Pompon mum-like ionic covalent organic framework nanocomposites for efficient solid-phase extraction of nonsteroidal anti-inflammatory drugs.

Molecularly imprinted ionic covalent organic framework nanocomposites (MI-IC-COF@SnO2) were prepared as potential adsorbents for the enhanced adsorption of nonsteroidal anti-inflammatory drugs (NSAIDs) from aqueous solution. The resulting material exhibited a pompon mum-like structure, featuring a large surface area, and well-defined mesopores. The presence of uniform positive ions within the three-dimensional skeleton of MI-IC-COF@SnO2 facilitated a rapid adsorption rate and high adsorption capacity for target analytes. Thermodynamic fitting revealed the adsorption process of NSAIDs to be feasible, endothermic, and spontaneous. Additionally, the adsorbent material exhibited respectable selectivity, as evidenced by imprinting factor values ranging from 2.8 to 6.7. Utilizing MI-IC-COF@SnO2 as the sorbent, a solid-phase extraction method coupled with high-performance liquid chromatography-ultraviolet detection (SPE-HPLC-UV) was developed and optimized. The proposed method demonstrated good linear range with determination coefficients of 0.998-0.999, and low limit of detection (0.18-1.35 µg L-1). Recoveries of NSAIDs in urine and river water samples were 78.1 %-106.1 %, with relative standard deviations lower than 12.5 %. This rapid and sensitive method enables the determination of NSAIDs at trace levels in complex matrices, providing reliable and reproducible results.

Modification of cellulose substrate by in situ synthesis of metal-organic framework-5 for thin film microextraction of some non-steroidal anti-inflammatory drugs and their measurement by high-performance liquid chromatography-ultraviolet detector.

This work, reports the successful preparation a thin film by a simple and inexpensive process for quantification of a model analytes in the urine sample using HPLC-UV. To this end, cellulose paper was employed as a substrate for the in-situ synthesis of MOF-5, to increase the resistance of the prepared film. The prepared film can be reused 26 times with no reduction in its performance. The thin film prepared by MOF-5 modified cellulose substrate was utilized in thin film microextraction (TFME) method for the extraction and preconcentration of naproxen, aspirin, tolmetin, and celecoxib. Under optimal conditions, the linear dynamic range of the target analytes was 2-500 µg L-1 with correlation coefficients (R2) ranging from 0.9961 to 0.9990. Also, the limits of detection (LODs), the limits of quantification (LOQs) and relative standard deviation (RSD%) of the proposed method for selected analytes ranged between 0.57 and 0.77 µg L-1, 1.7 to 2.3 and 3.5 % to 6.2 %, respectively. Moreover, relative recoveries varied from of 94 % to 108 %, indicating the absence of matrices effect in the proposed method. Eventually, the TFME was successfully used for the extraction of selected analytes from urine samples.

In-situ synthesis of nanocubic cobalt oxide @ graphene oxide nanocomposite reinforced hollow fiber-solid phase microextraction for enrichment of non-steroidal anti-inflammatory drugs from human urine prior to their quantification via high-performance liquid chromatography-ultraviolet detection.

The in-situ synthesis and application of nanocubic Co3O4-coated graphene oxide (Co3O4@ GO) was introduced for the first time to present a cost-effective, stable and convenient operation and a simple device for hollow fiber solid-phase microextraction (HF-SPME) of four selected nonsteroidal anti-inflammatory drugs (NSAIDs) including diclofenac, mefenamic acid, ibuprofen and indomethacin. The extracted analytes were desorbed by an appropriate organic solvent and analyzed via high-performance liquid chromatography-ultraviolet detection (HPLC-UV). The prepared sorbent was approved using different characterization methods such as X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDX). The variables effective on the Co3O4@GO-HF-SPME method including extraction time, desorption time, desorption solvent volume, sample pH, stirring rate and ionic strength were screened via Plackett-Burman design and then optimized by Box-Behnken design. Under optimal condition, the calibration curves were linear within the range of 1.0-200.0 µg L-1 of analyte concentration with detection limits of 0.18-1.1 µg L-1 and the relative standard deviations less than 10.1%. The limits of quantification (LOQs) were in the range of 0.60-3.67 µg L-1. Matrix effect was not observed with this method; therefore, standard addition is not necessary for quantification of target compounds. The enrichment factors were obtained in the range of 49-68. The relative recoveries of the urine sample analysis were calculated in the range of 93-102%. Finally, the presented method exhibited good sensitivity, excellent repeatability, high reusability and acceptable precision, which will be a promising method to analyze various nonsteroidal anti-inflammatory drugs in urine samples.

