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Biomedical subjects

G Geisslinger

Publications and source records attributed to G Geisslinger.

At least 127 records · Page 7Linked to original sources
PubMed1993

Stereoselectivity of biliary excretion of 2-arylpropionates in rats.

To examine the stereoselectivity of biliary excretion, the optically pure enanatiomers of ketoprofen (KT), ibuprofen (IBU), and flurbiprofen (FLU) were intravenously administered to normal and bile duct-cannulated rats at 10 mg/kg. The recovery of total KT in bile was significantly higher after administration of (S)-KT than after (R)-KT [90.1 +/- 3.5% vs 68.8 +/- 8.2%, n = 3, P < 0.05]. In normal rats the terminal half-life of (R)-KT was significantly shorter than that of (S)-KT after administration of (R)-KT (2.2 +/- 0.6 h vs 14.3 +/- 4.9 h, n = 3, P < 0.05). The terminal half-life of both enantiomers was significantly shorter in rats with continuous bile drainage as compared to normal rats. No significant differences in pharmacokinetic parameters could be found between both enantiomers in bile duct-cannulated animals. The total amount of IBU in bile was slightly higher after administration of (S)-IBU than after (R)-IBU administration. The percentage of (R)-IBU after (R)-IBU administration, however, was very low [(R)-IBU: 1.5 +/- 0.9%, (S)-IBU: 23.4 +/- 5.8%]. In normal rats the clearance of (R)-IBU was significantly higher as compared to (S)-IBU. Differences in pharmacokinetic parameters between normal and bile duct-cannulated rats were not statistically significant due to high interindividual variability. The total recovery of FLU, which was excreted in bile to a lower extent than either KT or IBU, also tended to be greater after S-enantiomer administration. Only small amounts of (S)-FLU could be recovered in bile after (R)-FLU administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Rapid determination of methadone in plasma, cerebrospinal fluid, and urine by gas chromatography and its application to routine drug monitoring.

Determination of methadone (MET) in biological fluids can serve to adjust dosages in patients suffering from cancer pain or participating in methadone maintenance programs. We developed a gas chromatographic assay using nitrogen-phosphorus detection. The method involves a single-step extraction from alkalized plasma, cerebrospinal fluid, or urine into n-hexane/isoamyl-alcohol (99/1, v/v). Dextropropoxyphene was used as internal standard. Separation was achieved with a silica SE-52-CB column (13 m x 0.25-mm I.D.). The method was validated for the determination of MET in plasma, urine, and cerebrospinal fluid with a quantification limit of 0.5 ng/mL. The coefficients of variation for within-day and between-day precision were within 10.2 and 14.1%, respectively. Approximately 100 samples can be analyzed by one person in the course of a working day, making the method applicable to routine drug monitoring. The method was demonstrated to be sensitive and accurate for pharmacokinetic studies in plasma, urine, or cerebrospinal fluid.

Chromatography, Gas↗
PubMed1993

Pharmacokinetics and pharmacodynamics of ketamine enantiomers in surgical patients using a stereoselective analytical method.

In a randomized, double-blind study, we have examined the stereoselective disposition and pharmacodynamic characteristics of ketamine in surgical patients after i.v. administration of S(+)-ketamine 1 mg/kg body weight (25 patients) or racemic ketamine 2 mg/kg body weight (25 patients). S(+)-Ketamine was not inverted to R(-)-ketamine. After racemate administration we observed statistically significant (P < 0.01) smaller clearance and volume of distribution for R(-)-ketamine compared with S(+)-ketamine. In contrast, the pharmacokinetic variables of S(+)-ketamine were not significantly different between treatment groups. Systolic and diastolic arterial pressure and heart rate increased significantly (P < 0.005) in both groups. At 1, 3 and 15 min after S(+)-ketamine administration, significantly greater increase in systolic and diastolic pressures were observed compared with the racemate group. There was no correlation between the changes in haemodynamic variables and plasma catecholamine concentrations, which remained unaffected after administration of the medications.

