Search PubMed⌕ Search

Biomedical subjects

K Brune

Publications and source records attributed to K Brune.

At least 19 recordsLinked to original sources
PubMed2007

Antipyretic analgesics: nonsteroidal antiinflammatory drugs, selective COX-2 inhibitors, paracetamol and pyrazolinones.

Antipyretic analgesics are a group of heterogeneous substances including acidic (nonsteroidal antiinflammatory drugs, NSAIDs) and nonacidic (paracetamol, pyrazolinones) drugs. Moreover, various selective cyclooxygenase-2 (COX-2) inhibitors with improved gastrointestinal tolerability as compared with conventional NSAIDs have been established for symptomatic pain treatment in recent years. The present review summarizes the pharmacology of all of these drugs with particular emphasis on their rational use based on the diverse pharmacokinetic characteristics and adverse drug reaction profiles. Referring to the current debate, potential mechanisms underlying cardiovascular side effects associated with long-term use of COX inhibitors are discussed.

Acetaminophen↗
PubMed2007

[Pain therapy with antipyretic analgesics].

The pharmacotherapy of musculoskeletal pain remains of high importance in Western countries. The present review concentrates on the use of acidic (nonsteroidal anti-inflammatory drugs) and nonacidic (paracetamol, selective cyclooxygenase-2 inhibitors) antipyretic analgesics in the therapy of musculoskeletal pain disorders with particular emphasis on the diverse pharmacokinetic properties and unwanted side effects of these substances.

Analgesics, Non-Narcotic↗
PubMed2006

Valdecoxib does not interfere with the CYP2D6 substrate metoprolol.

OBJECTIVE: We reported recently that celecoxib inhibits the metabolism of the cytochrome P450 (CYP)2D6 substrate metoprolol in volunteers. Valdecoxib, the active metabolite of parecoxib, has also been claimed to interfere with the metabolism of CYP2D6 substrates. However, little support for this contention is available despite the intensive use of parecoxib in the perioperative setting. Therefore, the objective of this study was to examine the effect of valdecoxib on the pharmacokinetics of the clinically relevant CYP2D6 substrate metoprolol. METHODS: An open, randomized, 3-period crossover study was performed in 15 healthy male volunteers. Metoprolol (50 mg) was given in all 3 periods without, or following a 7-day pre-treatment with valdecoxib (20 mg, o.d.) or rofecoxib (25 mg, o.d.), to achieve steady state conditions of COX-2 inhibitors in Periods 2 and 3. In a small group of extensive metabolizers (EM/EM), short-term application of twice the dose was investigated. RESULTS: No effect of valdecoxib (20 mg/d) or rofecoxib (25 mg/d) were detected on the area under the plasma concentration-time curve of metoprolol (323 +/- 333 to 324 +/- 296 or 309 +/- 256 microg x h/l) or at a higher dose. No significant changes of pharmacokinetic or pharmacodynamic parameters of metoprolol were apparent. CONCLUSION: We conclude that, at therapeutic doses, valdecoxib and rofecoxib do not influence the CYP2D6 substrate metoprolol.

Adult↗
PubMed2005

[Medication in a physicians network: modern treatment with no increase in costs?].

Practice networks are intended to improve drug treatment and render it more economical. To check whether these aims can be realized, two groups of physicians were observed over a period of two years. The first group stemmed from the Practice Network Nuremberg North (PNN), the other comprised a group of physicians in Augsburg similarly structured in terms of prescriptions, specialties and patients. A comparison was made of the application and costs of drugs for the following four different indications: bronchial asthma, diabetes mellitus, hypertension and osteoporosis. Within the practice network a mild increase in costswas observed forall four indications. This was in part explained by the increased used of modern, more expensive drugs, although savings were also achieved by a more liberal use of more economical, patent-free medications. No improvement in treatment outcome was seen, since prescription in accordance with recommended guidelines would have required the use of other drugs. Evaluation of treatment qualitywas not an aim of this study. Overall, the potentials in terms of improved and simultaneously more economical chemotherapy expected from the establishment of a practice network were not fully utilized. Perhaps the conclusion of a modified agreement Quality and Efficiency (QaE, 2003) might result in improved prescribing through evidence-based medicine, and greater savings.

