Non-steroidal Anti-inflammatory Ketoprofen Research Articles

Behavioral evaluation of the analgesic effects of ketoprofen in lame dairy cows

Lameness in dairy cattle decreases productivity and diminishes animal welfare. Alleviating the pain associated with lameness would improve animal welfare and could improve productivity and enhance recovery. In dairy cows, lameness is associated with increased duration and frequency of lying bouts, abnormal locomotion, and increased weight shifting behavior. Weight shifting between the rear limbs can be used to objectively quantify pain levels and responses to pain-relieving drugs. The hypothesis of this study was that administration of the non-steroidal anti-inflammatory drug (NSAID) ketoprofen would decrease pain-associated behaviors in lame dairy cows.

Characterization and biological properties of copper(II)-ketoprofen complexes

From the reaction of Cu(II) with the non-steroidal anti-inflammatory drug ketoprofen (Hketo), complex [Cu2(keto)4(H2O)2] was isolated, while the presence of a N,N′-donor heterocyclic ligand 2,2′-bipyridylamine (bipyam), 1,10-phenanthroline (phen) or 2,2′-bipyridine (bipy) led to the formation of complexes of the formula [Cu(keto)2(N,N′-donor)(H2O)]. The complexes were characterized by physicochemical and spectroscopic techniques and the crystal structure of [Cu(keto)2(bipyam)(H2O)] was determined by X-ray crystallography. The ability of ketoprofen and its complexes to scavenge 1,1-diphenyl-picrylhydrazyl, 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) and hydroxyl radicals was evaluated; the complexes were more active scavengers than free Hketo. The interaction of the complexes with serum albumins was investigated by fluorescence emission spectroscopy and the binding constant of the compounds to the albumins were calculated. Diverse techniques including UV spectroscopy, cyclic voltammetry and viscosity measurements as well as fluorescence emission spectroscopy for the competitive studies of the compounds with ethidium bromide, were employed in our attempt to examine the interaction of the compounds with calf-thymus DNA; as a conclusion, intercalation is the most possible mode of binding.

ChemInform Abstract: Chemoselective Transformation of Diarylethanones to Arylmethanoic Acids and Diarylmethanones and Mechanistic Insights.

The chemoselective transformation of diarylethanones via either aerobic oxidative cleavage to give arylmethanoic acids or tandem aerobic oxidation/benzilic acid rearrangement/decarboxylation to give diarylmethanones has been developed. The transformation is controllable and applicable to a broad spectrum of substrates and affords the desired products in good to excellent yields. Mechanistic insights with control reactions, 1H NMR tracking, and single-crystal X-ray diffraction reveal a complex mechanistic network in which two common intermediates, α-ketohydroperoxide and diarylethanedione, and three plausible pathways are proposed and verified. These pathways are interlinked and can be switched reasonably by changing the reaction conditions. This method enables scalable synthesis and access to a number of valuable compounds, including vitamin B3, diphenic acid, and the nonsteroidal anti-inflammatory drug ketoprofen. The present protocol represents a step forward in exploiting complex mechanistic networks t...

Effects of the noncompetitive N-methyl-d-aspartate receptor antagonists ketamine and MK-801 on pain-stimulated and pain-depressed behaviour in rats.

Pain is a significant public health concern, and current pharmacological treatments have problematic side effects and limited effectiveness. N-methyl-d-aspartate (NMDA) glutamate receptor antagonists have emerged as one class of candidate treatments for pain because of the significant contribution of glutamate signalling in nociceptive processing. This study compared effects of the NMDA receptor antagonists ketamine and MK-801 in assays of pain-stimulated and pain-depressed behaviour in rats. The nonsteroidal anti-inflammatory drug ketoprofen was examined for comparison as a positive control. Intraperitoneal injection of dilute acid served as an acute visceral noxious stimulus to stimulate a stretching response or depress intracranial self-stimulation (ICSS) in male Sprague-Dawley rats. Ketamine (1.0-10.0 mg/kg) blocked acid-stimulated stretching but failed to block acid-induced depression of ICSS, whereas MK-801 (0.01-0.1mg/kg) blocked both acid-stimulated stretching and acid-induced depression of ICSS. These doses of ketamine and MK-801 did not alter control ICSS in the absence of the noxious stimulus; however, higher doses of ketamine (10mg/kg) and MK-801 (0.32mg/kg) depressed all behaviour. Ketoprofen (1.0mg/kg) blocked both acid-induced stimulation of stretching and depression of ICSS without altering control ICSS. These results support further consideration of NMDA receptor antagonists as analgesics; however, some NMDA receptor antagonists are more efficacious at attenuating pain-depressed behaviours. NMDA receptor antagonists produce dissociable effects on pain-depressed behaviour. Provides evidence that pain-depressed behaviours should be considered and evaluated when determining the antinociceptive effects of NMDA receptor antagonists.

