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At least 19 recordsLinked to original sources
PubMed2000

Opposite effects of flurbiprofen and the nitroxybutyl ester of flurbiprofen on apoptosis in cultured guinea-pig gastric mucous cells.

The nitric oxide (NO)-donating nitroxybutyl ester of flurbiprofen (NO-flurbiprofen), shows reduced gastro-intestinal toxicity relative to flurbiprofen. NO may exert either pro- or anti-apoptotic effects, while non-steroidal anti-inflammatory drugs may induce apoptosis. The aim of the present work was therefore to compare the effects of flurbiprofen and NO-flurbiprofen on apoptosis in guinea-pig gastric mucous cells. Apoptotic activity was assessed by assay of caspase activity and from the fragmentation and condensation of nuclei. Incubation with flurbiprofen for 24 h produced a concentration-dependent induction of apoptosis in cells attached to the culture plate (caspase 3-like activity increased by 257% at 500 microM), while NO-flurbiprofen inhibited basal apoptosis (caspase 3-like activity decreased by 71% at 500 microM). Caspase activity and nuclear fragmentation were substantially increased in cells that had spontaneously detached from the culture plate. NO-flurbiprofen inhibited caspase activity (55% at 500 microM) but not nuclear fragmentation in these detached cells. NO flurbiprofen inhibited the activation of apoptosis by 25 microM C(6)-ceramide in cells attached to the culture plate. Inhibition of caspase activity by NO-flurbiprofen was detectable after 6 h of incubation with intact cells, but by contrast with the NO-donor S-nitrosyl-N-acetyl-penicillamine, was not demonstrable with cell homogenates. Activation of caspase 3-like activity by flurbiprofen was slow (>6 h incubation needed) and was inhibited by cycloheximide. The presence of a nitroxybutyl ester moiety on flurbiprofen prevents the pro-apoptotic activity of the parent compound and may contribute to the reduced gastro-intestinal toxicity of NO-flurbiprofen.

Acid Phosphatase↗
PubMed1995

Efficacy of topical flurbiprofen and indomethacin in preventing pseudophakic cystoid macular edema. Flurbiprofen-CME Study Group I.

We evaluated two topical cyclo-oxygenase inhibitors (COIs), 0.03% flurbiprofen and 1% indomethacin, for their ability to prevent pseudophakic cystoid macular edema (CME). The study was a randomized, double-masked, vehicle-controlled, parallel group, clinical trial for six months at eight sites in Canada and two in Germany. The study population consisted of 681 patients who had extracapsular cataract extraction and posterior chamber lens implantation. Flurbiprofen, indomethacin, or the vehicle was instilled into the eye four times daily for two days preoperatively and three months postoperatively. Results were measured by angiographic and clinical CME at visit 5 (day 21-60) and visit 7 (day 121-240) and by contrast sensitivity and Snellen visual acuity at all five postoperative visits. At visit 5, the incidence of angiographic CME was comparable in the two COI treatment groups (16.8% flurbiprofen, 12.4% indomethacin) and was significantly lower than in the vehicle group (32.2%). The incidence of clinical CME was also significantly lower in the COI-treated groups (10.7% flurbiprofen, 9.6% indomethacin) than in the vehicle group (21.9%). By visit 7, the incidence of angiographic CME had declined to between 4% and 8% and the incidence of clinical CME was less than 2% in all three groups. At visit 5, contrast sensitivity scores were significantly worse in vehicle-treated patients with angiographic CME than in those without CME, and Snellen visual acuity was one line worse in patients with CME. Flurbiprofen-treated patients achieved good Snellen visual acuity (better than 20/40) sooner than vehicle-treated patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Topical↗
PubMed1977

Serum concentrations of flurbiprofen in rheumatoid patients receiving flurbiprofen over long periods of time.

Serum concentrations of flurbiprofen were measured following single oral doses of 50 mg to 200 mg in patients who previously had received flurbiprofen over long periods of time. The apparent elimination half-lives in groups of patients who received different doses were not significantly different from each other nor from the value previously obtained in a group of healthy volunteers given a single oral dose of 50 mg. Areas under serum concentration versus time curves were linearly related to dose over the range of doses examined. The results indicate that the pharmacokinetics of flurbiprofen are not significantly dose-dependent over the range of doses studied and that administration of relatively high doses of flurbiprofen over long periods of time neither induces nor inhibits flurbiprofen metabolism.

