Non-steroidal Anti-inflammatory Ketoprofen Research Articles

Revisiting and Updating the Interaction between Human Serum Albumin and the Non-Steroidal Anti-Inflammatory Drugs Ketoprofen and Ketorolac.

Ketoprofen (KTF) and ketorolac (KTL) are among the most primarily used non-steroidal anti-inflammatory drugs (NSAIDs) in humans to alleviate moderate pain and to treat inflammation. Their binding affinity with albumin (the main globular protein responsible for the biodistribution of drugs in the bloodstream) was previously determined by spectroscopy without considering some conventional pitfalls. Thus, the present work updates the biophysical characterization of the interactions of HSA:KTF and HSA:KTL by 1H saturation-transfer difference nuclear magnetic resonance (1H STD-NMR), ultraviolet (UV) absorption, circular dichroism (CD), steady-state, and time-resolved fluorescence spectroscopies combined with in silico calculations. The binding of HSA:NSAIDs is spontaneous, endothermic, and entropically driven, leading to a conformational rearrangement of HSA with a slight decrease in the α-helix content (7.1% to 7.6%). The predominance of the static quenching mechanism (ground-state association) was identified. Thus, both Stern-Volmer quenching constant (KSV) and binding constant (Kb) values enabled the determination of the binding affinity. In this sense, the KSV and Kb values were found in the order of 104 M-1 at human body temperature, indicating moderate binding affinity with differences in the range of 0.7- and 3.4-fold between KTF and KTL, which agree with the previously reported experimental pharmacokinetic profile. According to 1H STD-NMR data combined with in silico calculations, the aromatic groups in relation to the aliphatic moiety of the drugs interact preferentially with HSA into subdomain IIIA (site II) and are stabilized by interactions via hydrogen bonding and hydrophobic forces. In general, the data obtained in this study have been revised and updated in comparison to those previously reported by other authors who did not account for inner filter corrections, spectral backgrounds, or the identification of the primary mathematical approach for determining the binding affinity of HSA:KTF and HSA:KTL.

Quinolinyl-based multitarget-directed ligands with soluble epoxide hydrolase and fatty acid amide hydrolase inhibitory activities: Synthetic studies and pharmacological evaluations

Simultaneous inhibition of soluble epoxide hydrolase (sEH) and fatty acid amide hydrolase (FAAH) with a single small molecule represents a novel therapeutic approach in treating inflammatory pain, since both targets are involved in pain and inflammation processes. In this study using multi-target directed ligands methodology we designed and synthesized 7 quinolinyl-based dual sEH/FAAH inhibitors, using an optimized microwave-assisted Suzuki-Miyaura coupling reaction and tested their potency in human FAAH and human, rat, and mouse sEH inhibition assays. The structure-activity relationship study showed that quinolinyl moiety is well tolerated in the active sites of both enzymes, yielding several very potent dual sEH/FAAH inhibitors with the IC50 values in the low nanomolar range. The most potent dual inhibitor 4d was further evaluated in stability assay in human and rat plasma where it performed better than the standard Warfarin while in vivo study revealed that 1 mg/kg 4d can inhibit acute inflammatory pain in male rats to a similar degree as the traditional nonsteroidal anti-inflammatory drug ketoprofen (30 mg/kg) after intraperitoneal injection. ADMET prediction studies for this dual inhibitor show favorable pharmacokinetic properties which will guide the future in vivo evaluations.