Immunomodulatory properties of gamithromycin and ketoprofen in lipopolysaccharide-challenged calves with emphasis on the acute-phase response

Macrolide antibiotics and non-steroidal anti-inflammatory drugs (NSAIDs) have been reported to be modulators of the innate immune response, irrespectively of their antimicrobial and anti-inflammatory actions. Therefore, it was our objective to evaluate whether the macrolide gamithromycin (GAM) and the NSAID ketoprofen (KETO) attenuate the acute-phase response in calves, and whether their combined administration is beneficial due to synergistic and/or additive effects. To this end, both drugs, as well as their combination, were studied in a previously developed inflammation model, i.e., the induction of an acute-phase response by an intravenous lipopolysaccharide (LPS) challenge (0.5μg/kg body weight). Sixteen 4-week-old Holstein–Friesian calves were randomized into 4 groups: a positive control (+CONTR) group, receiving LPS but no pharmacological treatment (n=4) and a GAM (n=4), a KETO (n=4) and a GAM–KETO (n=4) group, receiving the respective drugs 1h prior to LPS administration. Clinical scoring and blood collection were performed at regular time points until 72h post LPS challenge. Plasma concentrations of the selected cytokines (tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6)), acute-phase protein (serum amyloid A (SAA)) and prostaglandin E2 (PGE2) were subsequently quantified. Pre-treatment with GAM had no effect in the inflammation model compared to the +CONTR group. KETO, on the other hand, completely inhibited depression, anorexia and fever. This remarkable influence was associated with a significant reduction of PGE2 synthesis by KETO, while the effect on TNF-α, IL-6 and SAA was not straightforward. The combined administration of GAM and KETO provided no synergistic or additive effects in this model, neither clinically nor regarding the studied inflammatory mediators. In conclusion, KETO entirely inhibited PGE2 synthesis, fever development and depression, while GAM did not exert any effect in this model. These results promote the concomitant use of an antimicrobial drug and a NSAID in the treatment of calf diseases associated with LPS, both to enhance clinical recovery and to improve animal welfare.

Chemoselective Transformation of Diarylethanones to Arylmethanoic Acids and Diarylmethanones and Mechanistic Insights.

The chemoselective transformation of diarylethanones via either aerobic oxidative cleavage to give arylmethanoic acids or tandem aerobic oxidation/benzilic acid rearrangement/decarboxylation to give diarylmethanones has been developed. The transformation is controllable and applicable to a broad spectrum of substrates and affords the desired products in good to excellent yields. Mechanistic insights with control reactions, (1)H NMR tracking, and single-crystal X-ray diffraction reveal a complex mechanistic network in which two common intermediates, α-ketohydroperoxide and diarylethanedione, and three plausible pathways are proposed and verified. These pathways are interlinked and can be switched reasonably by changing the reaction conditions. This method enables scalable synthesis and access to a number of valuable compounds, including vitamin B3, diphenic acid, and the nonsteroidal anti-inflammatory drug ketoprofen. The present protocol represents a step forward in exploiting complex mechanistic networks to control reaction pathways, achieving divergent syntheses from the same class of starting materials.

Nefopam analgesia and its role in multimodal analgesia: A review of preclinical and clinical studies.

