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
BACKGROUND: Oral suspensions are heterogeneous disperse systems, and the particle size distribution, crystalline form of the dispersed solid, and composition of the formulation can be listed as parameters that control the drug dissolution rate and its bioavailability. OBJECTIVE: The aim of this work was to develop a discriminative dissolution test, which, in association with in silico methodologies, can make it possible to safely anticipate bioavailability problems. METHODS: Nimesulide and ibuprofen (BCS class II) and cephalexin (BCS class I) oral suspensions were studied. Previously, solid-state structure and particle size in active pharmaceutical ingredients were characterized and the impact of differences on solubility was evaluated for the choice of discriminative medium. Afterwards, particle size distribution (0.1 to 360 µm), dissolution profile, and in vitro permeability in Caco-2 cell of commercial suspensions, were determined. These parameters were used as input for the establishment of the in vitro-in vivo correlation (IVIVC) for the suspensions using the GastroPlus™ with Wagner-Nelson and Loo- Riegelmann deconvolution approach. RESULTS: The predicted/observed pharmacokinetic model showed good correlation coefficients (r) of 0.960, 0.950, and 0.901, respectively. The IVIVC was established for one nimesulide and two ibuprofen suspensions with r between 0.956 and 0.932, and the percent prediction error (%PE) did not exceed 15%. CONCLUSION: In this work, we have performed a complete study combining in vitro/in silico approaches with the aim of anticipating the safety and efficacy of oral pharmaceutical suspensions in order to provide a regulatory tool for this category of products in a faster and more economical way.
Asunto(s)
Ibuprofeno , Sulfonamidas , Humanos , Disponibilidad Biológica , Ibuprofeno/química , Ibuprofeno/farmacocinética , Células CACO-2 , Solubilidad , SuspensionesRESUMEN
The thermal, physical, and morphological properties of diphenhydraminium ibuprofenate ([DIP][IBU]) adsorbed onto mesoporous silica (SiO2-60â¯Å and SiO2-90â¯Å) from solution were determined. The thermal, physical, and morphological properties of [DIP][IBU] supported on silica were determined. The adsorption of [DIP][IBU] on the pores and surface of silica was proven by N2 adsorption/desorption isotherms. Additionally, release profiles were determined for all systems, and the antinociceptive activity of neat [DIP][IBU] and [DIP][IBU] supported on silica were determined. The interaction of [DIP][IBU] and silica was dependent on pore size, with the formation of a [DIP][IBU] monolayer on SiO2-60 and a multilayer on SiO2-90. The release profile was sustained and slow and dependent on the pore size of the silica, in which the smaller the pore size, the faster the release. The nociceptive evaluation showed that [DIP][IBU] presents a greater (99.21⯱â¯0.85%) antinociceptive effect than the ibuprofen (46⯱â¯4.3%). Additionally, [DIP][IBU] on SiO2-60 (90⯱â¯5.8%) had a greater antinociceptive effect than on SiO2-90 (73⯱â¯13.2%), which indicates that in vivo tests are in accordance with the in vitro experiments.
