RESUMEN
The toxicity for the human body of non-steroidal anti-inflammatory drugs (NSAIDs) overdoses is a consequence of their low water solubility, high doses, and facile accessibility to the population. New drug delivery systems (DDS) are necessary to overcome the bioavailability and toxicity related to NSAIDs. In this context, UiO-66(Zr) metal-organic framework (MOF) shows high porosity, stability, and load capacity, thus being a promising DDS. However, the adsorption and release capability for different NSAIDs is scarcely described. In this work, the biocompatible UiO-66(Zr) MOF was used to study the adsorption and release conditions of ibuprofen, naproxen, and diclofenac using a theoretical and experimental approximation. DFT results showed that the MOF-drug interaction was due to an intermolecular hydrogen bond between protons of the groups in the defect sites, (µ3 - OH, and - OH2) and a lone pair of oxygen carboxyl functional group of the NSAIDs. Also, the experimental results suggest that the solvent where the drug is dissolved affects the adsorption process. The adsorption kinetics are similar between the drugs, but the maximum load capacity differs for each drug. The release kinetics assay showed a solvent dependence kinetics whose maximum liberation capacity is affected by the interaction between the drug and the material. Finally, the biological assays show that none of the systems studied are cytotoxic for HMVEC. Additionally, the wound healing assay suggests that the UiO-66(Zr) material has potential application on the wound healing process. However, further studies should be done.
Asunto(s)
Antiinflamatorios no Esteroideos , Sistemas de Liberación de Medicamentos , Liberación de Fármacos , Estructuras Metalorgánicas , Naproxeno , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/farmacocinética , Antiinflamatorios no Esteroideos/química , Estructuras Metalorgánicas/química , Naproxeno/administración & dosificación , Naproxeno/química , Naproxeno/farmacocinética , Ibuprofeno/administración & dosificación , Ibuprofeno/química , Ibuprofeno/farmacocinética , Humanos , Adsorción , Portadores de Fármacos/química , Diclofenaco/administración & dosificación , Diclofenaco/química , Diclofenaco/farmacocinética , Supervivencia Celular/efectos de los fármacos , Ácidos FtálicosRESUMEN
Naproxen is a widely used non-steroidal anti-inflammatory drug for the control of postoperative inflammatory signs and symptoms in dentistry. Its association with esomeprazole has been widely studied and has yielded good results for the control of acute pain, even with the delayed absorption of naproxen owing to the presence of esomeprazole. To further understand the absorption, distribution, and metabolism of this drug alone and in combination with esomeprazole, we will analyze the pharmacokinetic parameters of naproxen and its major metabolite, 6-O-desmethylnaproxen, in saliva samples. A rapid, sensitive, and selective liquid chromatography-tandem mass spectrometric method for the simultaneous determination of naproxen and 6-O-desmethylnaproxen in saliva will be developed and validated. Sequential saliva samples from six patients will be analyzed before and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6 8, 11, 24, 48, 72, and 96 h after the ingestion of one naproxen tablet (500 mg) and esomeprazole-associated naproxen tablets (500 + 20 mg), at two different times. After liquid-liquid extraction with ethyl acetate and HCl, the samples will be analyzed using an 8040 Triple Quadrupole Mass Spectrometer (Shimadzu, Kyoto, Japan). Separation of naproxen and its major metabolic products will be performed using a Shim-Pack XR-ODS 75Lx2.0 column and C18 pre-column (Shimadzu, Kyoto, Japan) at 40°C using a mixture of methanol and 10 mM ammonium acetate (70:30, v/v) with an injection flow of 0.3 mL/min. The total analytical run time will be 5 min. The detection and quantification of naproxen and its metabolite will be validated, which elucidate the pharmacokinetics of this drug, thereby contributing to its proper prescription for the medical and dental interventions that cause acute pain.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacocinética , Monitoreo de Drogas/métodos , Esomeprazol/farmacocinética , Naproxeno/análogos & derivados , Saliva/química , Administración Oral , Adolescente , Adulto , Antiinflamatorios no Esteroideos/aislamiento & purificación , Cromatografía Líquida de Alta Presión/métodos , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Esomeprazol/administración & dosificación , Esomeprazol/aislamiento & purificación , Femenino , Absorción Gastrointestinal , Humanos , Masculino , Metanol/química , Persona de Mediana Edad , Naproxeno/administración & dosificación , Naproxeno/aislamiento & purificación , Naproxeno/farmacocinética , Dolor Asociado a Procedimientos Médicos/tratamiento farmacológico , Reproducibilidad de los Resultados , Comprimidos , Espectrometría de Masas en Tándem/métodos , Adulto JovenRESUMEN
