Ketoprofen (KP), which causes photosensitivity by interacting with serum albumin (SA), and three drugs, ibuprofen (IBP), naproxen (NPX), and diazepam (DZP), which share the same binding site, were ...investigated for their interaction with bovine SA (BSA). For KP, DZP, and IBP, where drug-concentration-dependent quenching of BSA-intrinsic fluorescence was observed, a modified Stern–Volmer plot showed that dynamic quenching was dominant for KP and static quenching was dominant for DZP and IBP. However, this alone cannot be compared with NPX. Therefore, by performing singular value decomposition (SVD) fluorescence spectroscopy, we were able to find the behavior of the drug-concentration-dependent Langmuir-type principal component vectors. K SVD obtained by the Langmuir equation showed a high correlation with the static extinction constant V. Therefore, K SVD indicates the association constant of the drug with BSA and it was found that NPX and IBP had higher values than KP. Finally, in the analysis of the temperature factors of amino acid residues in each drug-binding region and Trp residues, KP and NPX significantly reduced these temperature factors whereas DZP and IBP hardly changed them. This result is consistent with the dynamic and static quenching dominance in the total quenching mechanism. Summarizing the results so far, it was shown that penetration into the hydrophobic core inside BSA can be achieved not only by one of the multiple aromatic rings and propionic acid groups but also by the joint effect of both. In this study, SVD enabled us to extract information on drug adsorption to BSA from fluorescence spectra. Furthermore, the application of SVD is expected to make it possible to perform fluorescence analysis for drug binding to proteins without being limited by the fluorescence properties of the drug.
Both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) convert arachidonic acid to prostaglandin H
, which has proinflammatory effects. The recently developed PET radioligand
C-PS13 has excellent ...in vivo selectivity for COX-1 over COX-2 in nonhuman primates. This study sought to evaluate the selectivity of
C-PS13 binding to COX-1 in humans and assess the utility of
C-PS13 to measure the in vivo potency of nonsteroidal antiinflammatory drugs.
Baseline
C-PS13 whole-body PET scans were obtained for 26 healthy volunteers, followed by blocked scans with ketoprofen (
= 8), celecoxib (
= 8), or aspirin (
= 8). Ketoprofen is a highly potent and selective COX-1 inhibitor, celecoxib is a preferential COX-2 inhibitor, and aspirin is a selective COX-1 inhibitor with a distinct mechanism that irreversibly inhibits substrate binding. Because blood cells, including platelets and white blood cells, also contain COX-1,
C-PS13 uptake inhibition from blood cells was measured in vitro and ex vivo (i.e., using blood obtained during PET scanning).
High
C-PS13 uptake was observed in major organs with high COX-1 density, including the spleen, lungs, kidneys, and gastrointestinal tract. Ketoprofen (1-75 mg orally) blocked uptake in these organs far more effectively than did celecoxib (100-400 mg orally). On the basis of the plasma concentration to inhibit 50% of the maximum radioligand binding in the spleen (in vivo
), ketoprofen (<0.24 μM) was more than 10-fold more potent than celecoxib (>2.5 μM) as a COX-1 inhibitor, consistent with the in vitro potencies of these drugs for inhibiting COX-1. Blockade of
C-PS13 uptake from blood cells acquired during the PET scans mirrored that in organs of the body. Aspirin (972-1,950 mg orally) blocked such a small percentage of uptake that its in vivo
could not be determined.
C-PS13 selectively binds to COX-1 in humans and can measure the in vivo potency of nonsteroidal antiinflammatory drugs that competitively inhibit arachidonic acid binding to COX-1. These in vivo studies, which reflect the net effect of drug absorption and metabolism in all organs of the body, demonstrated that ketoprofen had unexpectedly high potency, that celecoxib substantially inhibited COX-1, and that aspirin acetylation of COX-1 did not block binding of the representative nonsteroidal inhibitor
C-PS13.
► Direct UV photolysis of 3 pharmaceuticals in pure and waste water was investigated. ► Ketoprofen has higher photodegradion kinetics, followed by diclofenac and atenolol. ► MP/UV photodegradation ...products were identified for the 3 compounds. ► Photodegradation pathways were proposed to explain the obtained products. ► The persistent photoproducts were identified for each compound.