First Eu3+, Gd3+ and Tb3+ complexes containing the non-steroidal anti-inflammatory drug ketoprofen and N,N-donors ligands: Synthesis, solid state characterization and photoluminescence studies

Reports on lanthanide complexes derived from non-steroidal anti-inflammatory drug molecules are still quite scarce in the literature, despite the potential properties of these molecules as therapeutic agents and biological markers. The current literature reports only lanthanide compounds containing the ketoprofenate ligand, most of the time containing coordination water molecules, which causes serious luminescence suppression. This study reports three new classes of highly photoluminescent lanthanide ketoprofenates with general formulas [Ln2(keto)6(bpy)2] (1)–(3), [Ln2(keto)6(phen)2] (4)–(6) and [Ln2(keto)6(4,4′-dmbpy)2] (7)–(9) (where: Ln = Eu3+, Gd3+ e Tb3+; keto = ketoprofenate anion, bpy = 2,2′-bipyridine, phen = 1,10-phenanthroline and 4,4′-dmbpy = 4,4′-dimethyl-2,2′-bipyridine). These nine complexes were fully characterized and the photophysical studies were carried out in detail. Furthermore, the energy transfer mechanism was completely elucidated with the aid of theoretical calculations using the Sparkle/RM1 method, closely related to the nature of the employed ancillary ligand. The calculated luminescence spectroscopic parameters are in excellent agreement with those obtained experimentally, reinforcing the homobimetallic structure for these complexes. With the highest values of quantum efficiencies ( %η) ever reported for lanthanide ketoprofenates, these compounds comprise potential molecules for use as biological markers or anti-inflammatory agents.

Ethological and pathophysiolocal justification of the calcium gluconate usage for the treatment of calves with bronchopneumonia

A prominent feature of the pathogenesis of bronchopneumonia in calves is the development of an inflammatory reaction that negatively affects the structure (consolidation) and function of lung tissue. Due to the spread of the inflammatory reaction, structural and functional changes can become irreversible. The purpose of the study was to compare the effectiveness of calcium gluconate and the nonsteroidal anti–inflammatory drug ketoprofen in the treatment of calves with bronchopneumonia. The research was conducted on the basis of a dairy farm with an average annual yield of 8,500 kg of milk per cow and a scientific laboratory of the Department of Normal and Pathological Physiology of Animals of Bilotserkivsky Bila Tserkva National University. Sick animals aged 3–4.5 months were divided into two groups, control (16 heads) and experimental (12 heads). All sick calves were prescribed antibiotic therapy using the preparation Clamoxan (BioTestLab). Calves of the control group were additionally prescribed the non–steroidal anti–inflammatory drug Kefen (Merial, France), and calcium gluconate (UkrZooVet–organisation ) was prescribed to the calves of the experimental group. The course of bronchopneumonia in calves is characterized by the development of characteristic clinical signs (depressed general condition, tachypnea, tachycardia, cough, secretion of mucus from the nasal passages), minor leukocytosis (13.38±0.46) and signs of dehydration, which is evidenced by relatively high indicators of hematocrit (45.47±2.18%) and total protein (61.14±2.22 g/l). The dynamics of clinical and laboratory indicators were similar in sick calves of both groups. The pathogenetic effect and anti–inflammatory activity are equally effective in both studied drugs: caffeine and calcium gluconate. In calves with bronchopneumonia, a 3–10–fold delay in the conditioned feeding reflex was established. The normalization of clinical and laboratory indicators was accompanied by the restoration of the duration of the implementation of the conditioned feeding reflex, which allows recommending the use of the studied ethological indicators for monitoring the course of bronchopneumonia in calves. We consider the study of the effectiveness of calcium gluconate preparations in other inflammatory pathologies in animals and the extension of indications to the use of ethological indicators to monitor the course of diseases in domestic animals to be a promising direction for further research. Key words: calves, bronchopneumonia, treatment, calcium gluconate, behavior.

Conjugation with Tris Decreases the Risk of Ketoprofen-Induced Mucosal Damage and Reduces Inflammation-Associated Methane Production in a Rat Model of Colitis.

