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Injectable hydrogels have been extensively studied due to their minimally invasive properties, ease of application, and void-filling properties. In this work, we tested the possibility to prepare a new type of gels, so called eutectogels, where water is replaced by a natural deep eutectic system (NADES), conferring it longer stability. Eutectogels based on betaine : glycerol 1 : 2, were prepared by enzymatic mediated crosslinking, using horseradish peroxidase (HRP) as catalyst and gelatine-phenol conjugated polymer. In comparison to hydrogels, that required higher enzyme concentration (15 U mL -1 ) to have gelation time under 2 minutes, the eutectogels were obtained using 10 and 5 U mL -1 of HRP, with gelation times of 30 and 50 seconds, respectively. Finally, ketoprofen was loaded into the polymeric matrix, and release studies were conducted. The presence of NADES was essential for the formulation of the drug loaded gel, which was able to release up to 70% of the drug within 10 days, therefore, it was possible to conclude that these eutectogels work as matrix for the controlled delivery of ketoprofen in aqueous medium. The in vitro biological evaluation of the individual components of the eutectogel support no cytotoxic effect, an early indication of potential biocompatibility.

The present work is designed to explore the anti-inflammatory properties of AA and its modulatory effects on celecoxib (CEL) and ketoprofen (KET) through in vitro, ex vivo, in vivo, and in silico approaches. Different concentrations of AA were utilized to evaluate the membrane-stabilizing potential via egg albumin and the Human Red Blood Cell (HRBC) denaturation model. In the animal model, formalin (50 μL) was injected into the right hind paw of young chicks to induce inflammation. AA was administered at 20 and 40 mg/kg (p.o.) to the experimental animals. We used CEL and KET as positive controls. The vehicle was provided as a control group. Two combinations of AA with CEL and KET were also investigated in all tests to assess the modulatory activity of AA. In addition, in silico investigation was used for predictions about drug-likeness, pharmacokinetics, and toxicity of the selected chemical compounds, and the study also evaluated the binding affinity, visualization, and stability of ligand-receptor interactions through molecular dynamic (MD) simulation. Results manifested that AA concentration-dependently significantly inhibited the egg albumin denaturation (IC 50 : 27.53 ± 0.88 μg/ml) and breakdown of HRBC (IC 50 : 15.69 ± 0.75 μg/ml), indicating the membrane stabilizing potential compared to the control group. AA also significantly (p < 0.05) lessened the frequency of licking and alleviated the paw edema in a dose-dependent manner in an in vivo test. However, AA reduced the activity of CEL and KET in combination treatment. AA showed good pharmacokinetic characteristics to be considered as a therapeutic candidate. Additionally, the in silico study displayed that AA demonstrated a relatively higher docking score of -9.1 kcal/mol with the cyclooxygenase-2 (COX-2) enzyme and stable binding in MD simulation. Whereas the standard ligand (CEL) expressed the highest binding value of -9.2 kcal/mol to the COX-2., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financialinterestsor personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Ketoprofen and meloxicam, non-steroidal anti-inflammatory drugs widely used in clinical practice, lack comprehensive investigation regarding their impact on male reproductive health, particularly on epididymal duct contractions and sperm parameters. Therefore, this study investigated the negative effects of ketoprofen or meloxicam on the contractions of the epididymal duct, sperm parameters, and serum testosterone levels in rats. Firstly, we assessed the in vitro effects of ketoprofen or meloxicam (1-100 μM) on the contractions of the epididymal duct elicited by noradrenaline. Rats were also orally treated with 5 mg/kg ketoprofen or 1 mg/kg meloxicam for 15 days following evaluation of epididymal duct contractions, sperm parameters, and serum testosterone levels. In vitro exposure to meloxicam (100 μM), but not ketoprofen, significantly reduced the maximum effect of noradrenaline in epididymal duct. Moreover, in vivo administration of ketoprofen and meloxicam decreased testosterone levels, sperm production, and sperm count in the caput/corpus region of the rat epididymis. Conversely, the sperm count in the cauda epididymis remained unchanged in animals treated with both ketoprofen and meloxicam. Meloxicam, but not ketoprofen, caused a delay in sperm transit time in the cauda region of the epididymis. In vivo treatment with both ketoprofen or meloxicam hindered the noradrenaline-induced contractions in the epididymal duct. In conclusion, ketoprofen and meloxicam can modify sperm parameters by decreasing testosterone levels and the contractions of the epididymal duct isolated from the distal cauda region of the rat epididymis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Society for Biology of Reproduction & the Institute of Animal Reproduction and Food Research of Polish Academy of Sciences in Olsztyn. Published by Elsevier B.V. All rights reserved.)

Phototoxicity is a significant problem that occurs in a large part of the population and is often caused by commonly used pharmaceuticals, including over-the-counter drugs. Therefore, testing drugs with photosensitizing potential is very important. The aim of this study is to analyze the cytotoxicity and phototoxicity of ketoprofen towards human melanocytes and fibroblasts in three different treatment schemes in order to optimize the study. Cytometric tests (studies of viability, proliferation, intracellular thiol levels, mitochondrial potential, cell cycle, and DNA fragmentation), Western blot analysis (cytochrome c and p44/p42 protein levels), and confocal microscopy imaging were performed to assess the impact of the developed treatments on skin cells. Research on experimental schemes may help reduce or eliminate the risk of phototoxic reactions. In the case of ketoprofen, we found that the strongest phototoxic potential was exhibited in the treatment where the drug was present in the solution during the irradiation of cells, both pigmented and non-pigmented cells. These results indicate that the greatest risk of photosensitivity reactions related to ketoprofen occurs after direct contact with the drug and UV exposure.

Osteoarthritis (OA) is a chronic joint disease that results in biomechanical and morphological changes that contribute to cartilage degradation. Ketoprofen (KP), used in the treatment of OA, is a selective inhibitor of cyclooxygenase-2 (COX-2). Topical administration of KP bypasses gastric irritation as well as first-pass metabolism and increases localized delivery. The research intricates fabrication and optimization of KP-loaded transethosomes (KP-TEs) via Taguchi orthogonal array design and Central composite design (CCD). The optimized KP-TEs depicted an average vesicle size of 110.0 ± 1.70 nm, poly dispersibility index (PDI) of 0.103 ± 0.01, zeta potential -6.08 ± 0.27 mV, and conductivity of 0.049 ± 0.0001 mS/cm. The optimized KP-TEs were loaded in composite hyaluronic acid (HA) and poloxamer 407 (Px407) for an improvement of osteotrophic and chondroprotective transethosomal gel. The drug content of KP-TEs-HA/Px407 gel was found to be 90.08 ± 1.25 %. Preclinical research has been carried out by using the monosodium iodoacetate to develop model for osteoarthritis in male wistar rats. The X-ray imaging of KP-TEs-HA/Px407 gel treated group showed intact meniscus, healthy articular joint, and normal synovial lining same as the healthy control group. The IL - 1β IL-6, IL-22, TNF-α, and IL-10, levels, X-ray imaging, and studies on histopathology demonstrated the effectiveness of transethosomal gel in reducing pain and inflammation., Competing Interests: Declaration of competing interest Regarding this article, the authors disclosed no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The emergence and spread of antibiotic resistance in the environment pose a serious threat to global public health. It is acknowledged that non-antibiotic stresses, including disinfectants, pharmaceuticals and organic pollutants, play a crucial role in horizontal transmission of antibiotic resistance genes (ARGs). Despite the widespread presence of non-steroidal anti-inflammatory drugs (NSAIDs), notably in surface water, their contributions to the transfer of ARGs have not been systematically explored. Furthermore, previous studies have primarily concentrated on model strains to investigate whether contaminants promote the conjugative transfer of ARGs, leaving the mechanisms of ARG transmission among antibiotic resistant bacteria in natural aqueous environments under the selective pressures of non-antibiotic contaminants remains unclear. In this study, the Escherichia coli (E. coli) K12 carrying RP4 plasmid was used as the donor strain, indigenous strain Aeromonas veronii containing rifampicin resistance genes in Taihu Lake, and E. coli HB101 were used as receptor strains to establish inter-genus and intra-genus conjugative transfer systems, examining the conjugative transfer frequency under the stress of ketoprofen. The results indicated that ketoprofen accelerated the environmental spread of ARGs through several mechanisms. Ketoprofen promoted cell-to-cell contact by increasing cell surface hydrophobicity and reducing cell surface charge, thereby mitigating cell-to-cell repulsion. Furthermore, ketoprofen induced increased levels of reactive oxygen species (ROS) production, activated the DNA damage-induced response (SOS), and enhanced cell membrane permeability, facilitating ARG transmission in intra-genus and inter-genus systems. The upregulation of outer membrane proteins, oxidative stress, SOS response, mating pair formation (Mpf) system, and DNA transfer and replication (Dtr) system related genes, as well as the inhibition of global regulatory genes, all contributed to higher transfer efficiency under ketoprofen treatment. These findings served as an early warning for a comprehensive assessment of the roles of NSAIDs in the spread of antibiotic resistance in natural aqueous environments., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

