Biomedical subjects

G Geisslinger

Publications and source records attributed to G Geisslinger.

At least 73 records · Page 4Linked to original sources

PubMed1999

Peripheral antihyperalgesic effect of morphine to heat, but not mechanical, stimulation in healthy volunteers after ultraviolet-B irradiation.

UNLABELLED: The objective of this study was to evaluate direct peripheral analgesic effects of morphine using a peripheral model of hyperalgesia and the technique of IV regional anesthesia (IVRA), thus allowing the differentiation between central and peripheral mechanisms of action. Two spots on the ventral sides of both forearms in 12 volunteers were irradiated with ultraviolet (UV)-B to induce thermal and mechanical hyperalgesia. One day after the induction of the inflammatory reaction, 40 mL of morphine hydrochloride 0.01% was administered via IVRA. Calibrated heat and phasic mechanical stimuli were applied to differentially determine impairments of tactile and nociceptive perception. Touch and phasic mechanical stimuli of noxious intensity to normal skin did not reveal altered responsiveness caused by morphine. In contrast, the administration of morphine significantly increased heat pain thresholds in the UV-B-pretreated skin areas. The peripheral antihyperalgesic effects of morphine were demonstrated only in inflamed skin areas. Direct central analgesic effects were ruled out by the lack of measurable plasma concentrations of morphine and its metabolites. Morphine 0.01% significantly diminished thermal, but not mechanical, hyperalgesia by a peripheral mode of action, which suggests inhibition of effector pathways leading to heat, but not mechanical, sensitization. IMPLICATIONS: The peripheral analgesic effects of morphine were studied using modified IV regional anesthesia. When administered 1 day after the induction of dermal inflammation, morphine 0.01% diminished heat, but not primary mechanical, hyperalgesia. Therefore, suppression of mechanical hyperalgesia seen in previous studies could be predominantly due to inhibition of secondary (central) mechanical hyperalgesia.

Adult↗

PubMed1998

The effects of S- and R-flurbiprofen on the inflammation-evoked intraspinal release of immunoreactive substance P--a study with antibody microprobes.

Using antibody coated microprobes in anesthetized rats, we studied the intraspinal release of immunoreactive substance P during development of kaolin/carrageenan-induced inflammation in the knee joint, and the effects of S- and R-flurbiprofen on inflammation-evoked intraspinal release of immunoreactive substance P once inflammation was established. During the first 6 h after induction of acute inflammation, the basal release and the release of immunoreactive substance P evoked by innocuous pressure applied to the knee showed increases (n=4 rats). An intravenous dose of 9 mg/kg S-flurbiprofen (a potent inhibitor of cyclooxygenases that is anti-inflammatory and antinociceptive) did not significantly alter the pattern of inflammation-evoked release of immunoreactive substance P within 2 h although this dose reduced the responses of spinal cord neurons to pressure applied to the inflamed knee joint within 15 min to about 15% of the predrug value (Neugebauer et al., J. Pharmacol. Exp. Ther. 275 (1995) 618-628). The subsequent i.v. injection of 27 mg/kg S-flurbiprofen significantly changed the pattern of release of immunoreactive substance P showing a reduction of the level of immunoreactive substance P in the dorsal horn within 1 h (n=4 rats). The release of immunoreactive substance P was also reduced after the i.v. injection of 27 mg/kg R-flurbiprofen that is also antinociceptive but less anti-inflammatory (n=5 rats). These data show that both S- and R-flurbiprofen reduce the inflammation-evoked intraspinal release of immunoreactive substance P within hours. However, the reduction of release of immunoreactive substance P does not seem to be a prerequisite for the initial antinociceptive action of non-steroidal anti-inflammatory drugs. It may be rather important in the long term range.

Animals↗

PubMed1998

Differential effect of selective cyclooxygenase-2 (COX-2) inhibitor NS 398 and diclofenac on formalin-induced nociception in the rat.

