RESUMO
Previous reports have warned about the influence of spinal cord injury (SCI) on the pharmacokinetics of various drugs. However, the role of SCI in the efficacy and safety of pharmacotherapy remains unknown. Thereby, our aim was to explore the role of SCI on pharmacokinetics and anti-inflammatory effect of naproxen in response to a local inflammatory challenge. Rats received a severe contusive SCI at T9 or sham injury. Pharmacokinetics of a single intravenous dose of naproxen (10 mg kg-1) was studied at days 1 and 15 post-surgery. For the anti-inflammatory assessment, carrageenan was subcutaneously injected in forelimb and hindlimb paws at the same post-surgery periods, and naproxen efficacy was evaluated measuring paw swelling. Plasma protein concentrations and body weight changes were also determined. Plasma naproxen levels and pharmacokinetic parameters were unchanged by acute injury, but subacute injury generated alterations in volume of distribution, clearance, and bioavailability, resulting in significantly reduced plasma naproxen concentrations, in the absence of changes in plasma proteins. Assessment of naproxen anti-inflammatory activity during the acute stage of injury could not be determined because of carrageenan failure to elicit swelling. During the subacute stage, naproxen anti-inflammatory effect on forelimbs (above injury) was similar to that observed in sham-injured animals, while it was almost absent in paralyzed hindlimbs. Under conditions of SCI and peripheral inflammation, pharmacokinetics and anti-inflammatory activity of naproxen vary according to post-injury timing and neurological status of the assessed region.
Assuntos
Anti-Inflamatórios não Esteroides/sangue , Anti-Inflamatórios não Esteroides/uso terapêutico , Naproxeno/sangue , Naproxeno/uso terapêutico , Traumatismos da Medula Espinal/sangue , Traumatismos da Medula Espinal/tratamento farmacológico , Animais , Feminino , Mediadores da Inflamação/sangue , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Vértebras Torácicas/lesões , Resultado do TratamentoRESUMO
Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used by the general population to alleviate inflammation and pain after oral surgeries. Piroxicam is among the most commonly used NSAIDs and excels in controlling pain, swelling, trismus and other common symptoms of inflammation. This study aimed to evaluate different concentrations of piroxicam and its major metabolite, 5'-hydroxypiroxicam, in human plasma samples over time using high performance liquid chromatography (HPLC) after liquid-liquid extraction. Briefly, 10 volunteers participated in this study after approval by the Ethics Committee of Bauru School of Dentistry, Universidade de São Paulo - USP, Brazil. Volunteers received a single dose oral of piroxicam (20 mg) and had blood collected at various times following an established protocol. The methodology of liquid-liquid extraction was effective for determining concentrations of piroxicam in plasma using HPLC in 10 out of 10 volunteers while 5'-hydroxypiroxicam was only detected in 2 out of 10 volunteers.
Assuntos
Anti-Inflamatórios não Esteroides/sangue , Cromatografia Líquida de Alta Pressão/métodos , Extração Líquido-Líquido/métodos , Piroxicam/análogos & derivados , Piroxicam/sangue , Anti-Inflamatórios não Esteroides/farmacocinética , Humanos , Naproxeno/sangue , Naproxeno/farmacocinética , Piroxicam/farmacocinética , Valores de Referência , Reprodutibilidade dos Testes , Fatores de TempoRESUMO
A sensitive and fast liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) method was developed and validated for the simultaneous quantification of naproxen and sumatriptan in human plasma. A simple liquid-liquid extraction procedure, with a mixture of ethyl acetate, methyl tert-butyl ether, and dichloromethane (4:3:3, v/v), was used for the cleanup of plasma. Naratriptan and aceclofenac were employed as internal standards. The analyses were carried out using an ACE C18 column (50 × 4.6 mm i.d.; particle size 5 µm) and a mobile phase consisting of 2 mM aqueous ammonium acetate with 0.025 % formic acid and methanol (38:62, v/v). A triple-quadrupole mass spectrometer equipped with an electrospray source in the positive mode was set up in the selective reaction monitoring mode to detect the ion transitions m/z 231.67 â m/z 185.07, m/z 296.70 â m/z 157.30, m/z 354.80 â m/z 215.00, and m/z 336.80 â m/z 97.94 for naproxen, sumatriptan, aceclofenac, and naratriptan, respectively. The method was validated and proved to be linear, accurate, precise, and selective over the ranges of 2.5-130 µg mL(-1) for naproxen and 1-50 ng mL(-1) for sumatriptan. The validated method was successfully applied to a pharmacokinetic study with simultaneous administration of naproxen sodium and sumatriptan succinate tablet formulations in healthy volunteers.
