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Biomedical subjects

K Brune

Publications and source records attributed to K Brune.

At least 181 records · Page 10Linked to original sources
PubMed1990

Pharmacokinetics of S(+)- and R(-)-ibuprofen in volunteers and first clinical experience of S(+)-ibuprofen in rheumatoid arthritis.

S(+)-, R(-)- or racemic ibuprofen was administered orally to volunteers in doses of 150 mg, 300 mg and 500 mg pure S(+)-, 300 mg pure R(-)- and 600 mg racemic ibuprofen. The pharmacokinetic parameters in humans showed that S(+)-ibuprofen was not inverted to R(-)-ibuprofen, whereas R(-)-ibuprofen was inverted to S(+)-ibuprofen to a variable degree. S(+)-ibuprofen and R(-)-ibuprofen given alone more rapidly reached significantly higher maximal plasma concentrations than after the same doses of the racemic compound. The elimination half-lives and clearance values for all three forms of ibuprofen were comparable. The mean residence time of S(+)-ibuprofen after R(-)- and racemic ibuprofen was significantly longer than after administration of the pure S(+)-enantiomer. Judged by the AUC, the bioavailability of S(+)-ibuprofen was independent of the dose within the range tested. Administration of S(+)-ibuprofen to 6 rheumatic patients showed that the pharmacokinetic behaviour of S(+)-ibuprofen in patients was similar to that found in volunteers. S(+)-ibuprofen proved to be an effective analgesic antirheumatic drug in the dose range 1 to 1.5 g/day.

Adult↗
PubMed1990

The biliary elimination and enterohepatic circulation of ibuprofen in rats.

The biliary and urinary excretion of ibuprofen and its metabolites were determined in rats after intravenous and peroral administration of 25 and 100 mg/kg of the drug. Within 24 hours 48% of the low i.v. dose and 59% of the high i.v. dose were eliminated via bile as ibuprofen and its metabolites. Following oral administration 40 to 41% of the dose were recovered in bile, whereas 16 to 32% of the dose were eliminated in urine, resulting in an overall drug recovery of 66 to 79% within 24 hours. Upon infusion of bile containing ibuprofen and its metabolites into the duodenum substantial enterohepatic cycling of the drug occurred in the rat.

Animals↗
PubMed1990

Biliary elimination of non-steroidal anti-inflammatory drugs in patients.

In view of evidence in animals that enterohepatic recirculation of non-steroidal anti-inflammatory drugs contributes to small intestinal mucosal damage we have investigated the extent of biliary elimination of three nonsteroidals. Ibuprofen (n = 3), diclofenac (n = 2) and indomethacin (n = 3) were given to six patients with a percutaneous transhepatic cholangiodrainage placed in the bile duct system. One patient received all three drugs. The mean biliary elimination of ibuprofen was 0.82% of the given dose compared with 50.41% urinary excretion. When diclofenac or indomethacin was administered 4.62% and 6.40% of the dose were found in bile, whereas 34.73% and 32.22% (means) were recovered from urine, respectively. The mean percentage eliminated in bile as unchanged drug and active phase II metabolites was 0.15% for ibuprofen, 1.09% for diclofenac and 5.02% for indomethacin.

Adult↗
PubMed1990

Laminin interactions with ductal pancreatic adenocarcinoma cells: identification of laminin- and collagen-binding proteins.

Laminin promotes the modulation of human pancreatic adenocarcinoma cells from a proliferative to a resting phenotype. This process includes restoration of cell polarity, increase of protein biosynthesis, and increase of glycoprotein secretion. The growth correlates with the amount of laminin coated on the culture dish. Adenocarcinoma cells do not synthesize collagen type I, fibronectin or laminin. Prolonged propagation of the cells on laminin substratum enhances the expression of laminin-binding sites on the cell surface. Laminin binds to cell plasma membrane vesicles with a KB of about 2.2 x 10(10). By affinity chromatography of [35S]methionine-labeled, detergent-extracted, cells on immobilized laminin, a Mr 82,000 polypeptide could be enriched. By simultaneous chromatography on immobilized collagen type I, a Mr 34,000 polypeptide was retained. In laminin overlay experiments on transblotted plasma membrane proteins, Mr 82,000 and 70,000 polypeptides were labeled. Affinity chromatography on laminin-Sepharose of tumor cell membranes from cells grown in nude mice tumors retained Mr 100,000, 82,000, 70,000 and 55,000 polypeptides bound to the column. Endoglycosidase F treatment of these proteins reduced the number of higher Mr proteins, leaving a Mr 70,000 polypeptide, together with smaller peptides. Using the enriched binding protein fraction as antigens, monoclonal antibodies (mAbs) were prepared in mice. Two of the mAbs were further analysed; they recognized simultaneously the complete pattern of high and low Mr polypeptides identified to date by the other methods. Antibody 2A1-H7 was capable of inhibiting attachment and spreading of the cells on laminin and collagen I, but not on tissue-culture plastic. These data may indicate a molecular heterogeneity, partly based on diverse glycosylation, responsible for the variations in the molecular weight of the binding proteins. The adaptation processes of the tumor cells during growth on the extracellular matrix may indicate a regulatory function on tumor growth and metastasis in vivo.