We have designed a new compound from the non-steroidal anti-inflammatory drug (NSAID) ketoprofen (Ket) and 2-amino-2-(hydroxymethyl)-1,3-propanediol (Tris) precursors, with the aim to reduce the gastrointestinal (GI) side effects of NSAID therapies. We investigated mucosal reactions in a standard rat model of colitis together with methane generation as a possible indicator of pro-inflammatory activation under this condition (approval number: V./148/2013). Whole-body methane production (photoacoustic spectroscopy) and serosal microcirculation (intravital videomicroscopy) were measured, and mucosal damage was assessed (conventional histology; in vivo laser-scanning endomicroscopy). Inflammatory markers were measured from tissue and blood samples. Colitis induced an inflammatory response, morphological colonic damage and increased methane output. Ket treatment lowered inflammatory activation and colonic mucosal injury, but macroscopic gastric bleeding and increased methane output were present. Ket-Tris reduced inflammatory activation, methane emission and colonic mucosal damage, without inducing gastric injury. Conjugation with Tris reduces the GI side effects of Ket and still decreases the inflammatory response in experimental colitis. Methane output correlates with the mucosal inflammatory response and non-invasively demonstrates the effects of anti-inflammatory treatments.

A novel integrated platform enabling simultaneous microextraction and chemical analysis on-chip

The nature and size of biological, pharmaceutical or environmental analytes complicates their extraction and detection outside of laboratories and near the site of interest by the current chromatographic methods because they require the combination of bulky extraction and detection methods. In order to solve this inefficient centralized control, a ground-breaking and miniaturized proof of concept platform is developed in this work. The platform integrates for the very first time an electro-membrane extraction process and an accurate analyte quantification method in the same device, by using electrochemical impedance spectroscopy (EIS) as analytical technique. The microfluidic flow cell, including the microfluidic components, is fabricated in polymeric materials by rapid prototyping techniques. It comprises a four-electrode platinum thin-film chip that enables the control of the microextraction and the full characterization of the process, i.e., extraction efficiency determination, at the same time. The microfluidic system has been simulated by using computational tools, enabling an accurate prediction of the effect of the different experimental conditions in the microextraction efficiency. The platform has been validated in the microextraction of the nonsteroidal anti-inflammatory drug ketoprofen in a range from 0.5 ppm to 6 ppm. The predicted microextraction efficiency values obtained by EIS were compared with those calculated from the high-performance liquid chromatography coupled with a diode array detector (HPLC-DAD), showing an excellent agreement. This validates the high potential of this integrated and miniaturized platform for the simultaneous extraction by electro-membrane and also the analysis within the platform, solving one of the of most important limitations of current systems.

Efficient and Scalable Synthesis of Ketoprofen: A Pyrolytic Aromatization Approach

The practical synthesis of the representative nonsteroidal anti-inflammatory drug ketoprofen has been accomplished in 44% overall yield on the decagram scale. The key features in this synthetic work involve a TiCl4–Et3N mediated aldol/enol-lactonization annulation to affect dihydrobenzofuranone core formation and the use of a highly efficient pyrolytic aromatization condition to facilitate the construction of the vital 2-arylpropionic acid (2-APA) moiety. Furthermore, the avoidance of hazardous chemicals and crystallization of several intermediates would be greatly beneficial to the scalable synthesis of ketoprofen.

Climbing behavior by mice as an endpoint for preclinical assessment of drug effects in the absence and presence of pain.

This study evaluated climbing in mice as a tool to assess the expression and treatment of pain-related behavioral depression in male and female ICR mice. Mice were videotaped during 10-min sessions in a vertical plexiglass cylinder with wire mesh walls, and "Time Climbing" was scored by observers blind to treatments. Initial validation studies demonstrated that baseline climbing was stable across repeated days of testing and depressed by intraperitoneal injection of dilute lactic acid (IP acid) as an acute pain stimulus. Additionally, IP acid-induced depression of climbing was blocked by the positive-control non-steroidal anti-inflammatory drug (NSAID) ketoprofen but not by the negative control kappa opioid receptor agonist U69593. Subsequent studies examined effects of single-molecule opioids (fentanyl, buprenorphine, naltrexone) and of fixed-proportion fentanyl/naltrexone mixtures (10:1, 3.2:1, and 1:1) that vary in their efficacy at the mu opioid receptor (MOR). Opioids administered alone produced a dose- and efficacy-dependent decrease in climbing, and fentanyl/naltrexone-mixture data indicated that climbing in mice is especially sensitive to disruption by even low-efficacy MOR activation. Opioids administered as a pretreatment to IP acid failed to block IP acid-induced depression of climbing. Taken together, these findings support the utility of climbing in mice as an endpoint to evaluate candidate-analgesic effectiveness both to (a) produce undesirable behavioral disruption when the test drug is administered alone, and (b) produce a therapeutic blockade of pain-related behavioral depression. The failure of MOR agonists to block IP acid-induced depression of climbing likely reflects the high sensitivity of climbing to disruption by MOR agonists.

