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K Brune

Publications and source records attributed to K Brune.

At least 55 records · Page 3Linked to original sources
PubMed2000

Upregulation of cyclooxygenase-1 and the PGE2 receptor EP2 in rat and human mesangioproliferative glomerulonephritis.

OBJECTIVE AND DESIGN: Glomerular expression and localization of the two cyclooxygenase isoforms, Cox-1 and Cox-2, and the prostaglandin E2 receptor EP2 were investigated in a rat model of transient mesangioproliferative glomerulonephritis. Cox expression was also studied in biopsies from patients with IgA nephropathy. MATERIALS AND TREATMENT: After induction of glomerulonephritis by i.v. injection of a monoclonal anti-Thy1.1 antibody, rats were sacrificed at day 2, 6, 12 and 56. Changes in protein expression were detected by immunohistochemistry. Glomerular mRNA levels were analyzed by real time polymerase chain reaction (PCR). RESULTS: In normal rat kidney, immunoreactivity of Cox-1 was detected predominantly in collecting duct cells and that of Cox-2 in the macula densa. Cox-1 staining showed a massive transient increase in diseased glomeruli at day 6, localized mainly to mesangial cells coinciding with cell proliferation, which also peaked at day 6. Upregulation of Cox-1 was also evident at the mRNA level (4 fold). Cox-2 expression in the macula densa region transiently increased at day 6, but no significant upregulation of Cox-2 was observed in glomerular cells at any time point. Prostaglandin E2 receptor EP2 mRNA and protein were detected in rat glomeruli. EP2 immunoreactivity was prominent on podocytes in normal rats while at day 6 of the disease also mesangial cells stained positive. In biopsies of patients with IgA nephritis, predominant expression of Cox-1, but not Cox-2, was found in glomeruli, whereas Cox-2 was strongly expressed in infiltrating interstitial cells. CONCLUSIONS: The upregulation of glomerular Cox-1 but not Cox-2 and the parallel induction of the EP-2 receptor, which was shown to mediate cAMP accumulation in mesangial cells, suggest that induction of prostaglandin formation may contribute to the resolution rather than to the progression of anti-Thy1.1 nephritis. The expression pattern of Cox-1 and Cox-2 in human IgA nephritis points to a role for both Cox isoforms in human glomerular inflammation.

Animals↗
PubMed2000

[Specific cyclooxygenase-2 inhibitors. Basis and options of a pharmacotherapeutic concept].

The therapeutic and unwanted side effects of non-steroidal antiinflammatory drugs (NSAIDs) are attributable to inhibition of the cyclooxygenase (COX) enzyme which catalyzes the first step of the synthesis of prostanoids. In the early 1990s, COX was demonstrated to exist as two distinct isoforms. COX-1 is constitutively expressed as a 'housekeeping' enzyme in most tissues. In contrast, COX-2 can be upregulated by various proinflammatory agents, including endotoxin, cytokines and growth factors. Whereas many of the side effects of NSAIDs (e.g. gastrointestinal ulceration and bleeding, platelet dysfunctions) are due to a suppression of COX-1 activity, inhibition of COX-2-derived prostanoids facilitates the anti-inflammatory, analgesic and antipyretic effects of NSAIDs. Thus, the hypothesis that specific inhibition of COX-2 might have therapeutic actions similar to those of NSAIDs, but without causing the unwanted side effects, was the rationale for the development of specific inhibitors of the COX-2 enzyme as a new class of anti-inflammatory and analgesic agents with improved gastrointestinal tolerability. However, the simple concept that COX-2 is an exclusively proinflammatory and inducible enzyme cannot be supported any longer. Recently, COX-2 was shown to be also expressed under basal conditions in organs such as the ovary, uterus, brain, spinal cord, kidney and bone, suggesting that this isoenzyme may play a more complex physiological role than was expected. The present review assesses concept and molecular mechanism underlying specific COX-2 inhibition as well as indications, pharmakokinetics and unwanted side effects of the recently approved specific COX-2 inhibitors celecoxib and rofecoxib. Moreover, recent advances in COX-2 research, with particular emphasis on new insights into physiological functions of this isoenzyme will be discussed.

Animals↗
PubMed2000

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Journal Article↗
PubMed2000

Importance of Kupffer cells for T-cell-dependent liver injury in mice.

