Naproxen Concentrations Research Articles

Quantitation of naproxen by quenching of phosphorescence from a ternary complex of 2-bromo-6-methoxynaphthalene and α-cyclodextrin

A unique method, based on the measurement of phosphorescence lifetimes, is reported for use in analytically detecting the widely used anti-inflammatory drug naproxen. The reciprocal phosphorescence lifetime of a ternary complex containing α-cyclodextrin and 2-bromo-6-methoxynaphthalene increases linearly with naproxen concentration and has a quenching constant of 2.1 ± 0.05 × 106 M−1 s−1. Similar behavior is observed for quenching by the sodium salt of naproxen that has a quenching constant of 1.8 × 106 ± 0.05 M−1 s−1. The experimental sensitivity is sufficient to permit measurements of naproxen concentrations differing by 11 μg/ml. Phosphorescence lifetime measurements reveal that the quenching mechanism does not involve displacement of the unrelaxed triplet-state guest molecule by naproxen from the complex and may occur by energy transfer or electron transfer.

Occurrence and risk assessment of pharmaceutically active compounds in wastewater treatment plants. A case study: Seville city (Spain)

The occurrence of four anti-inflammatory drugs (diclofenac, ibuprofen, ketoprofen and naproxen), an antiepileptic drug (carbamazepine) and a nervous stimulant (caffeine) in influent and effluent samples from four wastewater treatment plants (WWTPs) in Seville was evaluated. Removal rates in the WWTPs and risk assessment of the pharmaceutically active compounds have been studied. Analytical determination was carried out by high performance liquid chromatography (HPLC) with diode array (DAD) and fluorescence (Fl) detectors after sample clean up and concentration by solid phase extraction. All pharmaceutically active compounds, except diclofenac, were detected not only in wastewater influents but also in wastewater effluents. Mean concentrations of caffeine, carbamazepine, ketoprofen and naproxen ranged between 0.28–11.44 μg l − 1 and 0.21–2.62 μg l − 1 in influent and effluent wastewater, respectively. Ibuprofen was present in the highest concentrations in the range 12.13–373.11 μg l − 1 and 0.78–48.24 μg l − 1 in influent and effluent wastewater, respectively. Removal rates of the pharmaceuticals ranged between 6 and 98%. Risk quotients, expressed as ratios between the measured environmental concentration (MEC) and the predicted no effect concentrations (PNEC) were higher than 1 for ibuprofen and naproxen in influent wastewater and for ibuprofen in effluent wastewater.

Attenuation of Wastewater-Derived Contaminants in an Effluent-Dominated River

Although wastewater-derived chemical contaminants undergo transformation through a variety of mechanisms, the relative importance of processes such as biotransformation and photolysis is poorly understood under conditions representative of large rivers. To assess attenuation rates under conditions encountered in such systems, samples from the Trinity River were analyzed for a suite of wastewater-derived contaminants during a period when wastewater effluent accounted for nearly the entire flow of the river over a travel time of approximately 2 weeks. While the concentration of total adsorbable organic iodide, a surrogate for recalcitrant X-ray phase contrast media in wastewater, was approximately constant throughout the river, concentrations of ethylenediamine tetraacetate, gemfibrozil, ibuprofen, metoprolol, and naproxen all decreased between 60% and 90% as the water flowed downstream. Comparison of attenuation rates estimated in the river with rates measured in laboratory-scale microcosms suggests that biotransformation was more important than photolysis for most of the compounds. Further evidence for biotransformation in the river was provided by measurements of the enantiomeric fraction of metoprolol, which showed a gradual decrease as the water moved downstream. Results of this study indicate that natural attenuation can result in significant decreases in concentrations of wastewater-derived contaminants in large rivers.

