The Experts below are selected from a list of 252 Experts worldwide ranked by ideXlab platform
Jenny Christian - One of the best experts on this subject based on the ideXlab platform.
-
demonstration of dose response of Flurbiprofen lozenges with the sore throat pain model
Clinical Pharmacology & Therapeutics, 2002Co-Authors: Bernard P. Schachtel, Harvey D Homan, Iain A Gibb, Jenny ChristianAbstract:The dose response of Flurbiprofen lozenges (2.5, 5.0, and 12.5 mg) was evaluated in the treatment of sore throat. A refined version of the sore throat pain model showed that 12.5 mg Flurbiprofen was significantly more effective than placebo at providing total pain relief and reducing throat soreness (p <.05). Flurbiprofen, 5.0 mg, was more effective than placebo for the reduction of throat soreness and the sensation of throat swelling (P <.05). The 2.5-mg Flurbiprofen lozenge was indistinguishable from placebo. For every milligram of increase in the dose of Flurbiprofen, there was an approximately 0.3-unit increase in total pain relief (P <.05). Flurbiprofen lozenges in all 3 dosages were well tolerated. Flurbiprofen lozenges are effective for sore throat at a dose between 5.0 mg and 12.5 mg; the sore throat pain model is a sensitive assay for demonstration of the dose-response relationship of an analgesic agent.
Kay Brune - One of the best experts on this subject based on the ideXlab platform.
-
inhibition of noxious stimulus induced spinal prostaglandin e2 release by Flurbiprofen enantiomers a microdialysis study
Journal of Neurochemistry, 2008Co-Authors: Gerd Geisslinger, Hans-georg Schaible, Kay Brune, Uta Muthselbach, Ovidiu Coste, Gregor Vetter, Andreas Schrodter, Irmgard TegederAbstract:Peripheral noxious stimuli have been shown to induce prostaglandin (PG) E2 release at the site of inflammation and in the spinal cord. The antiinflammatory and antinociceptive effects of cyclooxygenase-inhibiting drugs are thought to depend on the inhibition of PG synthesis. R-Flurbiprofen, however, does not inhibit cyclooxygenase activity in vitro but still produces antinociceptive effects. To find out whether R-Flurbiprofen acts via inhibition of spinal PG release, concentrations of PGE2 and Flurbiprofen in spinal cord tissue were assessed by microdialysis. The catheter was transversally implanted through the dorsal horns of the spinal cord at level L4. R- and S-Flurbiprofen (9 and 27 mg kg(-1), respectively) were administered intravenously 10-15 min before subcutaneous injection of formalin into the dorsal surface of one hindpaw. Flurbiprofen was rapidly distributed into the spinal cord with maximal concentrations after 30-45 min. Baseline PGE2 dialysate concentrations were 100.6 +/- 6.4 pg ml(-1) (mean +/- SEM). After formalin injection they rose about threefold with a maximum of 299.4 +/- 68.4 pg ml(-1) at 7.5 min. After approximately 1 h PGE2 levels returned to baseline. Both Flurbiprofen enantiomers completely prevented the formalin-induced increase of spinal PGE2 release and reduced PGE2 concentrations below basal levels. S- and R-Flurbiprofen at 9 mg kg(-1) produced a minimum of 15.8 +/- 5.2 and 27.7 +/- 14.9 pg ml(-1), respectively, and 27 mg kg(-1) S- and R-Flurbiprofen resulted in 11.7 +/- 1.7 and 9.3 +/- 4.7 pg ml(-1), respectively. PGE2 levels remained at the minimum up to the end of the observation period at 5 h. When 27 mg kg(-1) R-Flurbiprofen was injected intravenously without subsequent formalin challenge, baseline immunoreactive PGE2 concentrations were not affected. S-Flurbiprofen (27 mg kg(-1)), however, led to a moderate reduction (approximately 40%). The data suggest that antinociception produced by R-Flurbiprofen is mediated at least in part by inhibition of stimulated spinal PGE2 release and support the current view that increased spinal PGE2 release significantly contributes to nociceptive processing.