Prostaglandins (PGs) are known to be involved in inflammatory and nociceptive processing. Since the discovery of at least two isozymes of cyclooxygenase (COX), inhibition of COX-2 has been suggested to be responsible for the therapeutic effects of nonsteroidal anti-inflammatory drugs (NSAIDs). In the present study, the effects of a rather selective COX-2 inhibitor, NS-398 (0.3-27 mg/kg i.p.), were studied using the rat formalin test as a model of acute nociception. Diclofenac (non-selective COX inhibitor; 0.3-27 mg/kg i.p.) was used as a control. NS-398 revealed antinociceptive activity only at a dose (27 mg/kg) which results in plasma concentrations which most likely do not selectively inhibit COX-2. By contrast, diclofenac inhibited formalin-induced flinching behaviour over the whole dose range tested. Our results suggest that PGs mediating nociception in the formalin test of the rat are most likely produced via the COX-1 as well as COX-2 pathways. Thus, in an acute model of nociception a non-selective COX inhibitor may offer advantages as compared to a selective COX-2 inhibitor.

Animals↗

PubMed1998

Expression of cyclooxygenase isoforms in the rat spinal cord and their regulation during adjuvant-induced arthritis.

OBJECTIVE AND DESIGN: Spinal regulation of cyclooxygenase (COX) isoforms was investigated in the animal model of peripheral inflammation induced by injection of complete Freund's-type adjuvant (CFA) in the rat hindpaw. SUBJECTS AND TREATMENT: Peripheral inflammation was induced by intraplantar injection of CFA in one hind footpad of male Sprague Dawley rats (n = 3 per time point). METHODS: Spinal cord was removed after different times (3 h to 22 d). mRNA and protein were isolated and analyzed by comparative reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot analysis, respectively. RESULTS: Under the acute inflammatory stimulus 6h after CFA application, RT-PCR revealed a twofold increase in COX-2 mRNA that reached baseline again at day 3. This transient increase occurred in the lumbar spinal cord, but changes in COX-2 mRNA expression were also registered in RNA preparations from cervical sections, spinal COX-2 induction thus not being a spatially confirmed phenomenon. Western blot analysis of spinal membrane preparations reflected the transient COX-2 mRNA induction at protein levels. During the chronic phase of arthritis at day 22, COX-2 levels were again raised significantly (1.6 fold) over baseline. Spinal levels of COX-1 were not altered at any time point of the peripheral inflammation. CONCLUSION: These data imply a regulatory role for COX-2 but not COX-1 in the spinal modulation under acute and chronic peripheral inflammation.

Animals↗

PubMed1998

Cerebrospinal fluid prostaglandins after systemic dipyrone intake.

OBJECTIVE: The object of this study was to evaluate the time course of thromboxane B2 and prostaglandin E2 concentrations in cerebrospinal fluid after oral administration of dipyrone (INN, metamizole). METHODS: A single 1.0 gm oral dose of dipyrone was given to consenting patients undergoing elective diagnostic lumbar puncture 0.5, 1, 1.5, 2, 4, 6, 8, or 12 hours before the tap. RESULTS: For thromboxane B2 a time decrease in cerebrospinal fluid concentration was apparent. In contrast, for prostaglandin E2 cerebrospinal fluid levels no consistent trend was observed. CONCLUSIONS: A time-related decrease in cerebrospinal fluid thromboxane B2 level was noted in patients receiving dipyrone. Thirty minutes after dipyrone intake cerebrospinal fluid thromboxane B2 levels already tended to be lower than those seen in patients with neurologic diseases who were not receiving dipyrone. These results are consistent with the hypothesis that dipyrone acts in the central nervous system by inhibition of particular prostanoids.

Administration, Oral↗

PubMed1998

Pharmacokinetics of morphine-6-glucuronide and its formation from morphine after intravenous administration.