T cells seem to be responsible for liver damage in any type of acute hepatitis. Nevertheless, the importance of Kupffer cells (KCs) for T-cell-dependent liver failure is unclear. Here we focus on the role of KCs and tumor necrosis factor (TNF) production after T cell stimulation in mice. T-cell- and TNF-dependent liver injury were induced either by Pseudomonas exotoxin A (PEA), by concanavalin A (Con A), or by the combination of subtoxic doses of PEA and the superantigen Staphylococcus enterotoxin B (SEB). KCs were depleted by clodronate liposomes. Although livers of PEA-treated mice contained foci of confluent necrosis and numerous apoptotic cells, hardly any apoptotic cells were observed in the livers of Con A-treated mice. Instead, large bridging necroses were visible. Elimination of KCs protected mice from PEA-, Con A-, or PEA/SEB-induced liver injury. In the absence of KCs, liver damage was restricted to a few small necrotic areas. KCs were the main source of TNF. Hepatic TNF mRNA and protein production were strongly attenuated because of KC-depletion whereas plasma TNF levels were unaltered. Our results suggest that KCs play an important role in T cell activation-induced liver injury by contributing TNF. Plasma TNF levels are poor diagnostic markers for the severity of TNF-dependent liver inflammation.

ADP Ribose Transferases↗
PubMed2000

Localization and regulation of cyclo-oxygenase-1 and -2 and neuronal nitric oxide synthase in mouse spinal cord.

Prostaglandins are important mediators in spinal nociceptive processing. They are produced by cyclo-oxygenase isoforms, cyclo-oxygenase-1 and -2, which are both constitutively expressed in the central nervous system. The present immunohistochemical study details localization and regulation of cyclo-oxygenase-1 and -2 and neuronal nitric oxide synthase in lumbar spinal cord before and after induction of a painful paw inflammation in mice. Cyclo-oxygenase-1 immunoreactivity was found in glial cells of the dorsal and ventral horns, but not in neurons. In unstimulated mice, cyclo-oxygenase-2 immunoreactivity was found in motoneurons of the ventral horns and in lamina X, but not in dorsal horn neurons. After induction of a paw inflammation with zymosan, cyclo-oxygenase-2 immunoreactivity increased dramatically in dorsal horn neurons of laminae I-VI and X, paralleled by a significant increase in prostaglandin E(2) release from lumbar spinal cord. Cyclo-oxygenase-2 was co-localized with neuronal nitric oxide synthase immunoreactivity in several neurons in superficial laminae of the dorsal horns and in the area surrounding the central canal. Nitric oxide synthase was distributed in the cytoplasm and extended to processes of some neurons. In contrast, electron microscopy revealed that cyclo-oxygenase-2 immunoreactivity was restricted to the nuclear membrane and rough endoplasmic reticulum. It is shown in the present study that both cyclo-oxygenase isoforms are constitutively expressed in the spinal cord, cyclo-oxygenase-1 in glial cells of the dorsal and ventral horns and cyclo-oxygenase-2 in motoneurons. After induction of a hindpaw inflammation, several dorsal horn neurons express cyclo-oxygenase-2. Some of them are also positive for neuronal nitric oxide synthase, which is also induced following peripheral inflammation. Intracellularly, cyclo-oxygenase-2 is bound to the membranes of the nucleus and endoplasmic reticulum, whereas neuronal nitric oxide synthase is found in the cytoplasm.

Animals↗
PubMed2000

Population pharmacokinetics of fast release oral diclofenac in healthy volunteers: relation to pharmacodynamics in an experimental pain model.

PURPOSE: Population pharmacokinetics of a fast release diclofenac were assessed with special focus on pharmacodynamic implications. METHODS: In a double blind four-way crossover study, 20 healthy volunteers received orally 50 and 100 mg diclofenac-Na effervescent ("fast-release NSAID"), 50 mg diclofenac tablets ("control"), or placebo. Population pharmacokinetics of the fast release diclofenac were assessed using a nonlinear mixed effects modeling approach (NON-MEM). Analgesic effects were investigated by means of an experimental pain model based on both pain-ratings and cortical evoked potentials after specific stimulation of nasal nociceptors with short pulses of gaseous CO2. RESULTS: Pharmacokinetics of fast release diclofenac were best described by a two-compartment population model, with an estimated terminal half-life of 1.2 hours. Pharmacokinetics of diclofenac tablets were highly variable and a population pharmacokinetic model could not be obtained. As an indication of an early onset of analgesic effects, 100 mg fast release diclofenac but not the tablets significantly reduced the amplitudes of pain-related evoked potentials at 30 min after administration. CONCLUSIONS: Earlier drug absorption and lower pharmacokinetic variability of the fast-release formulation are likely to be preserved in a population.

Administration, Oral↗
PubMed2000

Prolyl isomerases in a minimal cell. Catalysis of protein folding by trigger factor from Mycoplasma genitalium.

