Biomedical subjects

Markus Müller

Publications and source records attributed to Markus Müller.

At least 55 records · Page 3Linked to original sources

PubMed2005

Acucise endopyelotomy: a technique with limited efficacy for primary ureteropelvic junction obstruction in adults.

AIM: To retrospectively evaluate the ef fi cacy of Acucise endopyelotomy in a series of patients with primary ureteropelvic junction obstruction (UPJO). METHODS: Twenty-four patients with a symptomatic primary UPJO underwent Acucise endopyelotomy. Patients with high-grade hydronephrosis and/or poor renal function were excluded. Patients were followed by ultrasound imaging, intravenous urography, diuretic renography, and clinical review. RESULTS: The overall success rate was 58% (14/24 patients), with a median follow up of 32 months. Of the ten patients in whom Acucise endopyelotomy failed, seven underwent open pyeloplasty, one required nephrectomy, and two received a permanent ureteral stent. A poor outcome was noted in patients without perioperative extravasation. CONCLUSIONS: Our experience with Acucise endopyelotomy indicates that the success rate is lower than initially reported. Larger studies are needed to clarify the role of Acucise endopyelotomy in comparison with other techniques.

Adolescent↗

PubMed2005

New perioperative management reduces bleeding in radical retropubic prostatectomy.

OBJECTIVE: To describe the effect of modifications to radical retropubic prostatectomy (RRP, known to be associated with severe bleeding) on blood loss in a retrospective analysis comparing RRPs by one experienced surgeon before and after the changes. PATIENTS AND METHODS: The new method comprised reducing the intravenously applied volume, using a peridural catheter and maintaining a 25-30 degrees Trendelenburg position. The difference in haemoglobin before and after RRP was analysed before the changes (group 1) and after (group 2). If transfusions were required the haemoglobin value was corrected, whereby 1 mL of erythrocyte concentrate increased the patient's haemoglobin by 0.03 g/L. RESULTS: Assessment was possible in 201 of 234 patients, 110 from group 1 and 91 from group 2. The mean transfusion-corrected difference in haemoglobin was 53 g/L in group 1 (20% transfusion rate) and 35.2 g/L in group 2 (1.09% transfusion rate; P > 0.001). The median intravenous volume applied was 5.96 L in group 1 and 3.49 L in group 2 (P < 0.001). The complication rate did not differ between the groups. CONCLUSION: This new method minimizes the intraoperative blood loss during RRP; transfusions are only necessary in rare cases and the complication rate remained unaltered.

Blood Loss, Surgical↗

PubMed2005

Increase of microcirculatory blood flow enhances penetration of ciprofloxacin into soft tissue.

The present study addressed the effect of microcirculatory blood flow on the ability of ciprofloxacin to penetrate soft tissues. Twelve healthy male volunteers were enrolled in an analyst-blinded, clinical pharmacokinetic study. A single intravenous dose of 200 mg of ciprofloxacin was administered over a period of approximately 20 min. The concentrations of ciprofloxacin were measured in plasma and in the warmed and contralateral nonwarmed lower extremities. The microdialysis technique was used for the assessment of unbound ciprofloxacin concentrations in subcutaneous adipose tissue. Microcirculatory blood flow was measured by use of laser Doppler flowmetry. Warming of the extremity resulted in an increase of microcirculatory blood flow by approximately three- to fourfold compared to that at the baseline (P < 0.05) in subcutaneous adipose tissue. The ratio of the maximum concentration (C(max)) of ciprofloxacin for the warmed thigh to the C(max) for the nonwarmed thigh was 2.10 +/- 0.90 (mean +/- standard deviation; P < 0.05). A combined in vivo pharmacokinetic (PK)-in vitro pharmacodynamic (PD) simulation based on tissue concentration data indicated that killing of Pseudomonas aeruginosa (ATCC 27853 and two clinical isolates) was more effective by about 2 log(10) CFU/ml under the warmed conditions than under the nonwarmed conditions (P < 0.05). The improvement of microcirculatory blood flow due to the warming of the extremity was paralleled by an increased ability of ciprofloxacin to penetrate soft tissue. Subsequent PK-PD simulations based on tissue PK data indicated that this increase in tissue penetration was linked to an improved antimicrobial effect at the target site.

Adult↗

PubMed2005

In vivo measurement of levofloxacin penetration into lung tissue after cardiac surgery.