A major cause of early embryonic losses is inadequate secretion of progesterone (P4) hormone due to luteal insufficiency in farm animals. Post-mating applications that directly or indirectly increasing serum P4 concentrations have a positive effect on fertility. The aim of this study was to investigate the effect of post-mating administration of ketoprofen on serum P4 concentration and fertility in Akkaraman ewes synchronized with a short-term protocol during the breeding season. Oestrus monitoring ewes after synchronization were hand-mated and randomly assigned to two equal groups (Ketoprofen vs. Control). Ewes in the ketoprofen group (KPG) (n = 40) were administered with ketoprofen (Rifen, Richter pharma, Austria) intramuscularly (im) at a dose of 3 mg/kg on days 9 and 10 after mating. In the control group (CG) ewes (n = 40) were administered with saline im on the same days. Blood samples were collected from ewes in both groups at four different time points of post-mating days (9, 12, 15 and 18 days). The results showed that there were no statistical differences between the KPG and CG groups on fertility parameters; pregnancy rates (85% vs. 72.5%), lambing rates (100% vs. 100%), single birth rates (55.9% vs. 55.2%), multiple birth rates (44.1% vs. 44.8%), litter sizes (1.56 vs. 1.55). In pregnant ewes, serum P4 concentrations on day 18 (4.35 ± 0.34 ng/mL) in the KPG group were higher than (3.27 ± 0.27 ng/mL) in CG group (P < 0.05). It was concluded that post-mating ketoprofen administration have no significant effect on fertility, but significantly increased the serum P4 concentration on day 18 in pregnant ewes., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Multiresponsive hydrogels are valuable as biomaterials due to their ability to respond to multiple biologically relevant stimuli, i.e., temperature, pH, or reactive oxygen species (ROS), which can be present simultaneously in the body. In this work, we synthesize triple-responsive hydrogels through UV light photopolymerization of selected monomer compositions that encompass thermoresponsive N -isopropylacrylamide (NIPAM), pH-responsive methacrylic acid (MAA), and a tailor-made ROS-responsive diacrylate thioether monomer (EG 3 SA). As a result, smart P[NIPAM x - co -MAA y - co -(EG 3 SA) z ] hydrogels capable of being manufactured by digital light processing (DLP) 4D printing are obtained. The thermo-, pH-, and ROS-response of the hydrogels are studied by swelling tests and rheological measurements at different temperatures (25 and 37 °C), pHs (3, 5, 7.4, and 11), and in the absence or presence of ROS (H 2 O 2 ). The hydrogels are employed as matrixes for the encapsulation of ketoprofen (KET), an anti-inflammatory drug that shows a tunable release, depending on the hydrogel composition and stimuli applied. The cytotoxicity properties of the hydrogels are tested in vitro with mouse embryonic fibroblasts (NIH 3T3) and RAW 264.7 murine macrophage (RAW) cells. Finally, the anti-inflammatory properties are assessed, and the results exhibit a ≈70% nitric oxide reduction up to base values of pro-inflammatory RAW cells, which highlights the anti-inflammatory capacity of P[NIPAM 80 - co -MAA 15 - co -(EG 3 SA) 5 ] hydrogels, per se , without being necessary to encapsulate an anti-inflammatory drug within their network. It opens the route for the fabrication of customizable 4D printable scaffolds for the effective treatment of inflammatory pathologies.

Improved solubility and anti-inflammatory (AI) properties are imperative for enhancing the effectiveness of poorly water-soluble drugs, particularly non-steroidal anti-inflammatory drugs (NSAIDs). To address these critical issues, our focus is on obtaining NSAID materials in the form of inclusion complexes (IC) with methyl-beta-cyclodextrin (MCD). Ketoprofen (KTP) is selected as the NSAID for this study due to its potency in treating various types of pain, inflammation, and arthritis. Our objective is to tackle the solubility challenge followed by enhancing the AI activity. Confirmation of complexation is achieved through observing changes in the absorbance and fluorescence intensities of KTP upon the addition of MCD, indicating a 1:1 stoichiometric ratio. Phase solubility studies demonstrated improved dissolution rates after the formation of ICs. Further analysis of the optimized IC is conducted using FT-IR, NMR, FE-SEM, and TG/DTA techniques. Notable shifts in chemical shift values and morphological alterations on the surface of the ICs are observed compared to their free form. Most significantly, the IC exhibited superior AI and anti-arthritic (AA) activity compared to KTP alone. These findings highlight the potential of ICs in expanding the application of KTP, particularly in pharmaceuticals, where enhanced stability and efficacy of natural AIs and AAs are paramount., (© 2024. The Author(s).)

This study explored the antimicrobial effects of ketoprofen, piroxicam, and celecoxib alone or combined with calcium hydroxide (CH) against two strains of Enterococcus faecalis (E. faecalis) and assessed the influence of such combinations on the pH of CH. Minimum inhibitory concentrations (MICs) of the three tested NSAIDs were determined. Tested pastes were placed into wells punched in seeded agar plates and the bacterial inhibition zones were measured. Antibiofilm activity was assessed against 3 weeks of biofilm induced in bovine dentine blocks. The pH of the pastes was measured at four-time intervals. MIC values were 3.12, 25, and 25 mg/ml for ketoprofen, piroxicam, and celecoxib, respectively, and were similar for both bacterial strains except for celecoxib, which showed 8% growth at the highest tested concentration against vancomycin-resistant E. faecalis. Ketoprofen had the largest mean inhibition zone that was comparable to CH. None of the six tested pastes exhibited antibiofilm activity of a significant level in comparison to CH. A noticeable increase in the antibiofilm activity was found when 20% NSAIDs were added to CH while maintaining an alkaline pH. Ketoprofen was found to be the most effective among the tested NSAIDs. Although its effect was comparable to CH, adding ketoprofen at a ratio of 20% resulted in 50% higher antimicrobial action than CH alone. Accordingly, incorporating NSAIDs in inter-appointment dressing has the potential to utilize their anti-inflammatory, local analgesic, and antibacterial actions, which overcome the limitations of CH and improve the outcome of root canal treatment., (© 2024. The Author(s), under exclusive licence to The Society of The Nippon Dental University.)