BACKGROUND: Morphine-6-beta-glucuronide is a primary morphine metabolite with potent opioid action. However, its low and slow brain permeability eventually prevents its central opioid effects after short-term intravenous administration. Research is needed to establish whether morphine-6-beta-glucuronide qualifies as an analgesic; this study provides the pharmacokinetic bases for such studies. METHODS: Plasma concentration-time data of morphine-6-beta-glucuronide and morphine obtained from 20 healthy volunteers after short-term intravenous administration of either morphine-6-beta-glucuronide or morphine were described by a biexponential disposition curve. Disposition parameters of morphine-6-beta-glucuronide and morphine were estimated by nonlinear regression, and basic pharmacokinetic parameters (clearance, volume of distribution at steady state, and mean disposition residence time) were derived. A new model of metabolite kinetics was applied, and the disposition parameters of morphine and morphine-6-beta-glucuronide were then used to fit the plasma concentration-time profile of morphine-6-beta-glucuronide formed from morphine. Thereby the fraction of morphine metabolized to morphine-6-beta-glucuronide and the mean transit time of morphine across the site of metabolism were estimated. RESULTS: The extent and time course of morphine-6-beta-glucuronide formation from morphine could be well described by a parametric model, with a fraction of morphine metabolized to morphine-6-beta-glucuronide of 7.55% +/- 1.24% and a mean metabolic transit time for morphine to morphine-6-beta-glucuronide of 0.28 +/- 0.21 hour. The underlying disposition of morphine and morphine-6-beta-glucuronide was characterized by clearance (morphine clearance, 32.7 +/- 6 ml.min-1.kg-1, morphine-6-beta-glucuronide clearance, 2.2 +/- 0.4 ml.min-1.kg-1), volume of distribution at steady state (morphine, 1.8 +/- 0.3 L.hr-1; morphine-6-beta-glucuronide, 0.12 +/- 0.02 L.hr-1), and mean disposition residence time (morphine, 1.8 +/- 0.4 hours; morphine-6-beta-glucuronide, 1.7 +/- 0.4 hours). CONCLUSIONS: The time course of morphine-6-beta-glucuronide formation kinetics was analyzed with use of the information on the disposition kinetics of both morphine and preformed morphine-6-beta-glucuronide, which was obtained by separate data fits. The transformation of morphine to morphine-6-beta-glucuronide could be described by two parameters characterizing the extent and delay of metabolite formation. The results of this study will serve as pharmacokinetic bases of future investigations of morphine-6-beta-glucuronide in human beings.

Adult↗

PubMed1998

Effect of clofibrate on the chiral inversion of ibuprofen in healthy volunteers.

OBJECTIVES: To determine the influence of the hypolipidemic drug clofibrate on the stereoselective metabolism of ibuprofen in humans. METHODS: Healthy male subjects (n = 12) ingested a dose of 400 mg pseudoracemic ibuprofen (200 mg R-ibuprofen, 160 mg S-ibuprofen, and 40 mg 13C-S-ibuprofen) on two occasions after either pretreatment with clofibrate (2 gm/day over 1 week) or no pretreatment in a randomized order. RESULTS: When subjects were pretreated with clofibrate, clearances of R-ibuprofen and 13C-S-ibuprofen increased significantly from 55.0 and 66.4 ml/min to 186.2 and 106.7 ml/min (p < 0.01), respectively. This increase was similarly reflected in the clearance by inversion of R-ibuprofen (control, 36.0 ml/min; treated, 118.8 ml/min; p < 0.01), as well as in the clearance by noninversion (control, 19.0 ml/min; treated, 67.4 ml/min; p < 0.01). Unbound clearance values significantly increased for R-ibuprofen (control, 19.5 L/min; treated, 38.7 L/min) but not for 13C-S-ibuprofen (11.8 versus 10.6 L/min, respectively). The fractional inversion of ibuprofen calculated from the urinary metabolite data was increased after clofibrate pretreatment (clofibrate group, 66.4%; control, 53.5%; p < 0.01). However, this was not evident when fractional inversion was calculated from the plasma concentration-time data for the unmetabolized drug. CONCLUSIONS: Clofibrate altered the stereoselective disposition of ibuprofen in healthy volunteers by increased formation of R-ibuprofenoyl-coenzyme A rather than by an effect on oxidative metabolism of ibuprofen. This interaction has potential therapeutic implications.