In Vivo Functional Effects of CYP2C9 M1L, a Novel and Common Variant in the Yup'ik Alaska Native Population.

Alaska Native people are under-represented in genetic research but have unique gene variation that may critically impact their response to pharmacotherapy. Full resequencing of CYP2C9 in a cross-section of this population identified CYP2C9 Met1Leu (M1L), a novel, relatively common single nucleotide polymorphism hypothesized to confer CYP2C9 poor metabolizer phenotype by disrupting the start codon. M1L is present at a minor allele frequency of 6.3% in Yup'ik Alaska Native people and thus can contribute to the risk of an adverse drug response from narrow-therapeutic-index CYP2C9 substrates such as (S)-warfarin. This study's objective was to characterize the catalytic efficiency of the Leu1 variant enzyme in vivo by evaluating the pharmacokinetic behavior of naproxen, a probe substrate for CYP2C9 activity, in genotyped Yup'ik participants. We first confirmed the selectivity of (S)-naproxen O-demethylation by CYP2C9 using activity-phenotyped human liver microsomes and selective cytochrome P450 inhibitors and then developed and validated a novel liquid chromatography mass spectrometry method for simultaneous quantification of (S)-naproxen, (S)-O-desmethylnaproxen, and naproxen acyl glucuronide in human urine. The average ratio of (S)-O-desmethylnaproxen to unchanged (S)-naproxen in urine was 18.0 ± 8.0 (n = 11) for the homozygous CYP2C9 Met1 reference group and 10.3 ± 6.6 (n = 11) for the Leu1 variant carrier group (P = 0.011). The effect of M1L variation on CYP2C9 function and its potential to alter the pharmacokinetics of drugs metabolized by the enzyme has clinical implications and should be included in a variant screening panel when pharmacogenetic testing in the Alaska Native population is warranted. SIGNIFICANCE STATEMENT: The novel CYP2C9 Met1Leu variant in Alaska Native people was recently identified. This study validated (S)-naproxen as a CYP2C9 probe substrate to characterize the in vivo functional activity of the CYP2C9 Leu1 variant. The results of this pharmacogenetic-pharmacokinetic study suggest that the CYP2C9 Leu1 variant exhibits loss of enzyme activity. This finding may be important to consider when administering narrow-therapeutic-index medications metabolized by CYP2C9 and also compels further investigation to characterize novel genetic variation in understudied populations.

3D flower-liked Fe3O4/C for highly sensitive magnetic dispersive solid-phase extraction of four trace non-steroidal anti-inflammatory drugs.

A low cost-effective and simple synthesis method was adopted to acquire three-dimensional flower-like structure Fe3O4/C that has large specific area, suitable pore structure and sufficient saturation magnetism. The obtained Fe3O4/C exhibits outstanding preconcentration ability and was applied to extracting non-steroidal anti-inflammatory drugs from complex environmental and biological samples. The parameters of magnetic solid-phase extraction were optimized by univariate and multivariate methods (Box-Behnken design). The high degree of linearity from 2.5 to 1000.0 ng mL-1 (R2 ≥ 0.9976), the limits of detection from 0.25 to 0.5 ng mL- 1 (S/N = 3), and the limits of quantitation from 1.0 to 2.0 ng mL- 1 (S/N = 10) were yielded by adopting this novel method after the optimization. Moreover, the recoveries of non-steroidal anti-inflammatory drugs from 89.6 to 107.0% were acquired in spiked plasma, urine and lake samples. In addition, the adsorption of non-steroidal anti-inflammatory drugs on Fe3O4/C was explored by adsorption isotherms and kinetic studies. Furthermore, the adsorption mechanism for non-steroidal anti-inflammatory drugs by Fe3O4/C was proposed, which was hydrogen bonding and π-π interaction between non-steroidal anti-inflammatory drugs and Fe3O4/C. Graphical abstract.

