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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.)

Objectives: To define likely targets (i.e. glia) and protocols (analgesic combinations) to improve postoperative pain outcomes and reduce chronic pain after surgery. Specifically, to assess the antihyperalgesic effects of the dexketoprofen : tramadol (DEX : TRM) combination, exploring the implication of glial activation., Methods: In a mouse model of postincisional pain, we evaluated mechanical nociceptive thresholds (Von Frey) for 21 days postoperatively. We assessed DEX and TRM alone and combined (1 : 1 ratio) on postoperative hyperalgesia (POH, day 1) and delayed latent pain sensitisation (substantiated by a naloxone challenge; PS, day 21). The interactions were analysed using isobolograms, and concomitant changes in spinal glial cell activation were measured., Key Findings: On day 1, DEX completely blocked POH, whereas TRM induced 32% inhibition. TRM, but not DEX, partially (47%) protected against PS, at 21 days. Co-administration of DEX : TRM (1 : 1 ratio) showed additivity for antihyperalgesia. Both drugs and their combination totally inhibited surgery-induced microglia activation on day 1, but had no effect on surgery-induced astrocyte activation (1 day) or re-activation after naloxone (21 days)., Conclusions: The DEX : TRM combination could have clinical advantages: a complete prevention of POH after surgery, together with a substantial (48%) inhibition of the development of PS by TRM. Microglia, but not astrocyte activation, could play a relevant role in the development of postoperative pain hypersensitivity., (© 2016 Royal Pharmaceutical Society.)

Background: Ketoprofen (KP) is widely used as a topical nonsteroidal anti-inflammatory drug that inhibits prostaglandin (PG) biosynthesis. As PGE(2) upregulates the antigen-presenting activity of Langerhans cells (LCs), i.e. migration to lymph nodes and expression of immunocompetent molecules, modulation of LC functions resulting from topical application of KP is an issue to be clarified., Objectives: To investigate the in vivo effect of KP application to the skin and the in vitro effect of KP addition to the culture on the antigen-presenting ability of murine LCs. Methods Ears of BALB/c mice were painted with picryl chloride (PCl) hapten, KP or both. An immunofluorescence study of epidermal sheets and a flow cytometric analysis of epidermal cell suspensions from the treated ears were performed., Results: PCl altered the morphology of LCs and reduced their number, and simultaneous application of 10% KP maintained LC morphology and number. KP at 5% or 10% clearly decreased the PCl-augmented expression of major histocompatibility complex class II and CD86 on LCs. In cultivation of freshly isolated epidermal cells, 5 mmol L(-1) KP inhibited the culture-promoted expression of these molecules on LCs, whereas 100 micromol L(-1) indomethacin was not inhibitory. The further addition of PGE(2) to the KP-containing epidermal cell culture did not restore the expression of these molecules. Moreover, topical application of 10% KP to the sensitizing sites suppressed the development of contact hypersensitivity to PCl., Conclusions: KP may have the potential to inhibit the antigen-presenting ability of LCs, in a PGE(2)-independent manner.

The present study investigated the cellular uptake mechanism of non-steroidal anti-inflammatory drugs (NSAIDs) in Caco-2 cells. Diflunisal, diclofenac, ketoprofen and naproxen exhibited a strong inhibition effect on the cellular uptake of [14C]-benzoic acid in Caco-2 cells with IC50 values of 0.05-0.44 mM. The inhibition of naproxen and ketoprofen against the membrane transport of [14C]-benzoic acid appeared to be competitive, with Ki values of 0.22 and 0.38 mM, respectively. The membrane permeability of naproxen and ketoprofen was concentration dependent, implying that the cellular uptake pathway of ketoprofen and naproxen was saturable at the higher concentration. Furthermore, the cellular accumulation of ketoprofen was significantly reduced in the presence of benzoic acid and L-lactic acid, two known substrates of monocarboxylic acid transporter 1 (MCT1). These results suggest that MCT1 contributes at least in part to the carrier-mediated transport of NSAIDs containing a carboxylic acid moiety across the apical membrane in Caco-2 cells.