Neonicotinoids and pharmaceuticals in hair of the Red fox (Vulpes vulpes) from the Cavallino-Treporti peninsula, Italy

Neonicotinoids (NEOs) and active pharmaceuticals ingredients (API) are contaminants widely diffused worldwide, causing increasing concern for potential adverse effects on wildlife. However, research on these contaminants have focused on target and non-target invertebrates, while information on potential effects in terrestrial mammals is lacking. We performed preliminary non-invasive monitoring of NEOs and API in a suburban and agricultural area using hair of the Red fox. The Red fox is a widely diffused mesopredator in Europe, and its plasticity in feeding habits makes it an excellent indicator for assessing exposure to environmental contamination. We observed the presence of NEOs in many Red fox hair samples (n = 11), including imidacloprid (IMI), acetamiprid (ACE), and clothianidin (CLO). The highest quantified concentrations were 6.4 ng g−1 dry weight (dw), 6.7 ng g−1 dw, and 0.9 ng g−1 dw for IMI, ACE, and CLO, respectively. The targeted APIs included non-steroidal anti-inflammatory drugs (NSAIDs) and antidepressants. APIs were less frequently detected than NEOs, and the compounds with the highest prevalence were the NSAID ketoprofen (36%), the antidepressant sertraline (36%), and its active metabolite norsertraline (27%). The presence of human pharmaceuticals such as the NSAID ibuprofen and the antidepressants sertraline, fluoxetine, and their active metabolites norsertraline and norfluoxetine suggest environmental contamination due to untreated and partially treated wastewater discharged in surface waters and soils of the study area. The detection and quantification of ketoprofen and flunixin also suggest the possible use of contaminated manure on farmland. Findings indicate that hair may be used for monitoring environmental exposure to NEOs and provide evidence that hair is a good marker of exposure for antidepressants and certain NSAIDs, including ibuprofen, ketoprofen, and flunixin.

Short-term effects of various non-steroidal anti-inflammatory drugs (NSAIDs) on Danio rerio embryos

Due to the widespread use of non-steroidal anti-inflammatory drugs (NSAIDs) without a medical prescription and their frequent prevalence in aquatic habitats, there are major health and environmental issues. NSAIDs have been found in surface water and wastewater in concentrations ranging from ng/L to μg/L all over the world. The purpose of this study was to determine the relationship between NSAIDs (diclofenac, ketoprofen, paracetamol and ibuprofen) exposure and associated adverse effects in the assessment of indirect human health risks posed by Danio rerio (zebrafish) and Environmental Risk Assessment (ERA) of these NSAIDs in aquatic environments. Therefore, the objectives of this study were to (i) reveal abnormality endpoints of early developmental stages, after exposure of zebrafish and (ii) perform an ecological risk assessment of aquatic organisms upon exposure to NSAIDs detected in surface waters based on the risk quotients (RQs) method. According to the toxicity data collected, all of the malformations appeared after diclofenac exposure at all concentrations. The most notable malformations were the lack of pigmentation and an increase in yolk sac volume, with EC50 values of 0.6 and 1.03 mg/L, respectively. The results obtained for the ERA revealed RQs higher than 1 for all the four NSAIDs chosen, posing ecotoxicological pressure in aquatic environments. Overall, our findings provide a critical contribution to the formulation of high-priority actions, sustainable strategies and strict regulations that minimize the negative effects of NSAIDs on the aquatic ecosystem.•To determine the LC50, lethal conditions such as coagulation, absence of heartbeat and blood flow, absence of tail separation and development of somites were taken into account.•The EC50 was calculated using sublethal parameters such as blood coagulation, pericardial edema, yolk sac edema or hypertrophy.•The 4 compounds present a high risk individually and in mixture with a RQ >> 1.