Nefopam is a non-opioid, non-steroidal, centrally acting analgesic drug used to prevent postoperative pain, primarily in the context of multimodal analgesia. This paper reviews preclinical and clinical studies in which nefopam has been combined with opioids, non-steroidal anti-inflammatory compounds, and paracetamol. This report focuses on the literature during the last decade and discusses the translational efforts between animal and clinical studies in the context of multimodal or balanced analgesia. In preclinical rodent models of acute and inflammatory pain, nefopam combinations including opioids revealed a synergistic interaction or enhanced morphine analgesia in six out of seven studies. Nefopam combinations including non-steroidal anti-inflammatory drugs (NSAIDs) (aspirin, ketoprofen or nimesulide) or paracetamol likewise showed enhanced analgesic effects for the associated compound in all instances. Clinical studies have been performed in various types of surgeries involving different pain intensities. Nefopam combinations including opioids resulted in a reduction in morphine consumption in 8 out of 10 studies of severe or moderate pain. Nefopam combinations including NSAIDs (ketoprofen or tenoxicam) or paracetamol also demonstrated a synergic interaction or an enhancement of the analgesic effect of the associated compound. In conclusion, this review of nefopam combinations including various analgesic drugs (opioids, NSAIDs and paracetamol) reveals that enhanced analgesia was demonstrated in most preclinical and clinical studies, suggesting a role for nefopam in multimodal analgesia based on its distinct characteristics as an analgesic. Further clinical studies are needed to evaluate the analgesic effects of nefopam combinations including NSAIDs or paracetamol.

Expression and pharmacological modulation of visceral pain-induced conditioned place aversion in mice

Pain encompasses both a sensory as well as an affective dimension and these are differentially processed in the brain and periphery. It is therefore important to develop animal models to reflect the non-reflexive assays in pain. In this study, we compared effects of the mu opioid receptor agonist morphine, the nonsteroidal anti-inflammatory drug ketoprofen and the kappa receptor opioid agonist U50,488H and antagonist JDTic on acetic acid-induced stretching and acetic acid-induced aversion in the condition place aversion (CPA) test in male ICR mice. Intraperitoneal administration of acetic acid (0.32–1%) was equipotent in stimulating stretching and CPA. Ketoprofen, morphine and U50,488H all inhibited the acid-induced stretching. Ketoprofen and morphine also blocked the acid-induced CPA but U50,488H failed to do so. The reversal ability of ketoprofen and morphine on acid-induced CPA is unique to pain-stimulated place aversion since these drugs failed to reduce non-noxious LiCl-induced CPA. Overall, this study characterized and validated a preclinical mouse model of pain-related aversive behavior that can be used to assess genetic and biological mechanisms of pain as well as improving the predictive validity of preclinical studies on candidate analgesics.

Spectroscopic studies on interactions of the tetrakis(acetato)chloridodiruthenium(II,III) complex and the Ru2(II,III)-NSAID-derived metallodrugs of ibuprofen and ketoprofen with human serum albumin

Diruthenium paddlewheel-structured complexes bearing a Ru2(II,III) multiply bonded core show promising potential in medicinal chemistry. This work reports studies on the interactions of the tetrakis(acetato)chloridodiruthenium(II,III) complex (RuAc), [Ru2(μ-O2CCH3)4Cl], and the corresponding Ru2(II,III)-non-steroidal anti-inflammatory drug (NSAID) metallodrugs of the NSAIDs ibuprofen (RuIbp) and ketoprofen (RuKet) with the human serum albumin (HSA). Circular dichroism (CD) studies showed that the three Ru2 complexes interact with the HSA and induce conformational changes on the secondary structure of the protein. The reaction of the RuAc complex with the protein was monitored and the RuAc/HSA binding constant was estimated on the basis of electronic absorption spectroscopy data. Fluorescence emission spectroscopy studies were performed for all the Ru2 complex/HSA systems and the Stern–Volmer constants and the thermodynamic parameters were determined for the RuAc/HSA binding. Mass spectrometry data confirmed the presence of the Ru2 complexes in the protein phase after ultrafiltration. The studies suggest that the nature of the RuAc binding to the HSA is distinct from that of the derived RuIbp and RuKet metallodrugs. Electrostatic forces, accompanied by coordination of the metal to the amino acid side chains of the protein, seem to be the main forces acting in the RuAc/HSA binding, while non-covalent/hydrophobic forces might be predominant in the Ru2-NSAID metallodrug/protein interactions. The findings suggest that the HSA protein might be a potential carrier in the blood plasma for the Ru2(II,III)-NSAID metallodrugs.