Peptidyl-prolyl cis/trans isomerases (PPIases) catalyze the isomerization of prolyl peptide bonds. Distinct families of this class of enzymes are involved in protein folding in vitro, whereas their significance in free living organisms is not known. Previously, we inspected the smallest known genome of a self-replicating organism and found that Mycoplasma genitalium is devoid of all known PPIases except the trigger factor. Despite the extensive sequence information becoming available, most genes remain hypothetical and enzyme activities in many species have not been assigned to an open reading frame. Therefore, we studied the PPIase activity in crude extracts of M. genitalium. We showed that this is solely attributed to a single enzyme activity, the trigger factor. Characterization of this enzyme revealed that its PPIase activity resides in a central 12-kDa domain. Only the complete trigger factor is able to cis/trans isomerize extended peptide substrates, while the PPIase domain alone can not. The N- and the C-terminal domains of the trigger factor seem to function in binding of proteins as substrates, as demonstrated by protein refolding experiments, in which the complete trigger factor catalyzed protein refolding towards a model protein 500-fold more efficiently than the isolated central PPIase domain. Protein modeling studies suggest that the PPIase domain can fold in a similar way as the PPIase domain of FK506 binding proteins (FKBPs), one class of PPIases, despite only very limited sequence homology. Differences at the active site explain why this enzyme is not inhibited by FK506 in contrast with FKBPs. Trigger factor expressed in Escherichia coli confirms its additional chaperone functions, as shown by its association with chaperones GroEL and GroES after induction of misfolding. In contrast, the isolated PPIase-domain lacks any association with chaperones from E. coli. In summary, trigger factor of M. genitalium is the single folding isomerase of this organism, which harbors an enzymatically active PPIase domain with structural homology to FKBPs. Its additional domains confer its ability to be an efficient catalyst of protein folding. The protein folding machinery is conserved and shows a dual function as a chaperone and a prolyl isomerase.

Amino Acid Sequence↗
PubMed2000

Inhibition of noxious stimulus-induced spinal prostaglandin E2 release by flurbiprofen enantiomers: a microdialysis study.

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.

Animals↗
PubMed2000

New insights into physiological and pathophysiological functions of cyclo-oxygenase-2.

During the past few years specific inhibitors of the cyclo-oxygenase-2 enzyme have emerged as important pharmacological tools for treatment of patients with rheumatoid arthritis or osteoarthritis. In comparison to traditional nonsteroidal anti-inflammatory drugs, specific cyclo-oxygenase-2 inhibitors may provide equal efficacy in terms of antiinflammatory and analgesic action, with significantly fewer gastrointestinal side effects. Although cyclo-oxygenase-2 was once regarded as a source of pathological prostanoids, recent studies have indicated that this isoenzyme also fulfills a variety of physiological functions within the organism. The present review assesses recent advances in cyclo-oxygenase-2 research, with particular emphasis on new insights into the biology of this isoenzyme.

Journal Article↗
PubMed2000

Olfactory and trigeminal event-related potentials in migraine.

BACKGROUND: Trigeminal/neuronal hyperexcitability and spreading depression activating the trigemino-vascular system are discussed in migraine-pathophysiology. This study investigated trigeminal and olfactory event-related potentials in migraineurs. METHODS: Nasal chemosensitivity was assessed in 19 female migraineurs with or without aura > 72 h before or after an attack and in 19 healthy females employing event-related cortical potentials (ERPs) after specific trigeminal stimulation of nasal nociceptors with short pulses of CO2, and specific olfactory stimulation with H2S. Odour thresholds and odour identification performance were also tested. RESULTS: Migraineurs exhibited greater responses to trigeminal stimulation, indicated by significantly larger ERP amplitudes N1. In contrast, olfactory ERP amplitudes P1N1 were significantly smaller in migraineurs. A leave-one-out classification procedure on the basis of these two parameters assigned 76.3% cases correctly. The olfactory ERP amplitude discriminated better between groups than trigeminal ERPs (71.1 vs. 68.4% correct classification). CONCLUSIONS: Our data suggest trigeminal hyperexcitability in migraineurs. A general increase of nasal chemosensitivity is not supported because of smaller olfactory ERP amplitudes in migraineurs. Olfactory ERPs discriminate better than trigeminal ERPs between migraineurs and controls, emphasizing the significance of the olfactory system in migraine.

Adult↗
PubMed2000

Incidence and costs of adverse drug reactions during hospitalisation: computerised monitoring versus stimulated spontaneous reporting.