Adult↗

PubMed1998

Computerized survelliance of adverse drug reactions in hospital: pilot study.

AIMS: To develop and assess the use of computerized laboratory data as a detection support tool of adverse drug reactions (ADRs) in hospital. METHODS: This was a retrospective observational study of 153 sequential medical admissions during a 2-month period to the 34-bed medical ward at the Hadassah University Hospital, Jerusalem, Israel. Measurements made were 1) Retrospective chart review for recognized and unrecognized adverse drug reactions (ADRs) and 2) Analysis of computerizied laboratory data according to defined automatic laboratory signals (ALS) for adverse reactions. RESULTS: Forty ADRs have been detected in 38 out of the 153 hospital admissions (24.8%). Nine reactions were considered severe. Altogether 212 ALS were generated involving 86 admissions. In 25 (65.8%) of the ADR-positive admissions ADRs were detected through automatic signals generated from the laboratory data. ALS were detected in 56 out of the 115 (48.7%) ADR-negative admissions. Twenty-four (60%) of the ADRs were not recognized as such by the attending physicians. Two of these reactions were severe. ALS could have generated an alert for 19 (79.2%) of the unrecognized reactions. CONCLUSIONS: Application of automatic laboratory signals can increase the rate of recognition of the ADRs and thereby improve medical care. The sensitivity and specificity of the method might be increased by refinement and redefinition of the signals.

Adult↗

PubMed1998

The real gordian knot: racemic mixtures versus pure enantiomers.

Many drugs exist as asymmetric three-dimensional (chiral) molecules and will therefore have several stereoisomers. There are often pharmacodynamic, pharmacokinetic and/or toxicological differences between enantiomers. The choice between developing a racemate or single enantiomers depends on therapeutic advances and developmental costs involved. Regarding the target environment for drug intervention, even if natural physiological mediators are achiral, their receptors may demonstrate a preference for the (-)- or (+)-enantiomer of agonists or antagonists. It is also obvious that the majority of enzymes and channels are stereospecific, at least to a variable extent. From a pharmacokinetics point of view, chirality can have an influence on drug absorption, distribution, metabolism and elimination. With a few exceptions, toxicological differences between isomers of known drugs are less dramatic than thought to be and only seldom substantiate the necessity of a racemic switch. The pharmaceutical industry is currently very interested in the so-called "racemic switch." Before proceeding to a racemic switch it is necessary to determine if 1) it is chemically feasible to produce a single enantiomer; 2) a clinical advantage is obtainable through a racemic switch; and 3) a marketing advantage is obtainable. The real goal of a racemic switch should be the rational development of compounds that are profitable for the company and--first of all--beneficial for the patient.

Journal Article↗

PubMed1998

Drug acetylation in liver disease.

N-Acetylation is a phase II conjugation reaction mediated in humans by the polymorphic N-acetyltransferase 2 (NAT2) and N-acetyltransferase 1 (NAT1). Acetylation of some drugs may be modestly decreased in patients with chronic liver disease, whereas acute liver injury has no effect on drug acetylation. For NAT2 substrates, the impairment in acetylation capacity seems to be phenotype-specific, with a more prominent effect being exerted in rapid than slow acetylators. Thus, in the presence of significant hepatic dysfunction, the activity of NAT2 may not exhibit its usual bimodal distribution, and hence phenotypic assignment may not be reliable. Furthermore, it remains to be evaluated whether the precautions advised for slow acetylators when treated with drugs metabolised by NAT2 apply to all patients (regardless of phenotype) with liver cirrhosis.

Acetylation↗

PubMed1998

Effect of clofibrate on the chiral disposition of ibuprofen in rats.