Effects of ketoprofen, morphine, and kappa opioids on pain-related depression of nesting in mice.

Pain-related functional impairment and behavioral depression are diagnostic indicators of pain and targets for its treatment. Nesting is an innate behavior in mice that may be sensitive to pain manipulations and responsive to analgesics. The goal of this study was to develop and validate a procedure for evaluation of pain-related depression of nesting in mice. Male ICR mice were individually housed and tested in their home cages. On test days, a 5- × 5-cm Nestlet was subdivided into 6 pieces, the pieces were evenly distributed on the cage floor, and Nestlet consolidation was quantified during 100-minute sessions. Baseline nesting was stable within and between subjects, and nesting was depressed by 2 commonly used inflammatory pain stimuli (intraperitoneal injection of dilute acid; intraplantar injection of complete Freund adjuvant). Pain-related depression of nesting was alleviated by drugs from 2 classes of clinically effective analgesics (the nonsteroidal anti-inflammatory drug ketoprofen and the μ-opioid receptor agonist morphine) but not by a drug from a class that has failed to yield effective analgesics (the centrally acting kappa opioid agonist U69,593). Neither ketoprofen nor morphine alleviated depression of nesting by U69,593, which suggests that ketoprofen and morphine effects were selective for pain-related depression of nesting. In contrast to ketoprofen and morphine, the kappa opioid receptor antagonist JDTic blocked depression of nesting by U69,593 but not by acid or complete Freund adjuvant. These results support utility of this procedure to assess expression and treatment of pain-related depression in mice.

Evaluating the efficacy of a topical anaesthetic formulation and ketoprofen, alone and in combination, on the pain sensitivity of dehorning wounds in Holstein-Friesian calves

The aim of this study was to investigate the effect of a topically applied local anaesthetic and the non-steroidal anti-inflammatory drug ketoprofen, alone and in combination, on the pain sensitivity response of calves to dehorning (mean age 2.2 months). Calves were randomly allocated and blocked by age to one of four groups. Groups were: scoop dehorning (D, n = 8), scoop dehorning + i.m. administration of 3 mg/kg ketoprofen (DK, n = 8), scoop dehorning + application of topical anaesthetic (DTA, n = 7) and scoop dehorning + application of topical anaesthetic and i.m. administration of ketoprofen (DKTA, n = 7). A pressure algometer was used to determine the mechanical nociceptive threshold (MNT), being the pressure (kg/f) at which calves withdrew from the stimulus. Measurements were taken before dehorning and at 1 min, 1, 2, 5 and 24 h post-dehorning at both the cut skin edge of the wound and the peri-wound area. The effect of treatment changed over time (P < 0.001). MNT was highest before treatment (MNT = 5.03 kg/f) and tended to decrease over time (MNT = 1.16 kg/f 24 h post-treatment). Overall, D calves exhibited the lowest MNT with an average of 1.77 kg/f. DTA calves had the highest MNT (3.89 kg/f), followed closely by DKTA calves (3.24 kg/f). DK calves exhibited an intermediate MNT of 2.61 kg/f. MNT of the cut skin edge was generally lower than that of the peri-wound area (2.01 vs 3.81 kg/f, respectively, P = 0.02).The topical anaesthetic formulation significantly reduced the pain sensitivity of dehorning wounds. There was no observed enhanced analgesic effect with addition of ketoprofen. The cut skin edge was more sensitive to pressure than the peri-wound area.