Pharmaceutical compounds such as ketoprofen, diclofenac and atenolol are frequently detected at relatively high concentrations in secondary effluents from wastewater treatment plants. Therefore, it is important to assess their transformation kinetics and intermediates in subsequent disinfection processes, such as direct ultraviolet (UV) irradiation. The photodegradation kinetics of these compounds using a medium pressure (MP) lamp was assessed in pure water, as well as in filtered and unfiltered treated wastewater. Ketoprofen had the highest time- and fluence-based rate constants in all experiments, whereas atenolol had the lowest values, which is consistent with the corresponding decadic molar absorption coefficient and quantum yield. The fluence-based rate constants of all compounds were evaluated in filtered and unfiltered wastewater matrices as well as in pure water. Furthermore, transformation products of ketoprofen, diclofenac and atenolol were identified and monitored throughout the irradiation experiments, and photodegradation pathways were proposed for each compound. This enabled the identification of persistent transformation products, which are potentially discharged from WWTP disinfection works employing UV photolysis.
Wastewater treatment plants are a major pathway for pharmaceuticals to the aquatic environment. Many pharmaceuticals, including non-steroidal anti-inflammatory drugs (NSAIDs), are chiral chemicals ...and the biological activity of their enantiomers can differ. Few studies have assessed the effects of different NSAID enantiomers on non-target organisms. However, this information is important for environmental risk assessment to ensure that the effects of more potent enantiomers are not overlooked. In the current study, enantiomers of naproxen, ibuprofen, ketoprofen and flurbiprofen were evaluated in bioassays with bacteria, algae and fish cells. All enantiomers induced bacterial toxicity, with (R)-naproxen more toxic than (S)-naproxen (EC50 0.75 vs 0.93 mg/L) and (S)-flurbiprofen more toxic than (R)-flurbiprofen (EC50 1.22 vs 2.13 mg/L). Both (R)-flurbiprofen and (S)-flurbiprofen induced photosystem II inhibition in green algae, with (R)-flurbiprofen having a greater effect in the assay after 24 h (EC10 5.47 vs 9.07 mg/L). Only the (R)-enantiomers of flurbiprofen and ketoprofen induced ethoxyresorufin-O-deethylase (EROD) activity in fish cells, while (S)-naproxen was 2.5 times more active than (R)-naproxen in the EROD assay. While enantiospecific differences were observed for all assays, the difference was less than an order of magnitude. This indicates that the risk of overlooking the effect of more potent NSAID enantiomers is minor for the studied test systems and supports the use of racemic (or single enantiomer) effect data for environmental risk assessment. However, further investigation of the (R)-enantiomer of commonly used NSAID ketoprofen is recommended as it was at least six times more potent in the EROD assay than the inactive (S)-ketoprofen.
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•Chiral pharmaceuticals, including NSAIDs, are present in wastewater effluent.•Few studies consider potential ecotoxicological differences of NSAID enantiomers.•Common NSAID enantiomers tested in bioassays with bacteria, algae and fish cells.•Enantiospecific differences observed, but differences less than order of magnitude.•Risk of overlooking more potent NSAID enantiomers is minor for studied test systems.
The adsorption of sulfamethoxazole (SMZ) and ketoprofen (KET) using carbon nanotubes (CNTs) and CNTs modified with ionic liquids (ILs) was investigated. Two ionic liquids (1-benzyl, 3-hexyl ...imidazolium, IL1 and 1-benzyl, 3-decahexyl imidazolium, IL2) were synthesized, and characterized by nuclear magnetic resonance (1H and 13C NMR) and high resolution-mass spectrometry (HR-MS). CNTs and modified CNTs were characterized using FT-IR, X-ray diffraction (XRD), surface area and porosity analysis, thermal gravimetric analysis (TGA), Zeta potential, Raman and scanning electron microscopy (SEM). Kinetics, isotherm and computational studies were carried out to determine the efficiency and adsorption mechanism of SMZ and KET on modified CNTs. A density functional theory (DFT) method was applied to shed more light on the interactions between the pharmaceutical compounds and the adsorbents at the molecular level. The effects of adsorbent dosage, concentration, solution pH, energetics and contact time of SMZ and KET on the adsorption process were investigated. The adsorption of SMZ and KET on CNTs and modified CNTs were pH dependent, and adsorption was best described by pseudo-second-order kinetics and the Freundlich adsorption isotherm. Ionic liquid modified CNTs showed improved adsorption capacities compared to the unmodified ones for both SMZ and KET, which is in line with the computational results showing performance order; CNT+KET/SMZ < CNT–ILs+SMZ < CNT–ILs+KET.