Adolescent↗
PubMed1993

Variability in the stereoselective disposition of ibuprofen in patients with rheumatoid arthritis.

1. Patients suffering from rheumatoid arthritis received oral doses of 600 mg racemic ibuprofen (n = 25; RAC) or 400 mg (S)-ibuprofen (n = 25; S-IBU) in a double-blind, randomized parallel-group study. 2. The pharmacokinetic parameters of (S)-ibuprofen were not statistically different between treatments (P > 0.05). Comparing (S)- and (R)-ibuprofen within the group receiving the racemate significantly higher Cmax (20.3 +/- 5.3 vs 17.7 +/- 4.4 micrograms ml-1; P < 0.02; 95% confidence interval for differences (CI): 0.5-4.6), AUC (86.2 +/- 23.5 vs 67.6 +/- 26.6 micrograms ml-1 h; P < 0.001; CI: 9.5-27.6), mean residence time (4.5 +/- 1.1 vs 4.1 +/- 1.2 h; P < 0.01; CI: 0.1-0.6) and renal clearance (0.8 +/- 0.6 vs 0.0 +/- 0.0 ml min-1; P < 0.001; CI: 0.5-1.0) values were observed for the (S)-enantiomer. 3. No difference was found (P > 0.05) between treatments in the percentage of the dose recovered in the urine as (R)- or (S)-ibuprofen plus metabolites (S-IBU: 80.2 +/- 8.47 vs RAC: 74.1 +/- 14.0%). 4. Interindividual variation in the pharmacokinetics of (S)-ibuprofen following administration of the racemate was similar to that following the administration of the single isomer suggesting that chiral inversion is not a major factor contributing to variability in the disposition of this drug.

Arthritis, Rheumatoid↗
PubMed1993

R-flurbiprofen: isomeric ballast or active entity of the racemic compound?

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.

Animals↗
PubMed1993

Metabolic chiral inversion of 2-arylpropionates in different tumor cell lines.

The study presented aimed at investigating whether tumor cell lines in continuous culture could be used as in vitro model for inversion experiments. The effect of culture conditions on the extent of inversion was examined. Under optimized culture conditions human and rat tumor cell lines were incubated with the enantiomers of ibuprofen, ketoprofen and flurbiprofen, respectively. Similarly to the situation in man in vivo, inversion of R-ibuprofen occurred in human hepatoma cells, where no inversion of R-ketoprofen or negligible inversion of R-flurbiprofen could be observed. In contrast to R-flurbiprofen the R-enantiomers of ibuprofen and ketoprofen were substantially inverted in the rat hepatoma cells in accordance with observations in the rat in vivo.

Animals↗
PubMed1992

Stereoselective determination of the enantiomers of methadone in plasma using high-performance liquid chromatography.

An enantioselective high-performance liquid chromatographic assay for the quantification of methadone in human and beagle plasma is described. The procedure involves extraction of methadone from alkalized plasma into hexane-isoamyl alcohol (99:1, v/v). Stereoselective separation was achieved with a silica column with covalently bound alpha 1-acid glycoprotein (Chiral-AGP) without any derivatization procedure. The detection wavelength was set at 215 nm. Using an internal standard provided reliable control of the extraction procedure as well as quantification of the enantiomers of methadone. The limit of quantification was found to be 2.5 ng/ml. The method was demonstrated to be sufficiently sensitive for stereoselective pharmacokinetic studies of methadone.

Adult↗
PubMed1992

Metabolic chiral inversion of 2-arylpropionates in rat H4IIE and human Hep G2 hepatoma cells. Relationship to in vivo metabolism.