Aged↗
PubMed2004

Bioinversion of R-flurbiprofen to S-flurbiprofen at various dose levels in rat, mouse, and monkey.

Information about the potential and extent of bioinversion of chiral drugs in laboratory animal species and humans is critical to the interpretation of preclinical pharm-tox studies with these drugs. Unlike in the dog, guinea pig, and rabbit, in humans the 2-arylpropionic acid (APA) R-flurbiprofen (R-FB) undergoes very little bioinversion to S-flurbiprofen. The primary objective of this research was to identify laboratory animal species with an R- to S-bioinversion profile similar to humans. Detailed evaluations of the pharmacokinetics parameters of R-flurbiprofen in male and female rats and mice, and male nude rats and monkeys demonstrated R- to S-bioinversion of 30% (average) in monkeys, 15-24% in mice, and approximately 4% in rats. To date, no laboratory animal species has been identified with an R-flurbiprofen bioinversion profile identical to humans. However, the rat has a bioinversion profile sufficiently similar to humans to be useful for preclinical.

Animals↗
PubMed1991

Effects of pure enantiomers of flurbiprofen in comparison to racemic flurbiprofen on eicosanoid release from various rat organs ex vivo.

The effects of oral treatment of rats with pure enantiomers of flurbiprofen in comparison to racemic flurbiprofen on ex vivo release of eicosanoids from gastric mucosa, jejunum, lung, brain and clotting whole blood were investigated. With the S(+) enantiomer and the racemate dose-dependent inhibition of release of cyclooxygenase products of arachidonate metabolism in all tissues tested was observed, while release of leukotriene (LT) C4 was inhibited in gastric mucosa, but not in jejunum and lung. On the other hand, the R(-) enantiomer inhibited cyclooxygenase in the various tissues less potently and to a variable degree with no significant effect in the jejunum. The R(-) enantiomer had no effect on LTC4 release from any of the tissues investigated. Furthermore, the effect of a high dose of 25 mg/kg of the S(+) enantiomer on release of cyclooxygenase products from the various tissues was much longer lasting than that of an identical dose of the R(-) enantiomer. Stereoselective pharmacokinetics of the flurbiprofen enantiomers and/or organ specific cyclooxygenase activities could underly these results. The more potent cyclooxygenase inhibition by the S(+) enantiomer correlates with its higher anti-inflammatory activity and gastrointestinal toxicity. On the other hand, both enantiomers have been shown previously to be almost equally effective analgesics. Inhibition of brain cyclooxygenase might contribute to this effect.

Animals↗
PubMed1993

Evaluation of flurbiprofen for prevention of reinfarction and reocclusion after successful thrombolysis or angioplasty in acute myocardial infarction. The Flurbiprofen French Trial.

Thirty-eight coronary care units (CCUs) in France participated in this double-blind, placebo-controlled, multicentre study to assess the efficacy of flurbiprofen, a non-steroidal anti-inflammatory agent (NSAID) with potent anti-platelet activity (PAA), in the prevention and recurrence of myocardial infarction (MI) and reocclusion of the infarct-related artery (IRA) in patients successfully treated for acute MI by thrombolysis and/or coronary angioplasty within 6 h of onset of symptoms. A coronary angiogram was performed within the first 24 h to confirm successful reperfusion. Two hundred and thirty-three patients (group 1) were randomly allocated to flurbiprofen 50 mg twice daily and 228 patients (group 2) to placebo. All patients complied with the entry criteria, and drug treatment was commenced within 48 h of MI. Patients were assessed at 3 weeks, 3 months and 6 months, data being recorded on major clinical events and survival status. Overall mortality was low (1.1%) and similar for both groups, confirming the benefit of early reperfusion therapy. The reinfarction rate documented during the 6-month follow-up was 3% (7/233) in group 1 and 10.5% (24/228) in group 2 (P < 0.001). The need for coronary angioplasty and/or coronary bypass graft was decreased by 51% (group 1: 39/233 = 17%; group 2: 75/228 = 33%) (P < 0.001). Coronary angiogram at 6 months showed a similar reocclusion rate between treatments. Flurbiprofen appears to be an effective drug for the prevention of reinfarction after coronary reperfusion and in reducing the need for secondary revascularization procedures. It may offer advantages over aspirin, but comparable efficacy remains to be established.