Comparison of three electromembrane-based extraction systems for NSAIDs analysis in human urine samples.

A comparative study on the extraction efficiency of five non-steroidal anti-inflammatories was carried out using three different electromembrane extraction (EME) devices with different geometries. The employed setups were (a) a hollow fiber configuration (HF-EME), (b) a microfluidic device that allows working in semi-dynamic mode (µF-EME), and (c) a static miniaturized flat membrane device (FM-EME). Each system was applied to the extraction of salicylic acid (SAC), ketoprofen (KTP), naproxen (NAX), diclofenac (DIC), and ibuprofen (IBU) and subsequent determination by high-performance liquid chromatography with UV and fluorescence detection (HPLC/UV-DAD-FLD). Voltage, pH composition, and extraction time were optimized for all devices. Additionally, volume ratio was investigated for HF-EME and FM-EME and flow rate for the microfluidic device. HF-EME provides the best result in terms of sensitivity with a limit of detection (LOD) between 0.1 and 1.5 ng mL-1 for SAC and KTP, respectively, while LODs for µF-EME were between 100 ng mL-1 and 400 ng mL-1 for SAC and DIC, respectively; however, a lower amount of sample was required. Finally, the obtained results, in terms of enrichment factors and extraction recoveries, were discussed to establish the advantages and disadvantages of each device. The proposed EME methods were successfully applied to the determination of the target analytes in fortified human urine samples. Graphical abstract.

Non-steroidal anti-inflammatory drugs increase urinary neutrophil gelatinase-associated lipocalin in recreational runners.

OBJECTIVES: To study the effects of running with/without the use of pain killers on urinary neutrophil gelatinase-associated lipocalin (uNGAL) and other parameters of kidney function in recreational runners. METHODS: Participants of the 10- and 21.1-km Weir Venloop race were enrolled and their urine samples collected before and after the run. Urine dipstick and other conventional tests used to assess kidney function were performed. The presence of ibuprofen, diclofenac, naproxen, and/or paracetamol was assessed by LC-MS/MS. uNGAL was measured with a two-step chemiluminescent immunoassay. RESULTS: NSAIDs/analgesics were detected in urine of 5 (14.4%) 10-km runners and 13 (28.9%) 21.1-km runners. Only half-marathon participants showed significant increases in uNGAL (pre: 11.7 [7.1-34.3] ng/mL; post: 33.4 [17.4-50.4] ng/mL; P = .0038). There was a significant effect of NSAID/analgesic use on uNGAL increase (F2, 76  = 4.210, P = .004). Post hoc tests revealed that uNGAL increased significantly in runners who tested positive for ibuprofen/naproxen compared to runners who did not use any medications (P = .045) or those who tested positive for paracetamol (P = .033). Running distance had a significant influence on the increase in uNGAL (F1, 53  = 4.741, P < .05), specific gravity (F1, 60  = 9.231, P < .01), urinary creatinine (F1, 61  = 10.574, P < .01), albumin (F1, 59  = 4.888, P < .05), and development of hematuria (χ2 (4) = 18.44, P = .001). CONCLUSIONS: Running distance and use of ibuprofen/naproxen were identified as risk factors for uNGAL increase in recreational runners.

A study to assess the correlation between plasma, oral fluid and urine concentrations of flunixin meglumine with the tissue residue depletion profile in finishing-age swine.