Ketoprofen (KET), commonly used for inflammation in clinical settings, leads to systemic adverse effects with prolonged use, mitigated by topical administration. Nanotechnology-based cutaneous forms, like films, may enhance KET efficacy. Therefore, this study aimed to prepare and characterize films containing KET nanoemulsions (F-NK) regarding mechanical properties, chemical composition and interactions, occlusive potential, bioadhesion, drug permeation in human skin, and safety. The films were prepared using a κ-carrageenan and xanthan gum blend (2 % w/w, ratio 3: 1) plasticized with glycerol through the solvent casting method. Non-nanoemulsioned KET films (F-K) were prepared for comparative purposes. F-NK was flexible and hydrophilic, exhibited higher drug content and better uniformity (94.40 ± 3.61 %), maintained the NK droplet size (157 ± 12 nm), and was thinner and lighter than the F-K. This film also showed increased tensile strength and Young's modulus values, enhanced bioadhesion and occlusive potential, and resulted in more of the drug in the human skin layers. Data also suggested that nano-based formulations are homogeneous and more stable than F-KET. Hemolysis and chorioallantoic membrane tests suggested the formulations' safety. Thus, the nano-based film is suitable for cutaneous KET delivery, which may improve the drug's efficacy in managing inflammatory conditions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Quorum sensing (QS) is the leading cause of persistent infections and recalcitrance to antibiotic treatment of Pseudomonas aeruginosa. Hence, QS inhibitors are promising agents for the potential treatment of P. aeruginosa infections., Methods and Results: Herein, the reducing effect of ketoprofen on virulence factors production including protease, hemolysin, pyocyanin, hydrogen cyanide, biofilm, and motility of P. aeruginosa strains was investigated. Furthermore, the quorum quenching activity of ketoprofen at the molecular level was examined by real-time PCR assessment. Our results showed that ketoprofen significantly attenuates virulence factors and biofilm formation in P. aeruginosa strains. Moreover, ketoprofen down-regulated the expression of lasI, lasR, rhlI, and rhlR genes, by 35-47, 22-48, 34-67, and 43-56%, respectively. As well, molecular docking simulation showed a high binding affinity of ketoprofen with QS regulatory proteins., Conclusions: Consequently, this study confirmed the quorum quenching activity of ketoprofen, which could be employed as a useful agent for the treatment of P. aeruginosa infections., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Acute upper respiratory infections (AURI) are widespread in adolescents. Infections are associated with inflammation which in turn is responsible for symptoms and fever occurrence. Ketoprofen lysine salt (KLS) has a potent anti-inflammatory activity associated with effective analgesic and antipyretic effects and has a valuable safety profile. In this regard, KLS could be advantageous in adolescents with AURI., Methods: A group of primary-care pediatricians retrospectively collected data from adolescents with AURI treated with KLS for three days. Fever and symptom perception were assessed by a visual analog scale and were monitored daily for five days. Adolescents (or parents) sent their data to doctors using a phone application (WhatsApp; Meta Platforms, Inc., Menlo Park, CA, USA)., Results: This retrospective analysis included sixty-one adolescents (mean age 13.4 years, females and males). KLS treatment markedly and quickly reduced fever and symptoms severity. In addition, the treatment was very well tolerated by all adolescents., Conclusions: Adolescents present peculiar psychological characteristics that may determine some difficulties in prompt management of AURI treatment, while an adolescent with a respiratory infection requires a prompt and adequate cure. KLS, thanks to its pharmacologic profile, could be favorably used in this context. In addition, the treatment was safe, and the acceptability was high.

Computer-based drug design is increasingly used in strategies for discovering new molecules for therapeutic purposes. The targeted drug is ketoprofen (KTP), which belongs to the family of non-steroidal anti-inflammatory drugs, which are widely used for the treatment of pain, fever, inflammation and certain types of cancers. In an attempt to rationalize the search for 72 new potential anti-inflammatory compounds on the COX-2 enzyme, we carried out an in silico protocol that successfully combines molecular docking towards COX-2 receptor (5F1A), ADMET pharmacokinetic parameters, drug-likeness rules and molecular electrostatic potential (MEP). It was found that six of the compounds analyzed satisfy with the associated values to physico-chemical properties as key evaluation parameters for the drug-likeness and demonstrate a hydrophobic character which makes their solubility in aqueous media difficult and easy in lipids. All the compounds presented good ADMET profile and they showed an interaction with the amino acids responsible for anti-inflammatory activity of the COX-2 isoenzyme. The calculation of the MEP of the six analogues reveals new preferential sites involving the formation of new bonds. Consequently, this result allowed us to understand the origin of the potential increase in the anti-inflammatory activity of the candidates. Finally, it was obtained that six compounds have a binding mode, binding energy, and stability in the active site of COX-2 like the reference drug ketoprofen, suggesting that these compounds could become a powerful candidate in the inhibition of the COX-2 enzyme.Communicated by Ramaswamy H. Sarma.

Upper respiratory infections are widespread, and they are mainly of viral etiology. It has to be remarked that every infection is always associated with an inflammatory response. Inflammation implicates a cascade of bothersome symptoms, including fever, pain (headache, myalgia, and arthralgia), malaise, and respiratory complaints. As a result, anti-inflammatory medications could be beneficial as they act on different pathogenetic pathways. The ketoprofen lysine salt (KLS) has a potent anti-inflammatory activity associated with effective analgesic and antipyretic effects and has a valuable safety profile. However, adolescents present peculiar psychological characteristics that determine their difficulty to be managed. In this regard, an adolescent with a respiratory infection requires a prompt and adequate cure. KLS, thanks to its pharmacologic profile, could be favorably used in this regard. A recent primary-care experience outlined its effectiveness in this issue.

Ketoprofen, a commonly used non-steroidal anti-inflammatory drug (NSAID), can enter farmland environments via sewage irrigation and manure application and is toxic to plants. However, there have been relatively few studies on the association of ketoprofen with nitrogen (N) assimilation and metabolic responses in plants. Accordingly, the goal of this study was to investigate the effects of ketoprofen on ATP synthesis and N assimilation in rice roots. The results showed that with increasing ketoprofen concentration, root vitality, respiration rate, ATP content, and H + -ATPase activity decreased and plasma membrane permeability increased. The expressions of OSA9, a family III H + -ATPase gene, and OSA6 and OSA10, family IV genes, were upregulated, indicating a response of the roots to ketoprofen. Nitrate, ammonium, and free amino acids content decreased with increased ketoprofen. The levels of enzymes involved in N metabolism, namely nitrate reductase, nitrite reductase, glutamine synthetase, glutamate synthetase, and glutamate dehydrogenase, also decreased under ketoprofen treatment. Principal component analysis revealed that ketoprofen treatment can significantly affect energy synthesis and nitrogen assimilation in rice roots, while these effects can be alleviated by the antioxidant response. Most of the metabolite contents increased, including amino acids, carbohydrates, and secondary metabolites. Key metabolic pathways, namely substance synthesis and energy metabolism, were found to be disrupted. Microbiome analysis showed that community diversity and richness of rice root microorganisms in solution increased with increasing levels of ketoprofen treatment, and the microbial community structure and metabolic pathways significantly changed. The results of this study provides new insights into the response of rice roots to ketoprofen., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

In this study we evaluated the acute (immobility/mortality) and chronic (survival and reproduction) effects of the drugs caffeine, diclofenac sodium salt, ketoprofen, paracetamol and salicylic acid on the cladoceran Ceriodaphnia silvestrii. The environmental risks of these substances for tropical freshwaters were estimated from the risk quotient MEC/PNEC. Sensitivity in acute exposures varied up on the drug as follows: salicylic acid (EC 50  = 69.15 mg L - 1 ) < caffeine (EC 50  = 45.94 mg L - 1 ) < paracetamol (EC 50  = 34.49 mg L - 1 ) < ketoprofen (EC 50  = 24.84 mg L - 1 ) < diclofenac sodium salt (EC 50  = 14.59 mg L - 1 ). Chronic toxicity data showed negative effects of the drugs on reproduction. Paracetamol and salicylic acid caused reduction in fecundity in concentrations starting from 10 mg L - 1 and 35 mg L - 1 , respectively. Ketoprofen caused total inhibition at 5 mg L - 1 . MEC/PNEC values were relatively low for all drugs. The risk was estimated as low or insignificant, except for caffeine, whose MEC/PNEC value was greater than 1 (moderate risk)., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Side effects of Ketoprofen and ketoprofen lysine salt (KLS) may be inter alia from the central nervous system, kidneys and liver. After binge drinking people often use ketoprofen, which increases the risk for the occurrence of side effects. The aim of the study was to compere effects of ketoprofen and KLS on the nervous system, kidneys and liver after ethyl alcohol intoxication. There were 6 groups of 6 male rats which received: ethanol; 0.9%NaCl; 0.9%NaCl and ketoprofen; ethanol and ketoprofen; 0.9%NaCl and KLS; ethanol and KLS. On day 2, the motor coordination test on a rotary rod and memory and motor activity test in the Y-maze were performed. Hot plate test was performed on day 6. After euthanasia brains, livers and kidneys were taken to histopathological tests. Motor coordination was significant worse in group 5 vs 1,3, p 0.05. Spontaneous motor activity of group 6 was significant better than that of groups 1,5. Pain tolerance of group 6 was significant worse than that of groups 1,4,5. Liver and kidney mass were significantly lower in group 6 vs group 3,5 and vs group 1,3, respectively. The histopathologic examination of the brains and kidneys revealed normal picture in all groups, without signs of inflammation. In the histopathologic examination of the livers in one animal in group 3 some of the specimens showed perivascular inflammation. After alcohol ketoprofen is a better painkiller than KLS. Spontaneous motor activity is better after KLS after alcohol. Both drugs have a similar effect on the kidneys and liver., Competing Interests: Declaration of Interest statement The authors declare that there are no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Bis-squaramide receptors L1-L4 bearing a dansyl moiety were synthesised and their potential applications as fluorescent probes towards non steroidal anti-inflammatory drugs naproxen and ketoprofen was investigated. A detailed photophysical characterization in CH 3 CN/DMSO solution (9 : 1 v/v) was conducted and demonstrated that the two macrocyclic receptors L1 and L2 show good sensitivity towards ketoprofen with an ON-OFF fluorescent response, while the two open chain receptors L3 and L4 behave similarly with the three guests considered. DFT theoretical calculations carried out on L2 and L4 as model receptors allowed to propose a possible coordination mode towards the guests. Finally, 1 H-NMR spectroscopy in DMSO- d 6 /0.5% water solution demonstrated that the four receptors interact with the considered guests via H-bonds.