Asthma↗
PubMed2004

Implementation of a computer-assisted monitoring system for the detection of adverse drug reactions in gastroenterology.

AIM: To investigate the effectiveness of a computer monitoring system that detects adverse drug reactions (ADRs) by laboratory signals in gastroenterology. METHODS: A prospective, 6-month, pharmaco-epidemiological survey was carried out on a gastroenterological ward at the University Hospital Erlangen-Nuremberg. Two methods were used to identify ADRs. (i) All charts were reviewed daily by physicians and clinical pharmacists. (ii) A computer monitoring system generated a daily list of automatic laboratory signals and alerts of ADRs, including patient data and dates of events. RESULTS: One hundred and nine ADRs were detected in 474 admissions (377 patients). The computer monitoring system generated 4454 automatic laboratory signals from 39 819 laboratory parameters tested, and issued 2328 alerts, 914 (39%) of which were associated with ADRs; 574 (25%) were associated with ADR-positive admissions. Of all the alerts generated, signals of hepatotoxicity (1255), followed by coagulation disorders (407) and haematological toxicity (207), were prevalent. Correspondingly, the prevailing ADRs were concerned with the metabolic and hepato-gastrointestinal system (61). The sensitivity was 91%: 69 of 76 ADR-positive patients were indicated by an alert. The specificity of alerts was increased from 23% to 76% after implementation of an automatic laboratory signal trend monitoring algorithm. CONCLUSION: This study shows that a computer monitoring system is a useful tool for the systematic and automated detection of ADRs in gastroenterological patients.

Adolescent↗
PubMed2004

Selective cyclooxygenase-2 inhibitors: similarities and differences.

The enzyme cyclooxygenase (COX) was shown to exist as two distinct isoforms about a decade ago. COX-1 is constitutively expressed as a 'housekeeping' enzyme in nearly all tissues, and mediates physiological responses (e.g. cytoprotection of the stomach, and platelet aggregation). On the other hand, COX-2, expressed by cells involved in inflammation (e.g. macrophages, monocytes, synoviocytes), has emerged as the isoform that is primarily responsible for the synthesis of prostanoids involved in acute and chronic inflammatory states. Consequently, the hypothesis that selective inhibition of COX-2 might have therapeutic actions similar to those of non-steroidal anti-inflammatory drugs, but without causing gastrointestinal side effects, was the rationale for the development of selective inhibitors of the COX-2 isoenzyme. Selective COX-2 inhibitors currently used in the clinic are the sulphonamides celecoxib and valdecoxib (parecoxib is a prodrug of valdecoxib), as well as the methylsulphones rofecoxib and etoricoxib. Furthermore, the phenylacetic acid derivative lumiracoxib has gained permission recently to be marketed in Europe. This review discusses the clinically relevant similarities and differences of these substances, with particular emphasis on their diverse pharmacokinetic characteristics.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2004

Safety of anti-inflammatory treatment--new ways of thinking.

The development of osteoarthritis may be accompanied by increased production of leukotrienes (LTs) and prostaglandins (PGs) from arachidonic acid. These products contribute to joint damage, pain and inflammation. Cyclooxygenase (COX)-1 and COX-2 are responsible for the production of PGs. Inhibition of these enzymes by non-steroidal anti-inflammatory drugs and selective COX-2 inhibitors reduces the levels of PGs, resulting in a reduction in pain and inflammation. However, this inhibition can cause alternative processing of arachidonic acid via the 5-lipoxygenase (5-LOX) pathway, resulting in increased production of proinflammatory and gastrotoxic LTs. Licofelone is a competitive inhibitor of 5-LOX, COX-1 and COX-2 that is currently being developed for the treatment of osteoarthritis. Licofelone decreases the production of both LTs and PGs, and thereby reduces inflammation and pain with low gastrotoxicity. Unlike selective COX-2 inhibitors, coadministration of licofelone and aspirin does not appear to be associated with an increase in gastrointestinal adverse events, at least under experimental conditions. Furthermore, there is evidence from animal models to suggest that licofelone may stop disease progression.