Adsorption behavior of pure enantiomers and racemic mixtures of nonsteroidal anti-inflammatory drugs (ibuprofen and naproxen) on human serum albumin (HSA) was evaluated. The HSA was immobilized by Sol-Gel technique and this biomaterial was used in a chromatographic system where frontal analysis experiments were performed at pH 7.4 and temperatures of 25°C and 37°C. The association constants for enantiomers of the drugs were determined by linear adjustment for data corrected just for dead volume. In uncorrected data for non-specific retention, an inverse ratio between the number of sites and the value of the association constant was found. The participation of non-specific retention was estimated by non-linear regression and the values of association constants (Kass), which were determined considering this information, are comparable to some values reported by other methods at 37°C: 1.4 x105 and 5.7 x104 for Ibuprofen (IBU) R and S, respectively, and 2.3 x105 and 1.8x105 for naproxen (NX) R and S, respectively.
Asunto(s)
Albúmina Sérica Humana/farmacocinética , Antiinflamatorios no Esteroideos/farmacocinética , Humanos , Ibuprofeno/farmacocinética , Naproxeno/farmacocinética , Transición de Fase , Albúmina Sérica Humana/química , EstereoisomerismoRESUMEN
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.
Asunto(s)
Antiinflamatorios no Esteroideos/sangre , Cromatografía Líquida de Alta Presión/métodos , Extracción Líquido-Líquido/métodos , Piroxicam/análogos & derivados , Piroxicam/sangre , Antiinflamatorios no Esteroideos/farmacocinética , Humanos , Naproxeno/sangre , Naproxeno/farmacocinética , Piroxicam/farmacocinética , Valores de Referencia , Reproducibilidad de los Resultados , Factores de TiempoRESUMEN
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.
Asunto(s)
Cromatografía Liquida/métodos , Naproxeno/sangre , Sumatriptán/sangre , Espectrometría de Masas en Tándem/métodos , Humanos , Naproxeno/farmacocinética , Plasma/química , Sumatriptán/farmacocinéticaRESUMEN
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.
Asunto(s)
Humanos , Piroxicam/análogos & derivados , Piroxicam/sangre , Antiinflamatorios no Esteroideos/sangre , Cromatografía Líquida de Alta Presión/métodos , Extracción Líquido-Líquido/métodos , Valores de Referencia , Factores de Tiempo , Piroxicam/farmacocinética , Antiinflamatorios no Esteroideos/farmacocinética , Naproxeno/sangre , Naproxeno/farmacocinética , Reproducibilidad de los ResultadosRESUMEN
This study investigated the effects of nanosuspension and inclusion complex techniques on in vitro trypsin inhibitory activity of naproxen—a member of the propionic acid derivatives, which are a group of antipyretic, analgesic, and non-steroidal anti-inflammatory drugs. Nanosuspension and inclusion complex techniques were used to increase the solubility and anti-inflammatory efficacy of naproxen. The evaporative precipitation into aqueous solution (EPAS) technique and the kneading methods were used to prepare the nanosuspension and inclusion complex of naproxen, respectively. We also used an in vitro protease inhibitory assay to investigate the anti-inflammatory effect of modified naproxen formulations. Physiochemical properties of modified naproxen formulations were analyzed using UV, IR spectra, and solubility studies. Beta-cyclodextrin inclusion complex of naproxen was found to have a lower percentage of antitryptic activity than a pure nanosuspension of naproxen did. In conclusion, nanosuspension of naproxen has a greater anti-inflammatory effect than the other two tested formulations. This is because the nanosuspension formulation reduces the particle size of naproxen. Based on these results, the antitryptic activity of naproxen nanosuspension was noteworthy; therefore, this formulation can be used for the management of inflammatory disorders.