Assuntos
Cromatografia Líquida/métodos , Naproxeno/sangue , Sumatriptana/sangue , Espectrometria de Massas em Tandem/métodos , Humanos , Naproxeno/farmacocinética , Plasma/química , Sumatriptana/farmacocinéticaRESUMO
Abstract Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used by the general population to alleviate inflammation and pain after oral surgeries. Piroxicam is among the most commonly used NSAIDs and excels in controlling pain, swelling, trismus and other common symptoms of inflammation. This study aimed to evaluate different concentrations of piroxicam and its major metabolite, 5'-hydroxypiroxicam, in human plasma samples over time using high performance liquid chromatography (HPLC) after liquid-liquid extraction. Briefly, 10 volunteers participated in this study after approval by the Ethics Committee of Bauru School of Dentistry, Universidade de São Paulo - USP, Brazil. Volunteers received a single dose oral of piroxicam (20 mg) and had blood collected at various times following an established protocol. The methodology of liquid-liquid extraction was effective for determining concentrations of piroxicam in plasma using HPLC in 10 out of 10 volunteers while 5'-hydroxypiroxicam was only detected in 2 out of 10 volunteers.
Assuntos
Humanos , Piroxicam/análogos & derivados , Piroxicam/sangue , Anti-Inflamatórios não Esteroides/sangue , Cromatografia Líquida de Alta Pressão/métodos , Extração Líquido-Líquido/métodos , Valores de Referência , Fatores de Tempo , Piroxicam/farmacocinética , Anti-Inflamatórios não Esteroides/farmacocinética , Naproxeno/sangue , Naproxeno/farmacocinética , Reprodutibilidade dos TestesRESUMO
Naproxen was loaded in poly-caprolactone (PCL) nanoparticles as an implantable sustained release system to prolong its anti-inflammatory activity. Naproxen-loaded nanoparticles were produced with the following characteristics: Nanometric size (< 300 nm), negative zeta potential, low polydispersity index (< 0.1), satisfactory encapsulation efficiency, low water content (< 1%), and spherical shape. In vitro naproxen release profile was sustained and the kinetic followed the Higuchi model. The PCL nanoparticles containing about 12.5% (w/w) of the naproxen (sample A3) was chosen for complementary studies of stability and in vivo release in rats. Nanoparticles did not suffer alteration during stability studies. In vivo release was sustained by one month. Thus, nanoparticles showed potential to act as an implantable sustained release system for chronic inflammatory diseases use.
Assuntos
Anti-Inflamatórios não Esteroides , Portadores de Fármacos/química , Nanopartículas/química , Naproxeno , Poliésteres/química , Tecnologia Farmacêutica/métodos , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/sangue , Anti-Inflamatórios não Esteroides/química , Cromatografia Líquida de Alta Pressão , Estabilidade de Medicamentos , Masculino , Modelos Químicos , Naproxeno/administração & dosagem , Naproxeno/sangue , Naproxeno/química , Tamanho da Partícula , Ratos , Ratos Wistar , SolubilidadeRESUMO
The bioavailability of naproxen sodium (CAS 26159-34-2) after administration of two oral suspensions, reference or test (Pactens), was compared in 24 healthy subjects. The volunteers received an oral dose of 250 mg (10 ml) in two separate sessions under fasting conditions according to a randomized cross-over design and blood samples were obtained at selected times for a period of 72 h. Plasma samples were analyzed by a high-performance liquid chromatographic method for determination of naproxen. Individual plasma concentration against time curves were constructed and pharmacokinetic parameters were obtained by non-compartmental techniques. The parameters obtained (mean +/- S.E.M.) were: C(max) 43.93 +/- 1.83 and 44.91 +/- 2.15 microg/ml, t(max) 2.38 +/- 0.21 and 1.83 < or = 0.19 h, AUC(72 h) 721.73 +/- 18.47 and 722.55 +/- 19.07 microg x h/ml for reference and test formulations, respectively. Maximal concentration, AUC(72 h) and AUC(infinity). were log transformed and compared by analysis of variance and ratios; in addition, 90% confidence limits were obtained. As confidence limits were included in the 80-125% range and the probability of exceeding these intervals was always lower than 0.05, it is concluded that the formulations tested are bioequivalent.
Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/farmacocinética , Naproxeno/administração & dosagem , Naproxeno/farmacocinética , Adulto , Anti-Inflamatórios não Esteroides/sangue , Área Sob a Curva , Disponibilidade Biológica , Química Farmacêutica , Cromatografia Líquida de Alta Pressão , Estudos Cross-Over , Meia-Vida , Humanos , Indicadores e Reagentes , Masculino , México , Naproxeno/sangue , Espectrofotometria Ultravioleta , SuspensõesRESUMO
A rapid and sensitive method for the determination of naproxen and salicylate in serum is presented. The employed strategy combines solid-phase extraction on a reverse-phase membrane with spectrofluorimetry. Solid-phase extraction under optimum pH conditions makes NX to be retained over the solid surface (where it is directly determined by a fluorimetric technique). Salicylate passes through the disk and is also fluorimetrically determined, but in solution. The linear calibration ranges for NX in the membrane and salicylate in solution were 0.014-0.250 and 0.010-0.250 microg ml(-1), respectively. The lowest value, in each case, is the corresponding limit of quantitation. The performance of the method is demonstrated with the successful determination of both drugs in spiked and real human serum samples.