BACKGROUND: Flunixin meglumine (FM) was investigated for the effectiveness of plasma, oral fluid, and urine concentrations to predict tissue residue depletion profiles in finishing-age swine, along with the potential for untreated pigs to acquire tissue residues following commingled housing with FM-treated pigs. Twenty pigs were housed in groups of three treated and one untreated control. Treated pigs received one 2.2 mg/kg dose of FM intramuscularly. Before treatment and at 1, 3, 6, 12, 24, 36, and 48 h (h) after treatment, plasma samples were taken. At 1, 4, 8, 12 and 16 days (d) post-treatment, necropsy and collection of plasma, urine, oral fluid, muscle, liver, kidney, and injection site samples took place. Analysis of flunixin concentrations using liquid chromatography/tandem mass spectrometry was done. A published physiologically based pharmacokinetic (PBPK) model for flunixin in cattle was extrapolated to swine to simulate the measured data. RESULTS: Plasma concentrations of flunixin were the highest at 1 h post-treatment, ranging from 1534 to 7040 ng/mL, and were less than limit of quantification (LOQ) of 5 ng/mL in all samples on Day 4. Flunixin was detected in the liver and kidney only on Day 1, but was not found 4-16 d post-treatment. Flunixin was either not seen or found less than LOQ in the muscle, with the exception of one sample on Day 16 at a level close to LOQ. Flunixin was found in the urine of untreated pigs after commingled housing with FM-treated pigs. The PBPK model adequately correlated plasma, oral fluid and urine concentrations of flunixin with residue depletion profiles in liver, kidney, and muscle of finishing-age pigs, especially within 24 h after dosing. CONCLUSIONS: Results indicate untreated pigs can be exposed to flunixin by shared housing with FM-treated pigs due to environmental contamination. Plasma and urine samples may serve as less invasive and more easily accessible biological matrices to predict tissue residue statuses of flunixin in pigs at earlier time points (≤24 h) by using a PBPK model.

Quantification and validation of nine nonsteroidal anti-inflammatory drugs in equine urine using gas chromatography-mass spectrometry for doping control.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used in therapeutic doses in human and veterinary medicine for the treatment of inflammation, pain, and fever. A method for the simultaneous determination of nine NSAIDs, known as therapeutic prohibited substances, in equine urine was developed and fully validated according to the European Commission Decision 2002/657/EC and Association of Official Racing Chemists criteria. The validation was performed for naproxen, flunixin, ketoprofen, diclofenac, eltenac, meclofenamic acid, phenylbutazone, vedaprofen, and carprofen in equine urine in accordance with the International Screening Limits (ISL) regulated by International Federation of Horseracing Authorities. After basic hydrolysis, samples were extracted with a C18 cartridge using automated solid-phase extraction. Several derivatization reagents were investigated, and trimethylphenylammonium hydroxide/methanol (20/80, v/v) was selected. Analyses were carried out using gas chromatography-mass spectrometry with selected ion monitoring mode, but the method can be applied to a large number of analytes. The within-laboratory reproducibility was not more than 12.8% (≤15%), and mean relative recoveries ranged from 91.1% to 104.1% for inter-day and intra-day precision. The decision limits (CCα) and detection capabilities (CCß) were evaluated at concentrations near the ISL for each therapeutic substance. The validation results demonstrated that the method is highly reproducible, easily applicable, and suitable for the analysis of some NSAIDs in equine urine that have not been previously published. Finally, the method was also applied to known positive samples.

Design of a pseudo stir bar sorptive extraction using graphenized pencil lead as the base of the molecularly imprinted polymer for extraction of nabumetone.