-
Flurbiprofen Enantiomers Inhibit Inducible Nitric Oxide Synthase Expression in RAW 264.7 Macrophages
Pharmaceutical Research, 2001Co-Authors: Burkhard Hinz, Kay Brune, Thomas Rau, Andreas PahlAbstract:Purpose . Using RAW 264.7 macrophages, the present study investigates the influence of optically pure enantiomers of the nonsteroidal anti-inflammatory drug Flurbiprofen on lipopolysaccharide (LPS)-induced inducible nitric oxide synthase (iNOS) expression. Methods . iNOS and cyclooxygenase-2 (COX-2) mRNA levels were measured by quantitative real-time reverse-transcription polymerase chain reaction (RT-PCR). Concentrations of nitrite (index of cellular NO production) and prostaglandin E_2 (index of COX-2 activity) in cell culture supernatants were determined by Griess assay and enzyme immunoassay, respectively. Results . R(−)- and S(+)-Flurbiprofen decreased LPS-induced iNOS mRNA and nitrite levels in an equipotent and concentration-dependent manner. Suppression of iNOS mRNA expression by R(−)- and S(+)-Flurbiprofen was gene-specific in that both substances failed to inhibit LPS-induced COX-2 mRNA expression. By contrast, Flurbiprofen enantiomers suppressed LPS-induced prostaglandin E_2 formation enantioselectively with S(+)-Flurbiprofen being considerably more potent than its R(−)-antipode. Conclusions . Our results show that R(−)- and S(+)-Flurbiprofen, albeit differing in their potency as inhibitors of COX-2 activity, equipotently suppress iNOS expression. Because sustained high NO levels are associated with pain and tissue injury under various pathological conditions, a suppression of the inducible NO pathway may contribute to the pharmacological action of both R(−)- and S(+)-Flurbiprofen.
-
inhibition of nf κb and ap 1 activation by r and s Flurbiprofen
The FASEB Journal, 2001Co-Authors: Irmgard Tegeder, Kay Brune, Ellen Niederberger, Eltahmash Israr, Hans Guhring, Christian Euchenhofer, Sabine Grosch, Gerd GeisslingerAbstract:R-Flurbiprofen is considered the 'inactive' isomer of the nonsteroidal anti-inflammatory drug (NSAID), Flurbiprofen, because it does not inhibit cyclooxygenase (COX) activity. However, previous studies have revealed that it has antinociceptive and antitum or effects not due to epimerization to the cyclooxygenase-inhibiting S-isomer. Here, we show that R-Flurbiprofen has additional anti-inflammatory activity comparable with that of dexamethasone in the zymosan-induced paw inflammation model in rats. Different criteria suggest that the observed effects are mediated at least in part through inhibition of NF-kB activation: R-Flurbiprofen inhibited i) LPS-induced NF-kB DNA binding activity in RAW 264.7 macrophages, ii) translocation of the p65 subunit of NF-kB into the nucleus of these cells, and iii) zymosan-induced NF-kB-dependent gene transcription in the inflamed paw and spinal cord of rats. S-Flurbiprofen produced similar effects but was less potent. In addition, R-Flurbiprofen inhibited DNA binding activity of AP-1, another key regulatory transcription factor in inflammatory processes. Because R-Flurbiprofen does not cause gastrointestinal mucosal damage or other side effects associated with long-term NSAID or glucocorticoid use, it might be a useful drug in inflammatory or other diseases in which increased or constitutive NF-kB and AP-1 activation are involved in the pathophysiological processes.
-
R-Flurbiprofen: isomeric ballast or active entity of the racemic compound?