Evaluation of treatments for claw horn lesions in dairy cows in a randomized controlled trial

Lameness is one of the most significant endemic disease problems facing the dairy industry. Claw horn lesions (principally sole hemorrhage, sole ulcer, and white line disease) are some of the most prevalent conditions. Despite the fact that thousands of animals are treated for these conditions every year, experimental evidence is limited on the most effective treatment protocols. A randomized, positively controlled clinical trial was conducted to test the recovery of newly lame cows with claw horn lesions. Animals on 5 farms were locomotion scored every 2wk. Cows were eligible for recruitment if they had 2 nonlame scores followed by a lame score and had a claw horn lesion on a single claw of a single foot. Following a therapeutic trim, enrolled cows were randomly allocated to 1 of 4 treatments: treatment 1—no further treatment (positive control; TRM), treatment 2—trim plus a block on the sound claw (TB), treatment 3—trim plus a 3-d course of the nonsteroidal anti-inflammatory drug (NSAID) ketoprofen (TN), treatment 4—trim plus a block plus ketoprofen (TBN). The primary outcome measure was locomotion score 35d after treatment, by an observer blind to treatment group. Descriptive statistics suggested that treatment groups were balanced at the time of enrollment, that is, randomization was successful. Based on a sound locomotion score (score 0) 35d after treatment, the number of cures was 11 of 45 (24.4%) for TRM, 14 of 39 (35.9%) for TB, 12 of 42 (28.6%) for TN, and 23 of 41 (56.1%) for TBN. The difference between TBN and TRM was significant. To test for confounding imbalances between treatment groups, logistic regression models were built with 2 outcomes, either sound (score 0) or nonlame (score 0 or 1) 35d after treatment. Compared with TRM, animals that received TBN were significantly more likely to cure to a sound outcome. Farm, treatment season, lesion diagnosis, limb affected, treatment operator, and stage of lactation were included in the final models. Our work suggests that lameness cure is maximized with NSAID treatment in addition to the common practices of therapeutic trimming and elevation of the diseased claw using a block when cows are newly and predominantly mildly lame.

Selective and simultaneous determination of NSAIDs in equine plasma by HPLC with molecularly imprinted solid-phase extraction.

Detection of nonsteroidal anti-inflammatory drugs (NSAIDs) in equine plasma is a significant analytical problem in veterinary anti-doping controls. A new HPLC method coupled to selective extraction with molecularly imprinted polymers was developed for the simultaneous determination in equine plasma of the NSAIDs phenylbutazone, flunixin, oxyphenbutazone, ketoprofen and naproxen. The analytical performances of the method have been evaluated both in standard solutions and equine plasma samples. Recovery: Molecularly imprinted polymers solid-phase extraction for all NSAIDs was >94% with intra-day values below 15.0% and inter-day values below 20%. Method quantification limit was 0.01 μg/ml. The developed method could be considered as a useful alternative to existing screening methods for the determination of NSAIDs in the context of studies of pharmacokinetics and anti-doping controls.

Propyphenazone-based analogues as prodrugs and selective cyclooxygenase-2 inhibitors.

Improving the gastrointestinal safety profile of nonsteroidal anti-inflammatory drugs (NSAIDs) is an important goal. Herein, we report two strategies, using the nonacidic propyphenazone structure, with potential to overcome the side effects of NSAIDs. Propyphenazone was employed to temporarily mask the free acid group of the widely used NSAIDs ibuprofen, diclofenac, and ketoprofen to develop three mutual prodrugs hypothesized to have minimal GI irritation. The three prodrugs exhibit in vivo anti-inflammatory and analgesic activities with improved potency over each parent drug when compared to a nonhydrolyzable control betahistine-propyphenazone (BET-MP). Additionally, ANT-MP formed by the irreversible coupling of propyphenazone and 4-aminoantipyrine, displayed exceptional COXII selectivity (COXII IC50 of 0.97 ± 0.04 μM, compared to no observed inhibition of COXI at 160 μM). Inhibition of COXII suppresses inflammatory diseases without affecting COXI-mediated GI tract events. ANT-MP exhibited maximal analgesic effect when tested in vivo in an abdominal writhing assay (100% protection) and its anti-inflammatory activity showed a peak at 2 h in a carrageenan-induced paw edema model. Its unique selectivity toward the COXII enzyme was investigated using molecular modeling techniques.

Ketoprofen-induced formation of amino acid photoadducts: possible explanation for photocontact allergy to ketoprofen.