Both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) convert arachidonic acid to prostaglandin H 2 , which has proinflammatory effects. The recently developed PET radioligand 11 C-PS13 has excellent in vivo selectivity for COX-1 over COX-2 in nonhuman primates. This study sought to evaluate the selectivity of 11 C-PS13 binding to COX-1 in humans and assess the utility of 11 C-PS13 to measure the in vivo potency of nonsteroidal antiinflammatory drugs. Methods: Baseline 11 C-PS13 whole-body PET scans were obtained for 26 healthy volunteers, followed by blocked scans with ketoprofen ( n = 8), celecoxib ( n = 8), or aspirin ( n = 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, 11 C-PS13 uptake inhibition from blood cells was measured in vitro and ex vivo (i.e., using blood obtained during PET scanning). Results: High 11 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 IC 50 ), 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 11 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 IC 50 could not be determined. Conclusion: 11 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 11 C-PS13., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Triple-negative breast cancer (TNBC) is an invasive phenotype with undesirable clinical features, poor prognosis, and therapy resistance. Ketoprofen is a Non-steroidal anti-inflammatory drug (NSAID) with anti-tumor properties., Aim: To investigate the effects of Ketoprofen on apoptosis and autophagy in TNBC cell line MDA-MB-231., Methods: The cytotoxic activity of Ketoprofen was assayed by the MTS method. Flowcytometry was utilized to measure the number of apoptotic MDA-MB-231 cells. The expression levels of apoptosis and autophagy markers, JAK2 and STAT3 were determined using quantitative real time-PCR (qRT-PCR) and western blotting methods., Results: Ketoprofen significantly decreased the proliferation of MDA-MB-231 cells compared to control cells. It also considerably induced apoptosis and apoptotic markers in these cells in comparison to controls. Treating the MADA-MB-231 cell line with Ketoprofen had an inhibitory effect on autophagy markers in this cell line. The use of FasL, as a death ligand, and ZB4, as an antibody that blocks the extrinsic pathway of apoptosis, revealed the involvement of the extrinsic pathway in the apoptosis-stimulating effect of Ketoprofen in the MADA-MB-231 cell line. Ketoprofen also hindered the phosphorylation and activation of JAK2 and STAT molecules leading to the inhibition of the JAK/STAT pathway in this TNBC cell line., Conclusion: The outcomes of this study uncovered the anti-TNBC activity of Ketoprofen by inducing apoptosis and inhibiting viability and autophagy in MADA-MB-231 cells. Our data also suggested that Ketoprofen impedes apoptosis in TNBC cells by two different mechanisms including the induction of the extrinsic apoptotic pathway and inhibition of the JAK/STAT signaling., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Objective: The objective of the study was to evaluate the effect of ketoprofen when locally applied to tissue-cultured nasal epithelium., Materials and Methods: Healthy primary nasal epithelial cells were grown in a tissue culture medium. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was used to evaluate cytotoxicity. Markers of cellular injury revealed by the MTT assay include fragmentation of DNA, condensed nuclei, and changes affecting the cellular outer membrane and cytoskeleton. Epithelial cells at body temperature in cell culture were exposed over a 24-hour period to ketoprofen. Following the MTT assay, the confocal microscopic examination was performed. The extent to which epithelial cells remained capable of proliferating was evaluated by inducing a scratch injury, waiting for the repair to occur, and then examining the result with the ordinary light microscope., Results: Topically applied ketoprofen does not affect the viability of tissue-cultured nasal epithelial cells within a 24-hour period. Furthermore, there were no cellular morphological alterations observed which would indicate toxicity from ketoprofen. In the scratch assay, the cells regained a normal confluent appearance within 24 hours. Thus, ketoprofen neither increases nor alters the rate at which nasal epithelial cells proliferate., Conclusions: Ketoprofen, when applied topically for 24 hours to nasal epithelial cells in cell culture, does not cause any alterations in cellular appearance which would suggest impairment of the ability to proliferate or indicate a cytotoxic effect. Extrapolating from these results, it appears acceptable to use ketoprofen topically within the nose in cases of rhinosinusitis (acute or chronic) or nasal pain since there is minimal risk of local toxic injury.

Aim: Quorum sensing (QS) inhibition is a promising strategy to suppress bacterial virulence and control infection caused by Gram-negative and Gram-positive bacteria. This study explores the QS inhibiting activity of the non-steroidal anti-inflammatory drugs (NSAIDs) in Acinetobacter baumannii., Methods and Results: Ketoprofen, piroxicam and indomethacin revealed QS inhibition via elimination of violacein production of the reporter strain Chromobacterium violaceum ATCC 12472 without affecting bacterial growth. The minimal inhibitory concentration (MIC) of ketoprofen, piroxicam and indomethacin was determined against A. baumannii strains ATCC 17978, ATCC 19606, A1, A11 and A27 by the microbroth dilution method. The MICs of ketoprofen against tested isolates were 0.7-6.25 mg ml -1 , piroxicam MICs were 1.25-2.5 mg ml -1 , and indomethacin MICs were 3.12-12.5 mg ml -1 . Those compounds significantly inhibited QS-associated virulence factors such as biofilm formation, and surface motility, as well as, significantly increased bacterial tolerance to oxidative stress without affecting bacterial growth. On the molecular level, the three compounds significantly inhibited the transcription of QS regulatory genes abaI/abaR and biofilm-regulated genes cusD and pgaB. Molecular docking analysis revealed the potent binding affinity of the three compounds with AbaI via hydrogen and/or hydrophobic bonds., Conclusion: These results indicate that NSAIDs, ketoprofen, piroxicam and indomethacin, could be potential inhibitors of the QS and could suppress the QS-related virulence factors of A. baumannii., Significance and Impact: Ketoprofen, piroxicam and indomethacin could provide promising implications and strategies for combating the virulence and pathogenesis of A. baumannii., (© 2022 Society for Applied Microbiology.)

This study performed population-pharmacokinetic/pharmacodynamic (pop-PK/PD) modeling of ketoprofen and flunixin in piglets undergoing routine castration and tail-docking, utilizing previously published data. Six-day-old male piglets (8/group) received either ketoprofen (3.0 mg/kg) or flunixin (2.2 mg/kg) intramuscularly. Two hours post-dose, piglets were castrated and tail docked. Inhibitory indirect response models were developed utilizing plasma cortisol or interstitial fluid prostaglandin E2 (PGE2) concentration data. Plasma IC50 for ketoprofen utilizing PGE2 as a biomarker was 1.2 μg/ml, and ED50 for was 5.83 mg/kg. The ED50 calculated using cortisol was 4.36 mg/kg; however, the IC50 was high, at 2.56 μg/ml. A large degree of inter-individual variability (124.08%) was also associated with the cortisol IC50 following ketoprofen administration. IC50 for flunixin utilizing cortisol as a biomarker was 0.06 μg/ml, and ED50 was 0.51 mg/kg. The results show that the currently marketed doses of ketoprofen (3.0 mg/kg) and flunixin (2.2 mg/kg) correspond to drug responses of 33.97% (ketoprofen-PGE2), 40.75% (ketoprofen-cortisol), and 81.05% (flunixin-cortisol) of the maximal possible responses. Given this information, flunixin may be the best NSAID to use in mitigating castration and tail-docking pain at the current label dose., (© 2022 The Authors. Journal of Veterinary Pharmacology and Therapeutics published by John Wiley & Sons Ltd.)