Molecularly imprinted polymer (MIP) was synthesized through the coprecipitation method on the graphene oxide anchored pencil lead as a substrate for the first time and applied as an efficient sorbent for pseudo stir bar sorptive extraction of nabumetone. The extracted analyte was determined by a novel spectrophotometric method based on the aggregation of silicate sol-gel stabilized silver nanoparticles in the presence of the analyte. The synthesized polymer was characterized using Fourier transform infrared spectroscopy and field emission scanning electron microscopy. Optimization of important parameters affecting the extraction efficiency was done using central composite design whereas the spectrophotometric method was optimized via one at a time variable. Under the optimal conditions, the calibration curve exhibited linearity in the concentration range of 1.5-20.0 µg L-1. A limit of detection of 0.20 µg L-1, an enhancement factor of 393 and relative standard deviations (at 10 µg L-1, n = 6) of 4.6% and 8.1% for intra- and inter-day analysis were obtained. The developed procedure was successfully utilized for the quantification of traces of nabumetone in tap water and biological samples with the complex matrix including human urine and serum.

Determination of grapiprant plasma and urine concentrations in horses.

OBJECTIVE: Non-steroidal anti-inflammatory drugs are inhibitors of cyclooxygenase (COX) in tissues and used as therapeutic agents in different species. Grapiprant, a member of the piprant class of compounds, antagonizes prostaglandin receptors. It is a highly selective EP4 prostaglandin E2 receptor inhibitor, thereby limiting the potential for adverse effects caused by wider COX inhibition. The objectives of this study were to determine if the approved canine dose would result in measurable concentrations in horses, and to validate a chromatographic method of analysis for grapiprant in urine and plasma. STUDY DESIGN: Experimental study. ANIMALS: A total of six healthy, adult mixed-breed mares weighing 502 ± 66 (397-600) kg and aged 14.8 ± 5.3 (6-21) years. METHODS: Mares were administered one dose of 2 mg kg-1 grapiprant via nasogastric tube. Blood and urine samples were collected prior to and up to 48 hours after drug administration. Drug concentrations were measured using high-performance liquid chromatography. RESULTS: Grapiprant plasma concentrations ranged from 71 to 149 ng mL-1 with the mean peak concentration (106 ng mL-1) occurring at 30 minutes. Concentrations were below the lower limit of quantification (50 ng mL-1) in four of six horses at 1 hour and in all six horses by 2 hours after drug administration. Grapiprant urine concentrations ranged from 40 to 4077 ng mL-1 and were still detectable at 48 hours after administration. CONCLUSIONS AND CLINICAL RELEVANCE: Currently, there are no published studies looking at the pharmacodynamics of grapiprant in horses. The effective concentration needed to control pain in dogs ranges 114-164 ng mL-1. Oral administration of grapiprant (2 mg kg-1) in horses did not achieve those concentrations. The dose was well tolerated; therefore, studies with larger doses could be conducted.

Nanocrystalline cellulose as a biotemplate for preparation of porous titania thin film as a sorbent for thin film microextraction of ketorolac, meloxicam, diclofenac and mefenamic acid.

The present study included the procedure of preparing porous titania thin film using a direct nanocrystalline cellulose templating (NCC) as a bio-template. The microextraction applicability of the porous film was investigated by thin film microextraction (TFME) of the nonsteroidal anti-inflammatory drugs (NSAIDs) including ketorolac, meloxicam, diclofenac and mefenamic acid from different types of urine sample. The extracted NSAIDs were analyzed by HPLC-UV. Under optimum conditions, the calibration curves were linear within the range of 1.0-500 µg L-1 (2.0-200 µg L-1 for ketorolac, 2.0-500 µg L-1 for meloxicam, 1.0-200 µg L-1 for diclofenac and 1.0-200 µg L-1 for mefenamic acid). The limit of detection was found to be between 0.2 and 0.5 µg L-1. The calculated intra- and inter-day relative standard deviations RSDs% (n = 3) at concentration level of 10 µg L-1 were less than 6.3% and 6.0%, respectively. Finally, the method was successfully applied to determine selected NSAIDs in urine samples from different human individuals.

