , Fenilbutazona/farmacologia , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/farmacocinética , Biomarcadores , Carbazóis/administração & dosagem , Carbazóis/efeitos adversos , Carbazóis/farmacocinética , Clonixina/administração & dosagem , Clonixina/efeitos adversos , Clonixina/farmacocinética , Clonixina/farmacologia , Testes de Função Hepática , Fenilbutazona/administração & dosagem , Fenilbutazona/efeitos adversos , Fenilbutazona/farmacocinética
9.
Appl Biochem Biotechnol ; 174(1): 1-5, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25069404

RESUMO

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the group of drugs having the therapeutic efficacy of analgesic and antipyretic. To detect health-threatening residues of NSAIDs, a fast and easy multiresidue method based on liquid chromatography tandem mass spectrometry (LC-MS/MS) was described. Ten NSAIDs were extracted from the tissues using 2 mL of acetonitrile and 0.1 mL of 2 mM ammonium formate in distilled water. After clean-up using C18 sorbent, it was evaporated under nitrogen, reconstituted with 1 mL distilled water and analyzed by LC-MS/MS. The method was validated based on guideline for residue testing laboratory. Furthermore, the method has also been applied successfully to detect ten NSAIDs from bovine, porcine, and chicken liver tissues. In a total of 315 liver samples tested, acetylic salicylic acid was detected from 28 porcine and 2 chicken liver tissues at levels of 13 ∼ 576 and 50 ∼ 53 ng/g, respectively. Subsequently, paracetamol was detected in 15 porcine liver tissues with a detection levels of 28 ∼ 381 ng/g. Phenylbutazone and its metabolite, oxyphenylbutazone, were detected at 247 and 15 ng/g range in one of the bovine liver tissue, respectively.


Assuntos
Acetaminofen/farmacocinética , Analgésicos não Narcóticos/farmacocinética , Anti-Inflamatórios não Esteroides/farmacocinética , Fígado/metabolismo , Fenilbutazona/farmacocinética , Acetaminofen/farmacologia , Analgésicos não Narcóticos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Bovinos , Galinhas , Cromatografia Líquida/métodos , Fenilbutazona/farmacologia , Suínos , Espectrometria de Massas em Tandem/métodos
10.
Am J Vet Res ; 75(7): 668-79, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24959734

RESUMO

OBJECTIVE: To compare the effects of 2 NSAIDs (phenylbutazone and meloxicam) on renal function in horses. ANIMALS: 9 Thoroughbred or Standardbred mares (mean ± SD age, 5.22 ± 1.09 years [range, 2 to 12 years]; mean body weight, 470 ± 25 kg [range, 442 to 510 kg]). PROCEDURES: A randomized blinded placebo-controlled crossover study was conducted to examine the effects of treatment with phenylbutazone, meloxicam, or a placebo (control solution) on renal responses to the administration of furosemide, dobutamine, and exercise (15 minutes at 60% of maximum heart rate). Renal function was assessed by use of bilateral ureteral catheterization for simultaneous determination of creatinine clearance, sodium excretion, and urine flow rate. RESULTS: Both phenylbutazone and meloxicam attenuated diuresis and natriuresis and reduced glomerular filtration rate, compared with results for the control solution, when horses were treated with furosemide. Mean arterial blood pressure, urine flow rate, and glomerular filtration rate were increased during or after (or both) dobutamine infusion. Both NSAIDs reduced urine flow rate and sodium excretion associated with dobutamine infusion and exercise but had no effect on glomerular filtration rate. CONCLUSIONS AND CLINICAL RELEVANCE: Responses to meloxicam, a cyclooxygenase (COX)-2 preferential agent, appeared comparable to those detected after phenylbutazone treatment, which suggested that COX-2 was the mediator of prostanoid-induced changes to renal function in horses and indicated that COX-2-preferential agents would be likely to have adverse renal effects similar to those for nonselective COX inhibitors in volume-depleted horses.