O objetivo do presente estudo foi investigar a atividade anti-inflamatória in vitro de nanossuspensões e do complexo de inclusão contendo naproxeno. Esse fármaco é derivado de ácido propiônico, com ação analgésica, antipirética e antiinflamatória. A obtenção dessas formulações teve por finalidade o aumento da solubilidade e da atividade anti-inflamatória do fármaco. Os métodos por precipitação em solução aquosa por evaporação e por empastagem foram modificados para a obtenção da nanossuspensão e do complexo de inclusão, respectivamente. Para a avaliação da atividade anti-inflamatória das formulações utilizou-se ensaio in vitro modificado de inibição de tripsina. As propriedades físico-químicas das formulações propostas foram determinadas utilizando espectroscopia UV e de infravermelho, além de estudos de solubilidade. O complexo de inclusão de naproxeno apresentou menor atividade antitripsina, quando comparado ao composto livre e à nanossuspensão. Em conclusão, entre as formulações avaliadas, a nanossuspensão de naproxeno apresentou maior efeito anti-inflamatório. Esse efeito foi devido à redução da dimensão das partículas de naproxeno para a escala nanométrica. Com base nos resultados obtidos, a atividade da nanossuspensão de naproxeno foi notável. Dessa forma, essa formulação apresenta potencial para o tratamento de distúrbios inflamatórios.
Asunto(s)
Inhibidores de Proteasas/farmacocinética , Naproxeno/farmacocinética , Solubilidad/efectos de los fármacos , Excipientes/farmacocinéticaRESUMEN
BACKGROUND: Naproxen sodium/paracetamol (acetaminophen) is a combination for the treatment of symptomatic pain and fever marketed both as a prescription and an over-the-counter product in Mexico. OBJECTIVE: The aim of these 2 studies was to compare the bioavailability and to determine the bioequivalence of 2 test formulations (an oral-tablet formulation containing the combination of naproxen sodium/paracetamol 275/300 mg and an oral-suspension formulation containing the combination of naproxen sodium/paracetamol 375/300 mg per 15 mL) with their corresponding listed reference-drug formulations in Mexico (a list issued by Mexican health authorities). METHODS: Two separate, single-dose, randomized, open-label, 2-period crossover, postmarketing studies were conducted. For each study, a different set of eligible subjects was selected comprising healthy Mexican adults of either sex, and subjects were randomly assigned to receive 1 test formulation of the combination of naproxen sodium/paracetamol followed by the corresponding reference-drug formulation, or vice versa, with a 1-week washout period between doses. After a 12-hour overnight fast, subjects received a single dose of naproxen sodium/paracetamol 275/300-mg tablet or naproxen sodium/paracetamol 375/300 mg per 15 mL suspension, depending on the study. For the analysis of pharmacokinetic parameters, including C(max), AUC from time 0 (baseline) to 48 hours (AUC(0-48)), and AUC from baseline to infinity (AUC(0-infinity)), blood samples were drawn at baseline and at 0.16, 0.33, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, and 48 hours after administration. The formulations were considered bioequivalent if the geometric mean ratios (test/reference) of the C(max) and AUC were within the predetermined range of 80% to 125%. Tolerability was determined by clinical assessment, monitoring vital signs, laboratory analysis results, and subject interviews regarding adverse events. RESULTS: A total of 26 subjects (15 men, 11 women; mean [SD] age, 29 [8] years [range, 20-50 years]; weight, 63.1 [9] kg [range, 51.4-84.4 kg]; height, 164 [9] cm [range, 149-179 cm]; and body mass index [BMI], 23.53 [2.18] kg/m(2) [range, 