Urinary chemical fingerprint left behind by repeated NSAID administration: Discovery of putative biomarkers using artificial intelligence.

Prediction and early detection of kidney damage induced by nonsteroidal anti-inflammatories (NSAIDs) would provide the best chances of maximizing the anti-inflammatory effects while minimizing the risk of kidney damage. Unfortunately, biomarkers for detecting NSAID-induced kidney damage in cats remain to be discovered. To identify potential urinary biomarkers for monitoring NSAID-based treatments, we applied an untargeted metabolomics approach to urine collected from cats treated repeatedly with meloxicam or saline for up to 17 days. Applying multivariate analysis, this study identified a panel of seven metabolites that discriminate meloxicam treated from saline treated cats. Combining artificial intelligence machine learning algorithms and an independent testing urinary metabolome data set from cats with meloxicam-induced kidney damage, a panel of metabolites was identified and validated. The panel of metabolites including tryptophan, tyrosine, taurine, threonic acid, pseudouridine, xylitol and lyxitol, successfully distinguish meloxicam-treated and saline-treated cats with up to 75-100% sensitivity and specificity. This panel of urinary metabolites may prove a useful and non-invasive diagnostic tool for monitoring potential NSAID induced kidney injury in feline patients and may act as the framework for identifying urine biomarkers of NSAID induced injury in other species.

Polymeric ionic liquid immobilized onto paper as sorptive phase in microextraction.

A new planar sorptive phase based on the simple immobilization of polymeric ionic liquids on paper is proposed. The sorptive phase can develop hydrophobic or mixed-mode (combining hydrophobic and ion exchange) interactions with the target analytes. The polymer is prepared by the Radziszewski reaction, which takes place in aqueous media, and it has been thoroughly characterized by different techniques including infrared spectroscopy, matrix-assisted laser desorption/ionization coupled to high-resolution mass spectrometry and proton nuclear magnetic resonance. Three different strategies aimed to immobilize the polymeric ionic liquid on paper have been evaluated. Among them, simple thermal curing at 120 °C was selected. The as-prepared paper has been evaluated for the extraction of several non-steroidal anti-inflammatory drugs from urine, the analytes being finally determined by liquid chromatography with tandem mass spectrometry. The method detection limits were 3.8, 7.2, 6.8, 9.4, 15.7, and 5.1 µg/L for indomethacin, diclofenac, tolmetin, ketoprofen, naproxen, and ibuprofen, respectively. Calibration models were linear (R2 > 0.9949) up to 1000 µg/L. The intra-day precision, expressed as relative standard deviation and calculated at three different concentrations levels (limit of quantification, 250 µg/L, and 1000 µg/L), varied between 1.1 and 13%. The accuracy, calculated as relative recovery, was in the range from 72 to 95%, thus being considered appropriate. The easiness of polymeric ionic liquid paper synthesis and the multi-sample extraction protocol designed allows the processing of a high number of samples at the same time.

Ultrasound treated cerium oxide/tin oxide (CeO2/SnO2) nanocatalyst: A feasible approach and enhanced electrode material for sensing of anti-inflammatory drug 5-aminosalicylic acid in biological samples.

In this work, we developed cerium oxide/tin oxide (CeO2/SnO2) nanocatalyst with the assistance of urea by a simple sonochemical method and utilized as an efficient electrode material for electrochemical sensing of anti-inflammatory drug 5-aminosalicylic acid (Mesalamine, MES). The CeO2/SnO2 nanoparticles (NPs) were systematically characterized in terms of their crystal structure, morphologies, and physicochemical properties using XRD, Raman, FESEM, HR-TEM, EDX, mapping, and XPS analysis. The characterization results clearly confirmed that the prepared NPs was formed in the phase of CeO2/SnO2 without any other impurities. The electrochemical properties of CeO2/SnO2 NPs were investigated by EIS, CV, and DPV techniques. The CeO2/SnO2 NPs (9.6 µA) modified GCE demonstrated an excellent and improved electrocatalytic activity in terms of higher anodic peak current and lower peak potential when compared to bare GCE (6.7 µA) and CeO2 NPs/GCE (8.2 µA) for the sensing of MES. The CeO2/SnO2 NPs/GCE shows broader linear response range and lower detection limit of 0.02-1572 µM and 0.006 µM, respectively. Moreover, other potentially interfering compounds such as a similar functional group containing biological substances and inorganic species have no interference effect towards MES sensing. In addition, the practicability of the CeO2/SnO2 NPs/GCE was tested by real sample analysis in commercial MES tablet, human urine, and serum samples with the appreciable recovery results.

