Naproxen Concentrations Research Articles

Removal of non‐steroidal anti‐inflammatory drugs from primary and secondary effluents in a photocatalytic membrane reactor

AbstractBACKGROUNDThe pollution of the aquatic environment by pharmaceuticals has become a serious problem. Conventional technologies applied in water or sewage treatment plants are not effective in drugs removal, therefore there is an urgent need to develop new methods.RESULTSThe removal of diclofenac (DCF), ibuprofen (IBU) and naproxen (NAP) sodium salts in a photocatalytic membrane reactor (PMR) utilizing direct contact membrane distillation and UV‐C radiation from ultrapure water, tap water, primary effluents (PE) and secondary effluents (SE) of municipal wastewater treatment plant is presented. When PE were used as feed and TiO2 loading of 0.5 g dm−3 was applied, DCF was removed completely, IBU amount decreased for 73% and NAP for 90%. In the case of SE, DCF, IBU and NAP concentrations decreased by 100%, 93% and 94%, respectively (1.5 gTiO2 dm−3). Mineralization was low and did not exceed 14% for PE and 23% for SE. No drugs were found in the distillate, however, it contained high level of N‐NH4+, especially in PE.CONCLUSIONThe hybrid system can be an effective technology for the removal of pharmaceuticals from SE and PE, however, owing to membrane fouling the latter should be pretreated before application in the PMR. © 2014 Society of Chemical Industry

Model-based analysis of thromboxane B2 and prostaglandin E2 as biomarkers in the safety evaluation of naproxen

The assessment of safety in traditional toxicology protocols relies on evidence arising from observed adverse events (AEs) in animals and on establishing their correlation with different measures of drug exposure (e.g., Cmax and AUC). Such correlations, however, ignore the role of biomarkers, which can provide further insight into the underlying pharmacological mechanisms. Here we use naproxen as a paradigm drug to explore the feasibility of a biomarker-guided approach for the prediction of AEs in humans. A standard toxicology protocol was set up for the evaluation of effects of naproxen in rat, in which four doses were tested (7.5, 15, 40 and 80mg/kg). In addition to sparse blood sampling for the assessment of exposure, thromboxane B2 and prostaglandin E2 were also collected in satellite groups. Nonlinear mixed effects modelling was used to evaluate the predictive performance of the approach. A one-compartmental model with first order absorption was found to best describe the pharmacokinetics of naproxen. A nonlinear relationship between dose and bioavailability was observed which leads to a less than proportional increase in naproxen concentrations with increasing doses. The pharmacodynamics of TXB2 and PGE2 was described by direct inhibition models with maximum pharmacological effects achieved at doses >7.5mg/kg. The predicted PKPD relationship in humans was within 10-fold of the values previously published. Moreover, our results indicate that biomarkers can be used to assess interspecies differences in PKPD and extrapolated data from animals to humans. Biomarker sampling should be used systematically in general toxicity studies.

Abstract C52: A phase Ib biomarker trial of naproxen in patients at risk for DNA mismatch repair deficient colorectal cancer