A potentially clinically important interaction has been described between clofibrate and ibuprofen in vitro. To determine whether this in vitro interaction is paralleled by a change in pharmacokinetics of ibuprofen in vivo two groups of rats were treated orally with clofibrate (n = 8, 280 mg/kg/day) or vehicle (n = 7) for 3 days. On day 3, 2 hr after the last dose of clofibrate, the rats were given an i.v. dose of pseudoracemic ibuprofen (20 mg/kg, 10 mg R-ibuprofen, 10 mg 13C-S-ibuprofen). Plasma concentrations of the enantiomers were monitored by a stereospecific gas chromatography mass spectrometry assay. The clearance of R-ibuprofen more than doubled in the clofibrate-treated group (mean +/- S.E.M.; 29.4 +/- 4.0 ml/min) as compared to control rats (13.0 +/- 1.4 ml/min; P = .003). This increase was similarly reflected in the clearance by inversion (treated, 23.2 +/- 3.2 ml/min, untreated, 10.0 +/- 1.2 ml/min; P = .003) and there was also an increase in the rate of inversion (treated, t1/2 inversion, 8.3 +/- 1.6 min; untreated, 13.9 +/- 1.4 min; P = .029). By contrast, the estimates of fractional chiral inversion were not affected by clofibrate and were in close agreement whether estimated by the area under the plasma concentration-time curve approach (treated, 0.79 +/- 0.02; untreated, 0.72 +/- 0.02) or by deconvolution (treated, 0.78 +/- 0.02; untreated, 0.73 +/- 0.02). There was a significant increase in volume of distribution at steady-state (treated, 4.42 +/- 1.12 liter/kg; untreated, 1.03 +/- 0.30 liter/kg; P = .017) observed for the R-enantiomer but not the S-enantiomer (treated, 1.04 +/- 0.13 liter/kg; untreated, 1.10 +/- 0.21 liter/kg). Pretreatment of rats with clofibrate significantly increased the concentrations of ibuprofen in fat, lung, brain and liver tissue. With respect to the protein levels of two key enzymes involved in chiral inversion, clofibrate pretreatment significantly induced expression of long chain acyl-coenzyme A synthetase, although the expression of the epimerase was unaltered. It is concluded, that clofibrate may increase the proportion of R-ibuprofen incorporated into long-lived lipid ("hybrid" lipid) stores.

Animals↗

PubMed1997

Spinally delivered nociceptin/orphanin FQ reduces flinching behaviour in the rat formalin test.

The aims of this study were to investigate the dose-dependent effects of spinally delivered nociceptin (0.3, 1, 3.3 and 10 nmol) on flinching behaviour in the rat formalin test and whether these effects were influenced by the concomitant systemic administration of naloxone (3 mg/kg, i.p.). The effect of the highest nociceptin dose differed statistically from vehicle, 0.3 and 1 nmol nociceptin. Following the administration of 1, 3.3 or 10 nmol nociceptin mean total flinches decreased dose-dependently. The effects of 10 nmol nociceptin were not reversed by a high dose of naloxone. We observed a decrease in flinching behaviour with intrathecally to the lumbar enlargement delivered nociceptin and conclude that nociceptin has antinociceptive effects in the rat formalin test.

Animals↗

PubMed1997

Improved technique for cannulation of the murine thoracic duct: a valuable tool for the dissection of immune responses.

Several experimental approaches have been used in the past for the cannulation of the thoracic duct in mice. Most, however, are characterized by a modest reproducibility and a low lymph yield. Here, we describe a cannulation technique modified with respect to the anesthesia, the use of a silicone cannula and a simple and efficient intraabdominal fixation of the drain. Surgery averaged 45 min with an intra- and postoperative mortality rate of zero. Postoperatively, mice were given access to an exercise wheel allowing increased mobility and consequently a good lymph flow, thus maintaining the function of the cannula. The mice yielded a mean of 29.3 ml/24 h (range 8-40 ml) thoracic duct lymph, which contained a mean of 2.2 x 10(6) lymphocytes/ml during the first 24 h, decreasing to 0.1 x 10(6) lymphocytes/ml on the 2nd day after cannulation. Patency of the cannulae was 100% after 3 days. Interestingly, we have detected strain dependent differences in the anatomy of the thoracic duct in the mouse and these need to be considered when cannulation procedures are attempted.

Animals↗

PubMed1997

Comparison of the antinociception produced by two oral formulations of ibuprofen: ibuprofen effervescent vs ibuprofen tablets.