This study aims to investigate the effect of commonly used non-steroidal anti-inflammatory drugs (NSAIDs) on the pharmacokinetics and the renal elimination of aciclovir in rats. Pharmacokinetic parameters were determined following an intravenous administration of aciclovir (5 mg kg(-1)) to rats in the presence and absence of ketoprofen or naproxen (25 mg kg(-1)). Compared with the control (given aciclovir alone), pre-treatment with ketoprofen or naproxen 30 min before aciclovir administration significantly altered the pharmacokinetics of aciclovir. Renal clearance of aciclovir was reduced by approximately two fold in the presence of ketoprofen or naproxen. Consequently, the systemic exposure (AUC) to aciclovir in the rats pre-treated with ketoprofen or naproxen was significantly (P < 0.05) higher than that from the control group given aciclovir alone. Furthermore, the mean terminal plasma half-life of aciclovir was enhanced by 4-5 fold by pre-treatment with ketoprofen or naproxen. These results suggest that NSAIDs, such as ketoprofen and naproxen, are effective in altering the pharmacokinetics of aciclovir by inhibiting the organic anion transporter-mediated tubular secretion of aciclovir. Therefore, concomitant use of ketoprofen or naproxen with aciclovir should require close monitoring for clinical consequence of potential drug interaction.

Aims: In patients with chronic heart failure (CHF), an overactive muscle ergoreceptor reflex (chemo-afferents sensitive to the products of muscle work) is thought to play an important role in the origin of dyspnoea. We sought to investigate whether raised intra-muscular prostaglandins (PG) and bradykinin, as estimated by levels within the venous effluent from exercising skeletal muscle may be involved in symptom generation through the stimulation of the ergoreflex., Methods and Results: In 19 stable CHF patients and 12 normal controls, cardiopulmonary exercise capacity (peak O2 consumption [peak VO2]) and the ergoreflex contribution to ventilation (post-handgrip regional circulatory occlusion method) were measured. Venous resting and exercise plasma PGE2, PGF1alpha and bradykinin concentrations were assessed. Eleven patients on angiotensin converting enzyme inhibitors and 10 controls were challenged with ketoprofen infusion (to inhibit PG synthesis and bradykinin activity). Patients vs. controls presented lower exercise tolerance (peak VO2 15.9+/-0.7 vs. 33.0+/-1.3 mL/kg/min), an increased ventilatory response to exercise (VE/VCO2 slope 43+/-2 vs. 27+/-0.9) (p<0.0001 for all comparisons). The overactive ergoreflex of CHF (5.1+/-1.3 vs. 0.1+/-0.3 L/min) was significantly related to the increase in PGF1alpha (adjusted R2=0.34, p<0.005) but not PGE2 (adjusted R2=0.16, p>0.05). The increased PG and bradykinin productions both at rest and during exercise in CHF were attenuated after ketoprofen infusion, associated with ergoreflex reduction (-5.1+/-2.2 L/min, p<0.05 vs. saline)., Conclusion: In CHF, overactive muscle ergoreflex is associated with elevated blood concentration of PG and bradykinin. Modulation of these metabolite concentrations acutely reduces the muscle ergoreflex activity, which suggests a causative role in triggering and/or mediating the ergoreflex response.

Non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to inhibit the renal tubular secretion of methotrexate. However, the relative contribution of the active S- and inactive R-enantiomers is unknown. This study examined the effect of racemic ketoprofen and its enantiomers on the renal disposition of methotrexate in the isolated perfused rat kidney (IPK). Nineteen kidneys were divided between a control and three treatment groups. Controls were perfused with methotrexate alone (25 micrograms mL-1, n = 5) over three 30-min periods. Treatment groups were perfused with methotrexate (25 micrograms m-1) for the first period, followed by a second period of methotrexate (25 micrograms mL-1) plus R- (n = 5), S- (n = 5) or RS-ketoprofen (n = 4) at 25 micrograms mL-1, and a third period of methotrexate (25 micrograms mL-1) plus R-, S- or RS-ketoprofen (50 micrograms mL-1). Perfusate and urine were collected over 10-min intervals. Methotrexate was measured by HPLC and its binding in perfusate by ultrafiltration. The clearance ratio (CR) for methotrexate was obtained by dividing the renal clearance by the product of its fraction unbound and the glomerular filtration rate. During control experiments, there was no significant change in the CR over 90 min. R-, S- and RS-ketoprofen at 50 micrograms mL-1 reduced the CR of methotrexate significantly, but there was no difference between the three groups. While the enantiomers of ketoprofen reduced the renal excretion of methotrexate, the interaction was not enantioselective.