Abstract Rationale: Approximately 15% of colorectal cancers (CRC) display Microsatellite Instability (MSI). The DNA mismatch repair (MMR) system is deficient in this tumor subtype secondary to a germline mutation in one of the MMR system genes (MLH1, MSH2, MSH6, PMS2) or to the presence of hypermethylation MLH1. Therefore, MSI tumors can have a genetic origin (Lynch syndrome) or a sporadic origin (hypermethylated MSI tumors). Patients and families diagnosed with Lynch Syndrome have an up to 70-80% lifetime risk of CRC. Therefore, this high-risk population may benefit from effective chemopreventive strategies. Results from the CAPP-II trial suggest that aspirin use is associated with reduction of risk for CRC and other tumors in Lynch syndrome; however the large doses needed and potential side effects present barriers to adoption. Other non-steroidal anti-inflammatory drugs (NSAID) with stronger efficacy and better tolerability may be reasonable alternatives for CRC chemoprevention. Naproxen is a NSAID that is widely used in the community with an excellent safety profile. Recent pre-clinical data sponsored by the Division of Cancer Prevention of the National Cancer Institute using a conditional mouse model of Lynch Syndrome (VC-MSH2-LoxP) have shown that Naproxen is the most effective agent from a panel of NSAIDs preventing CRC. Therefore, this clinical trial was designed to confirm the activity of Naproxen observed in vivo in patients diagnosed with Lynch Syndrome. Because NSAIDs exert their therapeutic effects through the inhibition of COX-1/-2 which in turn leads to a reduction in prostaglandin production, tissue level of prostaglandin E2 (PGE2) is a robust biomarker for the effect of NSAIDs. We wish to report herein the background and schema of this early-phase (Ib) cancer prevention trial to introduce the concept of NSAID chemoprevention strategy in this specialized and genetically well-defined patient population, and thus to also facilitate the identification of additional collaborators for potential further larger trials initiatives. Design: Eligible patients include individuals harboring a pathogenic mutation in one of the MMR genes and individuals who have been diagnosed with non-sporadic MSI-high tumors (i.e. no evidence of MLH1 hypermethylation or BRAF mutation). The primary endpoints are to test whether Naproxen at a once-daily 220 mg (low-) or 440 mg (high-) dose, administered for 6 months, reduces the concentration of PGE2 levels in normal colorectal mucosa, when compared to placebo; and to determine the safety profile and tolerability of Naproxen. A total of 60 participants will be randomized to achieve an evaluable sample size of 45 participants. Under the assumption of an effect size of 1.25, we will have 80% power for pairwise comparisons by the two-sample t-test among the three groups with 15 evaluable participants per group. Response to treatment will be defined as having a 30% reduction in the PGE2 level post-treatment. Secondary endpoints include the determination of Naproxen concentrations in plasma and in normal colorectal mucosa after 6 months of treatment, and levels of PGE2 in urine after 6 months of treatment, all measured by validated biomarker assays. The study will be conducted at three clinical sites (The University of Texas MD Anderson Cancer Center, The University of Michigan Comprehensive Cancer Center and Dana Farber Cancer Institute). Screening and accrual are expected to begin in the latter part of 2013. Supported by NCI, DCP Contract HHSN261201200034I to the UT MD Anderson Cancer Prevention Agent Development Program: Early Phase Clinical Research Consortium. Citation Format: Eduardo Vilar, Y. Nancy You, Lana A. Vornik, Elena M. Stoffel, Ramona M. Lim, Steven M. Lipkin, Marjorie Perloff, Powel H. Brown. A phase Ib biomarker trial of naproxen in patients at risk for DNA mismatch repair deficient colorectal cancer. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr C52.

Occurrence and removal of selected micropollutants in a water treatment plant

The levels of 14 micropollutants including nine pharmaceuticals, two pesticides, and three endocrine disruptors were measured in a water treatment plant (WTP) in Seoul, Korea. Among the measured micropollutants, 12 (excluding atrazine and triclocarban) were found in the influent and effluent from the WTP, at levels ranging from 2 to 482ngL−1. The removal efficiencies of the detected micropollutants in the WTP ranged from 6% to 100%. Among them diclofenac, acetaminophen, caffeine, carbamazepine, and 2,4-D were effectively removed (>80%). Metoprolol was unlikely to be removed (6%) in the WTP process. Concentrations of acetaminophen, metoprolol, ibuprofen, and naproxen were higher in winter, while levels of herbicides of 2,4-dichloro-phenoxyacetic acid (2,4-D) were higher in summer. Metoprolol was hardly removed in the water treatment process. Laboratory experiments showed that compounds with logKow>2.5 (especially bisphenol-A, 2,4-D, carbamazepine, triclocarban and 4-nonylphenol) were effectively removed by coagulation process, and adsorption effect increased in proportion with hydrophobicity of micropollutants and the turbidity of water. Sunlight photodegradation also effectively removed sulfamethoxazole, sulfamethazine, caffeine, diclofenac, ibuprofen, and acetaminophen, which are photosensitizes. Chlorination was relatively not effective for the removal of micropollutants due to the lower chlorine dosage (2mgL−1), lower contact time (1h), and already lower levels of micropollutants at the chlorination stage at WTP. Our results imply that micropollutants during coagulation stage at WTP can be removed not only by coagulation itself, but also by adsorption to clay particle especially for high turbidity water, and by sunlight photodegradation in the areas open to the atmosphere.