Assessment of pain responses and inflammation during animal surgery is difficult because traditional methods, such as visual analogue scores, are not applicable while under anaesthesia. Acute phase proteins (APPs), such as C-reactive protein and haptoglobin, that are typically monitored in veterinary research, do not show a significant change until at least 2 h post-surgery and therefore, immediate pathophysiological changes are uncertain. The current study used sequential window acquisition of all theoretical mass spectra (SWATH-MS) to investigate plasma proteome changes that occur immediately following surgery in dogs and also to assess the efficacy of a novel transdermal ketoprofen (TK) formulation. Castration was chosen as surgical model in this study. The procedure was performed on twelve dogs (n = 6 in two groups) and blood samples were collected at 0 h, 1 and 2 h after surgery for proteomic analysis. Following surgery, there was a general downregulation of proteins, including complement C- 3, complement factor B, complement factor D, transthyretin, and proteins associated with lipid, cholesterol, and glucose metabolisms, reflecting the systemic response to surgical trauma. Many of these changes were diminished in the transdermal group (TD) since ketoprofen, a non-steroidal anti-inflammatory drug (NSAID), inhibits prostanoids and the associated chemotactic neutrophil migration to site of tissue injury. SIGNIFICANCE: SWATH-MS Proteomic analysis revealed significant changes in plasma proteins, predominantly involved in early acute phase and inflammatory response at 1 & 2 h after surgery in castrated dogs. Pre-operative application of transdermal ketoprofen formulation had reduced the systemic immune response, which was confirmed by negligible alteration of proteins in transdermal treated group. A key outcome of this experiment was studying the efficacy of a novel transdermal NSAID formulation in dogs., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Dexketoprofen is an enantiomer of ketoprofen (S+) that belongs to nonsteroidal anti-inflammatory drugs and has analgesic, anti-inflammatory, and antipyretic properties. Dexketoprofen has a stronger effect than ketoprofen, which makes it a readily used preparation. The review aims to find in recent original publications data about dexketoprofen and its comparison with other painkilling medications. The systematic literature review was conducted in November 2021 (2018 onwards). We selected 12 articles from PubMed, Google Scholar, Medline Complete databases. In the last 4 years, there have been many publications that shed a new light on dexketoprofen. The article is a comparative analysis of dexketoprofen's action vs other nonsteroidal anti-inflammatory drugs and the combination of dexketoprofen with tramadol vs paracetamol with tramadol. The findings of the review confirm that dexketoprofen is a very good pain reliever more potent than paracetamol. Dexketoprofen produces similar effects to lidocaine and dexmedetomidine. Complex preparations containing dexketoprofen and tramadol are very effective painkilling tandem and are more effective than tramadol and paracetamol therapy in the treatment of acute pain., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Intrapleural injections of cholera toxin B conjugated to saporin (CTB-SAP) selectively eliminates respiratory (e.g., phrenic) motor neurons, and mimics motor neuron death and respiratory deficits observed in rat models of neuromuscular diseases. Additionally, microglial density increases in the phrenic motor nucleus following CTB-SAP. This CTB-SAP rodent model allows us to study the impact of motor neuron death on the output of surviving phrenic motor neurons, and the underlying mechanisms that contribute to enhancing or constraining their output at 7 days (d) or 28d post-CTB-SAP injection. 7d CTB-SAP rats elicit enhanced phrenic long-term facilitation (pLTF) through the Gs-pathway (inflammation-resistant in naïve rats), while pLTF is elicited though the Gq-pathway (inflammation-sensitive in naïve rats) in control and 28d CTB-SAP rats. In 7d and 28d male CTB-SAP rats and controls, we evaluated the effect of cyclooxygenase-1/2 enzymes on pLTF by delivery of the nonsteroidal anti-inflammatory drug, ketoprofen (IP), and we hypothesized that pLTF would be unaffected by ketoprofen in 7d CTB-SAP rats, but pLTF would be enhanced in 28d CTB-SAP rats. In anesthetized, paralyzed and ventilated rats, pLTF was surprisingly attenuated in 7d CTB-SAP rats and enhanced in 28d CTB-SAP rats (both p < 0.05) following ketoprofen delivery. Additionally in CTB-SAP rats: 1) microglia were more amoeboid in the phrenic motor nucleus; and 2) cervical spinal inflammatory-associated factor expression (TNF-α, BDNF, and IL-10) was increased vs. controls in the absence of ketoprofen (p < 0.05). Following ketoprofen delivery, TNF-α and IL-10 expression was decreased back to control levels, while BDNF expression was differentially affected over the course of motor neuron death in CTB-SAP rats. This study furthers our understanding of factors (e.g., cyclooxygenase-1/2-induced inflammation) that contribute to enhancing or constraining pLTF and its implications for breathing following respiratory motor neuron death., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aim: Epilepsy is one of the most common neurological diseases. Dexketoprofen (DEX) is a nonselective nonsteroidal anti-inflammatory drug that is used as an analgesic. The present study aimed to assess the efficiency of DEX on WAG/Rij rats by electrophysiologically and behaviorally., Material and Methods: Twenty-eight male WAG/Rij rats were used. The effects of acute treatment with DEX (5, 25, and 50 mg/kg, i.p) on absence-like seizures, and related psychiatric comorbidity were assessed. The ECoG recording was taken for 180 min before and after drug injection. After drug injection and EcoG recording, anxiety-depression-like behavior was tested with the open field test for 5 min., Results: The 5 mg/kg DEX significantly reduced the number and duration of SWDs percentage (p < 0.05) between 120 and 180 min, but 25 and 50 mg/kg DEX significantly increased the number and duration of SWDs percentage between 0 and 30 min (p < 0.05), and after 30 min the increase stopped (p > 0.05). And also, the 5 mg/kg DEX decreased the number and duration of SWDs percentage (p < 0.05) for 180 min (p < 0.05), but 25 and 50 mg/kg DEX administration did not alter (p > 0.05). The 5, 25, and 50 mg/kg doses of DEX significantly increased the duration of grooming (p < 0.05) but did not change the number of squares crossed (p > 0.05)., Conclusion: Low dose DEX reduced absence-like seizures, but care should be taken when using high doses in absence epilepsy. Also, it may be beneficial for painful diseases accompanied by anxiety-depression.

Development of efficient therapeutic strategies to combat protein misfolding and fibrillation is of great clinical significance. In the current study, efforts have been made to obtain qualitative and quantitative insights into interactions of anti-inflammatory drugs; ketoprofen and fenoprofen with the transport protein HSA and their inhibitory action on fibrillation by employing a combination of calorimetric, spectroscopic, microscopic, and molecular docking methods. Interestingly, both ketoprofen and fenoprofen are able to completely inhibit fibrillation of HSA when added at a concentration of 0.5 mM for fenoprofen or 1 mM ketoprofen. Further, no amorphous aggregates are formed. Isothermal titration calorimetric studies highlight the predominant role of polar interactions of these drugs with protein in prevention of fibrillation. The role of conformational flexibility of benzoyl and phenoxy groups of drugs has been correlated with inhibition efficiency. Such studies highlight the role of functionality required for an inhibitor in addressing neurodegenerative diseases., (© 2021 John Wiley & Sons Ltd.)

The present study reports the generation of 2-hydroxyethyl starch microparticles for co-delivery and controlled release of multiple agents. The obtained microparticles are characterized by using Fourier transform infrared spectroscopy, differential scanning calorimetry, X-ray diffraction analysis, energy-dispersive X-ray spectroscopy, and scanning electron microscopy. By using ofloxacin and ketoprofen as drug models, the release sustainability of the microparticles is examined at pH 1.2, 5.4, and 6.8 at 37 °C, with Fickian diffusion being found to be the major mechanism controlling the kinetics of drug release. Upon being loaded with the drug models, the microparticles show high efficiency in acting against Escherichia coli and Bacillus cereus . The results suggest that our reported microparticles warrant further development for applications in which co-administration of multiple bioactive agents is required.

Malignant melanoma is responsible for the majority of skin cancer-related deaths. The methods of cancer treatment include surgical removal, chemotherapy, immunotherapy, and targeted therapy. However, neither of these methods gives satisfactory results. Therefore, the development of new anticancer therapeutic strategies is very important and may extend the life span of people suffering from melanoma. The aim of this study was to examine the effect of ketoprofen (KTP) and UVA radiation (UVAR) therapy on cell proliferation, apoptosis, and cell cycle distribution in both melanotic melanoma cells (COLO829) and human melanocytes (HEMn-DP) in relation to its supportive effect in the treatment of melanoma. The therapy combining the use of pre-incubation with KTP and UVAR causes a significant increase in the anti-proliferative properties of ketoprofen towards melanoma cells and the co-exposure of melanotic melanoma cells induced apoptosis shown as the mitochondrial membrane breakdown, cell-cycle deregulation, and DNA fragmentation. Moreover, co-treatment led to GSH depletion showing its pro-apoptotic effect dependent on ROS overproduction. The treatment did not show a significant effect on normal cells-melanocytes-which indicates its high selectivity. The results suggest a possible benefit from the use of the ketoprofen and ultraviolet A irradiation as a new concept of melanotic melanoma therapy.