Assuntos
Dobutamina/farmacologia , Furosemida/farmacologia , Cavalos/fisiologia , Rim/efeitos dos fármacos , Fenilbutazona/farmacologia , Tiazinas/farmacologia , Tiazóis/farmacologia , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/farmacologia , Cardiotônicos/administração & dosagem , Cardiotônicos/farmacologia , Estudos Cross-Over , Ciclo-Oxigenase 2/metabolismo , Diuréticos/farmacologia , Dobutamina/administração & dosagem , Feminino , Furosemida/administração & dosagem , Taxa de Filtração Glomerular/efeitos dos fármacos , Rim/fisiologia , Masculino , Meloxicam , Fenilbutazona/administração & dosagem , Condicionamento Físico Animal/fisiologia , Sódio/farmacologia , Tiazinas/administração & dosagem , Tiazóis/administração & dosagem
11.
Growth Factors ; 30(4): 258-66, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22691166

RESUMO

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs for the suppression of inflammation and pain. However, the analgesic properties of NSAIDs are also associated with significant negative side effects, most notably in the gastrointestinal (GI) tract. Increasingly, evidence indicates that the ulcerogenic properties of some NSAIDs are not exclusively the result of inhibition of cyclooxygenase isoforms in the GI tract, and other mechanisms, including inhibition of cell migration and epithelial restitution, are being explored. Recently, microarray analysis was used to identify potential novel targets of NSAID activity in intestinal epithelial cells. Treated cells exhibited significant reductions in the gene expression of pleiotrophin (PTN), a cytokine and growth factor known to participate in angiogenesis and bone growth. This report aimed to confirm the microarray results reported previously, and to measure protein expression of PTN in intestinal epithelial cells. Furthermore, we also examined the effects of exogenous PTN on cell migration in the presence and absence of either NSAIDs with variable ulcerogenic potential or PTN-specific siRNA. Our results demonstrated that indomethacin and NS-398, two NSAIDs with ulcerogenic potential significantly decrease both gene and protein expressions of PTN in IEC-6 cells and protein expression in IEC-6-Cdx2 cells. Additionally, cell migration experiments with PTN siRNA showed that PTN is an important mediator of IEC-6 cell migration, and addition of exogenous PTN partially restores the deficits in cell migration caused by treatment with indomethacin and NS-398. Finally, measurement of PTN protein expression in the GI tract of horses treated with phenylbutazone showed that PTN expression is reduced by NSAIDs in vivo. Our results show that PTN is an important mediator of cell migration in IEC-6 cells, and PTN is a potential target through which NSAIDs may inhibit cell migration, epithelial restitution, and wound healing in the GI tract.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Proteínas de Transporte/biossíntese , Citocinas/biossíntese , Células Epiteliais/metabolismo , Mucosa Intestinal/metabolismo , Animais , Osso e Ossos/metabolismo , Linhagem Celular , Movimento Celular , Cavalos , Indometacina/farmacologia , Neovascularização Patológica , Nitrobenzenos/farmacologia , Análise de Sequência com Séries de Oligonucleotídeos , Fenilbutazona/farmacologia , Sulfonamidas/farmacologia , Distribuição Tecidual
12.
Med Chem ; 8(5): 874-82, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22741799

RESUMO

Indan derivatives, namely, 5-(5',6'-dichloroindan-1'-yl)-tetrazole (12a) and 5-(5',6'-dichloroindan-1'-yl)- methyltetrazole (12b), were synthesized conveniently from 5,6-dichloroindan-1-carboxylic acid (9a) and 5,6- dichloroindan-1-acetic acid (9b), respectively, as potential analgesic and anti-inflammatory agents. The analgesic and anti-inflammatory properties of 9a, 9b, 12a and 12b were evaluated by the acetic acid induced writhing in Swiss albino mice and the carrageenan-induced rat paw edema models, respectively. Compounds 9a and 12a exhibited significant analgesic activity with the doses of 50 and 100 mg/kg body weight, comparable to that of the positive controls, phenylbutazone, indomethacin and aminopyrine. The anti-inflammatory potencies of 9a and 12a were also comparable to that of the positive control, phenylbutazone. Compounds 9b and 12b showed analgesic and anti-inflammatory activities, but were weaker than that of compounds 9a and 12a.