OBJECTIVE: The aim of this study was to compare the dose-related effects of both ibuprofen tablets and ibuprofen effervescent [placebo, 400 and 800 mg ibuprofen (Aktren)] on phasic pain. PATIENTS: Twenty volunteers participated in this randomized, double-dummy, fivefold crossover study. METHODS: Measurements were obtained before and 15, 60 and 240 min after drug administration. Pain was produced by CO2 pulses applied to the left nostril. Subjects rated the intensity of the painful stimuli by means of a visual analogue scale. In addition, chemosomatosensory event-related potentials were recorded. RESULTS: In line with previous work, ibuprofen produced a dose-related decrease in pain-related potential amplitudes P1N1, indicating its antinociceptive effects. Higher plasma concentrations of ibuprofen were reached 15-40 min after administration of the effervescent while ibuprofen tablets had a tmax 60-90 min after administration. In addition, 60 min after intake of the effervescent a prolongation of the latencies of the potentials was observed, possibly reflecting superior antinociceptive properties when compared to ibuprofen tablets. In addition, the effervescent appeared to have more consistent effects on intensity estimates compared to ibuprofen tablets.

Administration, Oral↗

PubMed1997

Peripheral noxious stimulation releases spinal PGE2 during the first phase in the formalin assay of the rat.

Injection of formalin (5%; 50 microl) into the dorsal surface of the hind paw of rats evoked a characteristic biphasic flinching behaviour of the injured paw accompanied by a significant increase in the interstitial prostaglandin E2 (PGE2) concentration of the dorsal lumbar spinal cord. Interestingly, the increase in PGE2 concentration was only observed during the first phase of the formalin behavioural response (during the 0-10 and 10-20 min microdialysis-sample). Saline paw injection did not have a significant effect on behaviour or on PGE2 concentration. These data suggest that spinal release of PGE2 is involved in nociceptive processing in the formalin-induced hyperalgesia model of the rat during the first but not second phase.

Animals↗

PubMed1997

Elevated serum cyclophilin levels in patients with severe sepsis.

Several cytokines are considered to be important mediators in the pathophysiology of sepsis. Cyclophilins (Cyps), the main binding proteins for the immunosuppressive drug cyclosporine A, have been suggested to function as cytokines. This study was conducted to determine (i) if serum Cyp levels were elevated in critically ill patients suffering from either sepsis or other life-threatening diseases and (ii) if so, whether there was an association between Cyp levels and a certain diagnosis and/or outcome. Serum samples of 45 patients (22 severe sepsis, 23 other diagnoses) and 17 healthy controls were prospectively analyzed by an enzymatic assay using the ability of cyclophilins to catalyze cis/trans isomerisation of peptidylprolyl-peptide bonds (PPIase activity). In addition, western blotting was applied to differentiate both isoforms. PPIase activity was significantly higher in patients with severe sepsis than in patients with other diagnoses (P = 0.004) or in healthy subjects (P = 0.001). There was no difference between healthy subjects and other critically ill patients (P = 0.067). Elevated PPIase activity was associated with high mortality (P = 0.03). It is concluded that Cyps might play a role, probably as mediators in the pathophysiology of sepsis or as symptoms of diagnostic value.

Adult↗

PubMed1997

Effects of ibuprofen enantiomers and its coenzyme A thioesters on human prostaglandin endoperoxide synthases.