Asunto(s)
Analgésicos , Ibuprofeno , Dolor/tratamiento farmacológico , Dióxido de Silicio , Analgésicos/química , Analgésicos/farmacocinética , Analgésicos/farmacología , Animales , Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/farmacocinética , Preparaciones de Acción Retardada/farmacología , Evaluación Preclínica de Medicamentos , Ibuprofeno/análogos & derivados , Ibuprofeno/química , Ibuprofeno/farmacocinética , Ibuprofeno/farmacología , Masculino , Ratones , Dolor/metabolismo , Dolor/fisiopatología , Porosidad , Dióxido de Silicio/química , Dióxido de Silicio/farmacocinética , Dióxido de Silicio/farmacologíaRESUMEN
The search for new drugs with anti-inflammatory properties remains a challenge for modern medicine. Among the various strategies for drug discovery, deriving new chemical entities from known bioactive natural and/or synthetic compounds remains a promising approach. Here, we designed and synthesized CVIB, a codrug developed by association of carvacrol (a phenolic monoterpene) with ibuprofen (a non-steroidal anti-inflammatory drug). In silico pharmacokinetic and physicochemical properties evaluation indicated low aqueous solubility (LogP ≥5.0). Nevertheless, the hybrid presented excellent oral bioavailability, gastrointestinal tract absorption, and low toxicity. CVIB did not present cytotoxicity in peripheral blood mononuclear cells (PBMCs), and promoted a significant reduction in IL-2, IL-10, IL-17, and IFN-γ cytokine levels in vitro. The LD50 was estimated to be approximately 5000â¯mg/kg. CVIB was stable and detectable in human plasma after 24â¯h. In vivo anti-inflammatory evaluations revealed that CVIB at 10 and 50â¯mg/kgâ¯i.p. caused a significant decrease in total leukocyte count (pâ¯<â¯0.01) and provoked a significant reduction in IL-1ß (pâ¯<â¯0.01). CVIB at 10â¯mg/kgâ¯i.p. efficiently decreased inflammatory parameters better than the physical mixture (carvacrol + ibuprofen 10â¯mg/kgâ¯i.p.). The results suggest that the codrug approach is a good option for drug design and development, creating the possibility of combining NSAIDs with natural products in order to obtain new hybrid drugs may be useful for treatment of inflammatory diseases.
Asunto(s)
Antiinflamatorios , Cimenos , Ibuprofeno , Animales , Antiinflamatorios/química , Antiinflamatorios/farmacocinética , Antiinflamatorios/uso terapéutico , Antiinflamatorios/toxicidad , Carragenina , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Cimenos/química , Cimenos/farmacocinética , Cimenos/uso terapéutico , Cimenos/toxicidad , Citocinas/inmunología , Combinación de Medicamentos , Humanos , Ibuprofeno/química , Ibuprofeno/farmacocinética , Ibuprofeno/uso terapéutico , Ibuprofeno/toxicidad , Dosificación Letal Mediana , Leucocitos Mononucleares/efectos de los fármacos , Masculino , Ratones , Pleuresia/inducido químicamente , Pleuresia/tratamiento farmacológico , Pleuresia/inmunología , SolubilidadRESUMEN
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
Occupational toxicology and clinical pharmacology integration will be useful to understand potential exposure-drug interaction and to shape risk assessment strategies in order to improve occupational health. The aim of the present study was to evaluate the effect of exposure to ethanol fuel on in vivo activities of cytochrome P450 (CYP) isoenzymes CYP3A, CYP2C and CYP2D by the oral administration of the probe drugs verapamil, ibuprofen and fluoxetine. Male Wistar rats exposed to filtered air or to 2000 ppm ethanol in a nose-only inhalation chamber during (6 h/day, 5 days/week, 6 weeks) received single oral doses of 10 mg/kg verapamil or 25 mg/kg ibuprofen or 10 mg/kg fluoxetine. The enantiomers of verapamil, norverapamil, ibuprofen and fluoxetine in plasma were analyzed by LC-MS/MS. The area under the curve plasma concentration versus time extrapolated to infinity (AUC(0-∞)) was calculated using the Gauss-Laguerre quadrature. Inhalation exposure to ethanol reduces the AUC of both verapamil (approximately 2.7 fold) and norverapamil enantiomers (>2.5 fold), reduces the AUC(0-∞) of (+)-(S)-IBU (approximately 2 fold) and inhibits preferentially the metabolism of (-)-(R)-FLU. In conclusion, inhalation exposure of ethanol at a concentration of 2 TLV-STEL (6 h/day for 6 weeks) induces CYP3A and CYP2C but inhibits CYP2D in rats.