Photocontact allergy is a well-known side effect of topical preparations of the nonsteroidal anti-inflammatory drug ketoprofen. Photocontact allergy to ketoprofen appears to induce a large number of photocross allergies to both structurally similar and structurally unrelated compounds. Contact and photocontact allergies are explained by structural modification of skin proteins by the allergen. This complex is recognized by the immune system, which initiates an immune response. We have studied ketoprofen's interaction with amino acids to better understand ketoprofen's photoallergenic ability. Irradiation of ketoprofen and amino acid analogues resulted in four different ketoprofen photodecarboxylation products (6-9) together with a fifth photoproduct (5). Dihydroquinazoline 5 was shown to be a reaction product between the indole moiety of 3-methylindole (Trp analogue) and the primary amine benzylamine (Lys analogue). In presence of air, dihydroquinazoline 5 quickly degrades into stable quinazolinone 12. The corresponding quinazolinone (17) was formed upon irradiation of ketoprofen and the amino acids N-acetyl-l-Trp ethyl ester and l-Lys ethyl ester. The formation of these models of an immunogenic complex starts with the ketoprofen-sensitized formation of singlet oxygen, which reacts with the indole moiety of Trp. The formed intermediate subsequently reacts with the primary amino functionality of Lys, or its analogue, to form a Trp-Lys adduct or a mimic thereof. The formation of a specific immunogenic complex that does not contain the allergen but that can still induce photocontact allergy would explain the large number of photocross allergies with ketoprofen. These allergens do not have to be structurally similar as long as they can generate singlet oxygen. To the best of our knowledge, there is no other suggested explanation for ketoprofen's photoallergenic properties that can account for the observed photocross allergies. The formation of a specific immunogenic complex that does not contain the allergen is a novel hypothesis in the field of contact and photocontact allergy.

Molecular imprinted polymeric porous layers in open tubular capillaries for chiral separations

A new method has been developed for the preparation of molecular imprinted polymers as porous layers in open tubular (MIP-PLOT) capillary column formats for use in chiral separations by capillary liquid chromatography. The synthesis was based on ‘in-capillary’ ultraviolet (UV) initiated polymerization using light emitting diodes (LEDs) in conjunction with the continuous delivery of the pre-polymerization reagents into the polymerization zone of the capillary using an automated capillary delivery device. The relationships between exposure times, UV-light intensity and polymer layer thickness have been determined, as well as the effects of reagent delivery rate and multiple LED exposures on the layer thickness for various compositions of pre-polymerization mixtures. The polymer surface morphology was investigated by scanning electron microscopy (SEM). The non-steroidal anti-inflammatory drug S-ketoprofen was used as the template for the preparation of the MIP imprinted PLOT coatings. The separation performance with the ketoprofen racemate was investigated by capillary liquid chromatography. In contrast to alternative methods, which require the use of expensive chiral selectors, the described MIP PLOT stationary phases used non-chiral polymer precursors to create enantioselective nano-cavities through molecular self-assembly processes. The described fabrication methods provide a new avenue to tailor-make chiral MIP-PLOT capillary columns for the separation of chiral compounds present in complex or racemic analyte mixtures of chemical and biological origin.

Development of ketoprofen loaded proliposomal powders for improved gastric absorption and gastric tolerance: in vitro and in situ evaluation

The aim of the current investigation was to improve dissolution rate, gastric absorption and tolerance of a water insoluble non-steroidal anti-inflammatory drug ketoprofen by developing proliposomal powders. Ketoprofen proliposomal powders were prepared by solvent evaporation method with varying ratios of hydrogenated soyphosphatidyl choline (HSPC) and cholesterol. The prepared proliposomal powders were characterized for vesicle size, micromeritics, entrapment efficiency and in vitro dissolution behavior. Proliposomal powder (KPL3) composed of equimolar ratios of HSPC and cholesterol loaded on pearlitol SD 200 was selected as optimized formulation as it produced smaller liposomes (5.24 ± 1.35 μm) upon hydration with highest entrapment efficiency (53.16 ± 0.06%). All proliposomal powders showed improved dissolution characteristics than pure drug, however dissolution of drug from KPL3 was found to be highest (91.17 ± 6.3) and which is about 24 times higher than pure ketoprofen within 5 min. The transformation of crystalline ketoprofen to amorphous form was confirmed by solid state characterization. The absorption rate per hour for pure ketoprofen and proliposomal formulation (KPL3) was assessed in the stomach by conducting in situ gastric absorption studies in Wistar rats and was found to be 27 ± 1.22 and 36.98 ± 1.95%, respectively. In conclusion, enhanced dissolution and gastric absorption rate of ketoprofen from proliposomal powders suggest them as potential candidate for oral bioavailability improvement of ketoprofen.