New reliable Raman collection system using the wide area illumination (WAI) scheme combined with the synchronous intensity correction standard for the analysis of pharmaceutical tablets

A novel and reliable Raman collection system for the non-destructive analysis of pharmaceutical tablets has been proposed. The main idea was to develop and utilize the wide area illumination (WAI) scheme for Raman collection to cover a large surface area (coverage area: 28.3 mm 2) of solid tablet to dramatically improve the reliability in sample representation and the reproducibility of sampling due to less sensitivity of sample placement with regard to the focal plane. Simultaneously, the effective and synchronous standard configuration using isobutyric anhydride was harmonized with the WAI scheme to correct the problematic variation of Raman intensity from the change of laser power. To verify the quantitative performance of the proposed scheme, the compositional analysis of active ingredient in naproxen tablet has been performed. The average sample composition was successfully represented by using the WAI scheme compared to the conventional scheme with a much smaller illumination area. After the intensity correction using the non-overlapping peak of isobutyric anhydride standard and area normalization, a partial least squares (PLS) model was developed using an optimized spectral range and the concentrations of naproxen in tablets were accurately predicted. The prediction accuracy was not sensitive to changes in laser power or tablet position within ±2 mm. Additionally, the prediction accuracy was repeatable without systematic drift or need for re-calibration.

Correlation between in vitro and in vivo concentration–effect relationships of naproxen in rats and healthy volunteers

Understanding the mechanisms underlying the analgesic effect of new cyclooxygenase inhibitors is essential to identify dosing requirements in early stages of drug development. Accurate extrapolation to humans of in vitro and in vivo findings in preclinical species is needed to optimise dosing regimen in inflammatory conditions. The current investigation characterises the inhibition of prostaglandin E2 (PGE(2)) and thromboxane B2 (TXB(2)) by naproxen in vitro and in vivo in rat and human blood. The inhibition of PGE(2) in the absence or presence of increasing concentrations of naproxen (10(-8)-10(-1) M) was measured by ex vivo whole blood stimulation with LPS, whereas inhibition of TXB(2) was measured in serum following blood clotting. In further experiments, inhibition of PGE(2) and TXB(2) levels was also assessed ex vivo in animals treated with naproxen (2.5, 10, 25 mg kg(-1)). Subsequently, pharmacokinetic (PK)/pharmacodynamics (PD) modelling of in vitro and in vivo data was performed using nonlinear mixed effects in NONMEM (V). Inhibition of PGE(2) and TXB(2) was characterised by a sigmoid E(max) model. The exposure-response relationships in vitro and in vivo were of the same order of magnitude in both species. IC(80) estimates obtained in vitro were similar for PGE(2) inhibition (130.8 +/- 11 and 131.9 +/- 19 10(-6) M, mean +/- s.d. for humans and rats, respectively), but slightly different for TXB(2) inhibition (103.9+/-15 and 151.4 +/- 40 10(-6) M, mean +/- s.d. for humans and rats, respectively, P < 0.05). These differences, however, may not be biologically relevant. The results confirm the value of exposure-effect relationships determined in vitro as a means to predict the pharmacological activity in vivo. This analysis also highlights the need to parameterise concentration-effect relationships in early drug development, as indicated by the estimates of IC(80) for PGE(2) and TXB(2) inhibition.

Sensitive sequential injection determination of naproxen based on interaction with β-cyclodextrin

A sensitive sequential injection analysis (SIA) methodology for the fluorimetric determination of naproxen is proposed. The developed automatic analytical procedure is based on the complexation of naproxen with β-cyclodextrin (β-CD) yielding an enhanced fluorimetric signal ( λ ex = 280 nm, λ em = 356 nm). Linear calibration plots were obtained for naproxen concentrations up to 1 × 10 −5 mol l −1. The developed methodology exhibited a good precision, with a R.S.D. < 2.1% ( n = 15). The detection limit of the determination was 1.9 × 10 −7 mol l −1 with a sampling rate of about 70 h −1. The automatic method was applied to the determination of naproxen in pharmaceutical formulations. The obtained results were compared with those furnished by the reference procedure and the relative deviations were lower than 3.6%. No interference was found from the excipients usually used in solid pharmaceutical formulations.