The analgesic effects of intranasal delivery of leucine enkephalin (Leu-Enk) and its synthetic analogue [D-ala(2)]-leucine enkephalinamide (YAGFL) with or without enzyme inhibitors and/or absorption enhancers were investigated using the acetic acid-induced writhing test in mice. The analgesic activity was significantly affected by the time delay after the administration of Leu-Enk; the inhibition rates for the groups administered with acetic acid 5 min and 30 min after the administration of Leu-Enk were 56.40 +/- 8.54 and 17.98 +/- 7.07%, respectively. The addition of enzyme inhibitors and absorption enhancers markedly increased the inhibition rate of Leu-Enk and YAGFL; their inhibition rates were about four times and twice those without any enzyme inhibitor or absorption enhancer, respectively. The enzyme inhibitors and absorption enhancers that produced the highest inhibition rates of Leu-Enk and YAGFL were azelaic acid (1%), thimerosal (0.5 mM, TM), ethylenediamine-tetraacetic acid (5 mM, EDTA) and L-alpha-lysophosphatidylcholine (0.5%, LPC), and TM (0.5 mM), EDTA (5 mM), LPC (0.5%) and povidone (5%), respectively. The ED50 value of both enkephalins was also determined and found to be about 13 microg kg(-1), which is 850 and 60 times more potent than literature values for ketoprofen and morphine, respectively. Based on these results it was concluded that Leu-Enk or YAGFL could exert very high analgesic activity when administered nasally with a combination of inhibitors and absorption enhancers as compared with other analgesics.

It is known that non-steroidal anti-inflammatory drugs (NSAIDs) increase intestinal permeability. Increased intestinal permeability is believed to result from the opening of tight junctions because of NSAID-induced reduction of prostaglandin synthesis and/or energy-depletion. In this study, ketoprofen-induced changes in intestinal permeability were evaluated by measuring tissue electrical parameters, namely tissue electrical resistance (TER), short circuit current (I(sc)) and transepithelial potential difference (PD), and the transport of a paracellular marker, fluorescein, across rat jejunum in-vitro. Ketoprofen, added to the mucosal side of the tissue, decreased TER and increased fluorescein transport in a concentration-dependent manner. I(sc) values and the active transport of D-glucose were not affected at ketoprofen concentrations of less than 5 mM. Higher ketoprofen concentrations decreased I(sc) values and diminished active transport of D-glucose, while transport of fluorescein increased markedly. Similar effects on intestinal properties were observed when the metabolic inhibitor sodium azide was added to the incubation medium. The results of this study suggest that the increased intestinal permeability observed at lower ketoprofen concentrations (< 5 mM) is most probably a consequence of reduced prostaglandin tight junction control, whereas at higher concentrations, ATP depletion caused by ketoprofen seems to be the major mechanism for increased intestinal permeability.

Zidovudine (AZT) is widely used for the management of human immunodeficiency virus (HIV) infections. Non-steroidal anti-inflammatory drugs (NSAIDs) are often used for relief of non-specific fever and musculoskeletal pain in patients with HIV including those with AZT-induced myopathy. The effects of single oral doses of diclofenac and ketoprofen on AZT pharmacokinetics were studied in rats. The influence of AZT on the pharmacokinetics of diclofenac or ketoprofen was also investigated. The administration of diclofenac (3 mgkg(-1)) or ketoprofen (1 mgkg(-1)) did not significantly alter AZT (1.5 mgkg(-1)) pharmacokinetic parameters compared with administering AZT alone. There was no significant difference between the pharmacokinetics of ketoprofen given alone or in combination with AZT. However, the co-administration of AZT with diclofenac affected the pharmacokinetics of diclofenac. The Cmax of diclofenac was significantly (P < 0.05) increased by approximately threefold within a shorter time (0.6+/-0.2 h). The mean AUC value for diclofenac was increased from 2.29 to 5.04 microg mL(-1) h in the presence of AZT. AZT decreased the mean apparent clearance of diclofenac by 54%. The increase in diclofenac concentrations could be attributed to a decrease in its clearance or delay in its metabolite formation due to a competitive effect. The results show that diclofenac and AZT should be given with caution because of the possible increase of diclofenac toxicity, in anticipation of follow-up clinical studies to examine this finding in man. AZT and ketoprofen could be a safe combination since no pharmacokinetic interaction was detected.