Assuntos
Analgésicos/síntese química , Anti-Inflamatórios/síntese química , Edema/tratamento farmacológico , Indanos/síntese química , Dor/tratamento farmacológico , Tetrazóis/síntese química , Ácido Acético , Aminopirina/farmacologia , Analgésicos/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Carragenina , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Indanos/farmacologia , Indometacina/farmacologia , Camundongos , Dor/induzido quimicamente , Medição da Dor , Fenilbutazona/farmacologia , Ratos , Relação Estrutura-Atividade , Tetrazóis/farmacologia
13.
Am J Vet Res ; 73(1): 98-104, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22204294

RESUMO

OBJECTIVE: To assess gene expressions of cyclooxygenase-1 and -2 in oral, glandular gastric, and urinary bladder mucosae and determine the effect of oral administration of phenylbutazone on those gene expressions in horses. ANIMALS: 12 healthy horses. PROCEDURES: Horses were allocated to receive phenylbutazone or placebo (6 horses/group); 1 placebo-treated horse with a cystic calculus was subsequently removed from the study, and those data were not analyzed. In each horse, the stomach and urinary bladder were evaluated for ulceration via endoscopy before and after experimental treatment. Oral, glandular gastric, and urinary bladder mucosa biopsy specimens were collected by use of a skin punch biopsy instrument (oral) or transendoscopically (stomach and bladder) before and after administration of phenylbutazone (4.4 mg/kg, p.o., q 12 h) in corn syrup or placebo (corn syrup alone) for 7 days. Cyclooxygenase-1 and -2 gene expressions were determined (via quantitative PCR techniques) in specimens collected before and after the 7-day treatment period and compared within and between groups. Prior to commencement of treatment, biopsy specimens from 7 horses were used to compare gene expressions among tissues. RESULTS: The cyclooxygenase-1 gene was expressed in all tissues collected. The cyclooxygenase-2 gene was expressed in the glandular gastric and bladder mucosae but not in the oral mucosa. Cyclooxygenase gene expressions were unaffected by phenylbutazone administration. CONCLUSIONS AND CLINICAL RELEVANCE: Cyclooxygenase-2 was constitutively expressed in glandular gastric and bladder mucosae but not in the oral mucosa of healthy horses. Oral administration of phenylbutazone at the maximum recommended dosage daily for 7 days did not affect cyclooxygenase-1 or -2 gene expression.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Ciclo-Oxigenase 1/genética , Ciclo-Oxigenase 2/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Cavalos/metabolismo , Membrana Mucosa/efeitos dos fármacos , Fenilbutazona/farmacologia , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Cistoscopia/veterinária , Feminino , Gastroscopia/veterinária , Masculino , Boca/efeitos dos fármacos , Boca/patologia , Membrana Mucosa/patologia , Fenilbutazona/administração & dosagem , Reação em Cadeia da Polimerase/veterinária , RNA Mensageiro/metabolismo , Estômago/efeitos dos fármacos , Estômago/patologia , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/patologia
14.
Gen Comp Endocrinol ; 174(2): 225-31, 2011 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-21933675

RESUMO

A model of thyroidectomized sheep intravenously supplemented with thyroid hormone (TH) was developed to mimic endogenous TH exposure and to analyze the impact on plasma TH homeostasis of xenobiotic interference with TH binding to plasma proteins. TH was displaced from plasma protein binding sites by using phenylbutazone (PBZ) as a test xenobiotic, to compare the effect of PBZ on steady state free and total plasma TH concentrations between the in vivo situation and an in vitro system. While PBZ increased free TH in vitro, PBZ administration in vivo produced an immediate reduction in both total and free plasma TH. The decrease in the total TH was consistent with a PBZ-induced displacement of TH from its plasma binding proteins, leading to an increase in total TH plasma clearance. However, this reduction in total TH was not expected to be accompanied by a parallel decrease in free plasma TH since the free TH is determined by the clearance of the free plasma TH. This suggested that PBZ may also have interfered with the clearance mechanisms of free TH. It can be concluded that our thyroidectomized sheep model enables a dual action of a xenobiotic on plasma TH to be distinguished, namely a displacement of TH from its binding proteins leading to a decrease in the total plasma concentration, which is not relevant to thyroid function versus an interference with the intrinsic TH clearance leading to a change in the free plasma TH, which has a major impact in terms of thyroid disruption.