Detection of pharmaceuticals and personal care products (PPCPs) in near-shore habitats of southern Lake Michigan

Pharmaceuticals and personal care products (PPCPs) have been documented throughout the United States freshwaters but research has focused largely on lotic systems. Because PPCPs are designed to have a physiological effect, it is likely that they may also influence aquatic organisms. Thus, PPCPs may negatively impact aquatic ecosystems. The objectives of this research were to quantify PPCP abundance in near-shore habitats of southern Lake Michigan and identify factors related to PPCP abundance. Stratified sampling was conducted seasonally at four southern Lake Michigan sites. All sites and depths had measurable PPCP concentrations, with mean individual compound concentrations of acetaminophen (5.36ng/L), caffeine (31.0ng/L), carbamazepine (2.23ng/L), cotinine (4.03ng/L), gemfibrozil (7.03ng/L), ibuprofen (7.88ng/L), lincomycin (4.28ng/L), naproxen (6.32ng/L), paraxanthine (1,7-dimethylxanthine; 46.2ng/L), sulfadimethoxine (0.94ng/L), sulfamerazine (0.92ng/L), sulfamethazine (0.92ng/L), sulfamethoxazole (26.0ng/L), sulfathiazole (0.92ng/L), triclocarban (5.72ng/L), trimethoprim (5.15ng/L), and tylosin (3.75ng/L). Concentrations of PPCPs varied significantly among sampling times and locations (river mouth vs offshore), with statistical interactions between the main effects of site and time as well as time and location. Concentrations of PPCPs did not differ with site or depth. Temperature, total carbon, total dissolved solids, dissolved oxygen, and ammonium concentrations were related to total pharmaceutical concentrations. These data indicate that PPCPs are ubiquitous and persistent in southern Lake Michigan, potentially posing harmful effects to aquatic organisms.

Carbamazepine and naproxen: Fate in wetland mesocosms planted with Scirpus validus

Scirpus validus was grown hydroponically and exposed to the pharmaceuticals, carbamazepine and naproxen at concentrations of 0.5–2.0mgL−1 for an exposure duration of up to 21d. By the end of experiment, carbamazepine elimination from the nutrient solution reached to 74%, while nearly complete removal (>98%) was observed for naproxen. Photodegradation and biodegradation played only minor roles for carbamazepine elimination, while naproxen showed a high potential for both photodegradation and biodegradation. Levels of carbamazepine ranged from 3.3 to19.0μgg−1 (fresh weight) in the roots and 0.3–0.7μgg−1 (fresh weight) in the shoots, while naproxen concentrations were 0.2–2.4μgg−1 (fresh weight) in the roots and 0.2–2.8μgg−1 (fresh weight) in the shoots. Bioaccumulation factors (BAFs) for carbamazepine ranged from 5.5 to 13.0 for roots and 0.3–1.0 for shoots, and uptake by S. validus accounted for up to 22% of the total mass loss of carbamazepine in the nutrient solutions. All BAFs for naproxen were less than 4.2 and plant uptake accounted for less than 5% of the total mass loss of naproxen, implying that plant uptake was not significant in naproxen elimination. The rather limited plant uptake of naproxen was not surprising despite the fact that its log Kow is close to the optimal range (1.8–3.1) for maximal potential for plant uptake. Apparently, for ionizable compounds such as naproxen, the effects of pKa and pH partitioning might be more important than lipophilicity.