Hybrid monoliths with metal-organic frameworks in spin columns for extraction of non-steroidal drugs prior to their quantitation by reversed-phase HPLC.

A (glycidyl methacrylate)-co-(ethylene glycol dimethacrylate) polymer (poly(GMA-co-EDMA)) was functionalized with metal-organic frameworks (MOF) and used as a sorbent for solid-phase extraction (SPE). The polymeric sorbent was prepared in-situ by photopolymerization in a previously wall-modified spin column, and then modified with an amino-modified MOF of type NH2-MIL-101(Cr). The sorbents were used for the extraction of nonsteroidal anti-inflammatory drugs (NSAIDs) from human urine samples. The sorbent was compared with the parent monolith and embedded approach, where the MOF particles are admixed in the polymerization mixture before the in-situ polymerization in the modified spin column. SPE is performed by percolating the sample solutions in a centrifuge, which streamlines the SPE steps. The hybrid composites were characterized by scanning electron microscopy and nitrogen intrusion porosimetry. Three NSAIDs (ketoprofen, flurbiprofen, and ibuprofen) were tested. They were eluted from the sorbent with acidified water-acetonitrile mixtures and subsequently analyzed by reversed-phase HPLC with UV detection. The detection limits varied in the range from 0.1 to 7 µg·L-1, and the precisions (relative standard deviation) were <14% in all the cases. The recoveries were between 71.0 and 78.0% in spiked urine samples. Graphical abstractA hybrid monolith modified with amino-modified MOF [named NH2-MIL-101(Cr)] in wall-modified spin columns was prepared. The resulting micro-extraction device was applied to the extraction and preconcentration of non-steroidal anti-inflammatory drugs.

In vitro and human pharmacoscintigraphic evaluation of an oral 5-ASA delivery system for colonic release.

5-aminosalicylic acid (5-ASA) is the most widely used drug for the treatment of ulcerative colitis. The benefits of targeted delivery of 5-ASA to the large intestine are well known, resulting in reduced systemic absorption and increased local concentrations at the disease site. In the present study, a 5-ASA colon delivery system based on the time-dependent strategy, exploiting the relatively consistent small intestinal transit time (SITT), was manufactured and evaluated in vitro as well as in vivo. The system was obtained by successive spray-coating of an immediate-release tablet core with low-viscosity HPMC and Eudragit® L. The enteric film was effective in preventing release during the acidic stage of the in vitro test, while the HPMC coating brought about reproducible lag phases prior to release in phosphate buffer medium. A γ-scintigraphy investigation pointed out that, following administration to fasted and fed volunteers, disintegration of the units never occurred prior to colon arrival. In all cases, a lag time preceded the appearance of the drug and its N-acetyl metabolite in the bloodstream, which was found to correlate with the time of disintegration in a linear mode. The plasma levels of the drug and metabolite as well as their cumulative urinary recovery were relatively low with respect to those reported when 5-ASA is delivered to the small bowel.

Porphyrin-functionalized graphene oxide sheets: An efficient nanomaterial for micro solid phase extraction of non-steroidal anti-inflammatory drugs from urine samples.