Assuntos
Fenilbutazona/farmacologia , Glândula Tireoide/efeitos dos fármacos , Glândula Tireoide/metabolismo , Hormônios Tireóideos/sangue , Animais , Feminino , Fenilbutazona/farmacocinética , Ovinos , Tiroxina/sangue , Tri-Iodotironina/sangue
15.
Vet Anaesth Analg ; 38(5): 505-9, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21831057

RESUMO

OBJECTIVE: To characterize the cardiorespiratory and electrocardiographic effects of the combined administration of phenylbutazone and romifidine. STUDY DESIGN: Prospective four-period, four-treatment, blinded, randomized, crossover trial. ANIMALS: Five, healthy, mixed breed horses. METHODS: Prior to treatment administration, a catheter was introduced into the intra-thoracic cranial vena cava via the jugular vein and a subcutaneously located carotid artery was catheterised. All treatments were administered intravenously (IV) and consisted of saline placebo (PLC), phenylbutazone (PBZ, 4.4 mg kg(-1) ) romifidine (ROM, 80 µg kg(-1) ) and a combination of phenylbutazone (4.4 mg kg(-1) ) and romifidine (80 µg kg(-1) ). There was at least a 1 week washout period between treatments. Heart rate (HR), respiratory rate (f(R) ), systolic (SAP), diastolic (DAP) and mean (MAP) arterial pressures and central venous pressure (CVP) were recorded for baseline (prior to drug administration) and at 5 minute intervals thereafter for 30 minutes. Electrocardiographic abnormalities were recorded. Data were analyzed by anova. RESULTS: For the cardiovascular variables there were no statistically significant (p>0.05) differences between horses treated with ROM and PBZ_ROM. Statistically significant (p<0.05) differences only occurred between treatments with romifidine (ROM and PBZ_ROM) and without romifidine (PLC and PBZ). Within treatments, for ROM, changes over time were statistically significant (p<0.05) for HR, SAP, DAP, MAP and CVP. For PBZ_ROM, changes over time were statistically significant (p<0.05) for CVP. Sino-atrial and atrio-ventricular blocks occurred in horses treated with ROM and PBZ_ROM. CONCLUSIONS AND CLINICAL RELEVANCE: The combined IV administration of phenylbutazone and romifidine had no statistically significant effect on cardiorespiratory variables. These limited data suggest no evidence why both agents should not be included in a preoperative medication protocol for healthy horses but do not exclude the possibility of interactions occurring in a larger population.


Assuntos
Anestesia Intravenosa/veterinária , Anestésicos Combinados/administração & dosagem , Anestésicos Intravenosos/administração & dosagem , Imidazóis/administração & dosagem , Fenilbutazona/administração & dosagem , Anestesia Intravenosa/métodos , Anestésicos Combinados/farmacologia , Anestésicos Intravenosos/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Cavalos , Imidazóis/farmacologia , Fenilbutazona/farmacologia , Taxa Respiratória/efeitos dos fármacos
16.
Trop Anim Health Prod ; 43(7): 1389-93, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21503752