Constructed wetlands for the treatment of household organic micropollutants with contrasting degradation behaviour: Partially-saturated systems as a performance all-rounder

The degradability of specific organic micropollutants in constructed wetlands (CWs) may differ depending on the prevalence of oxic or anoxic conditions. These conditions are governed, among other factors, by the water saturation level in the system. This study investigated the removal of three environmentally-relevant organic micropollutants: bisphenol-group plasticizer bisphenol S (BPS), household-use insecticide fipronil (FPN) and non-steroidal anti-inflammatory drug ketoprofen (KTP) in the model CWs set up in an outdoor column system. BPS and KTP, in contrast to FPN, exhibit higher biodegradability potential under oxic conditions. The experimental CWs were operated under various saturation conditions: unsaturated, partially saturated and saturated, and mimicked the conditions occurring in unsaturated, partially-saturated intermittent vertical-flow CWs and in horizontal-flow CWs, respectively. The CWs were fed with synthetic household wastewater with the concentration of the micropollutants at the level of 30–45 μg/L. BPS and KTP exhibited contrasting behaviour against FPN in the CWs in the present experiment. Namely, BPS and KTP were almost completely removed in the unsaturated CWs without a considerable effect of plants, but their removal in saturated CWs was only moderate (approx. 50%). The plants had only a pronounced effect on the removal of BPS in saturated systems, in which they enhanced the removal by 46%. The removal of FPN (approx. 90%) was the highest in the saturated and partially-saturated CWs, with moderate removal (66.7%) in unsaturated systems. Noteworthy, partially-saturated CWs provided high or very high removal of all three studied substances despite their contrasting degradability under saturated and unsaturated conditions. Namely, their removal efficiencies in planted CWs were 95.9%, 94.5% and 81.6%, for BPS, KTP and FPN, respectively. The removal of the micropollutants in partially-saturated CWs was comparable or only slightly lower than in the best treatment option making it the performance all-rounder for the compounds with contrasting biodegradability properties.

Burrowing as an index of inflammatory pain in male vs. female rats.

The study objective was to determine whether burrowing behavior is useful as a functional index of pain in both male and female rats, and whether a 'no-training' protocol can be used to increase testing efficiency. Adult Sprague-Dawley rats were injected in one or both hindpaws with oil vehicle or complete Freund's adjuvant (CFA); starting the next day, the amount of gravel each rat burrowed out of a tube in 1 h was measured daily for ≤7 days. Without preliminary training on the burrowing procedure, CFA reliably suppressed burrowing for 2-3 days compared to controls, in both sexes. However, whereas unilateral CFA completely suppressed burrowing 1-day post-CFA in nearly all males, bilateral CFA was required to do so in females. When administered 30 min before testing, once daily for 5 days post-CFA, the nonsteroidal anti-inflammatory drug ketoprofen (0.01-3.2 mg/kg) and the opioid morphine (0.1-3.2 mg/kg) significantly increased CFA-suppressed burrowing, whereas the purported cannabinoid analgesic Δ 9 -tetrahydrocannabinol (0.01-2.0 mg/kg) did not. The benzodiazepine chlordiazepoxide (1.25-10 mg/kg), included as a 'true negative' control, also did not restore CFA-suppressed burrowing in either sex. However, in CFA-treated males only, chlordiazepoxide decreased burrowing, suggesting that anxiety may contribute to burrowing in males but not females that are in pain. Overall these results suggest that burrowing is a valid, functional index of inflammatory pain in both sexes, and training on the burrowing procedure is not necessary. However, females are more avid burrowers than males, which should be considered when both sexes are used in inflammatory pain testing.