In this work, porphyrin-functionalized graphene oxide nanosheets (GO@meso-tetrakis(4-hydroxyphenyl)porphyrin) were synthesized and employed as the sorbent. Porphyrins owing to their unique structures and tunable terminal functional groups are expected to be promising media for extraction of the desired analytes. Also, GO with a high specific surface area has exhibited good potential for the extraction purposes. Inspired by these intriguing properties, the combination of GO and porphyrin can benefit both of these amazing features. The synthesized sorbent was utilized for micro solid phase extraction of non-steroidal anti-inflammatory drugs followed by HPLC-UV. Optimization of the experimental factors including sorbent amount, sample pH, sample and eluent flowrates, eluent volume, and the number of desorption cycles were performed with the aid of central composite design. Under the optimal conditions, the calibration curves were linear within the range of 2.0-600 ng mL-1 and limits of detection were found between 0.5-2.0 ng mL-1. The preconcentration factors and absolute recoveries were obtained in the range of 4.80-9.79 and 29%-59%, respectively. The matrix effect for the urine samples varied between 81.9%-91.6% at two concentrations of 50 and 300 ng mL-1, respectively. Intra- and inter-day RSD% (n = 3) of the spiked urine samples at three level concentrations of 25, 100, and 300 ng mL-1 were less than 10%. The relative recoveries of the urine samples were calculated in the range of 85.2-98.6%. Eventually, the method exhibits proper sensitivity, excellent repeatability, high reusability, and acceptable precision and accuracy.

Combustion fabrication of magnetic porous carbon as a novel magnetic solid-phase extraction adsorbent for the determination of non-steroidal anti-inflammatory drugs.

Based on a one-step combustion fabrication approach, a novel magnetic porous carbon (MPC) was fabricated using filter paper as porous carbon source and iron salts as magnetic precursors. The textural properties of the MPC were characterized by transmission electron microscopy (TEM), Fourier transform infrared spectrometry (FT-IR), X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), vibration sample magnetometer (VSM) and nitrogen absorption-desorption isotherms. The as-prepared MPC possessed a high specific surface area, a microstructure comprised of mesopores and strong magnetic response. It was employed as a magnetic solid-phase extraction (MSPE) adsorbent for the determination of three non-steroidal anti-inflammatory drugs (NSAIDs) in environmental water and biological samples coupled with high performance liquid chromatography (HPLC). The main parameters affecting extraction efficiency were investigated in detail and a satisfactory performance was obtained under the optimal conditions. The calibration curves were linear over the concentration ranging from 1 to 1200 µg L-1 for ketoprofen (KET) and 2-1200 µg L-1 for naproxen (NAP) and diclofenac (DCF) with determination coefficients (R2) between 0.9995 and 0.9997. The limits of detection (LODs) were in the range of 0.2-0.4 µg L-1. The intra- and inter-day relative standard deviations (RSDs) were less than 4.03% and 8.72%, respectively. The recoveries ranged from 84.67% to 113.73% with RSDs less than 7.76%. The satisfactory results confirmed the great potential of the novel MPC adsorbent for the extraction of NSAIDs from complex sample matrices.

Identification of sulfonyl-loxoprofen as novel phase 2 conjugate in rat.

Loxoprofen is a prodrug that exerts strong analgesic and anti-inflammatory effects through its active trans-alcohol metabolite, which is produced in the liver by carbonyl reductase. Previous metabolic studies have evaluated loxoprofen, but its sulfate and taurine conjugates have not yet been studied. We characterized the metabolomic profile of loxoprofen in rat plasma, urine, and feces using high-resolution mass spectrometry. We identified 17 metabolites of loxoprofen in the three different biological matrices, 13 of which were detected in plasma and feces and 16 in urine. Amongst these metabolites, two novel taurine conjugates (M12 and M13) and two novel acyl glucuronides (M14, M15) were identified for the first time in rats. In addition, we detected three novel sulfate conjugates (M9, M10, and M11) of loxoprofen. Further study of these metabolites of loxoprofen is essential in order to assess their potency and toxicity.