Asunto(s)
Biocombustibles/toxicidad , Inductores de las Enzimas del Citocromo P-450/toxicidad , Inhibidores Enzimáticos del Citocromo P-450/toxicidad , Sistema Enzimático del Citocromo P-450/metabolismo , Etanol/toxicidad , Exposición por Inhalación/efectos adversos , Pruebas de Toxicidad Crónica/métodos , Contaminantes Ocupacionales del Aire/toxicidad , Animales , Hidrocarburo de Aril Hidroxilasas/antagonistas & inhibidores , Hidrocarburo de Aril Hidroxilasas/metabolismo , Cámaras de Exposición Atmosférica , Biomarcadores/sangre , Biotransformación/efectos de los fármacos , Citocromo P-450 CYP3A/química , Citocromo P-450 CYP3A/metabolismo , Inhibidores Enzimáticos del Citocromo P-450/sangre , Inhibidores Enzimáticos del Citocromo P-450/farmacocinética , Sistema Enzimático del Citocromo P-450/química , Inducción Enzimática/efectos de los fármacos , Fluoxetina/sangre , Fluoxetina/farmacocinética , Ibuprofeno/sangre , Ibuprofeno/farmacocinética , Limoneno Hidroxilasas/antagonistas & inhibidores , Limoneno Hidroxilasas/metabolismo , Masculino , Ratas Wistar , Verapamilo/análogos & derivados , Verapamilo/sangre , Verapamilo/química , Verapamilo/farmacocinéticaRESUMEN
OBJECTIVE: To assess the bioequivalence of three ibuprofen formulations (Test formulation: ibuprofen (400 mg capsule) manufactured by Cardinal Health Brasil 402 Ltda. (Sorocaba, Brazil) and licensed to Boehringer Ingelheim do Brasil Quim. e Farm. Ltda. (SA poundo Paulo, Brazil); Reference formulation (1): ibuprofen (AdvilA(R); 2 A 200 mg coated tablet) from Wyeth-Whitehall Ltda. (Itapevi, Brazil); Reference formulation (2): ibuprofen (AliviumA; 8 ml A 50 mg/ml solution) from Schering Plough S.A. (Rio de Janeiro, Brazil)) in 24 healthy volunteers of both sexes. METHODS: The study was conducted using an open, randomized, three-period crossover design with at least 5-day washout interval. Plasma samples were obtained over a 24-h period. Plasma ibuprofen concentrations were analyzed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) with negative ion electrospray ionization using multiple reaction monitoring (MRM). The following pharmacokinetic parameters were obtained from the ibuprofen plasma concentration vs. time curves: AUC(last), AUC(trunctmax), AUC(inf) and C(max). RESULTS: The limit of quantification for ibuprofen was 0.1 microg A ml(1). The geometric mean with corresponding 90% confidence interval (CI) for Test/Reference (1) percent ratios were 114.24% (90% CI = 105.67, 123.50%) for C(max), 98.97% (90% CI = 94.69, 103.44%) for AUC(last) and 99.40% (90% CI = 95.21, 103.78%) for AUC(inf). The geometric mean and respective 90% confidence interval (CI) for Test/Reference (2) percent ratios were 108.38% (90% CI = 100.19, 117.25%) for C(max), 100.79% (90% CI = 96.39, 105.40%) for AUC(last) and 101.26% (90% CI = 96.94, 105.77%) for AUC(inf); t(max) for the 400 mg Test capsule was shorter than that for the 2 A 200 mg Reference (1) tablets (p < 0.002). CONCLUSION: Since the 90% CI for AUC(last), AUC(inf) and Cmax ratios were within the 80 - 125% interval proposed by the US FDA, it was concluded that ibuprofen formulation manufactured by Cardinal Health Brasil 402 Ltda. and licensed to Boehringer Ingelheim do Brasil Quim. e Farm. Ltda. is bioequivalent to the AdvilA and AliviumA formulations with regard to both the rate and the extent of absorption.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacocinética , Ibuprofeno/farmacocinética , Administración Oral , Adolescente , Adulto , Antiinflamatorios no Esteroideos/administración & dosificación , Área Bajo la Curva , Disponibilidad Biológica , Cápsulas , Cromatografía Liquida , Estudios Cruzados , Formas de Dosificación , Femenino , Humanos , Ibuprofeno/administración & dosificación , Masculino , Persona de Mediana Edad , Comprimidos , Espectrometría de Masas en Tándem , Equivalencia TerapéuticaRESUMEN
The purpose of this research was to study the effect of the methyl branching of a high log P alkane solvent and the water activity in the organic medium on the initial rate and the enantioselectivity of ibuprofen esterification catalyzed by Candida rugosa lipase. Resolution of ibuprofen is important because S-(+)-ibuprofen has the desired pharmacological activity, whereas the R-(-)-enantiomer causes much of the side effects. The Candida rugosa lipase-catalyzed reaction in isooctane at 40ºC and 0.73 water activity gave the best results, both in terms of the initial reaction rate and the enantioselectivity of the reaction. An increase in water activity allowed a higher reaction rate and enantiomeric excess in each of the four solvents. An increase in methyl branching did not necessarily increase the initial reaction rate, but it allowed a higher enantioselectivity, evidenced by an increase in the substrate enantiomeric excess.