Binding of naproxen enantiomers to human serum albumin studied by fluorescence and room-temperature phosphorescence

The interaction of the enantiomers of the non-steroidal anti-inflammatory drug naproxen (NPX) with human serum albumin (HSA) has been investigated using fluorescence and phosphorescence spectroscopy in the steady-state and time-resolved mode. The absorption, fluorescence excitation, and fluorescence emission spectra of (S)-NPX and (R)-NPX differ in shape in the presence of HSA, indicating that these enantiomers experience a different environment when bound. In solutions containing 0.2M KI, complexation with HSA results in a strongly increased NPX fluorescence intensity and a decreased NPX phosphorescence intensity due to the inhibition of the collisional interaction with the heavy atom iodide. Fluorescence intensity curves obtained upon selective excitation of NPX show 8-fold different slopes for bound and free NPX. No significant difference in the binding constants of (3.8±0.6)×105M−1 for (S)-NPX and (3.9±0.6)×105M−1 for (R)-NPX was found. Furthermore, the addition of NPX quenches the phosphorescence of the single tryptophan in HSA (Trp-214) based on Dexter energy transfer. The short-range nature of this mechanism explains the upward curvature of the Stern–Volmer plot observed for HSA: At low concentrations NPX binds to HSA at a distance from Trp-214 and no quenching occurs, whereas at high NPX concentrations the phosphorescence intensity decreases due to dynamic quenching by NPX diffusing into site I from the bulk solution. The dynamic quenching observed in the Stern–Volmer plots based on the longest phosphorescence lifetime indicates an overall binding constant to HSA of about 3×105M−1 for both enantiomers.

The Anti-Inflammatory Drugs Diclofenac, Naproxen and Ibuprofen are found in the Bile of Wild Fish Caught Downstream of a Wastewater Treatment Plant

Pharmaceutical residues are ubiquitous in rivers, lakes, and at coastal waters affected by discharges from municipal wastewater treatment plants. In this study, the presence of 17 different pharmaceuticals and six different phase I metabolites was determined in the bile of two wild fish species, bream (Abramis brama) and roach (Rutilus rutilus). The fish were caught from a lake that receives treated municipal wastewater via a small river. Prior to analyses, the bile content was enzymatically hydrolyzed to convert the glucuronide metabolites into the original pharmaceuticals or phase I metabolites. The solid phase extracts of hydrolyzates were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in the multiple reaction monitoring mode. The anti-inflammatory drug naproxen could be detected in all the six bream and roach bile samples. Diclofenac was found in five of the bream and roach samples, while ibuprofen was detected in three bream and two roach samples. The observed bile concentrations of diclofenac, naproxen, and ibuprofen in bream ranged from 6 to 95 ng mL(-1), 6 to 32 ng mL(-1), and 16 to 34 ng mL(-1), respectively. The corresponding values in roach samples ranged from 44 to 148 ng mL(-1), 11 to 103 ng mL(-1) and 15 to 26 ng mL(-1), respectively. None of the other studied compounds could be detected. The study shows that pharmaceuticals originating from wastewater treatment plant effluents can be traced to the bile of wild bream and roach living in a lake where diclofenac, naproxen, and ibuprofen are present as pollutants.

Plasma and Cerebrospinal Fluid Pharmacokinetics of Naproxen in Children

The aim of this study was to characterize pediatric pharmacokinetics and central nervous system exposure of naproxen after oral administration. The pharmacokinetics of naproxen was studied in 53 healthy children aged 3 months to 12 years undergoing surgery with spinal anesthesia. Children received preoperatively a single dose of 10 mg/kg oral naproxen suspension. A single cerebrospinal fluid (CSF) sample (n = 52) was collected at the induction of anesthesia, and plasma samples (n = 270) were collected before, during, and after the operation (up to 51 hours after administration). A population pharmacokinetic model was built using the NONMEM software. Naproxen concentrations in plasma were well described by a 2-compartment model. The estimated oral clearance (CL/F) was 0.62 L/h when linearly scaled by weight to 70 kg. The apparent volume of distribution at steady state (Vss/F) was 12.5 L /70 kg. The findings are consistent with previously reported pharmacokinetic parameters for children older than 5 years. Naproxen permeated into the CSF and reached CSF concentrations that were 4 times higher than unbound plasma concentrations. Based on these data, weight can be used as a basis for naproxen dosing in children older than 3 months of age.