Voltammetric Assay of Naproxen in Pharmaceutical Formulations Using Boron‐Doped Diamond Electrode

AbstractThe electrooxidation of naproxen was studied, for the first time, using boron‐doped diamond (BDD) electrode by cyclic and differential pulse voltammetry (CV and DPV) in nonaqueous solvent supporting electrolyte system. The results were also compared with glassy carbon electrode (GC) under the same conditions. Naproxen undergoes one electron transfer resulting in the formation of cation radical for the first electrooxidation step, which follows other chemical and electrochemical steps such as deprotonation, removal of another electron and the attack of nucleophile (ECEC mechanism). BDD electrode provided higher signal to background ratio, well resolved and highly reproducible cyclic voltammograms than the GC electrode. With a scan rate of 50 mV s−1 and pulse height of 50 ms, respectively, the DPV technique was able to determine the naproxen concentrations in the range of 0.5 to 50 μM with a detection limit of 30 nM. The influence of interference compounds namely 2‐acetyl‐6‐methoxy naphthalene (AMN) on naproxen oxidation can also be followed successfully. Moreover, the percentage of AMN present in the standard chemical form of a mixture containing naproxen can be found accurately. Rapidity, precise and good selectivity were also found for the determination of naproxen in pharmaceutical formulations.

Curcumin Inhibits Formation of Amyloid β Oligomers and Fibrils, Binds Plaques, and Reduces Amyloid in Vivo

Alzheimer's disease (AD) involves amyloid beta (Abeta) accumulation, oxidative damage, and inflammation, and risk is reduced with increased antioxidant and anti-inflammatory consumption. The phenolic yellow curry pigment curcumin has potent anti-inflammatory and antioxidant activities and can suppress oxidative damage, inflammation, cognitive deficits, and amyloid accumulation. Since the molecular structure of curcumin suggested potential Abeta binding, we investigated whether its efficacy in AD models could be explained by effects on Abeta aggregation. Under aggregating conditions in vitro, curcumin inhibited aggregation (IC(50) = 0.8 microM) as well as disaggregated fibrillar Abeta40 (IC(50) = 1 microM), indicating favorable stoichiometry for inhibition. Curcumin was a better Abeta40 aggregation inhibitor than ibuprofen and naproxen, and prevented Abeta42 oligomer formation and toxicity between 0.1 and 1.0 microM. Under EM, curcumin decreased dose dependently Abeta fibril formation beginning with 0.125 microM. The effects of curcumin did not depend on Abeta sequence but on fibril-related conformation. AD and Tg2576 mice brain sections incubated with curcumin revealed preferential labeling of amyloid plaques. In vivo studies showed that curcumin injected peripherally into aged Tg mice crossed the blood-brain barrier and bound plaques. When fed to aged Tg2576 mice with advanced amyloid accumulation, curcumin labeled plaques and reduced amyloid levels and plaque burden. Hence, curcumin directly binds small beta-amyloid species to block aggregation and fibril formation in vitro and in vivo. These data suggest that low dose curcumin effectively disaggregates Abeta as well as prevents fibril and oligomer formation, supporting the rationale for curcumin use in clinical trials preventing or treating AD.

Screening New Drugs for Immunotoxic Potential: I. Assessment of the Effects of Conventional Nonsteroidal Anti-Inflammatory Drugs and Selective COX-2 Inhibitors on In Vitro and In Vivo Phagocytic Activity

Although both experimental and clinical literature contain reports suggestive of associations between enhanced susceptibility to soft tissue infections and nonsteroidal anti-inflammatory drug (NSAID) use, the immunotoxicological potential of this class of therapeutic agents has not been thoroughly investigated. In consideration of the widespread clinical use of these agents, we have initiated studies of the interaction between NSAIDs (both nonselective and selective COX-2 inhibitors) and the immune system. This communication describes the conduct and results of assessments of the effects of NSAIDs on the in vitro phagocytic activity of rat macrophages and canine neutrophils and on the functional activity of the intact murine mononuclear phagocytic system. During in vitro experiments 0.1 to 10 μM concentrations of naproxen, indomethacin, and experimental selective COX-2 inhibitors, SC-236, SC-245 and SC-791, caused marginal, but statistically significant, reductions in phagocytic activity of resident rat peritoneal macrophages. The effects were consistently small and there was no evidence of concentration-response relationships. An in vitro concentration of 10 μM of either SC-236 or SC-791 was required to decrease phagocytosis by dog neutrophils. Repeated oral doses of either naproxen or SC-236 (3, 10, or 30 mg/kg twice daily for 3 days) were without effect on the intact phagocytic system of the mouse. A potential immunotoxicologic effect based on direct impairment of phagocytic processes seems an unlikely explanation for drug-induced susceptibility to infection reported earlier. However, the results of these experiments do not support an unequivocal conclusion relative to immunotoxicological potential of either conventional NSAIDs or selective COX-2 inhibitors. Further studies on other components of the immune system are needed to fully explore possible immunomodulatory effects of NSAIDs.