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•Ionic liquids -functionalized carbon nanotubes are efficient pharmaceutical removal.•Comparison of other surfactant modified–CNT and ionic liquid modified-CNT.•Kinetic, isotherm and thermodynamics of adsorption were determined.•Adsorption results were supported by computational simulation.•Sorption capacities of CNT-ILs were better than unmodified CNT.
The mineralization of ketoprofen (KP) by anodic oxidation was studied by employing boron doped diamond (BDD) and Pt electrodes. The redox behavior of KP molecule, fouling of electrodes, generation of ...oxygen and active chlorine species were studied by cyclic voltammetry. The effect of electrolyte, pH of aqueous medium and applied current density on the mineralization behavior of KP was also investigated. The degradation and mineralization were monitored by UV–vis spectrophotometer and total organic carbon analyzer, respectively. The results were explained in terms of in situ generation of hydroxyl radical (
OH), peroxodisulfate (S
2O
8
2−), and active chlorine species (Cl
2, HOCl, OCl
−). The physisorbed
OH on BDD was observed to trigger the combustion of KP in to CO
2 and H
2O. The poor mineralization at both BDD and Pt anodes in the presence of NaCl as supporting electrolyte was ascribed to the formation of chlorinated organic compounds which are refractory. Complete mineralization of KP molecule was achieved using Na
2SO
4 as supporting electrolyte.
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•The permeability of drugs was investigated in the presence of a rotating magnetic field (RMF).•The RMF may increase the permeability of active pharmaceutical ingredients (APIs).•The ...enhancement of API permeation through the skin in the presence of RMF depends on the type of API used (variable diffusion profiles).
The paper presents a method of increasing the permeability of various active substances through the skin by means of a rotating magnetic field. The study used 50 Hz RMF and various active pharmaceutical ingredients (APIs) such as caffeine, ibuprofen, naproxen, ketoprofen, and paracetamol. Various concentrations of active substance solutions in ethanol were used in the research, corresponding to those in commercial preparations. Each experiment was conducted for 24 h. It was shown that, regardless of the active compound used, an increase in drug transport through the skin was observed with RMF exposure. Furthermore, the release profiles depended on the active substance used. Exposure to a rotating magnetic field has been shown to effectively increase the permeability of an active substance through the skin.
A green, quick and sensitive spectrofluorimetric technique was investigated and validated for the assay of three different drugs namely, ketoprofen (KPN), paracetamol (PAR), and chlorzoxazone (CLX). ...The method is based on fluorescence quenching of the fluorescence probe, silver nanoparticles (SNPs). The fluorescence quenching of SNPs may be attributed to the complexation between each of the studied drugs with SNPs. The fluorescence of SNPs alone or after complexation with the studied drugs were measured at 485 nm (
λ
ex
242 nm) without the need to extract the formed complex. Chemical reduction was employed for preparing SNPs, where silver nitrate was reduced by sodium borohydride in deionized water without adding organic stabilizer. SNPs were found soluble in water, had high stability and had a narrow emission band. The studied drugs were found to decrease the fluorescence of SNPs significantly through static quenching according to Stern-Volmer equation. Factors affecting the reaction between the drugs and NPs were carefully examined and optimized. Using the optimum conditions, the difference in the fluorescence intensity of SNPs before and after complexation with the studied drugs was in a good linear relationship with the concentration of the studied drugs, where (
R
2
= 0.9998, 0.9998 and 0.9991) in the ranges of 0.5-5.0, 0.15-3.0 and 0.5-9.0 μg mL
−1
for KPN, PAR and CLX, respectively. Validity of the proposed method was investigated according to ICH recommendations. The proposed technique was also employed for the analysis of each of the three drugs in commercial or laboratory prepared tablets and in spiked human plasma with very good recoveries as well as high level of accuracy and precision. This method was intended to the analysis of the proposed drugs in their single formulation and single drug administration. The suggested technique is considered an eco-friendly method, as it uses water as the safest and least expensive solvent. Moreover, the recommended technique does not involve solvent extraction of the formed complexes. Greenness assessment of the suggested procedure was accomplished by applying the four standard assessment tools. Consequently, the recommended method can be used in the routine quality control analysis of the cited drugs with minimum harmful effect on the environment as well as the individuals.
