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Biomedical subjects

K Brune

Publications and source records attributed to K Brune.

At least 73 records · Page 4Linked to original sources
PubMed1999

Application of microdialysis for the determination of muscle and subcutaneous tissue concentrations after oral and topical ibuprofen administration.

BACKGROUND: The topical administration of non-steroidal antiinflammatory drugs (NSAIDs) is widely used for the treatment of soft tissue pain. However, it is not known whether effective tissue concentrations are reached with the topical route. OBJECTIVE: To evaluate and compare unbound muscle and subcutaneous tissue ibuprofen concentrations with use of microdialysis after topical and oral administration. METHODS: In a 2-way crossover design, 11 healthy volunteers received either 800 mg oral ibuprofen or 16 g of 5% ibuprofen gel applied onto the skin of the thigh (defined area, 17 x 19 cm). Microdialysis catheters were inserted into the medial vastus muscle (25 to 30 mm) and into the subcutaneous adipose layer of the thigh (4 to 5 mm). Dialysate was collected in 20-minute intervals up to 5 hours. RESULTS: Essentially all of the orally administered dose was recovered in urine as ibuprofen or metabolites during 24 hours, but only about 0.55% of the topically administered dose was recovered. The relative systemic bioavailability of ibuprofen gel, based on urine recovery data, was (mean +/- SD) 0.57%+/-0.30%. Mean values of the dialysate areas under the drug concentration-time curves after topical and oral administration were 731.2+/-605.0 and 176.6+/-122.9 ng x h x mL(-1) for subcutaneous tissue and 63.5+/-90.3 and 213.4+/-117.2 ng x h x mL(-1) for muscle, respectively. Muscle dialysate concentrations after topical administration varied considerably among the subjects. CONCLUSION: These results suggest that, if target tissue concentrations correlate directly with the degree of pain relief, patients with pain caused by dermal or subcutaneous tissue damage will have greater pain relief after topical administration of ibuprofen accompanied with less systemic side effects. In addition, a proportion of patients with muscle pain may also experience pain relief from topical ibuprofen.

Administration, Cutaneous↗
PubMed1999

Retrospective analysis of the frequency and recognition of adverse drug reactions by means of automatically recorded laboratory signals.

AIMS: To estimate the frequency of adverse drug reactions (ADRs) identified through the use of automatic signals generated from laboratory data (ALS) in hospitalised patients. To determine the frequency of spontaneous recognition of these ADRs by the attending physicians and to assess the potential value of ALS for detection of ADRs. METHODS: Laboratory results of patients hospitalised in a nine bed medical ward were automatically recorded over a period of 17 months. Values exceeding defined boundaries were used as ALS. Charts of every third patient were analysed retrospectively with regard to adverse drug related reactions and causality was evaluated as well as whether the ADR had been recognised during the period of hospitalisation. RESULTS: The charts and ALS of 98 patients were analysed. In 18 cases a drug-related adverse reaction was probable. Awareness to the reaction by the treating physicians was evident in 6 out of these 18 ADRs. Approximately 80% of the ADRs were considered predictable. Three ADRs were regarded as serious. CONCLUSIONS: Adverse drug reactions are common and often preventable. Only one third of ADRs which could have been detected through ALS were recognised by the attending physicians. An increased doctor's awareness of the frequency of drug related abnormal laboratory results by means of ALS is likely to increase the recognition rate of ADRs and might help to prevent them.

Adult↗
PubMed1999

Visual evoked potentials in migraine patients: alterations depend on pattern spatial frequency.