Prostaglandin E2 (PGE2) has been implicated in postburn immunosuppression, which is responsible for septic complications. In the present work, seven non-steroidal anti-inflammatory drugs (NSAIDs), differing by their capacity to inhibit the cyclooxygenase pathway, were compared for their ability to restore T lymphocyte proliferative responses evaluated 4 days after thermal injury in rats. Salicylic acid, 5-aminosalicylic acid, and niflumic acid, given daily, fully restored spleen cell responses to concanavalin A (Con A) and phytohemagglutinin. These drugs were active only at doses that were below the anti-inflammatory doses and did not modify normal spleen cell responses. In these conditions, indomethacin slightly restored lymphocyte reactivity, whereas acetylsalicylic acid, ketoprofen, and piroxicam were ineffective. PGE2 production by Con A-stimulated spleen cells from untreated burned rats and after treatment with niflumic acid or 5-aminosalicylic acid did not correlate with the intensity of the proliferative response. Indomethacin, niflumic acid, and 5-aminosalicylic acid were added in vitro to spleen cells from normal and burned rats, at concentrations from 10(-7) to 10(-4) M. PGE2 production was strongly depressed by indomethacin and niflumic acid and not modified by 5-aminosalicylic acid. The proliferative response of normal spleen cells was depressed in a concentration-dependent manner by niflumic acid and slightly inhibited at the highest concentrations of indomethacin. In contrast, indomethacin concentration dependently restored the burn-impaired proliferative response, whereas niflumic acid further depressed it and 5-aminosalicylic acid had no effect. These results demonstrate that only some NSAIDs are able to restore T lymphocyte reactivity impaired after thermal injury and that this property is not related to inhibition of PGE2 production.

The effects of ketoprofen on frusemide-induced diuresis, natriuresis and renin release were studied in 12 healthy male volunteers. Each received frusemide 40 mg once daily with either ketoprofen 100 mg twice daily or placebo for two periods of 5 days separated by a treatment-free period according to a randomized, double-blind, cross-over study design. Ketoprofen significantly reduced frusemide-induced diuresis on Day 1 but not on Day 5 of treatment. The natriuresis induced by frusemide on Day 1 or Day 5 of treatment did not differ significantly whether ketoprofen or placebo was administered, although the mean urinary sodium excretion values were consistently lower following ketoprofen. Ketoprofen did not affect the kaliuretic response to frusemide on Day 1 or Day 5 of treatment. The increase in plasma renin activity after frusemide was inhibited by ketoprofen on both Day 1 and Day 5. These results suggest that ketoprofen reduces the diuresis and renin release induced by frusemide, but that the reduction in diuretic response may become less important after their repeated coadministration.

Intravenously co-administered ketoprofen decreased the plasma concentration of sulpha-dimethoxine (SDM) after intravenous bolus administration to fast acetylator rabbits, and significantly increased the total body clearance (CLtot) and steady-state volume of distribution (Vdss) of SDM. On the other hand, ketoprofen had little effect on the plasma concentration of SDM in slow acetylator rabbits. When SDM was intravenously administered in combination with ketoprofen, an increase in the plasma concentration of N4-acetylsulphadimethoxine, a major metabolite of SDM that strongly displaces SDM from its binding sites, was observed in all rabbits, but the increase was much larger in fast acetylators. We conclude that the acetylation capacity for SDM is a factor determining the pharmacokinetic interaction between SDM and ketoprofen in rabbits.

We investigated the in vivo effects of acetylsalicylic acid, diclofenac, indomethacin, ibuprofen, and ketoprofen on the concentrations of various blood constituents. Total protein, glucose, calcium, and inorganic phosphate were not significantly affected by any of these drugs. Ketoprofen had no definite influence on any constituent. Acetylsalicylic acid induced an increase in cholesterol, triglyceride, and iron; albumin, uric acid, and creatinine decreased with ibuprofen therapy. Urea nitrogen increased in patients treated with diclofenac or indomethacin. Our protocol for the study of in vivo drug effects is discussed.