18.54-26.82 kg/m(2)]) were enrolled to receive the suspension-dosage formulation; 13 subjects received the suspension-test formulation first. A total of 26 subjects (13 men, 13 women; mean [SD] age, 29 [8] years [range, 18-43 years]; weight, 64.3 [7.7] kg [range, 50.6-80.7 kg]; height, 165 [9] cm [range, 151-181 cm]; and BMI, 23.64 [2.43] kg/m(2) [range, 18.02-26.42 kg/m(2)]) were enrolled to receive the tablet-dosage formulation; 13 subjects received the tablet-test formulation first. No significant period or sequence effects were detected based on analysis of variance. For the suspension-dosage formulation, the 90% CIs for naproxen C(max), AUC(0-48), and AUC(0-infinity) were 93.06% to 104.00%, 93.50% to 98.44%, and 92.14% to 98.99%, respectively, and were 90.09% to 105.90%, 88.58% to 99.34%, and 91.43% to 101.55%, respectively, for paracetamol. For the tablet-dosage formulation, the 90% CIs for naproxen C(max), AUC(0-48), and AUC(0-infinity) were 102.83% to 117.15%, 96.59% to 104.26%, and 96.01% to 102.90%, respectively, and were 94.04% to 121.09%, 95.48% to 105.64%, and 96.64% to 105.42%, respectively, for paracetamol. CONCLUSIONS: In these 2 small studies in healthy Mexican adult subjects, a single dose of naproxen sodium/paracetamol 275/300 mg of the test formulation of the tablet-dosage formulation or a single dose of naproxen sodium/paracetamol 375/300 mg per 15 mL of the test formulation of the suspension-dosage formulation was found to be bioequivalent to the corresponding reference formulations according to the regulatory definition of bioequivalence based on the rate and extent of absorption. All formulations were generally well tolerated.
Asunto(s)
Acetaminofén/farmacocinética , Analgésicos no Narcóticos/farmacocinética , Antiinflamatorios no Esteroideos/farmacocinética , Naproxeno/farmacocinética , Acetaminofén/administración & dosificación , Acetaminofén/efectos adversos , Administración Oral , Adolescente , Adulto , Analgésicos no Narcóticos/administración & dosificación , Analgésicos no Narcóticos/efectos adversos , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/efectos adversos , Área Bajo la Curva , Disponibilidad Biológica , Estudios Cruzados , Combinación de Medicamentos , Femenino , Humanos , Masculino , México , Persona de Mediana Edad , Naproxeno/administración & dosificación , Naproxeno/efectos adversos , Suspensiones , Comprimidos , Equivalencia Terapéutica , Adulto JovenRESUMEN
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.
Asunto(s)
Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/farmacocinética , Naproxeno/administración & dosificación , Naproxeno/farmacocinética , Adulto , Antiinflamatorios no Esteroideos/sangre , Área Bajo la Curva , Disponibilidad Biológica , Química Farmacéutica , Cromatografía Líquida de Alta Presión , Estudios Cruzados , Semivida , Humanos , Indicadores y Reactivos , Masculino , México , Naproxeno/sangre , Espectrofotometría Ultravioleta , SuspensionesRESUMEN
The objective of this study was to determine the penetration of sodium naproxen, formulated in Pluronic F-127 (PF-127) gels containing Azone and Transcutol as penetration enhancers, through human skin in vivo. It was found that the combination of Azone and Transcutol in PF-127 gels enhanced sodium naproxen penetration, with enhancement ratios of up to two fold compared with the formulation containing only Transcutol. These results were confirmed by TEWL and ATR-FTIR spectroscopy, suggesting a synergic action for Azone and Transcutol. Because of the thermo-reversible behavior of Pluronic gels, the influence of the components added to the gel formulations on viscosity, as a function of temperature, was also studied.