Adenocarcinoma↗
PubMed1990

Is there a rational basis for the different spectra of adverse effects of nonsteroidal anti-inflammatory drugs (NSAIDs)?

NSAIDs, particularly those related to aspirin, are all known to cause adverse effects, notably in the gastrointestinal tract, blood, liver and kidney, in addition to allergic and pseudo-allergic reactions. In the past decade, there have been many attempts to elucidate the cause(s) of these adverse effects so that new NSAIDs which are widely devoid of them can be developed. As a result, a number of concepts have been formulated which may well have considerable influence upon the future development of NSAIDs.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1989

High-performance liquid chromatographic determination of ibuprofen, its metabolites and enantiomers in biological fluids.

An isocratic high-performance liquid chromatographic method to determine racemic ibuprofen (assay I) and its major metabolites (assay II) in biological fluids (plasma, urine, bile) using a conventional reversed-phase column is described. A third assay using beta-cyclodextrin as stationary phase (Cyclobond I) for the separation of the ibuprofen enantiomers is also described. A wavelength of 220 nm was used to monitor the substances. The sensitivity of the method was 0.1 microgram/ml for all three assays. The method was demonstrated to be suitable for stereoselective pharmacokinetic studies of ibuprofen in humans and animals.

Bile↗
PubMed1989

Pharmacological differences between R(-)- and S(+)-ibuprofen.

Ibuprofen (IBU) is a non-steroidal anti-inflammatory drug exhibiting optical isomerism. Only the racemate is in clinical use. In in vitro studies it has been demonstrated that only the S(+)-enantiomer inhibits the PG synthetase system. Nevertheless, it is widely believed that the sole use of the active isomer does not comprise any advantages since the inactive isomer is converted within the human body. In a triple cross-over study (300 mg S(+), 300 mg R(-), 600 mg racemic IBU; n = 8), we could show that the converted R(-)-IBU after racemate administration provides for only one third of the AUC of S(+)-IBU obtained after S(+)-application. Highest S(+)-peak plasma levels were reached after S(+)-IBU, lower ones after racemate. We, therefore, studied 4 patients with classical rheumatoid arthritis treated with 2-3 doses of 500 mg of S(+)-IBU/day over a two week period. Significant clinical recovery (Ritchie-index p less than 0.01; analogue scale pain p less than 0.05, motion p less than 0.01) was reached after one week. The results indicate that a reduction of dose and of metabolic load is possible if the S(+)-enantiomer is administrated.

Administration, Oral↗
PubMed1989

Development of an enzyme-linked immunosorbent assay of thromboxane B2 using a monoclonal antibody.

An inhibition enzyme-linked immunosorbent assay (ELISA) was developed using a monoclonal antibody against thromboxane B2 (TXB2). As a specific antigen, the bovine serum albumin conjugate of TXB2 was adsorbed onto polystyrene microtiter plates. The sensitivity of the monoclonal antibody was compared by means of three different enzyme conjugates, all commercially available. The detection limit with immunoglobulin conjugates of alkaline phosphatase and horseradish peroxidase was 0.04 ng of TXB2 per sample. The use of horseradish peroxidase coupled with an avidin-biotin complex allowed a tenfold increase in sensitivity to 0.0045 ng of TXB2 per sample. The suitability of the assay was checked with TXB2-containing human serum and urine samples, which yielded unchanged standard curves. Recovery experiments had an accuracy of r = 0.960 and r = 0.987. Validity was confirmed by a good correlation between radioimmunoassay and ELISA (r = 0.949). Results of an inhibition experiment with platelet-rich plasma in the presence and absence of ibuprofen demonstrated the practical applicability of this method.

Antibodies, Monoclonal↗
PubMed1989

Selective growth inhibition of ductal pancreatic adenocarcinoma cells by the lysosomotropic agent chloroquine.

Pancreatic adenocarcinoma cells show characteristics of macrophages as phagocytosis and exocytosis. These phagocytic activities can be inhibited in macrophages by antirheumatic drugs, e.g. gold compounds and antimalarials. We have now tested the activity of auranofin and chloroquine to inhibit growth of a pancreatic tumor cell line (PaTu II) and of human foreskin fibroblasts (HFF) as a control. We found that auranofin (greater than or equal to 2 microM) inhibits both PaTu II cell and HFF growth. In contrast, chloroquine (4-18 microM) selectively interferes with the growth of PaTu II cells. This specific vulnerability of PaTu II cells was confirmed in cocultures of tumor cells and fibroblasts.

Auranofin↗
PubMed1989

Mode of antinociceptive action of flupirtine in the rat.