Adult↗
PubMed2006

Gene expression profiling in R-flurbiprofen-treated prostate cancer: R-Flurbiprofen regulates prostate stem cell antigen through activation of AKT kinase.

We have used gene expression profiling to characterize genes regulated by the anti-tumor non-steroidal anti-inflammatory drug (NSAID)-like agent R-flurbiprofen (RFB) in murine TRAMP prostate cancer. Mice with spontaneous, palpable tumors were treated with RFB 25 mg/(kgd) x 7d orally, or vehicle only. RNA was then extracted from tumor tissue and used for microarray analysis with Affymetrix chips. Fifty-eight genes were reproducibly regulated by RFB treatment. One of the most highly up-regulated genes was prostate stem cell antigen (psca). We used TRAMP C1 murine prostate cancer cells to examine potential mechanisms through which RFB could regulate psca. RFB induced dose-dependent expression of PSCA protein, and activity of the psca promoter, in TRAMP C1 cells in culture. Increased psca promoter activity was also seen following treatment of cells with sulindac sulfone, another NSAID-like agent, but not with celecoxib treatment. RFB activation of the psca promoter could be attenuated by co-transfection of dominant-negative akt and h-ras constructs, but not by dominant-negative mek1 plasmids. Immunoblotting revealed that RFB increased expression of phosphorylated AKT at concentrations that stimulated psca promoter activity, and that increased PSCA protein expression. In addition, RFB-dependent up-regulation of PSCA protein expression could be blocked by AKT inhibitors. These data demonstrate that RFB, and possibly other NSAID-like analogs, can increase expression of the psca gene both in vivo and in culture. They further suggest the utility of combining RFB with AKT inhibitors or with monoclonal antibodies targeting PSCA protein, for treatment or prevention of prostate cancer.

Animals↗
PubMed1996

Human plasma concentrations of R, S, and racemic flurbiprofen given as a toothpaste.

Flurbiprofen, an arylpropionic acid (APA) class nonsteroidal antiinflammatory drug (NSAID), is commercially available only as the racemic mixture, although its pharmacologic effect has been credited primarily to the S isomer. In humans, the bioavailability of racemic flurbiprofen absorbed from the oral cavity has been studied measuring the total concentration of S- and R-flurbiprofen, and the pharmacokinetics of S- and R-flurbiprofen have been studied after oral administration of racemic flurbiprofen. In this study, the plasma concentrations of S-flurbiprofen and to some extent R-flurbiprofen were studied after brushing with a toothpaste containing different mixtures of S- and R-flurbiprofen. The toothpaste formulations contained 1% racemic (50:50), eutectic (14:86), 1%, 0.5%, and 0.25% (5:95) R- to S-flurbiprofen. Both S- and R-flurbiprofen were rapidly absorbed, with a time to reach maximum concentration (tmax) of 1.2 to 1.4 hours. Based on the AUC, the amount of S-flurbiprofen absorbed increased proportionally when given as the 0.25% (5:95) preparation to the 0.5% (5:95) mixture but did not increase significantly above the 0.5% (5:95) mixture when given as 1% (5:95) R- to S-flurbiprofen. This suggests that dose-proportional absorption of S-flurbiprofen is not maintained at higher concentrations. The elimination of S-flurbiprofen appears to be variable and prolonged after this mode of administration, as observed from plasma concentrations. Further controlled and more prolonged studies of S- and R-flurbiprofen are needed to confirm these observations.

Adult↗
PubMed1988

Stereoselective pharmacokinetics of flurbiprofen in humans and rats.