Nanostructured conducting molecularly imprinted polymer for selective uptake/release of naproxen by the electrochemically controlled sorbent

A conducting molecularly imprinted polymer (CMIP) film, based on polypyrrole, was electrosynthesized for selective uptake/release and determination of naproxen. The film was prepared by incorporation of a template anion (naproxen) during the electropolymerization of pyrrole into a platinum electrode using the cyclic voltammetry method. Overoxidized polypyrrole films with cavities complementary to the template were used as a potential-induced selective recognition element in the solid-phase sorbent. Various important fabricating factors, which control the performance of the CMIP film, were investigated using fluorescence spectroscopy. The measured fluorescence intensities of released solutions were related to the concentrations of naproxen taken up into the films. Several key parameters such as applied potential and time for uptake and release were varied to achieve the optimal sorption procedure. The film template with naproxen exhibited excellent selectivity over some interference. The calibration graphs were linear in the ranges of 5×10−8 to 3×10−7molml−1 and 7×10−6 to 8×10−4molml−1, and the limit of detection was 1×10−8molml−1. The CMIP films, as the electrochemically controlled solid-phase sorbent, were applied for the selective cleanup and quantification of trace amounts of naproxen from physiological samples. Scanning electron microscopy confirmed the nanostructure morphology of the films.

Enantiospecific fate of ibuprofen, ketoprofen and naproxen in a laboratory-scale membrane bioreactor

The enantiospecific fate of three common pharmaceuticals was monitored in a laboratory-scale membrane bioreactor (MBR). The MBR was operated with a hydraulic retention time of 24 h and a mixed liquor suspended solids concentration of 8.6–10 g/L. Standard solutions of ibuprofen, ketoprofen and naproxen were dosed into the synthetic feed of the MBR. Influent and permeate samples were then collected for enantiospecific analysis. The individual ( R)- and ( S)-enantiomers of the three pharmaceuticals were derivatised using a chiral derivatizing agent to form pairs of diastereomers, which could then be separated and analysed by gas chromatography–tandem mass spectrometry (GC–MS/MS). Accurate quantitation of individual enantiomers was undertaken by an isotope dilution process. By comparing the total concentration (as the sum of the two enantiomers) in the MBR influent and permeate, ibuprofen, ketoprofen and naproxen concentrations were observed to have been reduced as much as 99%, 43% and 68%, respectively. Furthermore, evidence of enantioselective biodegradation was observed for all three pharmaceuticals. ( S)-Ibuprofen was shown to be preferentially degraded compared to ( R)-ibuprofen with an average decrease in enantiomeric fraction ( EF) from 0.52 to 0.39. In contrast, ( R)-ketoprofen was preferentially degraded compared to ( S)-ketoprofen with a relatively minor increase in EF from 0.52 to 0.63. The use of a relatively pure enantiomeric solution of ( S)-naproxen resulted in a significant change in EF from 0.99 to 0.65. However, this experiment consistently revealed significantly increased concentrations of ( R)-naproxen during MBR treatment. It is hypothesised that the source of this ( R)-naproxen was the enantiomeric inversion of ( S)-naproxen. Such enantiomeric inversion of chiral pharmaceuticals during wastewater treatment processes has not previously been reported.

Modelling of pain intensity and informative dropout in a dental pain model after naproxcinod, naproxen and placebo administration

• Modelling has been used to describe the pain relief and dropout for a few non-steroidal anti-inflammatory drugs. • This study shows the relationship between dose, plasma concentration, pain intensity and dropout for naproxen and naproxcinod. It also extends previous models by using a visual analogue scale for pain intensity instead of modelling pain relief on a categorical scale, and shows the value of including informative dropout in the simulations for visual predictive checks. To describe pain intensity (PI) measured on a visual analogue scale (VAS) and dropout due to request for rescue medication after administration of naproxcinod, naproxen or placebo in 242 patients after wisdom tooth removal. METHODS Non-linear mixed effects modelling was used to describe the plasma concentrations of naproxen, either formed from naproxcinod or from naproxen itself, and their relationship to PI and dropout. Goodness of fit was assessed by simultaneous simulations of PI and dropout. Baseline PI for the typical patient was 52.7 mm. The PI was influenced by placebo effects, using an exponential model, and by naproxen concentrations using a sigmoid E(max) model. Typical maximal placebo effect was a decrease in PI by 20.2%, with an onset rate constant of 0.237 h(-1). EC(50) was 0.135 µmol l(-1). A Weibull time-to-event model was used for the dropout, where the hazard was dependent on the predicted PI and by the PI at baseline. Since the dropout was not at random, it was necessary to include the simulated dropout in visual predictive checks (VPC) of PI. This model describes the relationship between drug effects, PI and the likelihood of dropout after naproxcinod, naproxen and placebo administration. The model provides an opportunity to describe the effects of other doses or formulations, after dental extraction. VPC created by simultaneous simulations of PI and dropout provides a good way of assessing the goodness of fit when there is informative dropout.

