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Biomedical subjects

K Brune

Publications and source records attributed to K Brune.

At least 145 records · Page 8Linked to original sources
PubMed1993

Observer-blind study with metamizole versus tramadol and butylscopolamine in acute biliary colic pain.

To investigate the combined analgesic and spasmolytic effect of metamizole (dipyrone, Novalgin, CAS 68-89-3) this drug was compared with an opioid analgesic (tramadol) and a pure spasmolytic drug (butylscopolamine). In a multicentre, observer-blind, parallel-group study conducted in five German centres 74 patients suffering from "severe" or "excruciating" colic pain caused by a calculus in the bile duct were randomized to receive intravenously 2.5 g metamizole (25 patients), 100 mg tramadol (25 patients), or 20 mg butylscopolamine (24 patients). The three treatment groups were homogeneous for age, sex, height, weight and baseline pain intensity. Metamizole was significantly more effective in reducing pain than tramadol and butylscopolamine for the primary endpoint, pain intensity on a visual analogue scale (VAS) when evaluated as the area under the curve (AUC) from baseline to onset of analgesic action (p < 0.05) and the sum of pain intensity differences (SPID) for the observation period of 2 h (p < 0.005). The mean time until the onset of analgesic action occurred was shortest (p < 0.005) for metamizole (10.9 +/- 5.8 min) compared with tramadol (15.8 +/- 11.7 min) and butylscopolamine (25.6 +/- 24.3 min). Metamizole was also more effective for the secondary efficacy endpoint, pain intensity on a 5-point ordinal scale. In the patient's overall assessment of treatment efficacy at the end of the trial, metamizole was rated as the most effective drug (p < 0.005). Fewer patients in the metamizole (3) and the tramadol (1) groups than in the butylscopolamine group (8) needed a second injection of the "rescue" medication (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
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

Biliary elimination of aspirin after oral and intravenous administration in patients.

Five patients suffering from various diseases were investigated for biliary elimination of aspirin given i.v. (500 mg, n = 3; 1500 mg, n = 1) or orally (500 mg, n = 2). Two bile draining systems, t-tube and naso-biliary tube, were used to collect the bile fluid. The analysis of biliary secretion of salicylates revealed only small amounts of salicylic acid and its conjugates undergoing biliary elimination and subsequent enterohepatic circulation ranging between 0.02 and 1.89% of the given dose (median 0.18%). Urinary recovery was calculated between 22.4 and 101.78% (median 92.27%). From these data it is concluded that biliary elimination and subsequent enterohepatic circulation plays no (aspirin) or only a minor role (salicylic acid) in the excretion of aspirin in man.

Administration, Oral↗
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↗
PubMed1993

Ibuprofen as an over-the-counter drug: is there a risk for renal injury?

Ibuprofen has recently been introduced as over-the-counter drug in several countries. The question has been raised whether or not the increased availability and use of ibuprofen as over-the-counter drug will be associated with an increased incidence of nephrotoxic side-effects. It is unquestionable that ibuprofen can cause renal damage, including functional acute renal failure, water and electrolyte disorders, and interstitial nephritis. Analgesic nephropathy is not a documented consequence of ibuprofen therapy. Renal side-effects of ibuprofen appear to be dose-dependent, and were not reported at the recommended dosage as over-the-counter drug (0.2-0.8 g/d) except for a single child. Even at anti-inflammatory doses (> 1.6 g/d), renal side-effects are almost exclusively encountered in patients with low intravascular volume and low cardiac output particularly in old age. Alternative analgesic and antipyretic agents display no less risk for renal injury than ibuprofen.

Acute Kidney Injury↗
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

Peptidyl-prolyl cis-trans isomerase from Bacillus subtilis. A prokaryotic enzyme that is highly sensitive to cyclosporin A.

Cyclophylins are members of a class of proteins with peptidyl-prolyl cis-trans isomerase activity. These enzymes bind the immunosuppressive agent, cyclosporin A (CsA), which acts as a competitive inhibitor. The peptidyl-prolyl cis-trans isomerase from Bacillus subtilis (PPIase) was purified to homogeneity in a 4-step purification procedure, which resulted in a 100-fold protein purification with a yield of 5%. Coomassie blue-stained SDS-PAGE revealed a single band of about 18 kDa. PPIase activity was determined using synthetic peptides as substrates in a 2-step reaction coupled to chymotrypsin. Treatment of Bacillus subtilis PPIase by CsA revealed an inhibition constant of Ki = 175 nM, which differs from cyclophilin of enterobacteria such as E. coli or Salmonella typhimurium and is in the range of human enzymes.

Amino Acid Isomerases↗
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

Cytotoxic effects of rheumatoid arthritis sera on chondrocytes.

Human sera from patients with rheumatoid arthritis (RA) and also from healthy donors were found to be toxic to cultured chondrocytes. Immunoglobulins were found to bind to the surface of cultured cells and cells in chicken sternal cartilage, as detected by indirect immunofluorescence. In vitro, cell detachment from the substrate was caused by the incubation of chondrocyte monolayers with 5 per cent and less RA serum. Serum treatment caused cytotoxic degradation of the cells. This could be quantified by a chromium release assay. Heat inactivation of the serum abolished the cytotoxicity. The extent of the cytotoxic reaction was related to the complement content of the serum and also to the intensity of the disease, as determined by the Ritchie-index. Other cell types, as chondrosarcoma cells, normal fibroblasts and corneal epithelium, were not affected by RA sera.

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

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↗
PubMed1992

Differential analgesic effects of aspirin-like drugs.

Tissue damage, including that due to surgical manipulation, results in 2 distinct but connected changes in the pain perception pathway. Firstly, cells disintegrate at the site of tissue damage and release mediators, including prostaglandins. These mediators transform fine nerve endings, particularly high-threshold mechanoceptors, into nociceptors. In other words, fine nerve endings that are not normally activated by mechanical pressure or temperature changes become very sensitive and are depolarised after minor mechanical or thermal changes. Secondly, in the central nervous system (CNS) and, particularly, in the dorsal horn of the spinal cord, reflex activity is increased, metabolic activity of the neuronal cells is enhanced and, chronically, major rearrangements of mediator production and electrical activity of the dorsal horn cells may be observed. Both types of change contribute to the well known phenomenon of hyperalgesia, which is regularly observed in connection with tissue damage, including that produced by surgical manipulation. It has been shown that aspirin-like drugs reduce the enhanced nociceptor activity in damaged tissue, probably as a result of prostaglandin synthesis inhibition. Recently, there have been indications that these drugs may have an additional mechanism of action in the spinal cord or higher parts of the CNS. Using the pure enantiomers of flurbiprofen in pharmacodynamic experiments in the rat, we have observed that the R- and S-enantiomers may exert differential analgesic effects. The R-enantiomer, which does not inhibit cyclo-oxygenase in vitro, was almost as effective as the S-enantiomer, which does inhibit prostaglandin synthesis in different models of pain and nociception.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesia↗