Flurbiprofen, a 2-arylpropionic acid (2-APA) nonsteroidal anti-inflammatory drug (NSAID), exists as racemate and is used as such. Although the activity of 2-APAs is due mainly to their S-enantiomers, information on the pharmacokinetics of flurbiprofen is usually based on the measurement of total concentrations of S- and R-flurbiprofen. In this work, the pharmacokinetics of flurbiprofen enantiomers following single doses were studied in humans and rats. Upon iv administration of 10 mg/kg of racemic flurbiprofen to male Sprague-Dawley rats, the plasma concentrations were consistently higher for S-flurbiprofen than for R-flurbiprofen (AUC = 134 +/- 39 versus 41 +/- 9 mg.L-1 h). In bile duct-cannulated rats, the biliary excretion contained only 3.6-5.2% of the dose as conjugated flurbiprofen (S:R = 1.2-2.1). After administration of R-flurbiprofen to the rat, both enantiomers were found in plasma [AUC(R):AUC(S) = 0.10-0.16], indicating a limited extent of enantiomeric bioinversion. This is consistent with the previously reported limited extent of flurbiprofen uptake into fat. In healthy volunteers also, significant stereoselectivity was observed in the plasma concentration of the drug after 100-mg oral racemic doses [AUC-(S):AUC(R) = 45.4 +/- 12.7:40.1 +/- 14.3 mg.L-1.h]. As compared with the R-enantiomer, S-flurbiprofen has a smaller volume of distribution (7.23 +/- 1.9 versus 8.41 +/- 3.0 L) and total clearance (1.23 +/- 0.34 versus 1.47 +/- 0.50 L/h), but an equal half-life (4.21 +/- 1.2 versus 4.18 +/- 1.3 h). In urine, on the other hand, the R-configuration was predominant, as greater amounts of the R-enantiomer were found both as conjugated flurbiprofen and as an unidentified metabolite. Negligible amounts of intact flurbiprofen enantiomers were detected in urine. The observed stereoselectivity in humans cannot be attributed to enantiomeric bioinversion, as S-flurbiprofen was not detected in plasma and urine after oral administration of R-flurbiprofen.

Administration, Oral↗
PubMed1997

Efficacy and tolerability of a topical NSAID patch (local action transcutaneous flurbiprofen) and oral diclofenac in the treatment of soft-tissue rheumatism.

The efficacy and safety of local action transcutaneous flurbiprofen 40 mg [flurbiprofen LAT] patches and diclofenac sodium tablets, 50 mg b.d., were compared in an open, multicentre, randomized, parallel-group study in patients with soft-tissue rheumatism. Patches were replaced at 12-hourly intervals. Clinical assessments were performed after 7 and 14 days of treatment. Fifty-six patients were treated with flurbiprofen LAT and 53 with diclofenac. Six withdrawals (three from each group) occurred during the treatment period. A statistically significant difference was observed in favour of flurbiprofen LAT for the principal measure, namely the investigator's opinion of overall change in clinical condition: 49/53 (92%) patients treated with flurbiprofen LAT had improved by day 14 compared with 36/49 (73%) patients receiving diclofenac sodium (p = 0.03; eligible dataset). There were also statistically significant differences in favour of flurbiprofen LAT for the investigator's assessments of the overall severity of the clinical condition (p = 0.03; eligible dataset), for the severity of pain at the region treated (p = 0.04; intent-to-treat), and for the severity of tenderness (p < 0.001; intent-to-treat). Supplementary analgesia (paracetamol) was required by two patients in the flurbiprofen LAT group and by eight diclofenac-treated patients. The difference in favour of flurbiprofen LAT in the average daily consumption of paracetamol was significant (p = 0.04). The patients' assessment of severity of pain on movement also favoured flurbiprofen LAT (p = 0.049; eligible dataset), but there were no statistically significant differences in day or night pain or quality of sleep. For the patients' opinion of treatment there was, however, a statistically significant difference in favour of flurbiprofen LAT (p = 0.02). Of the patients receiving flurbiprofen LAT, 94% regarded it as a convenient form of treatment. With respect to tolerability 8/56 (14%) patients applying flurbiprofen patches reported a total of nine adverse effects (AEs) (mainly local, mild skin irritations), vs 9/52 (17%) patients receiving diclofenac, who reported 12 AEs. Most AEs in the enteric-coated diclofenac group were of a gastrointestinal nature (one of which was severe). In terms of the proportion of patients reporting AEs related to the digestive system, there was a statistically significant difference in favour of flurbiprofen LAT (p = 0.011). In conclusion, local treatment of soft-tissue rheumatism with flurbiprofen LAT was demonstrably superior to benchmark oral therapy with diclofenac sodium over a 2-week period in terms of both efficacy and gastrointestinal tolerability. Flurbiprofen LAT provided both an effective and convenient form of topical SAID treatment.