Acetates↗
PubMed2004

Readmissions and adverse drug reactions in internal medicine: the economic impact.

BACKGROUND: Recent studies show that nearly half of the hospitalized patients are readmitted within 6 months from discharge. No data exist about the relationship between adverse drug reactions (ADRs) and readmittance to a department of internal medicine. OBJECTIVES: The primary aims of the study were to determine if ADRs could be used as predictors for recurrent hospitalizations in internal medicine and to evaluate the economic impact of ADRs on hospitalization costs. DESIGN AND SETTING: A cohort-based, prospective, 18-month pharmacoepidemiological survey was conducted in the Department I of Internal Medicine at the University Hospital of Erlangen. All patients were intensively monitored for ADRs by a pharmacoepidemiological team. ADRs were evaluated for their offending drugs, probability, severity, preventability and classified by WHO-ART. During a 6-month period ADR-positive patients were matched to non-ADR patients applying diagnosis-related group categorization in order to measure the impact of ADRs on the duration and frequency of hospitalization. RESULTS: Of 1000 admissions 424 patients had single admissions and 206 patients had recurrent readmissions (min 1, max 9). The prevalence of readmissions was 37% (n = 370). In 145 (23%) of 630 patients, 305 ADRs were observed. The ADR incidence was similar in first admissions and readmissions. ADRs were not found to predict further readmissions and lack of ADRs did not preclude readmissions. ADRs caused hospitalizations in 6.2% of first admissions and in 4.2% of readmissions. According to the Schumock algorithm 135 (44.3%) ADRs were found to be preventable. The occurrence and numbers of ADRs per admission were found to prolong hospitalization period significantly (r = 0.48 and 0.51, P < 0.001, n = 135). Of 9107 treatment days 20% were caused by in-house (1130 days) and community-acquired ADRs (669 days). In admissions and readmissions 11% (>973 days) of all treatment days were judged to be preventable. CONCLUSIONS: Intensified drug monitoring supported by information technology in internal medicine is essential for early detecting and prevention of ADRs and saving hospital resources.

Adolescent↗
PubMed2002

Comparison of rofecoxib, celecoxib, and naproxen on renal function in elderly subjects receiving a normal-salt diet.

BACKGROUND: This study compared directly the renal effects of two selective cyclooxygenase (COX)-2 inhibitors (rofecoxib and celecoxib) with naproxen (dual COX-1/COX-2 inhibitor) and placebo in healthy elderly subjects on a sodium-replete diet. METHODS: A total of 67 elderly subjects stabilized in the clinic for weight and urinary sodium on a controlled 200-mEq sodium diet were randomized in a double-blind fashion to receive rofecoxib, 25 mg daily (n = 17); celecoxib, 200 mg twice daily (n = 17); naproxen, 500 mg twice daily (n = 17); or matching placebo (n = 16) for 28 days. Subjects were sequestered in the clinic for the first 14 treatment days on the controlled diet. RESULTS: Daily urinary sodium excretion during the first 72 hours of treatment (primary endpoint) significantly decreased in rofecoxib, celecoxib, and naproxen groups compared with baseline (P < or =.05). Rofecoxib and celecoxib decreases in urinary sodium excretion rates that were comparable with each other, on the basis of predefined boundaries (-39.5 versus -27.1 mEq/d, respectively) and to naproxen (-40.6, mEq/d). Rofecoxib, celecoxib, and naproxen increased mean systolic blood pressure to a similar degree (3.4, 4.3, and 3.1 mm Hg, respectively, versus -1.3 mm Hg for placebo) after 14 days of treatment; small changes also occurred in diastolic blood pressure (0.3, 0.8, and -0.4 mm Hg, respectively, versus -1.4 mm Hg for placebo). Changes from baseline in creatinine clearance, body weight, and urinary potassium excretion among active treatments were similar. After 28 days of treatment, findings were generally consistent with those at 14 days. No subject reported edema or discontinued treatment as the result of an adverse experience. CONCLUSION: In healthy elderly subjects on a sodium-replete diet, the COX-2 inhibitors rofecoxib and celecoxib did not differ from a nonselective nonsteroidal anti-inflammatory drug (naproxen), in influencing renal function as measured by urinary sodium excretion, systolic and diastolic blood pressure, creatinine clearance, or weight change.