OBJECTIVE: To implement a computer-based adverse drug reaction monitoring system and compare its results with those of stimulated spontaneous reporting, and to assess the excess lengths of stay and costs of patients with verified adverse drug reactions. DESIGN: A prospective cohort study was used to assess the efficacy of computer-based monitoring, and case-matching was used to assess excess length of stay and costs. SETTING: This was a study of all patients admitted to a medical ward of a university hospital in Germany between June and December 1997. PATIENTS AND PARTICIPANTS: 379 patients were included, most of whom had infectious, gastrointestinal or liver diseases, or sleep apnoea syndrome. Patients admitted because of adverse drug reactions were excluded. METHODS: All automatically generated laboratory signals and reports were evaluated by a team consisting of a clinical pharmacologist, a clinician and a pharmacist for their likelihood of being an adverse drug reaction. They were classified by severity and causality. For verified adverse drug reactions, control patients with similar primary diagnosis, age, gender and time of admission but without adverse drug reactions were matched to the cases in order to assess the excess length of hospitalisation caused by an adverse drug reaction. RESULTS: Adverse drug reactions were detected in 12% of patients by the computer-based monitoring system and stimulated spontaneous reporting together (46 adverse reactions in 45 patients) during 1718 treatment days. Computer-based monitoring identified adverse drug reactions in 34 cases, and stimulated spontaneous reporting in 17 cases. Only 5 adverse drug reactions were detected by both methods. The relative sensitivity of computer-based monitoring was 74% (relative specificity 75%), and that of stimulated spontaneous reporting was 37% (relative specificity 98%). All 3 serious adverse drug reactions were detected by computer-based monitoring, but only 2 out of the 3 were detected by stimulated spontaneous reporting. The percentage of automatically generated laboratory signals associated with an adverse drug reaction (positive predictive value) was 13%. The mean excess length of stay was 3.5 days per adverse drug reaction. 48% of adverse reactions were predictable and detected solely by computer-based monitoring. Therefore, the potential for savings on this ward from the introduction of computer-based monitoring can be calculated as EUR56 200/year ($US59 600/year) [ 1999 values]. CONCLUSION: Computer monitoring is an effective method for improving the detection of adverse drug reactions in inpatients. The excess length of stay and costs caused by adverse drug reactions are substantial and might be considerably reduced by earlier detection.

Adverse Drug Reaction Reporting Systems↗
PubMed1999

[Specific COX-2 inhibitors: prospects of therapy with new analgesic and anti-inflammatory substances].

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) activity, thereby suppressing the synthesis of proinflammatory prostaglandins. The identification and molecular-biological characterization of an inducible COX isoform (COX-2) in inflammatory cells led to the hypothesis that a selective inhibition of COX-2 would result in relief of inflammation and pain without causing the COX-1-dependent side effects (gastrointestinal ulceration, platelet dysfunction, kidney damage) of conventional NSAIDs. On the basis of data obtained in several laboratories by means of the "human whole blood assay" there is now convincing evidence that none of the currently available NSAIDs is a selective COX-2 inhibitor. Meanwhile, the specific COX-2 inhibitors celecoxib and rofecoxib are being tested worldwide in phase III clinical trials on patients with rheumatoid arthritis and osteoarthritis. However, the simple concept of COX-2 being an exclusively proinflammatory inducible enzyme cannot be upheld any longer. In addition, COX-2 is expressed constitutively in brain, spinal cord and kidney, as well as in numerous other organs. In the present review the perspectives and possible risks of specific COX-2 inhibitors are discussed, as well as additional indications for their implementation (e.g. colon cancer).

Analgesics↗
PubMed1999

Computerized surveillance of adverse drug reactions in hospital: implementation.

OBJECTIVE: To implement and measure the effects of automatic computerized laboratory signals (ALS) as a detection support tool of adverse drug reactions (ADRs) in hospital. METHODS: This was a prospective observational study of a total of 192 patients (199 sequential medical admissions) during a 2-month period in a 34-bed medical ward at the Hadassah University Hospital, Jerusalem, Israel. The study involved the routine (daily) distribution to staff physicians of lists of automatic signals generated from computerized laboratory data as potential indicators of ADRs. Patient charts were reviewed by the clinical pharmacology team for ADRs and to see whether these were recognized by the staff physicians. RESULTS: Seventy-one ADRs were detected in 64 of the 199 (32%) admissions. Twenty-seven per cent of the ADRs were serious, 9% of the admissions were due to ADRs. Two hundred and ninety-five ALS were generated involving 69% of the admissions. Sixty-one per cent of the ADRs were identified by ALS. ALS were present in 58% of the ADR negative admissions. Eighty-five per cent of the ADRs were recognized as such and 19% of the ALS-positive ADRs were not recognized by the staff physicians. CONCLUSIONS: The routine implementation of ALS doubled the number of ADRs recognized by the physicians while patients were hospitalized in the medical ward. The use of the system appeared valid, simple and potentially cost-effective.