Administration, Cutaneous↗
PubMed1998

Peripheral and/or central effects of racemic-, S(+)- and R(-)-flurbiprofen on inflammatory nociceptive processes: a c-Fos protein study in the rat spinal cord.

1. We have evaluated the effects of intravenous or intraplantar racemic-, S(+)- and R(-)-flurbiprofen on both the carrageenan-evoked peripheral oedema and spinal c-Fos immunoreactivity, an indirect index of neurons involved in spinal nociceptive processes. 2. Three hours after intraplantar injection of carrageenan (6 mg in 150 microl of saline) in awake rats, a peripheral oedema and numerous c-Fos protein-like immunoreactive (c-Fos-LI) neurons in L4 L5 segments were observed. c-Fos-LI neurons were essentially located in the superficial (I-II) and deep (V-VI) laminae of the dorsal horn. 3. Intravenous racemic-flurbiprofen (0.3, 3 and 9 mg kg(-1)) dose-relatedly reduced the carrageenan-evoked oedema and spinal c-Fos expression (r=0.64, r=0.88 and r=0.84 for paw diameter, ankle diameter and number of c-Fos-LI neurons; P<0.05. P<0.001 and P<0.001 respectively). 4. Similar effects to those of intravenous racemic-flurbiprofen were obtained with intravenous S(+)-flurbiprofen (0.3, 3 and 9 mg kg(-1)) which dose-relatedly reduced the number of c-Fos-LI neurons (r=0.69, P<0.01) and diameters of paw and ankle (r=0.56 and r=0.52 respectively, P<0.05 for both). 5. For the dose of 0.3 mg kg(-1) i.v., R(-)-flurbiprofen did not modify the number of c-Fos-LI neurons and produced a weak reduction of oedema at only the ankle level (23+/-12% reduction, P<0.05). However, a ten times higher dose of R(-)-flurbiprofen (3 mg kg(-1) i.v.) was necessary to obtain effects comparable to those of S(+)- or racemic-flurbiprofen (0.3 mg kg(-1) i.v.). 6. Intraplantar racemic-flurbiprofen (1, 10 and 30 microg) dose-relatedly reduced the carrageenan-enhanced ankle diameter (r=0.81, P<0.001) and the number of c-Fos-LI neurons in L4-L5 segments (r=0.83, P<0.001). with a 60+/-3% reduction of the number of c-Fos-LI neurons (P<0.001), and 30+/-3 and 67+/-7% reduction of paw and ankle diameter respectively (P<0.001 for both) for the dose of 30 microg. 7. For intraplantar S(+)-flurbiprofen (1, 10 and 30 microg) the dose-related effects (r=0.77, r=0.60 and r=0.59 for c-Fos-LI neurons, paw and ankle diameters respectively, P<0.001, P<0.01 and P<0.01) were similar to those of racemic-flurbiprofen. In contrast, intraplantar R(-)-flurbiprofen (1, 10 and 30 microg) did not have detectable effects on all studied parameters. 8. The present study provides clear evidence for potent anti-inflammatory and antinociceptive effects of both intravenous or intraplantar racemic- and S(+)-flurbiprofen. These results further demonstrate marked anti-inflammatory and antinociceptive effects of intravenous, but not intraplantar, R(-)-flurbiprofen. These results suggest that the main site of action of racemic- and S(+ )-flurbiprofen is in the periphery and indicate that the site of action of R(-)-flurbiprofen is mainly of central origin.

Analgesics↗
PubMed1996

New insights into the site and mode of antinociceptive action of flurbiprofen enantiomers.