Naproxen Metabolites Interfere With Certain Bilirubin Assays

A recent report indicated significant interference of naproxen with total bilirubin measurement when using the Jendrassik and Grof method. We explored the possibility of avoiding this interference by using a different method. We observed that naproxen has no effect on total bilirubin measurement by any method, but O-desmethylnaproxen (the naproxen metabolite) interfered significantly with total bilirubin assays using the Jendrassik and Grof method (Beckman Coulter [Brea, CA] and Siemens [Tarrytown, NY] bilirubin method). The Roche (Indianapolis, IN) bilirubin assay based on a different method was not affected. When serum samples of 9 patients receiving naproxen were analyzed for total bilirubin level, we observed good correlation in total bilirubin values measured by all 3 methods in 7 of 9 patients with therapeutic naproxen concentrations. In contrast, in 2 patients with elevated naproxen levels, the total bilirubin values observed by using the Beckman and Siemens methods were significantly higher than the value obtained by the Roche assay. The naproxen metabolite interferes with assays based on the Jendrassik and Grof method but not with the Roche bilirubin assay.

Infusions of albumin increase free fraction of naproxen in healthy volunteers: a randomized crossover study

In vitro and in vivo studies have indicated that stabilizers present in pharmaceutical-grade albumin influence the albumin-binding capacity for highly protein-bound drugs. However, the half-life of the stabilizers and the quantitative effect have been difficult to determine. A randomized crossover study including six healthy volunteers was performed. The study subjects received 750 mg of oral naproxen 2 h before the study. They were randomized to receive either 100 ml of 20% albumin or 100 ml of Ringer's acetate solution intravenously. Frequent blood samples were obtained. The experiment was repeated 4 weeks later with the alternate solution. The serum samples were analysed to determine the concentrations of albumin, N-acetyl-DL-tryptophan, caprylate, and naproxen. The free fraction of naproxen increased significantly after the infusion of albumin (P<0.05). The increase was concurrent with the appearance of N-acetyl-DL-tryptophan and caprylate in serum. The free fraction of naproxen declined rapidly after the albumin infusion was completed. N-acetyl-DL-tryptophan had a half-life of approximately 30 min. The half-life of caprylate was <15 min. A transfusion of albumin results in an increase in the free fraction of naproxen. The transient increase in free-fraction naproxen decreased together with the detectable levels of the stabilizers N-acetyl-DL-tryptophan and caprylate. N-acetyl-DL-tryptophan and caprylate have a short half-life in serum.