Aged↗
PubMed2001

HU-210 shows higher efficacy and potency than morphine after intrathecal administration in the mouse formalin test.

The discovery of endocannabinoids opens up new perspectives in experimental pain research. Here we present data for the excellent antinociceptive properties of the synthetic cannabinoid, R(-)-7-hydroxy-delta-6-tetra-hydrocannabinol-dimethylheptyl (HU-210), after intrathecal and oral administration in mice. It is known that cannabinoids depress motor activity. Therefore, these compounds are suspected of influencing antinociceptive tests. Our behavioural tests (RotaRod, tail flick) clearly show that HU-210 affects nociceptive behaviour even at dosages which do not yet influence motor activity. Moreover, spinal microdialysis (5 microl/min) in the dorsal horn of freely moving mice showed an enhancement of prostaglandin production during the formalin test. HU-210 applied via artificial cerebral spinal fluid during microdialysis perfusion increases prostaglandin concentrations under both baseline and formalin test conditions. Indomethacin reduces the HU-210 effect on pronociceptive prostaglandin production but does not reinforce the antinociceptive properties of HU-210. Thus, HU-210 shows antinociceptive properties that are independent of its influence on the prostaglandin pathway.

Analgesics, Opioid↗
PubMed2001

R(+)-methanandamide induces cyclooxygenase-2 expression in human neuroglioma cells via a non-cannabinoid receptor-mediated mechanism.

Cannabinoids affect prostaglandin (PG) formation in the central nervous system through as yet unidentified mechanisms. Using H4 human neuroglioma cells, the present study investigates the effect of R(+)-methanandamide (metabolically stable analogue of the endocannabinoid anandamide) on the expression of the cyclooxygenase-2 (COX-2) enzyme. Incubation of cells with R(+)-methanandamide was accompanied by concentration-dependent increases in COX-2 mRNA, COX-2 protein, and COX-2-dependent PGE(2) synthesis. Moreover, treatment of cells with R(+)-methanandamide in the presence of interleukin-1beta led to an overadditive induction of COX-2 expression. The stimulatory effect of R(+)-methanandamide on COX-2 expression was mimicked by the structurally unrelated cannabinoid Delta(9)-tetrahydrocannabinol. Stimulation of both COX-2 mRNA expression and subsequent PGE(2) synthesis by R(+)-methanandamide was not affected by the selective CB(1) receptor antagonist AM-251 or the G(i/o) protein inactivator pertussis toxin. Enhancement of COX-2 expression by R(+)-methanandamide was paralleled by time-dependent phosphorylations of p38 mitogen-activated protein kinase (MAPK) and p42/44 MAPK. Consistent with the activation of both kinases, R(+)-methanandamide-induced COX-2 mRNA expression and PGE(2) formation were abrogated in the presence of specific inhibitors of p38 MAPK (SB203580) and p42/44 MAPK activation (PD98059). Together, our results demonstrate that R(+)-methanandamide induces COX-2 expression in human neuroglioma cells via a cannabinoid receptor-independent mechanism involving activation of the MAPK pathway. In conclusion, induction of COX-2 expression may represent a novel mechanism by which cannabinoids mediate PG-dependent effects within the central nervous system.

Analgesics, Non-Narcotic↗
PubMed2001

Selective and rapid liquid chromatography-mass spectrometry method for the quantification of rofecoxib in pharmacokinetic studies with humans.

An easy, rapid and selective method for the determination of rofecoxib in human plasma is presented. The analytical technique is based on reversed-phase high-performance liquid chromatography coupled to atmospheric pressure chemical ionisation mass spectrometry (Finnigan Mat LCQ ion trap). The retention time of rofecoxib was 1.2 min. The method has been validated over a linear range from 1 to 500 microg/l using celecoxib as internal standard. After validation, the method was used to study the pharmacokinetic profile of rofecoxib in 12 healthy volunteers after administration of a single oral dose (12.5 mg). The presented method was sufficient to cover more than 95% of the area under the curve. The pharmacokinetic characteristics (mean+/-SD) were tmax: 2.4+/-1.0 h, Cmax: 147+/-34 microg/l, AUCinfinity: 2038+/-581 microg h/l and t 1/2: 11.3+/-2.1 h.