RESUMO

PURPOSE: The purpose of this study was to evaluate the brain, renal, and hepatic effects of three NSAIDs (flunixin meglumine, ketoprofen, and phenylbutazone) when administered IV to clinically normal Iranian fat-tailed sheep. METHODS: The experiments were conducted on twenty clinically normal adult female sheep. Sheep were randomly assigned to four groups: saline (n = 5), flunixin meglumine (n = 5), ketoprofen (n = 5), and phenylbutazone (n = 5). Drug administration was initiated at 8 AM: on day 1 and continued every 12 h for 12 days. Flunixin meglumine, ketoprofen, and phenylbutazone were administered at dose rate of 2.2, 4, and 4 mg/kg, respectively. Daily blood and urine samples were collected from all sheep for hematologic, enzymes activity, and urinalysis. Immediately after euthanasia, complete necropsy was performed on all sheep and gross lesions were recorded. RESULTS: Clinical, hematological, serum, and urine analysis and histopatholgical findings were described. CONCLUSION: When the use of these compounds is contemplated in clinical cases, the risk of adverse effects and the comparative toxic potential should be considered, along with the efficacy of the compound for the condition being treated.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Encéfalo/efeitos dos fármacos , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Carneiro Doméstico , Drogas Veterinárias/farmacologia , Análise de Variância , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Análise Química do Sangue , Clonixina/administração & dosagem , Clonixina/análogos & derivados , Clonixina/farmacologia , Feminino , Irã (Geográfico) , Cetoprofeno/administração & dosagem , Cetoprofeno/farmacologia , Fenilbutazona/administração & dosagem , Fenilbutazona/farmacologia , Urinálise , Drogas Veterinárias/administração & dosagem
17.
Nephrology (Carlton) ; 16(2): 156-62, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21272127

RESUMO

AIM: Hyperuricaemia is a significant factor in a variety of diseases, including gout and cardiovascular diseases. The kidney plays a dominant role in maintaining plasma urate levels through the excretion process. Human renal urate transporter URAT1 is thought to be an essential molecule that mediates the reabsorption of urate on the apical side of the proximal tubule. In this study the pharmacological characteristics and clinical implications of URAT1 were elucidated. METHODS: Madin-Darby canine kidney (MDCK) cells stably expressing URAT1 (MDCK-URAT1) were established and examined the interactions of URAT1 with various drugs such as benzbromarone and its metabolites including 6-hydroxybenzbromarone, angiotensin-converting enzyme inhibitors, non-steroidal anti-inflammatory drugs and urate transport inhibitors including E3040 and probenecid. RESULTS: MDCK-URAT1 cells exhibited a time- and dose-dependent increase in urate uptake, with a Km value of 570.7 µmol/L. When an URAT1-green fluorescent protein fusion protein construct was expressed in MDCK cells, the protein was sorted mainly to the apical side of the membrane. The drugs except for captoril dose-dependently inhibited urate uptake mediated by URAT1, with half maximal inhibitory concentration (IC(50) ) values ranging 0.05-716 µmol/L. CONCLUSION: Comparing these IC(50) values with intratubular concentrations of unbound drugs in humans, it is thought that URAT1 is a target molecule of uricosuric drugs, including 6-hydroxybenzbromarone, probenecid, indomethacin and salicylate, to inhibit urate reabsorption in vivo. In addition, a cell line that stably expressing URAT1 could be a useful tool for the development of uricosuric drugs.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Transportadores de Ânions Orgânicos/metabolismo , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Ácido Úrico/metabolismo , Uricosúricos/farmacologia , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Benzobromarona/análogos & derivados , Benzobromarona/farmacologia , Benzotiazóis/farmacologia , Transporte Biológico/efeitos dos fármacos , Captopril/farmacologia , Células Cultivadas , Cães , Enalapril/farmacologia , Indometacina/farmacologia , Concentração Inibidora 50 , Fenilbutazona/farmacologia , Probenecid/farmacologia , Piridinas/farmacologia , Salicilatos/farmacologia , Sulfimpirazona/farmacologia , Uricosúricos/administração & dosagem
18.
Comb Chem High Throughput Screen ; 14(4): 267-78, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21143179

RESUMO

Spatially addressable combinatorial libraries were synthesized by solution phase chemistry and screened for binding to human serum albumin. Members of arylidene diamide libraries were among the best hits found, having submicromolar binding affinities. The results were analyzed by the frequency with which particular substituents appeared among the most potent compounds. After immobilization of the ligands either through the oxazolone or the amine substituent, characterization by surface plasmon resonance showed that ibuprofen affected the binding kinetics, but phenylbutazone did not. It is therefore likely that these compounds bind to Site 2 in sub domain IIIA of human serum albumin (HSA).