Degradation of anti-inflammatory drug ketoprofen by electro-oxidation: comparison of electro-Fenton and anodic oxidation processes.

The electrochemical degradation of the nonsteroidal anti-inflammatory drug ketoprofen in tap water has been studied using electro-Fenton (EF) and anodic oxidation (AO) processes with platinium (Pt) and boron-doped diamond (BDD) anodes and carbon felt cathode. Fast degradation of the parent drug molecule and its degradation intermediates leading to complete mineralization was achieved by BDD/carbon felt, Pt/carbon felt, and AO with BDD anode. The obtained results showed that oxidative degradation rate of ketoprofen and mineralization of its aqueous solution increased by increasing applied current. Degradation kinetics fitted well to a pseudo-first-order reaction. Absolute rate constant of the oxidation of ketoprofen by electrochemically generated hydroxyl radicals was determined to be (2.8 ± 0.1) × 10(9) M(-1) s(-1) by using competition kinetic method. Several reaction intermediates such as 3-hydroxybenzoic acid, pyrogallol, catechol, benzophenone, benzoic acid, and hydroquinone were identified by high-performance liquid chromatography (HPLC) analyses. The formation, identification, and evolution of short-chain aliphatic carboxylic acids like formic, acetic, oxalic, glycolic, and glyoxylic acids were monitored with ion exclusion chromatography. Based on the identified aromatic/cyclic intermediates and carboxylic acids as end products before mineralization, a plausible mineralization pathway was proposed. The evolution of the toxicity during treatments was also monitored using Microtox method, showing a faster detoxification with higher applied current values.

Behaviour of nonsteroidal anti-inflammatory drugs and eight of their metabolites during wastewater treatment studied by hollow fibre liquid phase microextraction and liquid chromatography mass spectrometry

In this work hollow fibre liquid phase microextraction combined with liquid chromatography mass spectrometry was applied for the determination of the nonsteroidal anti-inflammatory drugs (NSAIDs) ketoprofen, naproxen, diclofenac and ibuprofen as well as eight of their known human metabolites in wastewater samples. Extraction time and addition of tri-n-octylphosphine oxide (TOPO) to the liquid membrane were evaluated resulting in a method with an optimal extraction time of 5h and 5% (w/V) TOPO addition to the membrane liquid (di-n-hexyl ether). With the optimized method, enrichment factors ranged between 778 and 4830. The method was applied for analysis of samples collected from Källby wastewater treatment plant in the city of Lund, Sweden. Samples were collected from the influent, water entering as well as exiting the conventional activated sludge treatment and the effluent to study the behaviour of these compounds during the treatment process. All twelve substances were found in the influent and for all four drugs, higher concentrations were detected of the metabolites than the parent compounds. Highest concentrations were detected of o-desmethylnaproxen, 2-hydroxyibuprofen and carboxyibuprofen (average influent concentrations of 45, 35 and 63μg/L respectively). The study showed only partial removal during the primary treatment whereas both parent compounds and metabolites were efficiently removed during the activated sludge process. In the effluent all analytes were detected in concentrations below 1μg/L thus showing that either the investigated metabolites do not belong to the NSAID transformation products formed during the activated sludge treatment or they are also quickly further transformed within the treatment.

New inhibitors of 5-lipoxygenase catalytic activity based on 2-(3-methylphenyl)propanoic acid and 4-substituted morpholine derivatives.

New potential inhibitors of 5-lipoxygenase (5-LOX) based on the structure of 2-(3-benzoylphenyl)propanoic acid (an active component of the nonsteroidal antiinflammatory drug Ketoprofen) were designed using the SARD-21 program. The docking of these compounds in the active site of 5-LOX suggested that seven compounds can interact with this enzyme. Two of them can also be dual inhibitors of 5-LOX and two isoforms of cyclooxygenase.