1. Flupirtine is a novel, centrally acting, non-opioid analgesic agent. The present investigation was undertaken to ascertain which neuronal systems might be responsible for its antinociceptive effect in rodents. The antinociceptive responses to the test compounds were examined in the tail-flick test. 2. The selective destruction of noradrenergic pathways by 6-hydroxydopamine considerably reduced the flupirtine-induced inhibition of nociceptive responses but not the clonidine-induced antinociception which was significantly enhanced. Depletion of spinal 5-hydroxytryptaminergic pathways by pretreatment with 5,7-dihydroxytryptamine failed to affect the action of flupirtine and clonidine. 3. The depletion of neurotransmitters by reserpine totally abolished the antinociceptive action of flupirtine. By contrast, clonidine-induced inhibition of nociceptive responses remained unchanged. 4. Inhibition of the synthesis of noradrenaline by alpha-methyl-L-p-tyrosine attenuated the antinociception induced by flupirtine. In contrast, inhibition of the synthesis of 5-hydroxytryptamine by (+/-)-6-fluorotryptophan did not influence the antinociceptive activity of flupirtine. 5. Inhibition of noradrenaline uptake by imipramine led to a significant augmentation of flupirtine-induced antinociception. 6. Selective antagonists at alpha-adrenoceptors significantly decreased the antinociceptive action of flupirtine. Antinociception induced by clonidine was significantly diminished by idazoxan but not by prazosin. 7. The 5-hydroxytryptamine (5-HT) antagonist, ketanserin diminished the antinociceptive activity of flupirtine, probably due to its additional alpha 1-adrenoceptor antagonist activity. The antinociceptive effect of clonidine was not influenced by ketanserin. 8. Cholinoceptor antagonists such as mecamylamine and pirenzepine did not alter the antinociceptive action of flupirtine. Flupirtine-induced antinociception also remained unchanged after pretreatment with haloperidol. 9. Flupirtine has no pharmacologically relevant affinity for alpha 1-, alpha 2-adrenoceptors, 5-HT1- and 5-HT2-receptors as shown in direct binding studies. 10. The present results indicate that the antinociceptive action induced by flupirtine depends on the descending noradrenergic pain-modulating system.

Adrenergic alpha-Antagonists↗
PubMed1989

Therapeutically relevant differences in the pharmacokinetical and pharmaceutical behavior of ibuprofen lysinate as compared to ibuprofen acid.

The pharmacokinetic properties of ibuprofen p.o. given either as a lysine salt or as acid to eight young, healthy male volunteers was investigated. Ibuprofen lysinate, administered after overnight fasting, produced peak plasma concentrations significantly earlier and higher than ibuprofen acid. A similar difference was observed when the drugs were given following a standardized breakfast. Under these conditions the lat-time was significantly shorter for the lysine salt than for the acid. The pharmacokinetic differences are likely to result from the faster dissolution rate of ibuprofen lysinate. They indicate that the administration of ibuprofen as lysine salt before meals may be advantageous if rapid and reliable onset of pain relief is required.

Adult↗
PubMed1988

A monoclonal anti-thromboxane B2 antibody.

A monoclonal antibody against thromboxane B2 which may be used in standard fluid phase radioimmunoassays with a detection limit of around 40 pg and a binding affinity of 1.98 X 10(9) M-1 is described. Limited crossreactivity could be observed only with structurally closely related compounds such as 2,3-dinor-thromboxane B2 (8.9%), thromboxane B1 (15.7%) and thromboxane B3 (39.7%). Detectable crossreactivity with 11-dehydro-thromboxane B2, omega-carboxy-thromboxane B2, omega-hydroxy-thromboxane B2, prostaglandins of the D-, E- and F-type as well as metabolites of prostacyclin was lacking. The monoclonal anti-thromboxane B2 antibody proved well suited for measuring the thromboxane B2 content in tissue culture supernatants as well as in human serum.

Animals↗
PubMed1988

Possible role of oxygen free radicals in ethanol-induced gastric mucosal damage in rats.

The involvement of oxygen free radicals in the development of the ethanol-induced gastric mucosal damage has been investigated. We found that oral administration of superoxide dismutase reduced the incidence of ethanol-induced mucosal lesions. Reduction of superoxide dismutase activity by diethyldithiocarbamate led to a pronounced aggravation of mucosal damage. Inhibition of the chloride-bicarbonate channel by a stilbene derivative also aggravated the ethanol-induced hemorrhagic lesions. Neither glutathione peroxidase, catalase, nor ceruloplasmin were capable of inhibiting the development of mucosal damage. Compounds with scavenging properties such as thiourea, 1-phenyl-3-(2-thiazolyl)-2-thiourea, dimethyl sulfoxide, various inorganic compounds (elements of the first and second subgroups and of the sixth group of the periodic table) and sulfhydryl-containing substances protected the gastric mucosa against ethanol-induced injury in a dose-related manner. Naturally occurring antioxidants such as alpha-tocopherol, beta-carotene, and coenzyme Q10 were ineffective. The present results suggest that superoxide free radicals are involved in the development of ethanol-induced gastric mucosal lesions, probably via an interaction with cellular membranes.

Animals↗