Agents and actions. Supplements, 1993Co-Authors: Gerd Geisslinger, S. Menzel-soglowek, W. S. Beck, Kay BruneAbstract:The enantioselective pharmacokinetic behaviour of the Flurbiprofen enantiomers was investigated following administration of optically pure R- or S-Flurbiprofen to various species. Only negligible inversion (< 5%) of Flurbiprofen occurred in the rat and in man. Consequently, pharmacodynamic experiments evaluating pain and inflammation as parameters have been carried out enantioselectively for both Flurbiprofen enantiomers in the rat. R-Flurbiprofen, which is not an inhibitor of prostaglandin synthesis in vitro, had only marginal anti-inflammatory effects as defined by the carrageenan edema of the rat paw in contrast to the S-enantiomer. In contrast, to S-Flurbiprofen, R-Flurbiprofen caused only marginal mucosal damage in the GI-tract. Both enantiomers, however, were of similar potency as antinociceptive drugs in the rat Randall-Selitto assay following the injection of interleukin-1 or baker's yeast. Using the pure enantiomers of Flurbiprofen it appears possible to establish a more specific drug treatment: the R-enantiomer in occasional pain, the S-enantiomer in rheumatic disorders.
-
Variability of inversion of (R)‐Flurbiprofen in different species
Journal of pharmaceutical sciences, 1992Co-Authors: Sabine Menzel‐soglowek, Gerd Geisslinger, W. S. Beck, Kay BruneAbstract:The anti‐inflammatory activity of 2‐arylpropionic acids like Flurbiprofen appears to be due to the S enantiomers only. A unique characteristic of the metabolism of this class of drugs is inversion of configuration. The present study examines whether chiral inversion occurs after administration of the optically pure Flurbiprofen enantiomers to various species (i.e., dogs, guinea pigs, rats, and gerbils). Concentrations of the enantiomers in plasma were analyzed by a stereoselective high‐performance liquid chromatographic assay with a chiral α1‐acid glycoprotein column. Pharmacokinetic parameters of the Flurbiprofen enantiomers were evaluated with a two‐compartment computer model. Inversion of (R)‐Flurbiprofen to its optical antipode occurred to a variable extent in the dog [fraction inverted (Fi) = 0.39; n = 3] and the guinea pig (Fi = 1.00; n = 3) and to a much lower extent in the rat (Fi = 0.02; n = 3) and the gerbil (Fi = 0.05; n = 3). After intravenous administration of (S)‐Flurbiprofen to dogs, guinea pigs, rats, and gerbils, (R)‐Flurbiprofen was not detected in plasma (limit of quantification was 0.05 μg/100 μL. of plasma).
Gerd Geisslinger - One of the best experts on this subject based on the ideXlab platform.
-
inhibition of noxious stimulus induced spinal prostaglandin e2 release by Flurbiprofen enantiomers a microdialysis study
Journal of Neurochemistry, 2008Co-Authors: Gerd Geisslinger, Hans-georg Schaible, Kay Brune, Uta Muthselbach, Ovidiu Coste, Gregor Vetter, Andreas Schrodter, Irmgard TegederAbstract:Peripheral noxious stimuli have been shown to induce prostaglandin (PG) E2 release at the site of inflammation and in the spinal cord. The antiinflammatory and antinociceptive effects of cyclooxygenase-inhibiting drugs are thought to depend on the inhibition of PG synthesis. R-Flurbiprofen, however, does not inhibit cyclooxygenase activity in vitro but still produces antinociceptive effects. To find out whether R-Flurbiprofen acts via inhibition of spinal PG release, concentrations of PGE2 and Flurbiprofen in spinal cord tissue were assessed by microdialysis. The catheter was transversally implanted through the dorsal horns of the spinal cord at level L4. R- and S-Flurbiprofen (9 and 27 mg kg(-1), respectively) were administered intravenously 10-15 min before subcutaneous injection of formalin into the dorsal surface of one hindpaw. Flurbiprofen was rapidly distributed into the spinal cord with maximal concentrations after 30-45 min. Baseline PGE2 dialysate concentrations were 100.6 +/- 6.4 pg ml(-1) (mean +/- SEM). After formalin injection they rose about threefold with a maximum of 299.4 +/- 68.4 pg ml(-1) at 7.5 min. After approximately 1 h PGE2 levels returned to baseline. Both Flurbiprofen enantiomers completely prevented the formalin-induced increase of spinal PGE2 release and reduced PGE2 concentrations below basal levels. S- and R-Flurbiprofen at 9 mg kg(-1) produced a minimum of 15.8 +/- 5.2 and 27.7 +/- 14.9 pg ml(-1), respectively, and 27 mg kg(-1) S- and R-Flurbiprofen resulted in 11.7 +/- 1.7 and 9.3 +/- 4.7 pg ml(-1), respectively. PGE2 levels remained at the minimum up to the end of the observation period at 5 h. When 27 mg kg(-1) R-Flurbiprofen was injected intravenously without subsequent formalin challenge, baseline immunoreactive PGE2 concentrations were not affected. S-Flurbiprofen (27 mg kg(-1)), however, led to a moderate reduction (approximately 40%). The data suggest that antinociception produced by R-Flurbiprofen is mediated at least in part by inhibition of stimulated spinal PGE2 release and support the current view that increased spinal PGE2 release significantly contributes to nociceptive processing.