Adverse Drug Reaction Reporting Systems↗
PubMed1999

Comparison of inhibitory effects of meloxicam and diclofenac on human thromboxane biosynthesis after single doses and at steady state.

OBJECTIVE: To evaluate the extent of human cyclooxygenase-1 (COX-1) inhibition by meloxicam, which has been reported to preferentially inhibit cyclooxygenase-2 (COX-2). The effects of meloxicam were compared with those of diclofenac, a nonselective COX inhibitor. METHODS: COX-1 inhibition was determined by measuring thromboxane B2 (TXB2)-generation from clotting whole blood ex vivo after single oral doses of 7.5 and 15 mg meloxicam and 75 mg diclofenac and at steady state (15 mg meloxicam daily and 150 mg diclofenac daily). The effect was expressed as percentage inhibition of serum TXB2 generation and was directly related to the serum drug concentration with use of a standard sigmoidal E(max) model. RESULTS: In terms of inhibition of TXB2 generation, diclofenac was about 1 order of magnitude more potent than meloxicam, indicated by a diclofenac EC50 (concentration of drug required to cause 50% of maximum effect) that was about 10 times lower than that of meloxicam (EC50 diclofenac single doses: 37.50+/-29.64; EC50 meloxicam single doses: 677.50+/-189.08). However, serum concentrations of meloxicam after administration of 15 mg were approximately 10-fold higher than those of diclofenac. Therefore there was no statistically significant difference in the area under the effect time curve (P = .115) and the mean effect (P = .424) between meloxicam and diclofenac. The EC50 of both drugs was significantly higher at steady state (diclofenac steady state: 87.07+/-55.24 ng/mL; meloxicam steady state: 1850.12+/-829.93 ng/mL) than after a single dose (P < .001). CONCLUSION: These data show that meloxicam inhibits TXB2 generation at clinically relevant doses, although less potently than diclofenac. Thus our data suggest that the COX-2 preference of meloxicam observed in vitro may not result in clinical advantages when the higher dose of 15 mg is needed. Because of the increase in EC50 at steady state, COX-1 is relatively spared when the lower dose of 7.5 mg is administered.

Administration, Oral↗
PubMed1999

Pharmacokinetics of meropenem in critically ill patients with acute renal failure undergoing continuous venovenous hemofiltration.

OBJECTIVE: Meropenem is a broad-spectrum antibiotic used for severe infections. In patients with chronic end-stage renal failure, meropenem clearance is reduced and doses must be adjusted according to the creatinine clearance. The aim of this study was to assess pharmacokinetic data of meropenem in patients with acute renal failure and to determine the amount of drug removed by continuous venovenous hemofiltration, an often-used renal replacement therapy in patients with acute renal failure. METHODS: Nine critically ill anuric patients with acute renal failure undergoing continuous venovenous hemofiltration received 500 mg meropenem 2 or 3 times daily. Plasma and hemofiltrate concentrations were determined during 1 dosing interval at steady state. Pharmacokinetic parameters were calculated for a 2-compartment open model and dose requirements were calculated. RESULTS: The total meropenem clearance was 52.0 +/- 8.4 mL/min, with a hemofiltration clearance of 22.0 +/- 4.7 mL/min and a nonrenal-nonhemofiltration clearance of 29.9 +/- 5.4 mL/min; 235.9 +/- 88.6 mg, or 47.2% +/- 17.7%, of the dose were removed through continuous venovenous hemofiltration. The terminal elimination half-life was 8.7 +/- 3.5 hours and the volume of distribution at steady state was 12.4 +/- 1.8 L. Peak and trough concentrations for a dosing interval of 12 hours were 38.9 +/- 9.7 mg/L and 7.3 +/- 1.3 mg/L, respectively. The corresponding concentrations for a dosing interval of 8 hours were 44.7 +/- 10.4 mg/L and 11.9 +/- 0.7 mg/L, respectively. CONCLUSION: Pharmacokinetic data of anuric patients with acute renal failure were similar to those of patients with end-stage renal failure. Because hemofiltration contributes significantly to meropenem elimination, the recommended dose for critically ill anuric patients receiving continuous venovenous hemofiltration should be increased by 100% to avoid potential underdosing.

Acute Kidney Injury↗