Use of NSAIDs in the management of lameness in dairy cattle

Evidence exists to support the use of the non-steroidal anti-inflammatory drug (NSAID) ketoprofen in the treatment and prevention of lameness. Recent published evidence has added to a raft of indicative studies which support the use of ketoprofen in the management of lame cows. Understanding the limitations of the use of NSAIDs is vital in ensuring client motivation when implementing a lameness control programme. While following the evidence base, we recommend that clinicians and farmers ensure that animal welfare is kept at the forefront of all decision making, with NSAID usage playing an important role in this process.

Computational Studies of the Photodegradation Mechanism of the Highly Phototoxic Agent Benoxaprofen.

Computational quantum chemistry within the density functional theory (DFT) and time-dependent density functional theory (TD-DFT) framework is used to investigate the photodegradation mechanism as well as the photochemical and photophysical properties of benoxaprofen (BP), a non steroid anti-inflammatory molecule (2-[2-(4-chlorophenyl)-1,3-benzoxazol-5-yl] propanoic acid). BP is a highly phototoxic agent that causes cutaneous phototoxicity shortly after its administration. On the grounds of concern about serious side effects, especially hepatotoxicity, it was withdrawn from the world market after only 2 years of its release. Our study shows that the drug has the capability to absorb radiation in the UV region, mainly between 300 and 340 nm, and undergoes spontaneous photoinduced decarboxylation from the triplet state. It shows very similar photochemical properties to the highly photolabile non-steroidal anti-inflammatory drugs (NSAIDs) ketoprofen, suprofen, and tiaprofenic acid. Like ketoprofen, BP can also decarboxylate from excited singlet states by overcoming low energy barriers. The differences in molecular orbital (highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO)) distributions between the neutral and deprotonated BP, their absorption spectra, and the energetics and fate of various photoproducts produced throughout the photodegradation are discussed. Initiation and termination of decarboxylated BP radical species and initiation of propagating lipid peroxidation reactions due to the addition of molecular oxygen giving rise to the corresponding peroxyl radical are also explored in detail.

Synthesis and study of antimicrobial activity of some tetrahydrocarbazole derivatives substituted with NSAID

New tetrahydrocarbazole derivatives substituted at the heteroatom (N) by non-steroidal anti-inflammatory drug (NSAIDs) were synthesized by reaction of cyclohehexanon (C.H.N.) with phenyl hydrazine (P.H.Z.) to form tetrahydrocarbazole (THCZ), where the latter is reacted with NSAID (Ketoprofen) via amide bond to yield
 substituted THCZ, compounds chemical structures were verified by: 1H, 13C NMR and FTIR spectroscopy.
 Antifungal activity of the synthesized compounds was investigated by docking study and in vitro test to reveal good antifungal activity, but the in vitro test also showed that the compounds have weak to moderate antibacterial activity.

Effects of routine treatment with nonsteroidal anti-inflammatory drugs at calving and when lame on the future probability of lameness and culling in dairy cows: A randomized controlled trial