The S-enantiomer of flurbiprofen has been shown to have both antiinflammatory and antinociceptive effects, whereas R-flurbiprofen is antinociceptive but not antiinflammatory. Importantly, only S-flurbiprofen inhibited prostaglandin biosynthesis in vitro at therapeutic concentrations. R-flurbiprofen did not undergo significant chiral inversion to S-flurbiprofen in rats and humans. A study was conducted to gain new insight into the possible sites and modes of action of flurbiprofen enantiomers. In a modified Randall Selitto assay, both enantiomers were antinociceptive in a dose-dependent manner after systemic administration. After local administration into the inflamed paw, only S-flurbiprofen produced significant dose-related antinociception. In a physiologic study, we recorded extracellularly from nociceptive spinal cord neurons that were rendered hyperexcitable. Intravenous administration of R- and S-flurbiprofen reduced responses of neurons to pressure applied to the inflamed knee and the noninflamed ankle and paw in a dose-dependent manner. When injected directly into the knee joint, only S-flurbiprofen but not R-flurbiprofen reduced responses to pressure. These results suggest a central site of antinociceptive action for R- and S-flurbiprofen and an additional peripheral site for S-flurbiprofen. The findings may be of clinical relevance, as it was demonstrated that both enantiomers also were antinociceptive in humans. Because R-flurbiprofen caused less toxicity in rats than the S-enantiomer or the racemic compound, a reduction in the quantitatively most important side effects in the gastrointestinal tract might be achieved with the use of R-flurbiprofen for pain therapy.

Analgesics↗
PubMed1984

Ocular and systemic bioavailability of ophthalmic flurbiprofen.

Flurbiprofen, a nonsteroidal antiinflammatory agent which is not ocularly metabolized, was employed as a probe compound to investigate the drug kinetic relationship between systemic and ocular humoral circulation. The ocular and systemic bioavailabilities of topically applied flurbiprofen were also quantitated. Anesthetized albino female rabbits received flurbiprofen doses intracamerally, topically, and intravenously at 2 to 4 week intervals. Aqueous humor and plasma were used as the sampling compartments. Plasma clearance values of flurbiprofen were 6.77 and 7.87 ml/min, after 6-mg and 208-micrograms intravenous doses, respectively. These values were not significantly different and indicated no dose-dependent disposition kinetics over a 30-fold dose range. Both ocular and systemic flurbiprofen dispositions followed a biexponential pattern with a rapid distribution phase. The systemic and ocular distribution half-lives of flurbiprofen were 12 min and 15 min, respectively. The plasma elimination half-life was 74 min and the aqueous humor elimination half-life was 93 min. The latter approximated the turnover rate of aqueous humor and suggested that aqueous humor drainage was the major process of flurbiprofen elimination from the globe. About 99% of flurbiprofen is bound to plasma protein. At distribution equilibrium, the plasma and aqueous humor concentrations of flurbiprofen differed by a hundredfold, suggesting that only free drug entered the aqueous humor after the administration of a systemic dose. In the ophthalmic studies, right eyes were instilled with 50 microliters of 0.3% flurbiprofen in saline (dose = 150 micrograms), and left eyes were instilled with 50 microliters of 0.15% flurbiprofen in saline (dose = 75 micrograms). When the area of the aqueous humor concentration-versus-time curve values was normalized by the administration dose, the 75-micrograms dose was 30% more available to ocular tissues than was the 150-micrograms dose. This demonstrated a disproportionate relationship between the administered dose and the fraction absorbed. The intracameral dose was considered to be completely bioavailable for intraocular effects. The ocular bioavailability of the ophthalmic dose was defined by using intracameral administration as a standard measurement. The ocular bioavailabilities of the 75-micrograms and 150-micrograms topical flurbiprofen doses were 10% and 7%, respectively. Systemic bioavailability after topical administration of 225 micrograms of flurbiprofen was 74%.

Administration, Topical↗
PubMed2006

Influence of age on flurbiprofen axetil requirements for preventing pain on injection of propofol in Japanese adult surgical patients: a prospective, randomized, double-blind, vehicle-controlled, parallel-group, dose-ranging study.