The inversion of 2-arylpropionic acids (2-APAs) has been investigated in vitro using rat H4IIE and human Hep G2 hepatoma cells in continuous culture. The effect of substrate concentration (15-150 micrograms/mL), cell density (1.5-12 x 10(6) cells/dish) and serum content of the culture medium (0-20%) on inversion was examined in rat H4IIE hepatoma cells using R-ibuprofen as model compound. Increasing R-ibuprofen concentrations and decreasing serum content of the medium resulted in increased inversion whereas variation of cell density had no effect. Furthermore, rat H4IIE and human Hep G2 hepatoma cells were incubated with the individual enantiomers of ibuprofen, ketoprofen and flurbiprofen under optimized culture conditions (serum-free culture medium). The elimination rate constants (kel) and fractions inverted (Fi) were determined. Although inversion occurred slowly in the tumor cells and thus long incubation periods (120 hr) were required, the hepatoma cells were nevertheless able to mimic qualitatively the species and substance specificity of inversion of 2-APAs as observed in vivo.

Animals↗
PubMed1992

Differential effects of ketamine enantiomers on NMDA receptor currents in cultured neurons.

The effects of R- and S-ketamine on N-methyl-D-aspartate receptor-activated cation currents (NMDA receptor currents) of voltage-clamped cultured rat hippocampal neurons were investigated using the whole-cell patch-clamp technique. Both enantiomers exhibited a voltage- and use-dependent blockade of NMDA receptor currents, with the S-enantiomer being about twice as potent as the R-enantiomer. Calculated relative forward and backward rates suggest that conformational differences influence the dissociation from the binding site more than the association with it.

Animals↗
PubMed1992

Stereoselective high-performance liquid chromatographic determination of flurbiprofen in human plasma.

An enantioselective high-performance liquid chromatographic assay for the quantitation of the enantiomers of flurbiprofen in human plasma is described. The procedure involved extraction of flurbiprofen from acidified plasma into hexane-diethyl ether (8:2, v/v). Stereoselective separation was achieved with a prepacked alpha 1-acid glycoprotein column without any derivatization procedure. A second assay using a conventional reversed-phase column to determine racemic flurbiprofen is also described. The detection wavelength was set at 246 nm. The limit of quantification was found to be 50 ng/ml for both assays. The method was demonstrated to be sufficiently sensitive for stereoselective pharmacokinetic studies of flurbiprofen.

Chromatography, High Pressure Liquid↗
PubMed1992

The effect of the enantiomers of ibuprofen and flurbiprofen on the beta-oxidation of palmitate in the rat.

The effects of the enantiomers of ibuprofen (0.25 and 0.50 mmol/kg b.w.) and flurbiprofen (0.01, 0.03, and 0.06 mmol/kg b.w.) on the beta-oxidation of palmitate were investigated in the rat. The mean cumulative exhalation of 14CO2 after ip administration of [U-14C]palmitic acid was significantly reduced over 6 h by ibuprofen at the higher dose but not at the lower dose for either enantiomer. There was no difference between the enantiomers, the reduction over 6 h being 31.3 and 33.0% for (R)- and (S)-ibuprofen, respectively. There was also a significant inhibition of beta-oxidation by flurbiprofen at all 3 doses. Again, there was no stereoselectivity evident in this inhibition. Flurbiprofen was much more potent than ibuprofen in eliciting this effect, the 0.01mmol/kg dose giving a similar reduction in beta-oxidation as observed for the 0.50 mmol/kg dose of ibuprofen. The data support the hypothesis that inhibition of the in vivo beta-oxidation of palmitate by ibuprofen and flurbiprofen is primarily via a nonstereoselective noncoenzyme A-dependent mechanism.

Animals↗
PubMed1992

Pure enantiomers of 2-arylpropionic acids: tools in pain research and improved drugs in rheumatology.