A green, quick and sensitive spectrofluorimetric technique was investigated and validated for the assay of three different drugs namely, ketoprofen (KPN), paracetamol (PAR), and chlorzoxazone (CLX).
The aim of the present study was to investigate the combined effect of PAMAM dendrimers and low-frequency ultrasound on the transdermal delivery of ketoprofen. Ketoprofen was subjected to in vitro ...and in vivo permeation studies involving passive diffusion (+/-PAMAM dendrimers (amine terminated; G1 to G4)) and sonophoretic permeation (+/-dendrimer application) across mouse skin. The dendrimer was applied to skin either along with the drug (simultaneous application) or prior to treatment with drug (pretreatment). Skin permeation studies for prepared drug-dendrimer complex were also performed. Both PAMAM dendrimers and sonophoresis used individually increased the transdermal permeation of the drug, but the combination of these two enhancement techniques showed a profound increase in the skin permeation of drug. Pretreatment mode of dendrimer application achieved higher drug permeation, both in presence and absence of ultrasound. Complexation of ketoprofen with G4 dendrimer resulted in lesser skin permeation of drug in the absence of ultrasound, and higher skin permeation in the presence of ultrasound. The combination of PAMAM dendrimer application along with ultrasound produced plasma drug levels similar to oral administration of ketoprofen. This study demonstrates the potential of combining PAMAM dendrimers with sonophoresis in achieving higher skin delivery of bioactive molecules.
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The objective of this randomized, controlled superiority trial was to assess the efficacy of ketoprofen for the treatment of spontaneous, culture-negative clinical mastitis cases that were not ...treated with antimicrobials. Holstein cows from 3 herds were eligible for inclusion if they had mild or moderate culture-negative clinical mastitis cases in 1 quarter or more. Upon detection of clinical mastitis, farm personnel performed on-farm culture (OFC) using commercially available bi-plates. Samples used for OFC were also cultured in a research laboratory. Cows with culture-negative clinical mastitis that met the inclusion criteria were randomly allocated to 1 of 2 experimental groups: in the ketoprofen (KET) group, cows received an intramuscular injection of 3 mg/kg of ketoprofen upon confirmation of a negative OFC result; and in the control (CON) group, cows received no treatment or placebo. Milk samples were collected 14 and 21 d after detection of clinical mastitis for microbiological examination and somatic cell counting. Study outcomes were clinical cure (within 7 d after inclusion in the study), relapse (within 14 d after inclusion) and recurrence of clinical mastitis (15 to 90 d after inclusion), risk of new intramammary infection, and quarter milk somatic cell count at 14 and 21 d. We used Cox proportional hazards, logistic regression, and repeated-measures models to compare each outcome between groups. After exclusion of moderate cases (n = 6), a total of 123 clinical mastitis cases (CON = 58 and KET = 65) were used for analyses. Risks of clinical cure 83.08% (54/65) and 91.23% (52/57); hazard ratio = 1.20, 95% confidence interval (CI) = 0.82–1.76, relapse 19.23% (10/52) and 18.00% (9/50); hazard ratio = 1.09, 95% CI = 0.45–2.62, and recurrence of clinical mastitis 17.31% (9/52) and 18.00% (9/50); hazard ratio = 1.26, 95% CI = 0.49–3.38 were not different between the KET and CON groups, respectively. The odds of a new intramammary infection at 14 d 20.75% (11/53) and 29.79% (14/47); odds ratio = 1.76, 95% CI = 0.66–4.73 or 21 d 28.57% (12/42) and 15.22% (7/46); odds ratio = 0.45, 95% CI = 0.16–1.30 were not different between the KET and CON groups, respectively. Mean somatic cell count was not different between the groups at 14 or 21 d. The results of this study suggest that a single intramuscular injection of ketoprofen as sole treatment for OFC-negative, mild clinical mastitis did not reduce time to clinical cure, relapse or recurrence of clinical mastitis, risk of subsequent intramammary infection, or milk somatic cell count compared with untreated controls.
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