Claw horn lesions (CHL) are reported as the most common cause of lameness in intensive dairy systems. Despite their prevalence, the underlying pathological mechanisms and preventive strategies for CHL remain poorly understood. Recent advances have pointed to the role of inflammation in disease aetiopathogenesis. Moderating inflammation from first calving may lead to long-term benefits and a viable intervention for treating and preventing disease. We conducted a 34-mo randomized controlled trial to investigate the effects of routine treatment with the nonsteroidal anti-inflammatory drug ketoprofen at calving and during treatment for lameness, on the future probability of lameness and culling, caused by exposure to normal farm conditions. A cohort of dairy heifers were recruited from a single, commercial dairy herd between January 8, 2018, and June 22, 2020, and randomly allocated to one of 4 treatment groups before first calving. The lactating herd was lameness scored every 2 wk on a 0 to 3 scale, to identify animals that became lame (single score ≥2a) and hence required treatment. Animals in group 1 received a therapeutic trim and a hoof block on the sound claw (if deemed necessary) every time they were treated for lameness. Animals in group 2 received the same treatment as group 1 with the addition of a 3-d course of ketoprofen (single dose daily) every time they were treated for lameness. Animals in group 3 received the same treatment as group 2 with the addition of a 3-d course of ketoprofen (single dose daily) starting 24 to 36 h after each calving. Animals in group 4 received a 3-d course of ketoprofen (single dose daily) every time they were identified with lameness. No therapeutic trim was administered to this group, unless they were identified as severely lame (a single score ≥3a). Animals were followed for the duration of the study (ending October 23, 2020). Probability of lameness was assessed by a lameness outcome score collected every 14 d. Data on culling was extracted from farm records. One hundred thirty-two animals were recruited to each group, with data from 438 animals included in the final analysis (111 in group 1, 117 in group 2, 100 in group 3, and 110 in group 4). Mixed effect logistic regression models were used to evaluate the effect of treatment group on the ongoing probability of lameness. Compared with the control group (group 1), animals in group 3 were less likely to become lame (odds ratio: 0.66) and severely lame (odds ratio: 0.28). A Cox proportional hazards survival model was used to investigate the effect of treatment group on time to culling. Compared with group 1, animals in groups 2 and 3 were at reduced risk of culling (hazard ratios: 0.55 and 0.56, respectively). The lameness effect size we identified was large and indicated that treating a cohort of animals with the group 3 protocol, would lead to an absolute reduction in population lameness prevalence of approximately 10% and severe lameness prevalence of 3%, compared with animals treated in accordance with conventional best practice (group 1).

Photoinduced Oxidation of Lipid Membranes in the Presence of the Nonsteroidal Anti-Inflammatory Drug Ketoprofen

The damage of cell membranes induced by photosensitive drugs has attracted the significant attention of researchers in various fields of medicine. Ketoprofen (KP) is known to be the most photosensitive among the nonsteroidal anti-inflammatory drugs. The phototoxic side effects of KP and other non-steroidal anti-inflammatory drugs are associated with the action of free radicals, but there is insufficient information about the nature of these radicals. In the present study, free radicals formed upon KP irradiation within lipid membranes were studied using nuclear magnetic resonance (NMR) and chemically induced dynamic nuclear polarization (CIDNP) methods, as well as a molecular dynamics simulation. Our study confirmed the effective penetration of KP into the lipid bilayer and showed a significant effect of the nature of the medium on the photolysis mechanism. While, in a homogeneous solution, the main channel of KP photolysis is free radical-mediated monomolecular decomposition with formation of radical pairs of benzyl and CO2H● radicals, then, in the lipid membrane, the reaction route shifts towards the bimolecular reaction of KP photoreduction. In addition, the effect of the presence an electron donor (the amino acid tryptophan) on lipid oxidation has been studied. It was found that photoreaction of KP with tryptophan proceeds more efficiently than with lipid molecules.

Acute pain-related depression of operant responding maintained by social interaction or food in male and female rats.

Clinically relevant pain is oftenassociated with functional impairment and behavioral depression, including depression of social behavior. Moreover, recovery of function is a major goal in pain treatment. We used a recently developed model of operant responding for social interaction in rats to evaluate the vulnerability of social behavior to an experimental pain manipulation and the sensitivity of pain-depressed social behavior to treatment with clinically effective analgesics. Sprague-Dawley male and female rats were trained to lever press for social access to another rat, and responding was evaluated after treatment with (a) intraperitoneal injection of dilute lactic acid (IP acid; 0.18-5.6%) administered alone as a visceral noxious stimulus, (b) the mu-opioid receptor (MOR) agonist morphine (0.32-10mg/kg) or nonsteroidal anti-inflammatory drug (NSAID) ketoprofen (10mg/kg) administered alone, or (c) morphine or ketoprofen administered before IP acid. For comparison, the same treatments were evaluated in separate rats trained to lever press for food delivery. Both IP acid alone and morphine alone more potently decreased responding maintained by social interaction than by food, whereas ketoprofen did not affect responding for either reinforcer. In general, analgesics were most effective to rescue operant responding when relatively low IP acid concentrations produced significant but submaximal behavioral depression; however, morphine was not effective to rescue responding for social interaction. Operant responding maintained by social interaction was more sensitive to pain-related disruption and less responsive to opioid analgesic rescue than food-maintained operant responding. Social behavior may be especially vulnerable to depression by pain states.