Visual information is conducted by two parallel pathways (luminance- and contour-processing pathways) which are thought to be differentially affected in migraine and can be investigated by means of pattern-reversal visual evoked potentials (VEPs). Components and habituation of VEPs at four spatial frequencies were compared between 26 migraineurs (13 without aura, MO; 13 with aura, MA) and 28 healthy volunteers. Migraineurs were recorded in the headache-free interval (at least 72 h before and after an attack). Five blocks of 50 responses to chequerboards of 0.5, 1, 2 and 4 cycles per degree (c.p.d.) were sequentially averaged and analysed for latency and amplitude. Differences in VEPs were dependent on spatial frequency. Only when small checks were presented, i.e. at high spatial frequency (2 and 4 c.p.d.), was the latency of N2 significantly prolonged in MA and did it tend to be delayed in MO subjects. Habituation behaviour was not significantly different between groups under the stimulating conditions employed. Prolonged N2 latency might be explained by the lack or attenuation of a contour-specific component N130 in migraineurs, indicating an imbalance of the two visual pathways with relative predominance of the luminance-processing Y system. These results reflect an interictally persisting dysfunction of precortical visual processing which might be relevant in the pathophysiology of migraine.

Adult↗
PubMed1999

Acetaminophen inhibits spinal prostaglandin E2 release after peripheral noxious stimulation.

BACKGROUND: Prostaglandin play a pivotal role in spinal nociceptive processing. At therapeutic concentrations, acetaminophen is not a cyclooxygenase inhibitor. inhibitor. Thus, it is antinociceptive without having antiinflammatory or gastrointestinal toxic effects. This study evaluated the role of spinal prostaglandin E2 (PGE2) in antinociception produced by intraperitoneally administered acetaminophen. METHODS: The PGE2 concentrations in the dorsal horn of the spinal cord were measured after formalin was injected into the hind paw of rats. The effect of antinociceptive doses of acetaminophen (100, 200, and 300 mg/kg given intraperitoneally) on PGE2 levels and flinching behavior was monitored Spinal PGE2 and acetaminophen concentrations were obtained by microdialysis using a probe that was implanted transversely through the dorsal horn of the spinal cord at L4. Furthermore, the effects of acetaminophen on urinary prostaglandin excretion were determined. RESULTS: Intraperitoneal administration of acetaminophen resulted in a significant decrease in spinal PGE2 release that was associated with a significant reduction in the flinching behavior in the formalin test Acetaminophen was distributed rapidly into the spinal cord with maximum dialysate concentrations 4560 min after intraperitoneal administration. Urinary excretion of prostanoids (PGE2, PGF2alpha, and 6-keto-PGF1alpha) was not significantly altered after acetaminophen administration. CONCLUSIONS: The data confirm the importance of PGE2 in spinal nociceptive processing. The results suggest that antinociception after acetaminophen administration is mediated, at least in part, by inhibition of spinal PGE2 release. The mechanism, however, remains unknown. The finding that urinary excretion of prostaglandins was not affected might explain why acetaminophen is antinociceptive but does not compromise renal safety.

Acetaminophen↗
PubMed1999

Quantitative detection of Borrelia burgdorferi by real-time PCR.

Currently, no easy and reliable methods allowing for the quantification of Borrelia burgdorferi in tissues of infected humans or animals are available. Due to the lack of suitable assays to detect B. burgdorferi CFU and the qualitative nature of the currently performed PCR assays, we decided to exploit the recently developed real-time PCR. This technology measures the release of fluorescent oligonucleotides during the PCR. Flagellin of B. burgdorferi was chosen as the target sequence. A linear quantitative detection range of 5 logs with a calculated detection limit of one to three spirochetes per assay reaction mixture was observed. The fact that no signals were obtained with closely related organisms such as Borrelia hermsii argues for a high specificity of this newly developed method. A similar method was developed to quantify mouse actin genomic sequences to allow for the standardization of spirochete load. The specificity and sensitivity of the B. burgdorferi and the actin real-time PCR were not altered when samples were spiked with mouse cells or spirochetes, respectively. To evaluate the applicability of the real-time PCR, we used the mouse model of Lyme disease. The fate of B. burgdorferi was monitored in different tissues from inbred mice and from mice treated with antibiotics. Susceptible C3H/HeJ mice had markedly higher burdens of bacterial DNA than resistant BALB/c mice, and penicillin G treatment significantly reduced the numbers of spirochetes. Since these results show a close correlation between clinical symptoms and bacterial burden of tissues, we are currently analyzing human biopsy specimens to evaluate the real-time PCR in a diagnostic setting.

Animals↗
PubMed1998

[2-Arylpropionic acids. Role in pain therapy].