BACKGROUND: Pain on injection is a recognized adverse event (AE) of propofol administration for the induction of general anesthesia. Preceded by venous occlusion, flurbiprofen axetil, a prodrug of the NSAID flurbiprofen, has been associated with a reduction in pain induced by propofol injection. A review of the literature determined that no published data were available on the influence of age on the requirements for flurbiprofen axetil dose. OBJECTIVE: This study was undertaken to examine the influence of age on flurbiprofen axetil requirements for the treatment of propofol-induced pain on injection in Japanese adult surgical patients. METHODS: This prospective, randomized, double-blind, vehicle-controlled, parallel-group, dose-ranging study was conducted at the Department of Anesthesiology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Japan. Young (age 20-40 years) and older (age 60-80 years) Japanese patients scheduled for various types of surgery (eg, cholecystectomy) were eligible. Patients were randomized to receive flurbiprofen axetil at 1 of 2 doses (25 or 50 mg, regardless of body weight) or inactive vehicle (saline), preceded by manual venous occlusion with a rubber tourniquet for 2 minutes and followed by the infusion of the first 25% of calculated propofol dose (0.5 mg/kg at room temperature, 23 degrees C) into the largest dorsal vein of the hand through a 20-G IV cannula (without local anesthesia), followed by the release of the occlusion and delivery of propofol 2 mg/kg. An investigator blinded to treatment questioned each patient about pain intensity during propofol injection which was assessed using a verbal rating scale: 0 = none; 1 = mild; 2 = moderate; and 3 = severe. The overall prevalence of pain was calculated in each group. AEs at the injection site (pain, edema, wheal, inflammation) were assessed by the study investigator for 24 hours after surgery using spontaneous reporting and patient interview. RESULTS: A total of 150 patients, 75 young adults (38 men, 37 women; mean [SD] age, 31 [5] years; mean [SD] height, 163 [7] cm; mean [SD] body weight, 58 [9] kg) and 75 older adults (38 men, 37 women; mean [SD] age, 70 [6] years; mean [SD] height, 154 [8] cm; mean [SD] body weight, 53 [10] kg), were enrolled. Each treatment group comprised 25 patients. No differences in demographic characteristics were observed among the 3 study groups. In young patients, the overall prevalence of propofol-induced pain was significantly lower in patients who received flurbiprofen axetil 50 mg (12 [48%]) compared with that in patients who received flurbiprofen axetil 25 mg (20 [80%]) or vehicle (22 [88%]) (P < 0.05 and P < 0.01, respectively). The median pain intensity score was significantly lower in patients who received flurbiprofen axetil 50 mg (0) compared with that in patients who received flurbiprofen axetil 25 mg (1) or vehicle (2) (P < 0.05 and P < 0.01, respectively). In older patients, the overall prevalences of pain on propofol injection were 9 (36%) in the flurbiprofen axetil 50-mg group and 11 (44%) in the flurbiprofen axetil 25-mg group compared with 21 (84%) in the vehicle group (both, P < 0.01). The median pain score was significantly lower in patients who received flurbiprofen 50 mg (0) or 25 mg (0) than in those who received vehicle (1) (both, P < 0.01). All treatments were well tolerated. CONCLUSIONS: In this small clinical trial in Japanese surgical patients undergoing general anesthesia, flurbiprofen axetil requirements for the reduction of pain during injection of propofol were found to be 50 mg in young adults (age 20-40 years) and 25 or 50 mg in older adults (age 60-80 years), regardless of weight, preceded by venous occlusion for 2 minutes.

Adult↗
PubMed2002

NO-flurbiprofen maintains duodenal blood flow, enhances mucus secretion contributing to lower mucosal injury.

This study investigates possible mechanisms behind the reduced gastrointestinal ulcerogenicity of nitric oxide (NO)-flurbiprofen compared with flurbiprofen. The duodenal mucosa of Inactin-anaesthetised rats was exteriorized for intravital microscopy. Blood flow was measured with laser-Doppler flowmetry (LDF), mucus thickness with micropipettes, ICAM-1 and P-selectin expression with dual-labeled antibody technique, and mucosal integrity by (51)Cr-EDTA permeability. Exposure of the duodenum to flurbiprofen (1.0 mg/ml) for 90 min significantly reduced LDF to 70 +/- 4%, whereas NO-flurbiprofen (1.3 mg/ml) had no significant effect. Mucus accumulation after 60-min exposure was 75 +/- 23 microm (control), -1 +/- 17 microm (flurbiprofen), and 104 +/- 35 microm (NO-flurbiprofen). Mucosal permeability to (51)Cr-EDTA was unchanged in the control and NO-flurbiprofen groups but increased significantly from 1.0 +/- 0.2 to 3.7 +/- 0.7 microl x min(-1) x g(-1) after 90-min exposure to flurbiprofen. Expression of ICAM-1 was significantly increased after oral flurbiprofen but not by NO-flurbiprofen. Positive effects of NO-flurbiprofen compared with flurbiprofen on mucus formation, blood flow, and adhesion molecule expression likely contribute to the reduced mucosal injury observed with NO-flurbiprofen.