Antibiotics are usually used for the treatment of bacterial infections, but multidrug-resistant strains are a phenomenon that has been growing at an increasing rate worldwide. Thus, there is an increasing need for novel strategies for combatting infectious diseases. Many pathogenic bacteria apply quorum sensing (QS) to regulate their pathogenicity and virulence factors production. This circuit makes the QS system an attractive target for antibacterial therapy. In the present study, an important member of non-steroidal anti-inflammatory drugs (NSAIDs), by reducing the biofilm and producing QS-regulated virulence factors, ketoprofen and its synthetic derivatives were screened against the Pseudomonas aeruginosa PAO1. All compounds showed anti-biofilm activity (16-79%) and most of them presented anti-virulence activity. In the co-treatment of ketoprofen, G20, G21, or G77 with tobramycin, biofilm is significantly reduced (potentiated to > 50%) in the number of cells protected inside the impermeable matrix. The in silico studies in addition to the similarities between the chemical structures of PqsR natural ligands and ketoprofen derivatives reinforce the possibility that the mechanism of action is through PqsR inhibition. Based on the results, the anti-pathogenic effect was more appreciable in ketoprofen, G77, and G20., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

A side-by-side electrospinning process characterized by a home-made eccentric spinneret was established to produce the Janus beads-on-a-string products. In this study, ketoprofen (KET) and methylene blue (MB) were used as model drugs, which loaded in Janus beads-on-a-string products, in which polyvinylpyrrolidone K90 (PVP K90) and ethyl cellulose (EC) were exploited as the polymer matrices. From SEM images, distinct nanofibers and microparticles in the Janus beads-on-a-string structures could be observed clearly. X-ray diffraction demonstrated that all crystalline drugs loaded in Janus beads-on-a-string products were transferred into the amorphous state. ATR-FTIR revealed that the components of prepared Janus nanostructures were compatibility. In vitro dissolution tests showed that Janus beads-on-a-string products could provide typical double drugs controlled-release profiles, which provided a faster immediate release of MB and a slower sustained release of KET than the electrospun Janus nanofibers. Drug releases from the Janus beads-on-a-string products were controlled through a combination of erosion mechanism (linear MB-PVP sides) and a typical Fickian diffusion mechanism (bead KET-EC sides). This work developed a brand-new approach for the preparation of the Janus beads-on-a-string nanostructures using side-by-side electrospinning, and also provided a fresh idea for double drugs controlled release and the potential combined therapy.

The primary aim of this study was to examine sex differences in acute antinociceptive and anti-inflammatory effects of nonsteroidal anti-inflammatory drugs (NSAIDs) in rats. Complete Freund's adjuvant (CFA) was administered to adult Sprague-Dawley rats to induce pain and inflammation in one hindpaw; 2.5 h later, vehicle or a single dose of the NSAIDs ibuprofen (1.0-32 mg/kg) or ketoprofen (0.1-10 mg/kg), or the COX-2-preferring inhibitor celecoxib (1.0-10 mg/kg) was injected i.p. Mechanical allodynia, heat hyperalgesia, biased weight-bearing, and hindpaw thickness were assessed 0.5-24 h after drug injection. Ibuprofen and ketoprofen were more potent or efficacious in females than males in reducing mechanical allodynia and increasing weight-bearing on the CFA-injected paw, and celecoxib was longer-acting in females than males on these endpoints. In contrast, ketoprofen and celecoxib were more potent or efficacious in males than females in reducing hindpaw edema. When administered 3 days rather than 2.5 h after CFA, ketoprofen (3.2-32 mg/kg) was minimally effective in attenuating mechanical allodynia and heat hyperalgesia, and did not restore weight-bearing or significantly decrease hindpaw edema, with no sex differences in any effect. Neither celecoxib nor ketoprofen effects were significantly attenuated by cannabinoid receptor 1 or 2 (CB1 or CB2) antagonists in either sex. These results suggest that common NSAIDs administered shortly after induction of inflammation are more effective in females than males in regard to their antinociceptive effects, whereas their anti-inflammatory effects tend to favor males; effect sizes indicate that sex differences in NSAID effect may be functionally important in some cases., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

The purpose of this study was to evaluate the antinociceptive interaction between dexketoprofen and tapentadol in three different dose ratios, as well as the ulcerogenic activity of this combination. Dose-response curves were carried out for dexketoprofen, tapentadol, and dexketoprofen-tapentadol combinations in the acetic acid-induced writhing test in mice. On the other hand, the gastric damage of all treatments was assessed after the surgical extraction of the stomachs. Intraperitoneal administration of dexketoprofen and tapentadol induced a dose-dependent antinociceptive effect, reaching a maximal effect of about 58% and 99%, respectively. Isobolographic analysis and the interaction index showed that the three proportions produced an analgesic potentiation (synergistic interaction). Interestingly, the 1:1 and 1:3 ratios of the drugs combination produced minor gastric injury in comparison with the 3:1 proportion. Our data suggest that all proportions of the dexketoprofen-tapentadol combination produced a synergistic interaction in the acetic acid-induced visceral pain model in mice with a low incidence of gastric injury., (© 2020 Société Française de Pharmacologie et de Thérapeutique.)

The l-type amino acid transporter 1 (LAT1, SLC7A5) imports dietary amino acids and amino acid drugs (e. g., l-DOPA) into the brain, and plays a role in cancer metabolism. Though there have been numerous reports of LAT1-targeted amino acid-drug conjugates (prodrugs), identifying the structural determinants to enhance substrate activity has been challenging. In this work, we investigated the position and orientation of a carbonyl group in linking hydrophobic moieties including the anti-inflammatory drug ketoprofen to l-tyrosine and l-phenylalanine. We found that esters of meta-carboxyl l-phenylalanine had better LAT1 transport rates than the corresponding acylated l-tyrosine analogues. However, as the size of the hydrophobic moiety increased, we observed a decrease in LAT1 transport rate with a concomitant increase in potency of inhibition. Our results have important implications for designing amino acid prodrugs that target LAT1 at the blood-brain barrier or on cancer cells., (© 2020 Wiley-VCH GmbH.)