Naproxen removal from water by chlorination and biofilm processes

Naproxen is an anti-inflammatory pharmaceutical that has been detected in natural and engineered aquatic environments. The primary aim of this research was to study chemical transformations of naproxen following chlorine oxidation, which is common in water and wastewater treatment systems. Synthetic waters containing elevated concentrations of naproxen were oxidized by free chlorine at naproxen:chlorine molar ratios of 0.02-3:1 and pH values of 5-9. The formation of naproxen products was dependent on pH, chlorine dosage and contact time. This study demonstrates that naproxen readily reacts with free chlorine and forms disinfection products. The formation of specific reaction products can vary depending on the characteristics of the water or wastewater and treatment operating conditions. More research is needed to identify intermediate and chemical reaction end products and to understand the reaction kinetics of naproxen chlorination for a range of water and wastewater treatment conditions. A secondary aim of this research was to study effects of naproxen and its chlorination products on biofilm processes, which are common in water and wastewater treatment systems and natural aquatic environments. A bioreactor was fed a naproxen solution and then fed a solution at the same naproxen concentration following contact with free chlorine. Results indicate that naproxen was not degraded biologically for the conditions of this study. In contrast, the naproxen solution containing products of chlorination caused an adverse response by discharging biomass from the bioreactor. Results therefore demonstrate that naproxen products of chlorination can adversely affect a biofilm process, which potentially can impact the performance of biofilm processes in natural and engineered aquatic environments. More research is needed to study naproxen chlorination reactions at low concentrations and in complex matrices, and to understand the toxicological relevance of naproxen and its products of chlorination in natural and engineered aquatic environments.

Differential activation of CYP2C9 variants by dapsone

Studies have shown that CYP2C9.1 mediated metabolism of flurbiprofen or naproxen is activated by co-incubation with dapsone. However, dapsone activation has not been examined in the known variant forms of CYP2C9. Six concentrations of flurbiprofen (2–300 μM) or naproxen (10–1800 μM) were co-incubated with six concentrations of dapsone (0–100 μM) and with reconstituted, purified CYP2C9.1, CYP2C9.2 (R144C), CYP2C9.3 (I359L), or CYP2C9.5 (D360E), in order to assess degrees of activation. Dapsone increased the efficiency ( V m/ K m) of flurbiprofen 4′-hydroxylation by CYP2C9.1, CYP2C9.2, CYP2C9.3, and CYP2C9.5 by 8-, 31-, 47-, and 22-fold, respectively. In similar experiments using the substrate naproxen, dapsone increased the efficiency of naproxen demethylation 7-, 15-, 13-, and 22-fold, in CYP2C9.1, CYP2C9.2, CYP2C9.3, and CYP2C9.5, respectively. Also, dapsone normalized naproxen’s kinetic profile from biphasic (CYP2C9.1 and CYP2C9.2) or linear (CYP2C9.3 and CYP2C9.5) to hyperbolic for all variant forms. Thus, amino acid substitutions of CYP2C9 variants affect the degree of dapsone activation in a genotype-dependent fashion. Furthermore, the degree of effect noted across variants appeared to be dependent on the substrate studied.

Gabapentin and pregabalin can interact synergistically with naproxen to produce antihyperalgesia.