Nosocomial pneumonia is a severe complication after cardiac surgery (CS). Levofloxacin, a fluoroquinolone, qualifies for the therapy of postoperative pneumonia. However, penetration properties of levofloxacin into the lung tissue could be substantially affected by CS: atelectasis, low cardiac output after CS, high volume loads, and inflammatory capillary leak potentially influence drug distribution. The aim of our study was to gain information on interstitial antibiotic concentrations in lung tissue in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass. Therefore, six patients undergoing elective CS participated in this prospective study. A dose of 500 mg of levofloxacin was administered intravenously in addition to standard antibiotic prophylaxis immediately after the end of surgery. Time versus concentration profiles of levofloxacin in the interstitial lung tissue and plasma were determined. A microdialysis technique was used for lung interstitial concentration measurements. The microdialysis procedure was well tolerated in all patients and no adverse events were observed. The median area under the concentration curve (AUC) of levofloxacin in interstitial lung fluid was 18.6 microg.h/ml (range, 10.1 to 33.6). The median AUC for tissue (AUC(tissue)) of unbound levofloxacin/AUC(total) in plasma was 0.6 (range, 0.4 to 0.9). The median unbound AUC(tissue)/MIC was 2.4 (range, 1.3 to 4.2) for Pseudomonas aeruginosa. Our study demonstrated the feasibility and safety of microdialysis in human lung tissue in vivo after CS. The unbound AUC/MIC ratio revealed that levofloxacin used in the described manner was borderline sufficient for the treatment of nosocomial pneumonia caused by Klebsiella pneumoniae and insufficient for the treatment of pneumonia caused by Pseudomonas aeruginosa, because the breakpoint of 30 to 40 for AUC/MIC could not be reached by the conventionally used dosage schema in our post-CS setting. Penetration was lower than in previous reports.

Aged↗

PubMed2005

Pharmacokinetics and pharmacodynamics of cefpirome in subcutaneous adipose tissue of septic patients.

The objective of the present study was to evaluate whether cefpirome, a member of the latest class of broad-spectrum cephalosporins, sufficiently penetrates subcutaneous adipose tissue in septic patients. After the administration of the drug at 2 g, tissue cefpirome concentrations in septic patients (n = 11) and healthy controls (n = 7) were determined over a period of 4 h by means of microdialysis. To assess the antibacterial effect of cefpirome at the target site, the measured pharmacokinetic profiles were simulated in vitro with select strains of Staphylococcus aureus and Pseudomonas aeruginosa. The tissue penetration of cefpirome was significantly impaired in septic patients compared with that in healthy subjects. For subcutaneous adipose tissue, the area under the concentration-versus-time curve values from 0 to 240 min were 13.11 +/- 5.20 g . min/liter in healthy subjects and 6.90 +/- 2.56 g . min/liter in septic patients (P < 0.05). Effective bacterial growth inhibition was observed in all in vitro simulations. This was attributed to the significantly prolonged half-life in tissue (P < 0.05), which kept the tissue cefpirome levels above the MICs for relevant pathogens for extended periods in the septic group. By consideration of a dosing interval of 8 h, the values for the time above MIC (T > MIC) in tissue were greater than 60% for pathogens for which the MIC was </=4 mg/liter in all septic patients. The present data indicate that cefpirome is an appropriate agent for the treatment of soft tissue infections in septic patients. However, due to the high interindividual variability of the pharmacokinetics of cefpirome in tissue, dosing intervals of not more than 8 h should be preferred to ensure that susceptible bacterial strains are killed in each patient.

Adipose Tissue↗

PubMed2005

Penetration of linezolid into soft tissues of healthy volunteers after single and multiple doses.

The present study tested the ability of linezolid to penetrate soft tissues in healthy volunteers. Ten healthy volunteers were subjected to linezolid drug intake at a dose of 600 mg twice a day for 3 to 5 days. The first dose was administered intravenously. All following doses were self-administered orally. The tissue penetration of linezolid was assessed by use of in vivo microdialysis. In the single-dose experiments the ratios of the area under the concentration-time curve from 0 to 8 h (AUC0-8) for tissue to the AUC0-8 for free plasma were 1.4+/-0.3 (mean+/-standard deviation) and 1.3+/-0.4 for subcutaneous adipose and muscle tissue, respectively. After multiple doses, the corresponding mean ratios were 0.9+/-0.2 and 1.0+/-0.5, respectively. The ratios of the AUC from 0 to 24 h (AUC0-24) for free linezolid in tissues to the MIC were between 50 and 100 for target pathogens with MICs between 2 and 4 mg/liter. In conclusion, the present study showed that linezolid penetrates rapidly into the interstitial space fluid of subcutaneous adipose and skeletal muscle tissues in healthy volunteers. On the basis of pharmacokinetic-pharmacodynamic calculations, we suggest that linezolid concentrations in soft tissues can be considered sufficient to inhibit the growth of many clinically relevant bacteria.