Background: Cancer Stem Cells (CSCs) play an important role in various stages of cancer development, advancement, and therapy resistance. Ketoprofen-RGD has been revealed to act as an anti-cancer agent against some tumors., Objective: We aimed to explore the effects of a novel Ketoprofen-RGD compound on the suppression of Breast Cancer Stem-like Cells (BCSCs) and their parental cells., Methods: Mammospheres were developed from MCF-7 cells and assessed by CSC surface markers through flowcytometry. The anti-proliferative and pro-apoptotic activities of Ketoprofen-RGD were measured by MTS assay and flowcytometry. The expression levels of stemness markers and JAK2/STAT proteins were measured by quantitative Real Time-PCR (qRT-PCR) and western blotting, respectively. Intracellular Reactive Oxygen Species (ROS) was measured using a cell permeable, oxidant-sensitive fluorescence probe (carboxy-H2DCFDA)., Results: Ketoprofen-RGD significantly reduced the mammosphere formation rate and the expression of three out of six stemness markers and remarkably decreased viability and induced apoptosis of spheroidal and parental cells compared to controls. Further experiments using CD95L, as a death ligand, and ZB4 antibody, as an extrinsic apoptotic pathway blocker, showed that Ketoprofen-RGD induced intrinsic pathway, suggesting a mechanism by which Ketoprofen-RGD triggers apoptosis. ROS production was also another way to induce apoptosis. Results of western blot analysis also revealed a marked diminish in the phosphorylation of JAK2 and STAT proteins., Conclusion: Our study, for the first time, elucidated an anti-BCSC activity for Ketoprofen-RGD via declining stemness markers, inducing toxicity, and apoptosis in these cells and parental cells. These findings may suggest this compound as a promising anti-breast cancer., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Racemic ketoprofen (RS-KP) and its enantiomer, dexketoprofen (S(+)-KP) are widely used non-steroidal anti-inflammatory drugs (NSAIDs), and commonly detected in the aquatic environment. The present study has evaluated the toxicological effects of RS-KP and S(+)-KP on biotransformation and oxidative stress responses in gills and liver of Atlantic salmon. Fish were exposed for 10 days using different concentrations of RS-KP (1, 10 and 100 μg/L) and S(+)-KP (0.5, 5 and 50 μg/L). Biotransformation and oxidative stress responses were analysed at both transcript and functional levels. In the gills, significant inhibitory effect at transcriptional and enzymatic levels were observed for biotransformation and oxidative stress responses. On the contrary, biotransformation responses were significantly increased at transcriptional and translational levels in the liver, while the associated enzymatic activities did not parallel this trend and were inhibited and further demonstrated by principal component analysis (PCA). Our findings showed that both compounds produced comparable toxicological effects, by producing organ-specific effect differences. RS-KP and S(+)-KP did not bioaccumulate in fish muscle, either due to rapid metabolism or excretion as a result of their hydrophobic properties. Interestingly, the inhibitory effects observed in the gills suggest that these drugs may not undergo first pass metabolism, that might result to downstream differences in toxicological outcomes., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Aims: The covalent linking of nonsteroidal anti-inflammatory drugs to a hydrogen sulfide (H 2 S)-releasing moiety has been shown to dramatically reduce gastrointestinal (GI) damage and bleeding, as well as increase anti-inflammatory and analgesic potency. We have tested the hypothesis that an H 2 S-releasing derivative of ketoprofen (ATB-352) would exhibit enhanced efficacy without significant GI damage in a mouse model of allodynia/hyperalgesia. Results: ATB-352 was significantly more potent and effective as an analgesic than ketoprofen and did not elicit GI damage. Pretreatment with an antagonist of the CB1 cannabinoid receptor (AM251) significantly reduced the analgesic effects of ATB-352. The CB1 antagonist exacerbated GI damage when coadministered with ketoprofen, but GI damage was not induced by the combination of ATB-352 and the CB1 antagonist. In vitro , ATB-352 was substantially more potent than ketoprofen as an inhibitor of fatty acid amide hydrolase, consistent with a contribution of endogenous cannabinoids to the analgesic effects of this drug. Blood anandamide levels were significantly depressed by ketoprofen, but remained unchanged after treatment with ATB-352. Innovation: Ketoprofen is a potent analgesic, but its clinical use, even in the short term, is significantly limited by its propensity to cause significant ulceration and bleeding in the GI tract. Covalently linking an H 2 S-releasing moiety to ketoprofen profoundly reduces the GI toxicity of the drug, while boosting analgesic effectiveness. Conclusion: This study demonstrates a marked enhancement of the potency and effectiveness of ATB-352, an H 2 S-releasing derivative of ketoprofen, in part, through the involvement of the endogenous cannabinoid system. This may have significant advantages for the control and management of pain, such as in a postoperative setting.

During inflammation of the mammary gland, the blood-milk barrier, which is predominantly composed of mammary epithelial cells, loses its integrity and gradients between blood and milk cannot be maintained. Nonsteroidal anti-inflammatory drugs (NSAID) are commonly used systemically in combination with local administration of antimicrobials in mastitis treatments of dairy cows to improve the well-being of the cow during the disease. However, the knowledge about their effects on the blood-milk barrier is low. This study aimed to investigate effects of different NSAID, with different selectivity of cyclooxygenase-inhibition, on the transepithelial electrical resistance (TEER) and capacitance, cell viability, and expression of tumor necrosis factor α of bovine mammary epithelial barriers in vitro. Primary mammary epithelial cells of 3 different cows were challenged with lipopolysaccharide (LPS) from Escherichia coli with or without addition of ketoprofen (1.25 mg/mL or 4 mM), flunixin meglumine (1.0 mg/mL or 4 mM), meloxicam (0.25 mg/mL, 0.75 mg/mL, or 4 mM), diclofenac (0.75 mg/mL or 4 mM) or celecoxib (0.05 mg/mL) for 6 h. Concentrations were adapted to comparable relations of the recommended dosage for systemic application. Additionally, a similar molar concentration of all NSAID was used. Lipopolysaccharide with or without NSAID induced a decrease in TEER within 5 h, which returned to control level within 14 h. Viability of cells challenged with LPS only was not affected. However, the cell viability was decreased with increasing concentrations of NSAID and this effect was amplified with simultaneous LPS challenge. Ketoprofen at both dosages, flunixin meglumine at 1.0 mg/mL, and meloxicam at 0.75 mg/mL accelerated the recovery of TEER in comparison to LPS only (return to control level within 9 h). The comparison of NSAID effects at the same molecular quantity of 4 mM showed different effect on the barrier in which ketoprofen accelerated the recovery after LPS-induced barrier opening, whereas meloxicam and diclofenac slowed down the recovery (return to control level after 24 h). In conclusion, NSAID do not prevent the mammary epithelial barrier opening by LPS; however, ketoprofen, flunixin meglumine, and meloxicam obviously support the re-establishment of the barrier integrity. Used in mastitis therapy at an optimized dosage the tested NSAID would likely support the recovery of milk composition. However, an overdose of NSAID would likely cause tissue irritation and in turn, a delayed recovery of the barrier permeability., (Copyright © 2020 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

Ketoprofen is a widely used NSAID which incurs gastric mucosal damage. The high mobility group Box 1 (HMGB1) protein is a DNA-binding protein which exerts robust inflammatory actions, however, its role in ketoprofen-induced gastric damage has not been explored. Additionally, no previous studies have linked HMGB1/RAGE/NF-κB, DJ-1/Nrf2/HO-1 and PI3K/mTOR pathways in ketoprofen-induced gastropathy. The current work aimed to explore the potential of morin, a flavonoid with marked antioxidant/anti-inflammatory actions, to protect against ketoprofen-evoked gastric damage. Moreover, the underlying mechanisms, including the impact of morin on HMGB1/RAGE/NF-κB, DJ-1/Nrf2/HO-1 and PI3K/mTOR pathways were addressed. Immunoblotting and ELISA were used to examine the expression of target signals. Morin (50 mg/kg, p. o.) attenuated the severity of gastric injury via lowering of ulceration/hemorrhage and macroscopic damage scores. Meanwhile, it attenuated the histopathologic aberrations/damage scores. In the context of inflammation, morin suppressed TNF-α and myeloperoxidase levels and enhanced IL-10. Furthermore, it inhibited HMGB1/RAGE/NF-κB pathway through downregulating HMGB1, RAGE and phospho-NF-κBp65 protein expression. Morin successfully inhibited gastric mucosal oxidative stress through lowering of lipid peroxides and boosting of reduced glutathione, glutathione peroxidase and total antioxidant capacity. It also boosted DJ-1/Nrf2/HO-1 pathway via upregulating DJ-1, Nrf2 and HO-1 protein expression. Additionally, morin counteracted the apoptotic events by downregulating the proapoptotic Bax and Bax/Bcl-2 ratio and augmenting the PI3K/mTOR pathway through upregulating PI3Kp110α and phospho-mTOR protein expression. In conclusion, the current study demonstrates, for the first time, that morin shows a promise for the management of ketoprofen-induced mucosal insult through targeting of HMGB1/RAGE/NF-κB, DJ-1/Nrf2/HO-1 and PI3K/mTOR pathways., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The progressive consumption growth of non-steroidal anti-inflammatory drugs (NSAIDs) has progressively raised the attention toward the gastrointestinal, renal, and cardiovascular toxicity. Increased risk of cardiovascular diseases was strictly associated with the usage of COX-2 selective NSAIDs. Other studies allowed to clarify that the cardiovascular risk is not limited to COX-2 selective but also extended to non-selective NSAIDs, such as Diclofenac and Ketoprofen. To date, although a less favorable cardiovascular risk profile for Diclofenac as compared to Ketoprofen is reported, the mechanisms through which NSAIDs cause adverse cardiovascular events are not entirely understood. The present study aimed to evaluate the effects of Ketoprofen in comparison with Diclofenac in immortalized human cardiomyocytes. The results obtained highlight the dose-dependent cardiotoxicity of Diclofenac compared to Ketoprofen. Despite both drugs induce the increase in ROS production, decrease of mitochondrial membrane potential, and proteasome activity modulation, only Diclofenac exposure shows a marked alteration of these intracellular parameters, leading to cell death. Noteworthy, Diclofenac decreases the proteasome 26S DC and this scenario may be dependent on the intracellular overload of oxidized proteins. The data support the hypothesis that immortalized human cardiomyocytes exposed to Ketoprofen are subjected to tolerable stress events, conversely Diclofenac exposition triggers cell death.