Animals↗
PubMed1999

Phospholipid-based microemulsions of flurbiprofen by the spontaneous emulsification process.

The purpose of this study was to investigate the possibility for parenteral delivery of flurbiprofen without chemical modification using a phospholipid-based microemulsion system. Microemulsions composed of ethyl oleate, lecithin and distearoylphosphatidyl-ethanolamine-N-poly(ethyleneglycol) 2000 (DSPE-PEG) were prepared using ethanol as a cosolvent. The effect of formulation variables on the particle size of the microemulsion was investigated. Flurbiprofen concentrations in plasma and various organs after the intravenous administration of flurbiprofen-loaded microemulsion were measured and compared with those after the intravenous administration of flurbiprofen axetil-entrapped emulsion (Lipfen(R), 50 mg/5 ml as flurbiprofen axetil) and flurbiprofen solution. Phospholipid-based microemulsions could solubilize more than 10 mg ml-1 of flurbiprofen at the ratio of vehicle to drug at least 10:1, if the oil contents (10 or 20%) of common parenteral emulsions were used. The half-life, AUC and MRT of flurbiprofen loaded in microemulsion (ethyl oleate:lecithin:DSPE-PEG:flurbiprofen=8:3:1:1.2) increased significantly. The biodistribution of flurbiprofen loaded in this microemulsion was quite different from others. Reticuloendothelial uptake of flurbiprofen loaded in microemulsion decreased compared with that in solution or Lipfen(R). It is concluded that the current microemulsion system might be applicable to formulate the parenteral dosage form of poorly water-soluble flurbiprofen without chemical modification.

Animals↗
PubMed2003

Activation of c-Jun-N-terminal-kinase is crucial for the induction of a cell cycle arrest in human colon carcinoma cells caused by flurbiprofen enantiomers.

The unselective cyclooxygenase (COX) inhibitor S-flurbiprofen and its-in terms of COX-inhibition-"inactive" enantiomer R-flurbiprofen have been previously found to inhibit tumor development and growth in various animal models. The underlying mechanisms are unknown. Here, we show that both R- and S-flurbiprofen reduce survival of three colon cancer cell lines, which differ in the expression of COX-2 (HCT-15, no COX-2; Caco-2, inducible COX-2; and HT-29, constitutive COX-2). The IC50 for S- and R-flurbiprofen ranged from 250 to 450 microM. Both flurbiprofen enantiomers induced apoptosis in all three cell lines as indicated by DNA- and PARP-cleavage. In addition, R- and S-flurbiprofen caused a G1-cell cycle block. The latter was associated with an activation of c-Jun N-terminal kinase (JNK), an increase of the DNA binding activity of the transcription factor AP-1 and down-regulation of cyclin D1 expression. Western blot analysis, as well as supershift experiments, revealed that the AP-1 activation was associated with a change of AP-1 composition toward an increase of JunB. The JNK inhibitor SP600125 antagonized R- and S-flurbiprofen-induced AP-1 DNA binding, suppression of cyclin D1 expression, and the G1-cell cycle block. However, JNK inhibition had no effect on flurbiprofen-induced apoptosis. Hence, the cell cycle arrest is obviously mediated, at least in part, through JNK-activation, whereas R- and S-flurbiprofen-induced apoptosis is largely independent of JNK. Although in vitro effects of R- and S-flurbiprofen were indistinguishable, only R-flurbiprofen inhibited HCT-15 tumor growth in nude mice, suggesting the involvement of additional in vivo targets, which are differently affected by R- and S-flurbiprofen.

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