Gabapentin and pregabalin are anticonvulsants with antihyperalgesic effects in animal models of neuropathic and inflammatory nociception. This study characterized the manner in which gabapentin or pregabalin interacts with naproxen to suppress thermal hyperalgesia and inflammation in the carrageenan model of peripheral inflammation. Gabapentin, pregabalin, naproxen, or a fixed-dose ratio of gabapentin + naproxen or pregabalin + naproxen was administered orally to rats after the induction of inflammation by intraplantar injection of lambda-carrageenan in one hind paw. Nociceptive thresholds were determined by the radiant heat paw-withdrawal test. Paw edema was measured by plethysmometry. Drug plasma concentrations were determined by a liquid chromatography-mass spectroscopy-mass spectroscopy method. Gabapentin, pregabalin, and naproxen alone reversed thermal hyperalgesia with ED50 values of 19.2, 6.0, and 0.5 mg/kg, respectively. Mixtures of gabapentin + naproxen in fixed-dose ratios of 50:1, 10:1, or 1:1 interacted synergistically to reverse carrageenan-induced thermal hyperalgesia. However, 1:50 gabapentin + naproxen produced only additive effects. No combination of gabapentin + naproxen decreased paw edema in a manner greater than additive. Plasma concentrations of gabapentin and naproxen were unaltered by the addition of the other drug. The mixture of 10:1 of pregabalin + naproxen interacted synergistically to reverse thermal hyperalgesia on the inflamed hind paw, whereas mixtures of 1:1 or 1:10 produced additive effects. These data suggest that gabapentin + naproxen and pregabalin + naproxen can interact synergistically or additively to reverse thermal hyperalgesia associated with peripheral inflammation. Therefore, the use of gabapentin or pregabalin in low-dose combinations with naproxen may afford therapeutic advantages for clinical treatment of persistent inflammatory pain.

A Possible Mechanism of Naproxen‐Induced Lipid Peroxidation in Rat Liver Microsomes

Abstract: Previous papers from our laboratory report that naproxen and salicylic acid induced lipid peroxidation in rat liver microsomes, however, the mechanism is still unclear. In the present paper, ferrous iron release, nicotinamide‐adenine dinucleotide phosphate reduced form (NADPH) oxidation and hydrogen peroxide (H2O2) formation have been measured to find out which mechanisms are involved in naproxen‐ and salicylic acid‐induced lipid peroxidation. While the increase of ferrous iron release was observed with high concentrations of naproxen, salicylic acid did not stimulate ferrous iron release. Neither of these drugs stimulated NADPH oxidation and H2O2 formation. However hexobarbital and perfluorohexane, known as uncouplers of cytochrome P450, stimulated microsomal NADPH oxidation, O2 consumption, H2O2 formation and water (H2O) formation involving four‐electron oxidase reaction. These results suggest that ferrous iron release contributes to naproxen‐induced microsomal lipid peroxidation and that naproxen and salicylic acid are not uncouplers of cytochrome P450. Apparently H2O2 does not play an important role in naproxen‐ and salicylic acid‐induced microsomal lipid peroxidation.

A possible mechanism of naproxen-induced lipid peroxidation in rat liver microsomes.

Previous papers from our laboratory report that naproxen and salicylic acid induced lipid peroxidation in rat liver microsomes, however, the mechanism is still unclear. In the present paper, ferrous iron release, nicotinamide-adenine dinucleotide phosphate reduced form (NADPH) oxidation and hydrogen peroxide (H2O2) formation have been measured to find out which mechanisms are involved in naproxen- and salicylic acid-induced lipid peroxidation. While the increase of ferrous iron release was observed with high concentrations of naproxen, salicylic acid did not stimulate ferrous iron release. Neither of these drugs stimulated NADPH oxidation and H2O2 formation. However hexobarbital and perfluorohexane, known as uncouplers of cytochrome P450, stimulated microsomal NADPH oxidation, O2 consumption, H2O2 formation and water (H2O) formation involving four-electron oxidase reaction. These results suggest that ferrous iron release contributes to naproxen-induced microsomal lipid peroxidation and that naproxen and salicylic acid are not uncouplers of cytochrome P450. Apparently H2O2 does not play an important role in naproxen- and salicylic acid-induced microsomal lipid peroxidation.

Renal changes associated with naproxen sodium administration in cynomolgus monkeys.