The antipyretic analgesics still comprise the most widely used group of analgesic compounds. Until twenty years ago, aspirin, phenazone derivatives and acetaminophen had been used as standard remedies for intercurrent harmless pain conditions in connection with infections, trauma, small surgeries, but also for tension headache and other painful conditions. During the last decades, this group has been supplemented by a variety of 2-arylpropionic acids being primarily developed for the treatment of rheumatic pain and inflammation. Some of them (e.g. ibuprofen, ketoprofen and naproxen) have been given over-the-counter status in some countries because of their relative safety at low doses. Nevertheless, pharmacodynamic and pharmacokinetic differences among the various substances of this group make them suitable to a different degree for the treatment of pain conditions.

English Abstract↗
PubMed1998

Leishmania major parasites express cyclophilin isoforms with an unusual interaction with calcineurin.

The immunosuppressive effects of the fungal metabolite cyclosporin A (CsA) are mediated primarily by binding to cyclophilins (Cyps). The resulting CsA-Cyp complex inhibits the Ca2+-regulated protein phosphatase calcineurin and down-regulates signal transduction events. Previously we reported that CsA is a potent inhibitor of infections transmitted by the human pathogenic protozoan parasite Leishmania major in vitro and in vivo, but does not effect the extracellular growth of L. major itself. It is unknown how L. major exerts this resistance to CsA. Here we report that a major Cyp, besides additional isoforms with the same N-terminal amino acid sequence, was expressed in L. major. The cloned and sequenced gene encodes a putative 174-residue protein called L. major Cyp 19 (LmCyp19). The recombinant LmCyp19 exhibits peptidyl-prolyl cis/trans isomerase activity with a substrate specificity and an inhibition by CsA that are characteristic of other eukaryotic Cyps. To determine whether calcineurin is involved in the discrimination of the effects of CsA we also examined the presence of a parasitic calcineurin and tested the interaction with Cyps. Despite the expression of functionally active calcineurin by L. major, neither LmCyp19 nor other L. major Cyps bound to its own or mammalian calcineurin. The amino acid sequence of most Cyps includes an essential arginine residue around the calcineurin-docking side. In LmCyp19 this is replaced by an asparagine residue. This exchange and additional charged residues are apparently responsible for the lack of LmCyp19 interaction with calcineurin. These observations indicate that resistance of L. major to CsA in vitro is mediated by the lack of complex formation with calcineurin despite CsA binding by parasitic Cyp.

Amino Acid Sequence↗
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

Modulation of transcription factor NF-kappaB by enantiomers of the nonsteroidal drug ibuprofen.

1. The nonsteroidal drug ibuprofen exists as an R(-)- and S(+)-enantiomer. Only the S(+)-enantiomer is an effective cyclo-oxygenase inhibitor, while the R(-)-enantiomer is inactive in this respect. Thus the molecular mechanism by which R(-)-ibuprofen exerts its anti-inflammatory and antinociceptive effects remains unknown. 2. In this study the effects of the enantiomers of ibuprofen on modulation of transcription factors have been examined with electrophoretic mobility-shift assay (EMSA), transient transfection experiments, confocal immunofluorescence and nuclear import experiments, to determine their selectivity and potency as inhibitors of the activation of transcription factor nuclear factor-kappaB (NF-kappaB). 3. R(-)-ibuprofen (IC50: 121.8 microM) as well as the S(+)-enantiomer (IC50: 61.7 microM) inhibited the activation of NF-kappaB in response to T-cell stimulation. The effect of ibuprofen was specific because, at concentrations up to 10 mM, ibuprofen did not affect the heat shock transcription factor (HSF) and the activation of NF-kappaB by prostaglandin E2 (PGE2). Very high concentrations of ibuprofen (20 mM) did not prevent NF-kappaB binding to DNA in vitro. Immunofluorescence and nuclear import experiments indicate that the site of ibuprofen action appeared to be upstream of the dissociation of the NF-kappaB-IkappaB-complex. 4. Our data raise the possibility that R(-)-ibuprofen exerts some of its effects by inhibition of NF-kappaB activation.

Amino Acid Sequence↗
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

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↗