Asunto(s)
Naproxeno/farmacocinética , Poloxámero/química , Absorción Cutánea , Piel/metabolismo , Adulto , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacocinética , Azepinas/química , Cromatografía Líquida de Alta Presión/métodos , Glicoles de Etileno/química , Femenino , Geles , Humanos , Masculino , Naproxeno/administración & dosificación , Naproxeno/química , Espectroscopía Infrarroja por Transformada de Fourier/métodos , Viscosidad , Pérdida Insensible de Agua/efectos de los fármacosRESUMEN
We performed a prospective, randomized, open-label equivalence study comparing the use of naproxen to aspirin in 33 patients with rheumatic fever. The mean time until resolution of arthritis was 2.9+/-2.9 days in both groups. Liver enzyme elevations were more frequent in the aspirin group (P=.002). We conclude that naproxen is as effective, is easier to use, and is safer than aspirin in the treatment of the arthritis of rheumatic fever.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacocinética , Antiinflamatorios no Esteroideos/uso terapéutico , Aspirina/farmacocinética , Aspirina/uso terapéutico , Naproxeno/farmacocinética , Naproxeno/uso terapéutico , Fiebre Reumática/tratamiento farmacológico , Adolescente , Niño , Preescolar , Femenino , Humanos , Masculino , Estudios Prospectivos , Equivalencia Terapéutica , Factores de Tiempo , Resultado del TratamientoRESUMEN
El objetivo de la presente investigación fue comparar la actividad analgésica de clonixinato de lisina con el naproxeno sódico en el dolor postoperatorio subsecuente a la cirugía oral. Utilizando el método doble-ciego, dosis únicas de clonixinato de lisina 125 mg. o de naproxeno sódico 550 mg. se administraron por selección al azar a 92 pacientes con dolor postoperatorio después de efectuar extracciones de terceros molares incluidos. Durante un periodo de control de 4 horas posterior a la ingestión oral de cada una de las medicaciones estudiadas, se evaluaron en cada paciente
Asunto(s)
Humanos , Clonixina/farmacocinética , Naproxeno/farmacocinética , Dolor Postoperatorio/tratamiento farmacológico , Analgesia/estadística & datos numéricos , Método Doble Ciego , Procedimientos Quirúrgicos OralesRESUMEN
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.
Asunto(s)
Antiinflamatorios no Esteroideos/sangre , Diclofenaco/sangre , Animales , Antiinflamatorios no Esteroideos/farmacocinética , Área Bajo la Curva , Calibración , Cromatografía Líquida de Alta Presión , Diclofenaco/farmacocinética , Electroquímica , Semivida , Masculino , Naproxeno/sangre , Naproxeno/farmacocinética , Ratas , Ratas WistarRESUMEN
The relationship between the plasma concentration and the anti-inflammatory effect of naproxen (CAS 22204-53-1) after oral administration of a 6 mg.kg-1 dose was studied in rats with galactosamine-induced acute hepatitis and under control conditions. In control animals naproxen peak plasma levels of 35 +/- 0.4 micrograms.ml-1 were reached in 0.5 +/- 0 h. Concentration then decayed, half-life being 5.2 +/- 0.4 h. AUC was 131 +/- 5 micrograms.h.ml-1. In intoxicated rats peak plasma levels of 29 +/- 0.3 micrograms.ml-1 were reached in 0.7 +/- 0.1 h, half-life was increased to 11.1 +/- 1.3 h, and the AUC reached 259 +/- 21 micrograms.h.ml-1. In control rats the protective effect of naproxen against carrageenan-induced inflammation increased slowly, reaching a maximum of 38% in 4 h. The protective effect against plasma concentration curve exhibited a clear counterclockwise hysteresis, probably due to a slow naproxen transport from the circulation to its site of action. In animals with hepatitis, the protective effect remained quite constant at about 40% despite variations in plasma levels, probably because the maximal effect was reached. No clear hysteresis was observed in the effect-plasma concentration curve, suggesting that naproxen arrival to its site of action was faster. Results show that the relationship between naproxen plasma concentration and its anti-inflammatory effect is complex and therefore predictions on the pharmacological response in liver damage cannot be readily made by solely considering pharmacokinetic data.