Naproxen sodium was administered to cynomolgus monkeys (Macaca fascicularis) by oral gavage at daily doses of 44, 88, or 176 mg/kg for 2 wk (2 monkeys/gender) or of 44 mg/kg for 13 wk (4 monkeys/gender). Body weight loss occurred in at least one monkey in all naproxen sodium-dosed groups in the 2-wk (up to 16% loss) and 13-wk (up to 22% loss) studies. Increases in plasma naproxen concentrations were dose proportional between 44 and 88 mg/kg but were less than dose proportional between 88 and 176 mg/kg. Up to 2-fold increases in creatinine and/or serum urea nitrogen values as well as higher renal weights occurred in monkeys receiving 176 mg/kg for 2 wk or 44 mg/kg for 13 wk. Microscopically, renal changes were observed in all naproxen sodium-dosed groups. Renal findings after 2 wk of exposure included increased interstitial ground substance, tubular dilatation, and tubulointerstitial nephritis; in the 13-wk study, cortical tubular atrophy and interstitial fibrosis were also observed. These studies identify the kidney as the target organ of naproxen sodium in cynomolgus monkeys.

Effect of Chronic Bile Duct Obstruction and LPS Upon Targeting of Naproxen to the Liver Using Naproxen-Albumin Conjugate

Naproxen covalently linked to human serum albumin (NAP-HSA) is efficiently targeted to endothelial and Kupffer cells of the liver and may offer a new therapeutic approach in the treatment of liver disease associated with inflammatory processes. In the present investigation we explored the pharmacokinetic behaviour of targeted and non-targeted naproxen as well as the pharmacokinetic properties of the active metabolite, Naproxen-lysine (Nap-lysine), in rats rendered fibrotic by bile duct ligation (BDL) for 4 weeks. Furthermore, we studied the effect of endotoxemia, experimentally induced by intravenous injection of 800μg/kg lipopolysaccaride (LPS) upon the pharmacokinetics of these agents in order to investigate the feasibility of targeting naproxen to non-parenchymal cells in the inflamed and fibrotic liver. Our studies demonstrate that liver disease altered the pharmacokinetic behaviour of the different naproxen compounds. Thus, initial plasma concentrations of NAP-HSA and naproxen were markedly lower in BDL rats accompanied by an increase of the volume of distribution during the terminal elimination phase (Vdβ BDL vs control 114 ± 63 vs 50 ± 7 and 202 ± 24 vs 115 ± 11 ml/kg for naproxen and NAP-HSA, respectively). After injection of LPS, no significant change in the pharmacokinetics of NAP-HSA was found whereas the naproxen treated control animals showed an increase in the terminal volume of distribution (176 ±34 vs 115 ± 11 ml/kg) as well as an elevation of the plasma half-life (171 ± 27 vs 116 ± 14 min). The feasibility of targeting naproxen to the chronically diseased liver could be clearly demonstrated: 15 min after administration of the conjugate 46% and 55% of the administered dose was found in the liver of CTR and BDL rats, whereas after injection of free naproxen only 5% and 12% of the dose was detected in liver tissue, respectively.We conclude that targeting albumin-linked naproxen to non-parenchymal cells in the liver is still feasible under the pathological conditions induced in the present study. Liver fibrosis induced significant alterations in the pharmacokinetic behaviour of the studied compounds.

Displacement of valproic acid and carbamazepine from protein binding in normal and uremic sera by tolmetin, ibuprofen, and naproxen: presence of inhibitor in uremic serum that blocks valproic acid-naproxen interactions.

Displacement of valproic acid (90-95% bound to albumin) and carbamazepine (80% bound to albumin) by salicylate, leading to higher concentrations of pharmacologically active free drugs, has been reported. We studied the possibility of displacement of valproic acid and carbamazepine by other strongly albumin-bound nonsteroidal antiinflammatory drugs tolmetin, ibuprofen, and naproxen. We observed statistically significant displacement of carbamazepine from protein binding in uremic serum at higher therapeutic concentrations of all three antiinflammatory drugs we studied, whereas in normal serum, we observed statistically significant displacement only with 75 micrograms/ml of naproxen. For valproic acid, we observed significant displacement even at lower therapeutic concentrations with all three drugs when the study was conducted using a normal serum pool. In the uremic serum pool, we observed significant displacements only with tolmetin and ibuprofen, whereas we observed no significant displacement of valproic acid even with higher concentrations of naproxen. We conclude that tolmetin, naproxen, and ibuprofen can displace both carbamazepine and valproic acid from protein binding, but uremic serum contains an inhibitor that blocks valproic acid-naproxen interaction.