Leaching potential of nonsteroidal anti‐inflammatory drugs in soils

Nonsteroidal anti-inflammatory drugs (NSAIDs) in soils resulting from application of municipal wastewater or biosolids may migrate through soils intact or be transformed and reach groundwater. In the present study, the leaching potential of four NSAIDs (ibuprofen, naproxen, ketoprofen, and diclofenac sodium) in three U.S. cropland soils was evaluated, and the effect of CaCl(2) solution (as an index of salinity), dissolved organic matter (DOM), and polyacrylamide (PAM) amendment was investigated. The soils were spiked with selected NSAIDs, incubated for 24 h followed by 7-d storage in glass flasks, and then packed into stainless steel columns and leached with deionized water (DIW), 10 mM CaCl(2), DOM (DOC 34 mg/L), and PAM solution (1.0 mg/L) by gravity. Initial concentrations of ibuprofen, naproxen, ketoprofen, and diclofenac sodium in the three packed soils were 1.93 to 2.07, 1.74 to 2.27, 1.79 to 2.16, and 1.99 to 2.13 mg/kg, respectively. Maximum concentrations of the above NSAIDs in column effluents were 1.23, 0.92, 0.69, and 1.12 mg/L, respectively, when the soil was leached with 10 pore volumes of water, which occupied 17.4, 11.1, 9.6, and 15.2% of the total chemicals in each soil column. Dissolved organic matter or PAM solution did not facilitate the NSAIDs release from soils. The CaCl(2) solution, however, reduced the amounts of NSAIDs leached from all three soils. Leaching of NSAIDs differed among the three tested soils. The results suggest that the leaching of NSAIDs through soil to water is significant, and the mobility of NSAIDs in soil is related to their chemicals' characteristics (such as pK(a) values) and soil properties (such as soil organic matter and clay content). Amending soil with DOM or PAM does not significantly affect the leaching behavior of NSAIDs in soil, whereas increasing the salinity of the irrigation water may decrease the extent of contamination of groundwater posed by NSAIDs.

Comparative Bioavailability of a Generic and Two Compounded Naproxen Sodium Suspensions Administered to Rats

The purpose of this study was to determine naproxen concentrations in rat plasma samples by HPLC and to compare the bioavailability of a generic and two compounded naproxen sodium suspensions (test 1 and test 2). Analysis was run at a fl ow rate of 1.2 mL.min-1 with a mobile phase of acetonitrile: NaH2PO4 0.01 M pH 4.00 (50:50, v/v) at 280 nm, using a C18 column (150 mm x 4.6 mm, 5 μm). The calibration curve was linear (R2 = 0.9987) over the range of 0.25 - 200 μg.mL-1. The precision for inter and intra-day analysis ranged from 2.46% to 12.39%. Cmax, Tmax and AUCt were 191.25 ± 11.17 μg.mL-1, 1.00 ± 0.106 h and 2438.16 ± 291.34 μg.h.mL-1 for the reference drug, 188.22 ± 24.78 μg.mL-1, 1.06 ± 0.092 h and 1755.02 ± 228.90 μg.h.mL-1 for test 1, and 160.50 ± 10.58 μg.mL-1, 0.66 ± 0.102 h and 1955.28 ± 142.80 μg.h.mL-1 for test 2. No signifi cant differences were found based on analysis of variance, with mean values and 90% CI of test2/reference ratio (Cmax 83.92% and AUCt 80.19%). For test1/reference ratio, the result was Cmax 98.41% and AUCt 71.98%. Based on these results, it can be concluded that the validated method was successfully applied to this study; the test 1 formulation failed to demonstrate a bioequivalence to the reference drug; however, the test 2 and reference naproxen sodium suspension were bioequivalent in terms of the rate and extent of absorption under these conditions.

Winter accumulation of acidic pharmaceuticals in a Swedish river

In this study, seasonal variations in the concentration profile of four analgesics and one lipid regulator were monitored on their way from a wastewater treatment plant (WWTP) effluent, along a river, and into a lake. From December 2007 to December 2008, water samples were collected monthly (n=12) from an upstream point, the effluent, four downstream points of the WWTP, and at the point where the river merges with the lake, and the concentrations of ibuprofen, naproxen, bezafibrate, diclofenac, and ketoprofen were determined. The analytical methodology involved solid-phase extraction of the target compounds from water samples followed by liquid chromatography coupled with tandem mass spectrometry for compound separation and detection. The studied pharmaceuticals were found in the effluent at concentrations ranging from 31 to 1,852 ng l(-1) depending on the season. In the river and lake, the concentrations were much lower (6-400 ng l(-1)) mainly due to dilution but also to a season-dependent contribution from natural transformation processes. The mean mass flow of all analgesics was highest during winter while the highest mean mass flow of the lipid regulator bezafibrate was observed in spring. The WWTP is the main source of the target compounds in the aquatic environment. The observed winter accumulation signifies the importance of natural transformation processes, which can only be estimated based on mass flow data, on the fate of pharmaceuticals in the environment.