The mode of action of aspirinlike drugs in pain is widely referred to as inhibition of prostaglandin synthesis. Salicylic acid, however, at low doses, is an analgesic but not a potent anti-inflammatory agent. This "enigma" may be resolved by recent findings employing 2-arylpropionic acids. Pure enantiomers of these chiral drugs show a different pharmacodynamic and pharmacokinetic profile. Using pure enantiomers of flurbiprofen, ibuprofen, and ketoprofen, we could show that (1) R-enantiomers of these drugs are inverted to S-enantiomers to a different degree in different species, including humans, (2) the pharmacokinetic parameters of both pure enantiomers differ in a drug- and a species-specific manner, and (3) both enantiomers exert differential analgesic effects. It appears particularly interesting that R-flurbiprofen, for instance, which is not or only to a small extent inverted in humans and rats, is practically devoid of prostaglandin synthesis inhibition in vitro. Consequently, in line with current thinking, R-flurbiprofen is not toxic to the gastrointestinal tract and shows no anti-inflammatory effects. In contrast to current concepts, however, this enantiomer does exert analgesic activity in different models of pain and nociception. It is concluded that R-flurbiprofen and, possibly, other R-enantiomers of 2-arylpropionic acids may exert novel analgesic effects independently of peripheral prostaglandin synthesis inhibition in inflamed tissue.

Animals↗
PubMed1992

Variability of inversion of (R)-flurbiprofen in different species.

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 alpha 1-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 microgram/100 microL of plasma).

Animals↗
PubMed1992

Differential effects of dipyrone, ibuprofen, and paracetamol on experimentally induced pain in man.

In a double-blind cross-over study on 22 healthy subjects the analgesic efficacies of the antipyretic analgesic drugs ibuprofen, dipyrone and paracetamol were tested against placebo using a model of experimentally induced pain. To this purpose interdigital webs were pinched repeatedly for 2 min periods. The painfulness of these stimuli was assessed by the subjects on an electronically controlled visual analogue scale at 10 sec intervals. In addition to the subjective pain ratings the stimulus induced reflex diminution of the blood flow in the stimulated hand was measured with photoplethysmography and laser Doppler flow analysis. The flare response around the stimulated area was assessed with infrared thermography. In this assay system ibuprofen and dipyrone, but not paracetamol, showed statistically significant analgesic effects by preventing hyperalgesia which is normally induced by the repeated stimulation of a skin site. This hypoalgesic effect was not related to the subjective impression of the subjects of the analgesic potency of the respective drug. Sympathetic reflex vasoconstriction was not quantitatively related to the drug induced hypoalgesia. Ibuprofen and, to a minor extent, the other antipyretic analgesic drugs also diminished the stimulus induced flare reaction around the stimulated skin sites.

Acetaminophen↗
PubMed1991

Stereoselective high-performance liquid chromatographic determination of the enantiomers of ketamine and norketamine in plasma.

An enantioselective high-performance liquid chromatographic assay for the quantitation of the enantiomers of ketamine and its major metabolite norketamine in human plasma is described (assay I). The procedure involved extraction of the compounds from alkalized plasma into cyclohexane. Stereoselective separation was achieved with a prepacked alpha 1-acid glycoprotein column without any derivatization procedure. A second assay using a conventional reversed-phase column to determine total (racemic) ketamine and norketamine is also described. Because of interfering plasma peaks (assay II) the cyclohexane solution was reextracted into 1 M hydrochloric acid. The detection wavelength was 215 nm for all substances. The limit of quantification of the method was ca. 40 ng/ml in plasma. The assays were sensitive and reproducible. The method was demonstrated to be sensitive for stereoselective pharmacokinetic studies of ketamine after clinical doses.

Chromatography, High Pressure Liquid↗
PubMed1991

Aspirin-like drugs may block pain independently of prostaglandin synthesis inhibition.

Using flurbiprofen, a chiral anti-inflammatory and analgesic 2-arylpropionic acid derivative, the enantiomers of which are not converted to each other (less than 5%) in rats or man, we obtained evidence that prostaglandin synthesis inhibition is primarily mediating the anti-inflammatory activity but prostaglandin synthesis independent mechanisms contribute to the analgesic effects. Thus, the S-form inhibited prostaglandin synthesis, inflammation and nociception in rats. The R-form had much less effect on prostaglandin synthesis and did not affect inflammation. It did, however, block nociception in rats almost as potently as the S-form. S-flurbiprofen, in contrast to the R-form, was clearly ulcerogenic in the gastrointestinal mucosa. These results indicate additional molecular mechanisms of analgesia and suggest the use of R-arylpropionic acids as analgesics.

Animals↗