Asunto(s)
Alcanos , Ibuprofeno/farmacocinética , Ibuprofeno/farmacología , Candida/química , LipasaRESUMEN
OBJECTIVE: To assess the effectiveness and safety of high-dose ibuprofen when used as part of routine therapy in patients with cystic fibrosis (CF). STUDY DESIGN: In this multicenter, double-blinded, placebo-controlled trial, a total of 142 patients age 6 to 18 years with mild lung disease (forced expiratory volume in 1 minute [FEV1] > 60 predicted) were randomized to receive either high-dose ibuprofen (70 subjects, 20 to 30 mg/kg/twice daily, adjusted to a peak serum concentration of 50 to 100 mug/mL) or placebo (72 subjects) for a 2-year period. The primary outcome was the annualized rate of change in FEV1% predicted. RESULTS: The patients in the high-dose ibuprofen group exhibited a significant reduction in the rate of decline of forced vital capacity percent predicted (0.07 +/- 0.51 vs -1.62 +/- 0.52; P = .03), but not FEV1%. The ibuprofen group also spent fewer days in hospital after adjusting for age (1.8 vs 4.1 days per year; P = .07). A total of 11 patients (4 in the ibuprofen group and 7 in the placebo group) withdrew due to adverse events. CONCLUSIONS: High-dose ibuprofen has a significant effect on slowing the progression of lung disease in CF and generally is well tolerated.
Asunto(s)
Antiinflamatorios no Esteroideos/administración & dosificación , Fibrosis Quística/tratamiento farmacológico , Ibuprofeno/administración & dosificación , Adolescente , Antiinflamatorios no Esteroideos/farmacocinética , Canadá , Niño , Cromatografía Líquida de Alta Presión , Método Doble Ciego , Femenino , Volumen Espiratorio Forzado , Humanos , Ibuprofeno/farmacocinética , Masculino , Selección de Paciente , Análisis de Regresión , Capacidad VitalRESUMEN
Ibuprofen is used for closing the ductus arteriosus in premature newborn infants. Ibuprofen interferes with bilirubin-albumin binding and increases the unbound bilirubin in pooled newborn plasma to levels similar to those produced by sulfisoxazole, a drug that causes kernicterus in premature newborn infants.
Asunto(s)
Albúminas/metabolismo , Antiinflamatorios no Esteroideos/farmacocinética , Bilirrubina/sangre , Ibuprofeno/farmacocinética , Ictericia Neonatal/sangre , Sitios de Unión , Humanos , Ibuprofeno/sangre , Recién Nacido , Sulfisoxazol/farmacocinéticaRESUMEN
This paper reports the development of a rapid method for the enantioselective analysis of the nonsteroidal anti-inflammatory drug ibuprofen in human plasma by capillary electrophoresis employing the anionic cyclodextrin-modified electrokinetic chromatography mode. Sample cleanup was carried out by acidification with HCl followed by liquid-liquid extraction with hexane:isopropanol (99:1 v/v). The complete enantioselective analysis was performed within 10 min, using 100 mmol L(-1) phosphoric acid/triethanolamine buffer, pH 2.6, containing 2.0% w/v sulfated beta-cyclodextrin as chiral selector; fenoprofen, another nonsteroidal anti-inflammatory drug, was used as internal standard. The calibration curves were linear over the concentration range of 0.25-125.0 microg mL(-1) for each enantiomer of ibuprofen. The mean recoveries for ibuprofen enantiomers were up to 85%. The enantiomers studied could be quantified at three different concentrations (0.5, 5.0 and 50.0 microg mL(-1)) with a coefficient of variation and relative error not higher than 15%. The quantitation limit was 0.2 microg mL(-1) for (+)-(S)- and (-)-(R)-ibuprofen using 1 mL of human plasma. The plasma endogenous compounds and other drugs did not interfere with the present assay. The analysis of real plasma samples obtained from a healthy volunteer after administration of 600 mg of racemic ibuprofen showed a maximum plasma level of 29.6 and 39.9 microg mL(-1) of (-)-(R)- and (+)-(S)-ibuprofen, respectively, and the area under plasma concentration-time curve AUC(0-infinity) (+)-(S)/AUC(0-infinity) (-)-(R) ratio was 1.87.