1. Ibuprofen enantiomers and their respective coenzyme A thioesters were tested in human platelets and blood monocytes to determine their selectivity and potency as inhibitors of cyclo-oxygenase activity of prostaglandin endoperoxide synthase-1 (PGHS-1) and PGHS-2. 2. Human blood from volunteers was drawn and allowed to clot at 37 degrees C for 1 h in the presence of increasing concentrations of the test compounds (R-ibuprofen, S-ibuprofen, R-ibuprofenoyl-CoA, S-ibuprofenoyl-CoA, NS-398). Immunoreactive (ir) thromboxane B2 (TXB2) concentrations in serum were determined by a specific EIA assay as an index of the cyclo-oxygenase activity of platelet PGHS-1. 3. Heparin-treated blood from the same donors was incubated at 37 degrees C for 24 h with the same concentrations of the test compounds in the presence of lipopolysaccharide (LPS, 10 microg ml[-1]). The contribution of PGHS-1 was suppressed by pretreatment of the volunteers with aspirin (500 mg; 48 h before venepuncture). As a measure of LPS induced PGHS-2 activity immunoreactive prostaglandin E2 (irPGE2) plasma concentrations were determined by a specific EIA assay. 4. S-ibuprofen inhibited the activity of PGHS-1 (IC50 2.1 microM) and PGHS-2 (IC50 1.6 microM) equally. R-ibuprofen inhibited PGHS-1 (IC50 34.9) less potently than S-ibuprofen and showed no inhibition of PGHS-2 up to 250 microM. By contrast R-ibuprofenoyl-CoA thioester inhibited PGE2 production from LPS-stimulated monocytes almost two orders of magnitude more potently than the generation of TXB2 (IC50 5.6 vs 219 microM). 5. Western blotting of PGHS-2 after LPS induction of blood monocytes showed a concentration-dependent inhibition of PGHS-2 protein expression by ibuprofenoyl-CoA thioesters. 6. These data confirm that S-ibuprofen represents the active entity in the racemate with respect to cyclo-oxygenase activity. More importantly the data suggest a contribution of the R-enantiomer to therapeutic effects not only by chiral inversion to S-ibuprofen but also via inhibition of induction of PGHS-2 mediated by R-ibuprofenoyl-CoA thioester. 7. The data may explain why racemic ibuprofen is ranked as one of the safest non-steroidal anti-inflammatory drugs (NSAIDs) so far determined in epidemiological studies.

Blood Platelets↗

PubMed1997

Disposition and effects of flurbiprofen enantiomers in human serum and blister fluid.

AIMS: To investigate the pharmacokinetics of the enantiomers of flurbiprofen and inhibition of prostanoid production in blister fluid and serum. METHODS: Eleven healthy volunteers received 75 mg R-, 75 mg S-flurbiprofen or no medication in a randomized 3-way cross-over study. Flurbiprofen concentrations were determined by h.p.l.c. TXB2 and PGE2 were determined by enzyme immunoassay and chemiluminescence immunoassay respectively. RESULTS: S-flurbiprofen produced almost complete (> 99% vs baseline) inhibition of thromboxane B2 (TXB2) in serum in all volunteers and significant inhibition of prostaglandin E2 (PGE2) generation in blister fluid, but there was a considerable inter-individual variation in the response ranging from -78 to +190% change from control PGE2 AUC. After administration of R-flurbiprofen, there was a mean maximum TXB2 inhibition of 65.2 +/- 15.0% in serum but no significant changes of PGE2 levels in blister fluid were observed. The pharmacokinetic parameters in serum and blister fluid were not significantly different between enantiomers. R- to S-inversion did not occur to a clinically relevant extent. For R-flurbiprofen, the complex rate constant of transfer into blister fluid was greater at the u.v.-exposed site (0.110 +/- 0.050) than at the control site (0.079 +/- 0.026, P < 0.05) which corresponded to a higher AUC and Cmax of R-flurbiprofen in u.v.-exposed blister as compared with control. For inhibition of TXB2 generation after administration of S-flurbiprofen, a sigmoidal log-linear concentration-response relationship was established in all subjects (EC50: 0.123 +/- 0.092 microgram ml-1). In contrast, inhibition of PGE2 production in blister showed no clear concentration-response relationship when correlated with concentrations of S-flurbiprofen in either serum or blister fluid. After administration of R-flurbiprofen, no concentration-effect relationship could be established. CONCLUSIONS: It is concluded that the blister model may have value for studying the pharmacokinetics and pharmacodynamics of antiinflammatory drugs in humans. Interestingly, inter-individual variation in the pharmacokinetics of flurbiprofen enantiomers could not account for the variability in response observed in the blister model.

Adult↗