-
inhibition of nf κb and ap 1 activation by r and s Flurbiprofen
The FASEB Journal, 2001Co-Authors: Irmgard Tegeder, Kay Brune, Ellen Niederberger, Eltahmash Israr, Hans Guhring, Christian Euchenhofer, Sabine Grosch, Gerd GeisslingerAbstract:R-Flurbiprofen is considered the 'inactive' isomer of the nonsteroidal anti-inflammatory drug (NSAID), Flurbiprofen, because it does not inhibit cyclooxygenase (COX) activity. However, previous studies have revealed that it has antinociceptive and antitum or effects not due to epimerization to the cyclooxygenase-inhibiting S-isomer. Here, we show that R-Flurbiprofen has additional anti-inflammatory activity comparable with that of dexamethasone in the zymosan-induced paw inflammation model in rats. Different criteria suggest that the observed effects are mediated at least in part through inhibition of NF-kB activation: R-Flurbiprofen inhibited i) LPS-induced NF-kB DNA binding activity in RAW 264.7 macrophages, ii) translocation of the p65 subunit of NF-kB into the nucleus of these cells, and iii) zymosan-induced NF-kB-dependent gene transcription in the inflamed paw and spinal cord of rats. S-Flurbiprofen produced similar effects but was less potent. In addition, R-Flurbiprofen inhibited DNA binding activity of AP-1, another key regulatory transcription factor in inflammatory processes. Because R-Flurbiprofen does not cause gastrointestinal mucosal damage or other side effects associated with long-term NSAID or glucocorticoid use, it might be a useful drug in inflammatory or other diseases in which increased or constitutive NF-kB and AP-1 activation are involved in the pathophysiological processes.
-
New Insights into the Site and Mode of Antinociceptive Action of Flurbiprofen Enantiomers
Journal of clinical pharmacology, 1996Co-Authors: Gerd Geisslinger, Hans-georg SchaibleAbstract: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.
-
R-Flurbiprofen: isomeric ballast or active entity of the racemic compound?
Agents and actions. Supplements, 1993Co-Authors: Gerd Geisslinger, S. Menzel-soglowek, W. S. Beck, Kay BruneAbstract:The enantioselective pharmacokinetic behaviour of the Flurbiprofen enantiomers was investigated following administration of optically pure R- or S-Flurbiprofen to various species. Only negligible inversion (< 5%) of Flurbiprofen occurred in the rat and in man. Consequently, pharmacodynamic experiments evaluating pain and inflammation as parameters have been carried out enantioselectively for both Flurbiprofen enantiomers in the rat. R-Flurbiprofen, which is not an inhibitor of prostaglandin synthesis in vitro, had only marginal anti-inflammatory effects as defined by the carrageenan edema of the rat paw in contrast to the S-enantiomer. In contrast, to S-Flurbiprofen, R-Flurbiprofen caused only marginal mucosal damage in the GI-tract. Both enantiomers, however, were of similar potency as antinociceptive drugs in the rat Randall-Selitto assay following the injection of interleukin-1 or baker's yeast. Using the pure enantiomers of Flurbiprofen it appears possible to establish a more specific drug treatment: the R-enantiomer in occasional pain, the S-enantiomer in rheumatic disorders.