Asunto(s)
Ciclodextrinas/química , Electroforesis Capilar/métodos , Ibuprofeno/sangre , Cromatografía Capilar Electrocinética Micelar , Monitoreo de Drogas/métodos , Humanos , Ibuprofeno/administración & dosificación , Ibuprofeno/farmacocinética , Reproducibilidad de los Resultados , EstereoisomerismoRESUMEN
Avaliaram-se as características físicas e físico-químicas de diferentes lotes de quatro especialidades farmacêuticas contendo ibuprofeno (produtos A, B, C e D), sob a forma de comprimidos de liberação imediata, disponíveis no mercado nacional e comercializados como similares intercambiáveis, enfatizando-se o estudo comparativo da cinética de dissolução do fármaco. Utilizou-se equipamento para dissolução de formas sólidas de acordo com a USP 23, empregando-se tampão fosfato pH 7,2 como meio de dissolução a 37,0 ñ 0,5 ºC e aparato 1 na velocidade de 150 rpm. Os produtos A e B e os produtos C e D, respectivamente, poderiam, teoricamente, ser considerados equivalentes farmacêuticos, segundo a definição da Food and Drug Administration (FDA-USA)...
Asunto(s)
Medicamentos Genéricos , Ibuprofeno/farmacocinética , Similar , Disponibilidad Biológica , Evaluación de Medicamentos , Comprimidos , Equivalencia TerapéuticaRESUMEN
Os autores apresentam uma revisäo sobre as propriedades farmacológicas do ibuprofeno, droga antiinflamatória-näo-esteroidal (AINE), e seu emprego na dismenorréia primária (DP), enfermidade de importante aspecto sócio-econômico devido a seus sintomas incapacitantes quando na forma severa. Säo abordados aspectos sobre farmacocinética, farmacodinâmica, indicaçöes clínicas, interaçöes medicamentosas e efeitos adversos da droga, revelando-se o ibuprofeno como o AINE que apresenta, na vigência de seu uso, a menor incidência de distúrbios gastrointestinais quando comparado aos demais AINE. Em relaçäo a seu uso na DP, säo analisados estudos onde compara-se a eficácia do ibuprofeno à eficácia de outros AINES em relaçäo ao alívio dos sintomas dismenorreícos. Conclui-se ser o ibuprofeno, devido à sua ótima eficácia no alívio da dor e sua baixíssima incidência efeitos adversos, e a droga de escolha no tratamento da DP, tendo nesta sua grande indicaçäo
Asunto(s)
Humanos , Femenino , Dismenorrea/tratamiento farmacológico , Dismenorrea/fisiopatología , Ibuprofeno/efectos adversos , Ibuprofeno/farmacocinética , Ibuprofeno/uso terapéutico , Antiinflamatorios no Esteroideos/farmacocinética , Antiinflamatorios no Esteroideos/uso terapéuticoRESUMEN
OBJECTIVES: The objectives of this study were to compare the pharmacokinetic parameters of ibuprofen administered as a suspension, chewable tablet, or tablet in children with cystic fibrosis and to determine the optimal blood sampling times for measuring ibuprofen peak concentrations. STUDY DESIGN: A single oral 20 mg/kg dose of ibuprofen was administered, and blood samples were obtained at 15, 30, 45, 60, 120, 240, and 360 minutes after the dose was administered. Peak plasma concentration (Cmax ), time to peak concentration (Tmax ), and other pharmacokinetic parameters were determined and compared (analysis of variance and analysis of covariance). RESULTS: Thirty-eight children were included (22, 4, and 12 in the suspension, chewable tablet, and tablet groups, respectively). Tmax was the only parameter for which statistical differences were noted (suspension vs tablet, P
Asunto(s)
Fibrosis Quística/metabolismo , Ibuprofeno/farmacocinética , Administración Oral , Adolescente , Análisis de Varianza , Área Bajo la Curva , Niño , Preescolar , Cromatografía Líquida de Alta Presión , Femenino , Semivida , Humanos , Ibuprofeno/administración & dosificación , Ibuprofeno/sangre , Masculino , Pruebas de Función Respiratoria , Suspensiones , ComprimidosRESUMEN