Enhanced Removal of Non-Steroidal Inflammatory Drugs from Water by Quaternary Chitosan-Based Magnetic Nanosorbents

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most common pharmaceuticals used worldwide. They are widely detected in natural waters due to their persistence in wastewater treatment, and their removal is desirable in wastewater management. As a contribution to tackle this challenge, this study explores magnetic quaternary chitosan-based nanosorbents for the effective magnetically assisted removal of three NSAIDs (diclofenac, naproxen, and ketoprofen) from water. Toward this goal, silane groups were grafted onto the backbone of trimethyl chitosan through the reaction with an epoxide functionalized silane. Once silanized, the modified chitosan was employed to coat Fe3O4 nanoparticles. The prepared materials were characterized using FTIR spectroscopy and solid-state 29Si and 13C NMR spectroscopy, which confirmed the encapsulation of Fe3O4 nanoparticles with a hybrid siliceous material enriched in trimethyl chitosan. The effect of the initial NSAIDs concentration, pH, and contact time in the adsorption behavior was investigated. The kinetic data were well described by the pseudo-second-order kinetic model, indicating a chemisorption mechanism. The maximum adsorption capacities estimated from the Langmuir model were 188.5 mg/g (0.5925 mmol/g), 438.1 mg/g (1.7371 mmol/g), and 221.5 mg/g (0.8710 mmol/g) for diclofenac, naproxen, and ketoprofen, respectively. These adsorption capacities are higher than those of most reported sorbents, indicating the potential of these biosorbents to remove the selected NSAIDs using low-energy magnetically assisted separation.

Effects of Ketoprofen and Morphine on Pain-Related Depression of Nestlet Shredding in Male and Female Mice.

A primary goal in pain treatment is restoration of behaviors that are disrupted by pain. Measures of pain interference indicate the degree to which pain interferes with activities in pain patients, and these measures are used to evaluate the effects of analgesic drugs. As a result of the emphasis on the expression and treatment of functional impairment in clinical settings, preclinical pain researchers have attempted to develop procedures for evaluation of pain-related functional impairment in laboratory animals. The goal of the present study was to develop and validate a low cost procedure for the objective evaluation of pain-related depression of home cage behavior in mice. On test days, a 5 × 5 cm Nestlet was weighed prior to being suspended from the wire lid of the home cage of individually housed male and female ICR mice. Over the course of experimental sessions, mice removed pieces of the suspended Nestlet, and began to build a nest with the material they removed. Thus, the weight of the pieces of Nestlet that remained suspended at various time points in the session provided an indicator of the rate of this behavior. The results indicate that Nestlet shredding was stable with repeated testing, and shredding was depressed by intra-peritoneal injection of 0.32% lactic acid. The non-steroidal anti-inflammatory drug ketoprofen blocked 0.32% lactic acid-induced depression of shredding, but did not block depression of shredding by a pharmacological stimulus, the kappa opioid receptor agonist U69,593. The μ-opioid receptor agonist morphine did not block 0.32% lactic acid-induced depression of shredding when tested up to doses that depressed shredding in the absence of lactic acid. When noxious stimulus intensity was reduced by decreasing the lactic acid concentration to 0.18%, morphine was effective at blocking pain-related depression of behavior. In summary, the data from the present study support consideration of the Nestlet shredding procedure for use in studies examining mechanisms, expression, and treatment of pain-related functional impairment.