-
Variability of inversion of (R)‐Flurbiprofen in different species
Journal of pharmaceutical sciences, 1992Co-Authors: Sabine Menzel‐soglowek, Gerd Geisslinger, W. S. Beck, Kay BruneAbstract:The anti‐inflammatory activity of 2‐arylpropionic acids like Flurbiprofen appears to be due to the S enantiomers only. A unique characteristic of the metabolism of this class of drugs is inversion of configuration. The present study examines whether chiral inversion occurs after administration of the optically pure Flurbiprofen enantiomers to various species (i.e., dogs, guinea pigs, rats, and gerbils). Concentrations of the enantiomers in plasma were analyzed by a stereoselective high‐performance liquid chromatographic assay with a chiral α1‐acid glycoprotein column. Pharmacokinetic parameters of the Flurbiprofen enantiomers were evaluated with a two‐compartment computer model. Inversion of (R)‐Flurbiprofen to its optical antipode occurred to a variable extent in the dog [fraction inverted (Fi) = 0.39; n = 3] and the guinea pig (Fi = 1.00; n = 3) and to a much lower extent in the rat (Fi = 0.02; n = 3) and the gerbil (Fi = 0.05; n = 3). After intravenous administration of (S)‐Flurbiprofen to dogs, guinea pigs, rats, and gerbils, (R)‐Flurbiprofen was not detected in plasma (limit of quantification was 0.05 μg/100 μL. of plasma).
Ferdinand Devinsky - One of the best experts on this subject based on the ideXlab platform.
-
Does stereochemistry influence transdermal permeation of Flurbiprofen through the rat skin?
Archives of Dermatological Research, 2010Co-Authors: Jindra Valentová, Leila Farah, Katarína Bauerová, Ferdinand DevinskyAbstract:The possible enantioselectivity in the permeation of the chiral anti-inflammatory drug Flurbiprofen across hairless rat skin was studied. The transdermal permeability of individual enantiomers from donor solution containing racemic Flurbiprofen (0.1%) and pure enantiomers (0.05%) in isopropyl myristate solution was determined using side-by-side diffusion cells. The permeation profiles of enantiomers ( R )- and ( S )-Flurbiprofen from donor solution containing racemic ( RS )-Flurbiprofen are comparable. When donor solution contained pure enantiomers, marked differences were observed between the permeation rates of ( R )- and ( S )-Flurbiprofen. The steady-state flux and permeability coefficient were significantly higher for ( R )-Flurbiprofen in comparison with ( S )-Flurbiprofen (the flux ratio R/S = 2.04; p
Bernard P. Schachtel - One of the best experts on this subject based on the ideXlab platform.
-
demonstration of dose response of Flurbiprofen lozenges with the sore throat pain model
Clinical Pharmacology & Therapeutics, 2002Co-Authors: Bernard P. Schachtel, Harvey D Homan, Iain A Gibb, Jenny ChristianAbstract:The dose response of Flurbiprofen lozenges (2.5, 5.0, and 12.5 mg) was evaluated in the treatment of sore throat. A refined version of the sore throat pain model showed that 12.5 mg Flurbiprofen was significantly more effective than placebo at providing total pain relief and reducing throat soreness (p <.05). Flurbiprofen, 5.0 mg, was more effective than placebo for the reduction of throat soreness and the sensation of throat swelling (P <.05). The 2.5-mg Flurbiprofen lozenge was indistinguishable from placebo. For every milligram of increase in the dose of Flurbiprofen, there was an approximately 0.3-unit increase in total pain relief (P <.05). Flurbiprofen lozenges in all 3 dosages were well tolerated. Flurbiprofen lozenges are effective for sore throat at a dose between 5.0 mg and 12.5 mg; the sore throat pain model is a sensitive assay for demonstration of the dose-response relationship of an analgesic agent.