Adult↗
PubMed2001

Expression of rat liver long-chain acyl-CoA synthetase and characterization of its role in the metabolism of R-ibuprofen and other fatty acid-like xenobiotics.

Our investigations of fatty acid metabolism and epimerization of the 2-arylpropionic acid derivative, R-ibuprofen, resulted in the successful purification of an acyl-CoA synthetase from rat liver microsomes that catalyzes the formation of both palmitoyl-CoA and R-ibuprofenoyl-CoA. To investigate whether R-ibuprofenoyl-CoA synthetase and long-chain acyl-CoA synthetase (LACS) are identical enzymes, we cloned the cDNA from LACS into the pQE30 expression vector and transformed the construct into Escherichia coli M15[pREP4]. Induction of the bacterial protein synthesis with 0.2 mM isopropyl-beta-D-galactoside resulted in a strong, time-dependent increase in LACS protein as determined by Western blot analysis using a polyclonal rabbit anti-LACS antibody. Incubations of the recombinantly expressed protein with palmitic acid as physiological LACS substrate or R-ibuprofen in the presence of Mg2+, ATP, and CoA resulted in a 5-fold increase in the thioesterification of both substrates. Western blot analysis using tissue homogenates of rat liver, heart, kidney, lung, brain, and ileum showed that LACS was found in every tissue investigated, with the greatest expression in the liver. Similar results were obtained with activity measurements using R-ibuprofen and palmitic acid as substrates. Northern blot analysis revealed a hybridization with a 3.8-kb mRNA transcript in rat liver, heart, and kidney, but no signal was observed in lung, brain and ileum, suggesting the expression of different LACS isoform(s) in these organs. In summary, our results further show that R-ibuprofenoyl-CoA synthetase and long-chain acyl-CoA synthetase are identical enzymes that are involved in the metabolism of various xenobiotics.

Acyl Coenzyme A↗
PubMed2001

Constitutive expression and localization of COX-1 and COX-2 in rabbit iris and ciliary body.

Prostaglandins are involved in the regulation of intraocular pressure and the blood-aqueous barrier of the eye, and are used for the treatment of glaucoma. The decrease of the constitutively expressed PG-synthesizing enzyme cyclooxygenase-2 (COX-2) has been demonstrated in the ciliary non-pigmented epithelial layer of patients with primary open angle glaucoma. Little is known about the distribution of COX-1 and COX-2 in animals. We investigated this in the iris and ciliary body of the normal rabbit eye. The presence of COX-1 and COX-2 in freshly excised iris and ciliary body tissue from adult New Zealand White albino rabbits was demonstrated by real-time RT-PCR, and Western blot analysis. The localization of both isoforms and of the neuron-specific protein gene product 9.5 was determined by indirect immunofluorescence. Both enzymes are expressed in the iris and the ciliary body. Immunofluorescence studies including double staining techniques localized COX-1 and COX-2 to about 50% of cells in the stromal tissue of iris and ciliary body, mainly on the corneal side. They were co-localized in about 75% of these cells. Whereas all stained cells were positive for COX-1, COX-2 showed a gradient-like distribution in the stroma, with some restriction of expression near the epithelial layers, which we clearly showed to be completely negative for both COX-1 and COX-2. Also, neuronal elements did not show COX-1 or COX-2 immunoreactivity. These results establish the presence of COX-1 and COX-2 on the RNA and protein levels in normal, unstimulated rabbit iris and ciliary body. The pattern of distribution suggests a role for both enzymes in maintaining the physiology of the eye. In contrast to our results in man, non-pigmented epithelial cells of the ciliary body did not express immunoreactivity. This could account for differences in the regulation of intraocular pressure and/or blood-aqueous barrier between human and rabbit eyes.

Animals↗