Effects of age on the pharmacodynamics of naproxen in the rat.

The pharmacodynamics of naproxen were evaluated in 5- and 24-month-old male Fischer 344 rats. Plasma naproxen concentrations and thromboxane B2 (TxB2) concentrations were measured as a function of time after intravenous administration of 25 mg/kg naproxen. Age-dependent alterations in naproxen pharmacokinetics were attributed to significant reductions in free plasma clearance (CLfree) and free steady-state volume of distribution (VSSfree), suggesting a decline in metabolic activity and naproxen binding to tissue components in aged rats, respectively. The time course of TxB2 production as a function of unbound naproxen concentrations was described by a sigmoid Emax model. Age had no significant effect on the pharmacodynamic parameter Emax, the maximum percent inhibition of TxB2 formation. Age also had no statistically significant effect on EC50, the drug concentration producing 50% of the maximum effect, however, average EC50 values were 35% higher in the aged rats. The duration of TxB2 inhibition was unaffected by age, possibly owing to similar relative decreases in receptor sensitivity (increased EC50) and increases in free naproxen concentrations (decreased free clearance and volume of distribution). Alternatively, the age-related changes in pharmacokinetic parameters were not of sufficient magnitude to produce a significant change in drug response, naproxen, pharmacokinetics, pharmacodynamics, age, rats, thromboxane B2, nonsteroidal anti-inflammatory drugs.

Comparativein vitro andin vivo bioavailability of naproxen from tablet and caplet formulations

A 500 mg dose of naproxen in a caplet formulation (product A) or a tablet (Naprosyn 500, product B) was administered to 14 fasting healthy subjects on two separate occasions, separated by a 1-2 week washout period in an open, randomized crossover. Blood samples were drawn periodically and plasma naproxen concentrations measured by HPLC. The median time Tmax to reach peak concentration for product A was shorter than that for product B (1.025 h versus 1.5 h) but A and B were similar with respect to median peak plasma concentration Cmax (77.9 mg l-1 versus 71.4 mg l-1), and average area AUC0-infinity under the plasma concentration-time curve (1210.2 mg l-1 h versus 1211.0 mg l-1 h). In vitro parameters (A versus B) of mean dissolution time MDT (5.03 min versus 15.0 min), and time for 70% dissolution T70 (6.67 min versus 20.2 min), differed significantly.

Sodium naproxen: concentration and effect on inflammatory response mediators in human rheumatoid synovial fluid.

Twelve patients suffering from rheumatoid arthritis and having swollen knees were treated with 1.1 g/day of sodium naproxen administered in one dose, daily for 5 days. The 72-h wash-out period was verified by the absence of any nonsteroidal anti-inflammatory drug using a HPLC screening. Blood and synovial fluid samples were drawn just before treatment and 24 h after the last dose. Eicosanoids (PGE2, 6-keto-PGF1 alpha, TXB2, LTB4, LTC4) in synovial fluid were determined by immunoenzymatic assays. In plasma and synovial fluid, hyaluronic acid was assayed by radiometric assay and sodium naproxen by HPLC. Free drug was determined by equilibrium dialysis. Statistical analysis used nonparametric tests. Pain relief (evaluated on a visual scale), morning stiffness, and scores on the Lee and Ritchie indices all decreased significantly, as did PGE2 and LTB4 concentrations. The decrease in 6-keto-PGF1 alpha and TXB2 was not significant. No significant change was found for LTC4 and hyaluronic acid. Total concentrations of sodium naproxen were equivalent in plasma (16.1 micrograms.ml-1) and synovial fluid (18.9 micrograms.ml-1). Free fractions were significantly higher in synovial fluid (0.14%) than in plasma (0.11%), as shown by binding of the drug to human serum albumin, at various protein concentrations. Interestingly, the clinical efficacy, as shown by decreases in morning stiffness and in the Lee index score, correlated with the free concentration of naproxen in synovial fluid.