Managing severe acute nociceptive pain in buprenorphine-maintained individuals for opioid use disorder management is challenging owing to the high affinity and very slow dissociation of buprenorphine from μ-opioid receptors that hinders the use of full agonist opioid analgesics. In a translational approach, the aim of this study was to use an animal setting to investigate the effects of a chronic high dose of buprenorphine treatment on nociceptive thresholds before and after applying a severe acute nociceptive traumatic surgery stimulus and to screen postoperative pharmacological analgesic strategies. A chronic treatment of mice with a high dose of buprenorphine (BUP HD, 2 × 200 μg/kg/day; i.p.) revealed significant mechanical allodynia. One and two days after having discontinued buprenorphine administration and having induced a severe nociceptive acute pain by a closed tibial fracture, acute administration of morphine at a dose which has analgesic effects in absence of pretreatment (4.5 mg/kg; i.p.), was ineffective to reduce pain in the BUP HD group. However, mimicking multimodal analgesia strategy used in human postoperative context, the combination of morphine (administered at the same dose) with a NMDA receptor antagonist (ketamine) or an NSAID (ketoprofen) produced antinociceptive responses in these animals. The mouse model of closed tibial fracture could be useful to identify analgesic strategies of postoperative pain for patients with chronic exposure to opioids and suffering from hyperalgesia., Competing Interests: Declaration of competing interest None., (Copyright © 2019. Published by Elsevier B.V.)

We have developed a co-assembled nanosystem based on fenofibrate and ketoprofen by tactfully utilizing their simultaneous benzophenone interaction, which greatly enhances the bioavailability of fenofibrate and plays a role in the dual-targeted treatment of NAFLD by reducing hepatic lipid accumulation and inflammatory responses.

The nonsteroidal anti-inflammatory drug (NSAID) ketoprofen is commonly used as a pain reliever, but its role in mediating the energy metabolism in lipids is unclear. This paper reports for the first time the critical role of ketoprofen in ameliorating white fat browning and alleviating diet-induced obesity. The effects of ketoprofen were evaluated using C57BL/6 mice fed a high fat diet and the expression levels of the target genes and proteins in the lipid metabolisms were determined by quantitative real-time PCR, immunoblot analysis, histopathology study, immunofluorescence, and molecular docking techniques. Ketoprofen induced browning in cultured 3T3-L1 white adipocytes and inguinal white adipose tissue by increasing the expression of core fat browning marker proteins as well as beige-specific genes through COX-2 activation. Ketoprofen also led to the robust activation of brown adipocytes and enhanced brown fat adipogenesis. In addition, ketoprofen elevated lipolysis, thereby increasing mitochondrial biogenesis resulting in higher fat oxidation. Furthermore, the molecular docking and mechanistic study demonstrated the recruitment of beige fat by ketoprofen via mTORC1-p38-mediated activation of the COX-2 pathway. Overall, these results indicate the unique role of ketoprofen in body weight reduction by enhancing thermogenesis, suggesting its therapeutic potential in the treatment of obesity.

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., (Copyright © 2020 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

A novel composite hydrogel was prepared as a dual drug delivery carrier. Poly(hydroxybutyrate-co-hydroxyvalerate) (PHBV) microparticles were prepared to encapsulate simultaneously ketoprofen and mupirocin, as hydrophobic drug models. These microparticles were embedded in a physically crosslinked hydrogel of κ-carrageenan/locust bean gum. This composite hydrogel showed for both drugs a slower release than the obtained release from microparticles and hydrogel separately. The release of both drugs was observed during a period of 7 days at 37 °C. Different kinetic models were analyzed and the results indicated the best fitting to a Higuchi model suggesting that the release was mostly controlled by diffusion. Also, the drug loaded microparticles were spherical with average mean particle size of 1.0 μm, mesoporous, and distributed homogeneously in the hydrogel. The composite hydrogel showed a thermosensitive swelling behavior reaching 183% of swelling ratio at 37 °C. The composite hydrogel showed the elastic component to be higher than the viscous component, indicating characteristics of a strong hydrogel. The biocompatibility was evaluated with in vitro cytotoxicity assays and the results indicated that this composite hydrogel could be considered as a potential biomaterial for dual drug delivery, mainly for wound healing applications., Competing Interests: Declaration of competing interest None., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Angiogenesis is a fundamental process of wound healing, embryogenesis etc. but occurs in cancer and chronic inflammation pathologically. HET-CAM assay is a useful, well established and animal alternative test to screen anti-inflammatory potentials of pharmaceutical products as well as nano-formulations. Dexketoprofen trometamol (DT) belongs to the nonsteroidal anti-inflammatory drug (NSAID) group which is a rapidly acting analgesic ingredient. Because DT has a short half-life, high and frequent dosing is used in treatment. The need of design and producing a new oral prolonged-release dosage form containing DT is the major aim of the study with low dose and low side effects. Chitosan (CS) has been widely used in the pharmaceutical area because of its favorable biological properties. In this study, DT loaded CS nanoparticles (CS-NPs) were produced by spray drying method for oral drug delivery. Structures of CS-NPs were elucidated by particle size, zeta potential, SEM, DSC, FT-IR and 1 H NMR. High encapsulation efficiency was obtained (73-84%) for the prepared formulations. In vitro release was examined in pH 1.2 buffer and pH 6.8 buffer. DT-loaded CS-NPs showed prolonged release, particularly at pH 6.8. Weibull kinetic model was found to fit best to DT release from CS-NPs in both release medium. The anti-inflammatory activity of optimum formulation (M-DT) was examined using the in vivo HET-CAM assay. The anti-inflammatory activity results indicated that M-DT coded NPs formulation showed significantly good anti-inflammatory potential with closer inhibition value to the standard anti-inflammatory DT at one fifth lower dosage. According to the proposed method and results it can be successfully applicable to the NP preparation containing DT and it could be concluded that DT loaded CS-NPs seem to be a promising prolonged release drug delivery system for oral administration with low dose and high efficiency., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: The aim of the present work is to examine the effects of treatment with sertraline with and without ketoprofen on serum levels of zinc and copper in association with immune-inflammatory biomarkers in drug-naïve major depressed patients. Methods: We measured serum zinc and copper, interleukin (IL)-1β, IL-4, IL-6, IL-18, interferon-γ, and transforming growth factor-β1 in 40 controls and 133 depressed patients. The clinical efficacy of the treatment was measured using the Beck Depression Inventory-II (BDI-II) at baseline and 8 weeks later. Results: We found significantly reduced serum zinc and copper in association with upregulation of all cytokines, indicating activation of the immune-inflammatory responses system (IRS) and the compensatory immune regulatory system (CIRS). Treatment with sertraline significantly increased zinc and decreased copper. During treatment, there was a significant inverse association between serum zinc and immune activation. The improvement in the BDI-II during treatment was significantly associated with increments in serum zinc coupled with attenuation of the IRS/CIRS. Conclusions: Lower zinc is a hallmark of depression, while increments in serum zinc and attenuation of the immune-inflammatory response during treatment appear to play a role in the clinical efficacy of sertraline.

Various animal models, especially rodents, are used to study pain, due to the difficulty of studying it in humans. Many drugs that produce analgesia have been studied and there is evidence among which NSAIDs deserve to be highlighted. Dexketoprofen (DEX) provides a broad antinociceptive profile in different types of pain; therefore, this study was designed to evaluate the profile of antinociceptive potency in mice. Analgesic activity was evaluated using the acetic acid abdominal constriction test (writhing test), a chemical model of visceral pain. Dose-response curves for i.p. DEX administration (1, 3, 10, 30 and 100 mg/kg), using at least six mice in each of at least five doses, was obtained before and 30 min after pre-treatment with different pharmacological agents. Pretreatment of the mice with opioid receptor antagonists was not effective; however, the serotonin receptor antagonist and nitric oxide synthase inhibitor produce a significant increase in DEX-induced antinociception. The data from the present study shows that DEX produces antinociception in the chemical twisting test of mice, which is explained with difficulty by the simple inhibition of COX. This effect appears to be mediated by other mechanisms in which the contribution of the NO and 5-HT pathways has an important effect on DEXinduced antinociception.