Assuntos
Cromatografia de Afinidade/métodos , Técnicas de Química Combinatória , Ligantes , Albumina Sérica/metabolismo , Sítios de Ligação/efeitos dos fármacos , Ligação Competitiva , Reagentes para Ligações Cruzadas , Ensaios de Triagem em Larga Escala , Humanos , Ibuprofeno/farmacologia , Cinética , Oxazolona/química , Fenilbutazona/farmacologia , Ligação Proteica , Estrutura Terciária de Proteína , Albumina Sérica/química , Ressonância de Plasmônio de Superfície
19.
Cell Biol Int ; 35(3): 235-48, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21087205

RESUMO

In equine medicine, stem cell therapies for orthopaedic diseases are routinely accompanied by application of NSAIDs (non-steroidal anti-inflammatory drugs). Thus, it has to be analysed how NSAIDs actually affect the growth and differentiation potential of MSCs (mesenchymal stem cells) in vitro in order to predict the influence of NSAIDs such as phenylbutazone, meloxicam, celecoxib and flunixin on MSCs after grafting in vivo. The effects of NSAIDs were evaluated regarding cell viability and proliferation. Additionally, the multilineage differentiation capacity and cell migration was analysed. NSAIDs at lower concentrations (0.1-1 µM for celecoxib and meloxicam and 10-50 µM for flunixin) exert a positive effect on cell proliferation and migration, while at higher concentrations (10-200 µM for celecoxib and meloxicam and 100-1000 µM for flunixin and phenylbutazone), there is rather a negative influence. While there is hardly any influence on the adipogenic as well as on the chondrogenic MSC differentiation, the osteogenic differentiation potential, as demonstrated with the von Kossa staining, is significantly disturbed. Thus, it can be concluded that the effects of NSAIDs on MSCs are largely dependent on the concentrations used. Additionally, for some differentiation lineages, also the choice of NSAID is critical.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Agrecanas/genética , Agrecanas/metabolismo , Animais , Células da Medula Óssea/citologia , Celecoxib , Diferenciação Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Clonixina/análogos & derivados , Clonixina/farmacologia , Colágeno Tipo II/genética , Colágeno Tipo II/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Feminino , Cavalos , Masculino , Meloxicam , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Fenilbutazona/farmacologia , Pirazóis/farmacologia , Sulfonamidas/farmacologia , Tiazinas/farmacologia , Tiazóis/farmacologia
20.
Artigo em Inglês | MEDLINE | ID: mdl-19615934

RESUMO

The monitoring of drug concentration in blood serum is necessary in multi-drug therapy. Mechanism of drug binding with serum albumin (SA) is one of the most important factors which determine drug concentration and its transport to the destination tissues. In rheumatoid diseases drugs which can induce various adverse effects are commonly used in combination therapy. Such proceeding may result in the enhancement of those side effects due to drug interaction. Interaction of phenylbutazone and colchicine in binding to serum albumin and competition between them in gout has been studied by proton nuclear magnetic resonance ((1)H NMR) technique. The aim of the study was to determine the low affinity binding sites, the strength and kind of interaction between serum albumin and drugs used in combination therapy. The study of competition between phenylbutazone and colchicine in binding to serum albumin points to the change of their affinity to serum albumin in the ternary systems. This should be taken into account in multi-drug therapy. This work is a subsequent part of the spectroscopic study on Phe-COL-SA interactions [A. Sulkowska, et al., J. Mol. Struct. 881 (2008) 97-106].


Assuntos
Colchicina/administração & dosagem , Colchicina/metabolismo , Fenilbutazona/administração & dosagem , Fenilbutazona/metabolismo , Doenças Reumáticas/tratamento farmacológico , Albumina Sérica/metabolismo , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Colchicina/farmacologia , Combinação de Medicamentos , Interações Medicamentosas , Humanos , Imageamento por Ressonância Magnética/métodos , Modelos Biológicos , Fenilbutazona/farmacologia , Ligação Proteica/efeitos dos fármacos , Prótons , Doenças Reumáticas/sangue , Doenças Reumáticas/metabolismo
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