Assuntos
Naproxeno/sangue , Salicilatos/sangue , Fluorometria/métodos , Humanos , Naproxeno/química , Salicilatos/química , TemperaturaRESUMO
First- and second-order multivariate calibration of fluorescence data have been compared as regards the determination of anti-inflammatories and metabolites in the biological fluids serum and urine. The simultaneous resolution of naproxen-salicylic acid mixtures in serum and naproxen-salicylic acid-salicyluric acid mixtures in urine was accomplished and employed for a discussion of the relative advantages of the applied chemometric tools. The analysis of second-order fluorescence excitation-emission matrices was performed using iteratively reweighted generalized rank annihilation method (IRGRAM), parallel factor analysis (PARAFAC), and self-weighted alternating trilinear decomposition (SWATLD). The results were compared with first-order fluorescence emission data analyzed with partial least-squares regression (PLS). In all cases, the performance of the methods was improved through the formation of inclusion complexes of the analytes with beta-cyclodextrin. The concentration ranges in which the analytes could be determined were as follows: naproxen, 0-250 ng mL(-1) in serum and 0-200 ng mL(-1) in urine; salicylic acid, 0-500 ng mL(-1) in serum and 0-300 ng mL(-1) in urine, and salicyluric acid, 0-300 ng mL(-1) in urine.
Assuntos
Anti-Inflamatórios não Esteroides/sangue , Anti-Inflamatórios não Esteroides/urina , Espectrometria de Fluorescência/métodos , beta-Ciclodextrinas , Calibragem , Ciclodextrinas/química , Hipuratos/urina , Humanos , Análise dos Mínimos Quadrados , Análise Multivariada , Naproxeno/sangue , Naproxeno/urina , Ácido Salicílico/sangue , Ácido Salicílico/urina , Espectrometria de Fluorescência/normasRESUMO
A rapid and sensitive method for the determination of diclofenac (CAS 15307-86-5) in whole blood samples by high-performance liquid chromatography with amperometric detection has been developed. This method was then used to study the pharmacokinetics of oral diclofenac sodium in the rat. The method includes a single extraction of acidified whole blood with ethyl acetate. Extracts were analyzed on a reversed-phase column eluted with a mixture of acetonitrile and 0.075 mol/l sodium acetate solution (pH 3.3) and detected amperometrically at + 1.1 V against Ag/AgCl. Retention times for diclofenac and the internal standard (naproxen) were 3.5 and 6 min, respectively. The method was linear in the range of 25 to 2000 ng/ml and the detection limit of the method was 10 ng/ml, using 100 microliters of whole blood sample. Employing this method, the oral pharmacokinetics of diclofenac in the rat was studied. Wistar male rats received an oral dose of 1, 3.2 or 10 mg/kg of diclofenac and blood samples were drawn at selected times during 12 h. After administration of diclofenac, a rapid increase of circulating concentrations was observed reaching a maximum in about 10 min. Then concentration decayed with a half-life of about 15 h. It is concluded that the method here reported is adequate for realization of pharmacokinetic studies of diclofenac in small species.
Assuntos
Anti-Inflamatórios não Esteroides/sangue , Diclofenaco/sangue , Animais , Anti-Inflamatórios não Esteroides/farmacocinética , Área Sob a Curva , Calibragem , Cromatografia Líquida de Alta Pressão , Diclofenaco/farmacocinética , Eletroquímica , Meia-Vida , Masculino , Naproxeno/sangue , Naproxeno/farmacocinética , Ratos , Ratos WistarRESUMO
In this work we show that the pain-induced functional impairment model (PIFIR) can be used with cannulated rats as a useful procedure for pharmacokinetic/pharmacodynamic modelling. This model evaluates analgesia by measuring motor impairment of the right limb after intra-articular administration of uric acid. Time of contact with a rotating cylinder is referred to the control limb. We studied the pharmacokinetic and pharmacodynamics of naproxen after six peroral doses to Wistar rats, and we examined the adjuvant action of caffeine with naproxen. Surgery and blood sampling did not produce any difference on functional impairment either in rats without uric acid or in the dysfunction produced by uric acid. The relation between naproxen plasma concentration and the analgesic effect was obtained with few rats. Caffeine alone did not produce any significant modification in functional impairment but the co-administration significantly increased the effect of naproxen. Plasma levels of naproxen did not change when caffeine was co-administered. The PIFIR model with blood sampling is a suitable method for pharmacokinetic/pharmacodynamic relationship studies and is specially useful to characterize drug-drug interactions.