The effect of age on ibuprofen pharmacokinetics and antipyretic effect was studied in 49 infants and children aged 3 months to 10.4 years. The relationship of plasma concentration to antipyretic effect was examined in 38 of the children by using an iterative least squares technique that allows estimation of drug concentration with time in a theoretical effect compartment and rate constant for elimination of drug from the effect compartment. There was a delay of 1 to 3 hours between peak ibuprofen plasma concentration and peak temperature decrement. The mean elimination rate constant from the effect compartment was 0.6 hour-1, corresponding to a half-life of drug in the effect compartment of 1.1 hours. The mean slope of the effect compartment concentration versus temperature regression line was -0.242 degrees C/mg per liter. Age did not significantly influence the rate of absorption of ibuprofen, its plasma concentration, its rate of elimination, or the time course of ibuprofen concentration in the effect compartment. However, in younger children the onset of antipyresis was earlier, maximum antipyretic effect was greater, and the area under the curve of the percentage of change in temperature from baseline versus time was greater than in older children. We conclude that the greater relative body surface area in younger children may allow more efficient dissipation of heat in response to antipyretic-induced lowering of the temperature "set point" in the hypothalamus.
Asunto(s)
Envejecimiento/metabolismo , Fiebre/sangre , Ibuprofeno/farmacocinética , Enfermedad Aguda , Axila , Temperatura Corporal/efectos de los fármacos , Niño , Preescolar , Evaluación de Medicamentos , Femenino , Fiebre/tratamiento farmacológico , Fiebre/epidemiología , Semivida , Humanos , Ibuprofeno/administración & dosificación , Ibuprofeno/efectos adversos , Ibuprofeno/sangre , Lactante , Masculino , Análisis de Regresión , Suspensiones , Factores de TiempoRESUMEN
Antiinflammatory therapy with ibuprofen has been proposed to retard the progression of lund disease in cystic fibrosis (CF). The pharmacokinetics and toxicity of ibuprofen were investigated in a randomized, double-blind, placebo-controlled, 3-month dose-escalation study in 19 children with CF, 6 to 12 years of age. The subjects received orally and twice daily 300 mg of drug during the first month, 400 mg in the second month, and 600 mg in the third month. Ibuprofen pharmacokinetics and evaluation for adverse effects were performed at the beginning and end of each month. The dose of ibuprofen was increased if peak plasma concentration (Cmax) was less than 50 micrograms/ml. To preserve the blind nature of the study, the dose in matched subjects taking placebo was also increased. The subjects randomly assigned to receive ibuprofen (n = 13) completed 26 months of treatment; placebo subjects (n = 5) completed 12 months. With dose escalation, Cmax and the area under the concentration-time curve from zero to infinity significantly increased (p less than 0.01). The pharmacokinetics of ibuprofen in 13 children with CF who received 13.4 +/- 4.1 mg/kg (mean +/- SD) were compared with those in four healthy children who received a similar dose. Peak plasma concentration (48 +/- 17 micrograms/ml) was decreased by 27% (p = 0.06), the area under the concentration-time curve (6.1 +/- 1.7 mg.min/ml) was decreased by 46% (p less than 0.001), apparent total clearance (2.3 +/- 0.6 ml/min.kg-1) was increased by 77% (p less than 0.01), and apparent volume of distribution during terminal phase (291 +/- 91 ml/kg) was increased by 84% (p = 0.01) in the children with CF. Time to Cmax (66 +/- 20 minutes) and elimination half-life (92 +/- 27 minutes) were not significantly different. No subjects were withdrawn from the study because of side effects. No adverse effects could be attributed to ibuprofen. Thus ibuprofen administration has no significant toxic effects, but Cmax will need to be monitored for effective dosing in patients with CF.