Fluorescent polyacrylamide nanoparticles for naproxen recognition

We present the synthesis of fluorescent acrylamide nanoparticles (FANs) capable of recognizing non-steroidal anti-inflammatory drugs (NSAIDs) in buffered aqueous solutions. Within this important group, we selected naproxen, one of the 2-arylpropionic acids (profens), due to its use for the treatment of moderate pain, fever, and inflammation. The nanosensors were prepared under mild conditions of inverse microemulsion polymerization using aqueous acrylamide as the monomer and N,N'-methylenebisacrylamide as the cross-linker, employing the surfactants polyoxyethylene-4-lauryl ether (Brij 30) and sodium bis(2-ethylhexyl)sulfosuccinate in hexane. Furthermore, a fluorescent monomer, (E)-4-[4-(dimethylamino)styryl]-1-[4-(methacryloyloxymethyl)benzyl]pyridinium chloride (mDMASP) has been synthesized and incorporated into the nanoparticles. The nanosensors exhibit a broad absorbance at around 460 nm and a structureless fluorescence band with maximum at 590 nm in 0.5 M phosphate buffer (pH = 7.2). The recognition process is performed on the basis of ionic interactions which are monitored by the fluorescence increase at 590 nm upon addition of different concentrations of naproxen. The FANs show a size distribution in the range of 20-80 nm, with a hydrodynamic diameter of 34 nm. In order to assess the selectivity of the FANs, a systematic study was conducted on the effect produced by drugs and biomolecules that could interfere with the analysis of naproxen.

Runoff of pharmaceuticals and personal care products following application of biosolids to an agricultural field

Municipal biosolids are a source of nutrients for crop production. Beneficial Management Practices (BMPs) can be used to minimize the risk of contamination of adjacent water resources with chemical or microbial agents that are of public or environmental health concern. In this field study, we applied biosolids slurry at a commercial rate using either subsurface injection or broadcast application followed by incorporation. Precipitation was simulated at 1, 3, 7, 22, 36 and 266 days post-application on 2 m 2 microplots to evaluate surface runoff of 9 model pharmaceuticals and personal care products (PPCPs), atenolol, carbamazepine, cotinine, gemfibrozil, naproxen, ibuprofen, acetaminophen, sulfamethoxazole and triclosan. In runoff from the injected plots, concentrations of the model PPCPs were generally below the limits of quantitation. In contrast, in the broadcast application treatment, the concentrations of atenolol, carbamazepine, cotinine, gemfibrozil, naproxen, sulfamethoxazole and triclosan on the day following application ranged from 70–1477 ng L − 1 in runoff and generally declined thereafter with first order kinetics. The total mass of PPCPs mobilized in surface runoff per m 2 of the field ranged from 0.63 µg for atenolol to 21.1 µg for ibuprofen. For ibuprofen and acetaminophen, concentrations in runoff first decreased and then increased, suggesting that these drugs were initially chemically or physically sequestered in the biosolids slurry, and subsequently released in the soil. Carbamazepine and triclosan were detected at low concentrations in a runoff event 266 days after broadcast application. Overall, this study showed that injection of biosolids slurry below the soil surface could effectively eliminate surface runoff of PPCPs.

Potentiometric determination of ibuprofen, indomethacin and naproxen using an artificial neural network calibration

In this study, three anti-inflammatory agents, namely ibuprofen, indomethacin and naproxen, were titrated potentiometrically using tetrabutyl?ammonium hydroxide in acetonitrile solvent under a nitrogen atmosphere at 25?C. MATLAB 7.0 software was applied for data treatment as a multivariate calibration tool in the potentiometric titration procedure. An artificial neural network (ANN) was used as a multivariate calibration tool in the potentiometric titration to model the complex non-linear relationship between ibuprofen, indomethacin and naproxen concentrations and the millivolt (mV) of the solutions measured after the addition of different volumes of the titrant. The optimized network predicted the concentrations of agents in synthetic mixtures. The results showed that the employed ANN can precede the titration data with an average relative error of prediction of less than 2.30%.