Enhancing ketoprofen's solubility and anti-inflammatory efficacy with safe methyl-ß-cyclodextrin complexation.

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.

Effect of post-mating administration of ketoprofen on serum progesterone concentration and fertility in Akkaraman ewes.

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.

Ketoprofen promotes the conjugative transfer of antibiotic resistance among antibiotic resistant bacteria in natural aqueous environments.

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.

Multiresponsive 4D Printable Hydrogels with Anti-Inflammatory Properties.

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 (EG3SA). As a result, smart P[NIPAMx-co-MAAy-co-(EG3SA)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 (H2O2). 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[NIPAM80-co-MAA15-co-(EG3SA)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.

Carrageenan-xanthan nanocomposite film with improved bioadhesion and permeation profile in human skin: A cutaneous-friendly platform for ketoprofen local delivery.

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.

Evaluation of the antimicrobial efficacy of different nonsteroidal anti-inflammatory drugs alone or in combination with calcium hydroxide intracanal medicament: an in vitro study.

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.

Ketoprofen attenuates Las/Rhl quorum-sensing (QS) systems of Pseudomonas aeruginosa: molecular and docking studies.

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.

Clinical use of ketoprofen lysine salt: a reappraisal in adolescents with acute respiratory infections.

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 lysine salt treatment in adolescents with acute upper respiratory infections: a primary-care experience.

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.

Ketoprofen exposure perturbs nitrogen assimilation and ATP synthesis in rice roots: An integrated metabolome and microbiome analysis.

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.

Environmental Risk Assessment of Drugs in Tropical Freshwaters Using Ceriodaphnia silvestrii as Test Organism.

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 (EC50 = 69.15 mg L- 1) < caffeine (EC50 = 45.94 mg L- 1) < paracetamol (EC50 = 34.49 mg L- 1) < ketoprofen (EC50 = 24.84 mg L- 1) < diclofenac sodium salt (EC50 = 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).

Comparison of the effects of ketoprofen and ketoprofen lysine salt on the Wistar rats' nervous system, kidneys and liver after ethyl alcohol intoxication.

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.

Fluorescent sensing of non-steroidal anti-inflammatory drugs naproxen and ketoprofen by dansylated squaramide-based receptors.

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 CH3CN/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, 1H-NMR spectroscopy in DMSO-d6/0.5% water solution demonstrated that the four receptors interact with the considered guests via H-bonds.

Ketoprofen suppresses triple negative breast cancer cell growth by inducing apoptosis and inhibiting autophagy.

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.

Whole-Body PET Imaging in Humans Shows That 11C-PS13 Is Selective for Cyclooxygenase-1 and Can Measure the In Vivo Potency of Nonsteroidal Antiinflammatory Drugs.

Both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) convert arachidonic acid to prostaglandin H2, which has proinflammatory effects. The recently developed PET radioligand 11C-PS13 has excellent in vivo selectivity for COX-1 over COX-2 in nonhuman primates. This study sought to evaluate the selectivity of 11C-PS13 binding to COX-1 in humans and assess the utility of 11C-PS13 to measure the in vivo potency of nonsteroidal antiinflammatory drugs. Methods: Baseline 11C-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, 11C-PS13 uptake inhibition from blood cells was measured in vitro and ex vivo (i.e., using blood obtained during PET scanning). Results: High 11C-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 11C-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: 11C-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 11C-PS13.

Computer-aided analysis for identification of novel analogues of ketoprofen based on molecular docking, ADMET, drug-likeness and DFT studies for the treatment of inflammation.

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.

An evaluation of ketoprofen as an intranasal anti-inflammatory agent.

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.

Pharmacokinetic/pharmacodynamic modeling of ketoprofen and flunixin at piglet castration and tail-docking.

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.

Plasma proteomic changes in response to surgical trauma and a novel transdermal analgesic treatment in dogs.

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.

Ketoprofen, piroxicam and indomethacin-suppressed quorum sensing and virulence factors in Acinetobacter baumannii.

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.