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Naproxeno/sangre , Naproxeno/uso terapéutico , Animales , Carragenina , Enzimas/sangre , Fiebre/inducido químicamente , Fiebre/prevención & control , Galactosamina/toxicidad , Semivida , Pruebas de Función Hepática , Masculino , Naproxeno/farmacocinética , Ratas , Ratas WistarRESUMEN
The pharmacokinetics of intravenous naproxen (CAS 22204-53-1) 6 mg kg-1, were studied in Wistar rats under control conditions and 1, 3 and 10 days after the induction of acute hepatitis by a single intraperitoneal injection of galactosamine 375 mg kg-1. In non-intoxicated rats t1/2 was 5.31 +/- 0.90 h, Vd was 0.21 +/- 0.01 l.kg-1, Cl was 17 +/- 5 ml.h-1.kg-1, AUC was 354.4 +/- 8.8 micrograms.h.ml-1 and 99.18 +/- 0.09% of naproxen was bound to plasma proteins. One day after intoxication the liver was considerably damaged; cytochrome P450, the main enzymatic system for naproxen metabolism, was decreased in 90%. Naproxen t1/2 was increased to 11.9 +/- 1.2 h but Vd did not change significantly, therefore clearance was reduced to 37%. Binding to plasma proteins was decreased to 83.21 +/- 0.27%. At day 3 liver function and naproxen pharmacokinetics exhibited a partial recovery, t1/2 was 6.59 +/- 0.92 h and clearance was 12.2 +/- 5 ml.h-1.kg-1 being not significantly different from controls; notwithstanding AUC was still significantly different from that of non-intoxicated rats. 10 days after galactosamine injection all pharmacokinetic parameters, as well as those of liver function, returned to basal levels. The results indicate that acute hepatitis produces an important reduction in naproxen elimination. Changes in naproxen disposition, which exhibit a time course similar to that of liver damage, are mainly determined by a decrease in intrinsic hepatic clearance and in the binding to plasma proteins.
Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Naproxeno/farmacología , Naproxeno/farmacocinética , Animales , Antiinflamatorios no Esteroideos/farmacología , Proteínas Sanguíneas/metabolismo , Carragenina , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Galactosamina , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/patología , Inyecciones Intravenosas , Pruebas de Función Hepática , Regeneración Hepática/efectos de los fármacos , Masculino , Naproxeno/administración & dosificación , Unión Proteica , Ratas , Ratas WistarRESUMEN
El autor, después de revisar las principales caracteristicas farmacológicas de etodolac y su efecto terapéutico sobre algunas alteraciones reumatológicas crónicas, expone los resultados obtenidos con naproxén (1 g/día por vía oral) o con etodolac (400 mg/día por vía oral en el tratamiento de 62 pacientes del Servicio de Cirugía de Hombro y Miembro torácico del Hospital de Ortopedoa y Traumatología "Magdalena de las Salinas" del IMSS y con diagnóstico clínico de bursitis o tendinitis aguda. El estudio fue aleatorio, prospectivo y simple ciego. Después de siete días de tratamiento, ambos medicamentos produjeron disminución estadísticamente significativa del dolor en reposo, dolor al movimiento, dolor a la palpación y sobre la interferencia del dolor con el sueño; el análisis global de la mejoria o supresión del dolor mostró una diferencia estadísticamente significativa a favor de etodolac. Ambos antinflamatorios fueron bien tolerados. El autor concluye que por su favorable perfil de eficacia y tolerabilidad, el etodolac puede constituir una terapia farmacológica de primera elección en el manejo de alteraciones del sistema músculo-esquelético como bursitis y tendinitis agudas.