Acetamides↗

PubMed2005

Tissue penetration of cefpodoxime and cefixime in healthy subjects.

Microdialysis is a technique that allows the measurement of free antibiotic concentrations in different tissues, which are responsible for the antibacterial activity at the infection site. In an open, randomized, 2-way crossover study in healthy volunteers, the muscle penetration of orally administered cefpodoxime (400 mg) and cefixime (400 mg) was compared using microdialysis. The results show that the total plasma concentration-time profiles of each antibiotic were similar; the area under the curve for cefpodoxime was 22.4 +/- 8.7 versus 25.6 +/- 8.5 mg/L*h for cefixime. However, tissue penetration was twice as high for cefpodoxime (area under the curve 15.4 +/- 5.1 mg/L*h) as for cefixime (area under the curve 7.3 mg/L*h). This degree of tissue distribution is consistent with their protein binding of 21% for cefpodoxime and 65% for cefixime. After equilibration, the unbound tissue concentrations of both antibiotics were similar to their unbound plasma concentrations. Pharmacokinetic modeling was applied to describe the pharmacokinetic profiles in plasma and muscle. The study demonstrates that cefpodoxime shows greater tissue penetration than cefixime.

Anti-Bacterial Agents↗

PubMed2005

Simultaneous analysis of MDR1 C3435T, G2677T/A, and C1236T genotypes by multiplexed mutagenically separated PCR.

P-glycoprotein (PGP) encoded by the multi-drug-resistance 1 (MDR1) gene is a member of the ATP-binding cassette (ABC) transporter family, drug-transporting proteins involved in the bioavailability and pharmacokinetics of various drugs. Several single nucleotide polymorphisms (SNPs) in the MDR1 gene have been identified so far that may influence PGP expression levels and function. Thus, genotyping for MDR1 polymorphisms and determining specific haplotypes may become an important tool in predicting individual susceptibility to developing drug resistance. We developed a new multiplexed allele-specific PCR method based on the principle of mutagenically separated PCR (MS-PCR) for rapid and reliable simultaneous genotyping of the C3435T polymorphism in exon 26 of the MDR1 gene and two additional SNPs (G2677T/A in exon 21 and C1236T in exon 12), which are in linkage disequilibrium with MDR1 C3435T. The accuracy and reliability of this method was confirmed by sequencing the respective regions in the MDR1 gene. This newly developed MDR1 MS-PCR will facilitate fast, accurate and economic analysis of MDR1 genotypes and will provide important information in optimizing individual therapeutic approaches.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2005

Effect of information on reported adverse events in a placebo-controlled trial.

OBJECTIVE: Although placebo controls are a standard measure in clinical trials the mechanisms underlying placebo effects are still not fully understood. We hypothesised that information about the likelihood of receiving placebo might influence the perception of adverse effects in volunteers participating in a clinical trial. METHODS: Healthy subjects received either nifedipine 20 mg or placebo in an adaptive two-stage crossover study. Sixty subjects were randomised to a group given either correct (50% chance) or misleading (100% chance) information about the likelihood of receiving the active drug. A sum of the severity scores from visual analogue scales over all individual adverse effects was defined as the primary endpoint. RESULTS: The analysis revealed no difference in the primary endpoint between the two groups. This lack of difference may in part be attributable to a conditioning effect as on the first study day higher symptom scores were reported by the participants than on the second study day. Furthermore, the day effect seemed to arise mainly when the first day treatment was the placebo. For the placebo the day effect was clearly significant (p = 0.012), with higher scores on the first day. A further explorative finding in patients given placebo was a tendency for higher scores in the group with the misleading information (p = 0.08). Nothing of that sort was found in the analysis for active treatment. The day effect collapsed and the factor information did not show any tendency of being a potential influence. CONCLUSIONS: In the present study we did not find a statistically significant effect of misleading information on reported adverse events. The large treatment and day effects observed made it difficult to detect a potential small information effect. However, this study excluded a strong and relevant effect of information on the frequency and severity of reported adverse events.

Adult↗

PubMed2005

Microdialysis: current applications in clinical pharmacokinetic studies and its potential role in the future.

Microdialysis is a probe-based sampling method, which, if linked to analytical devices, allows for the measurement of drug concentration profiles in selected tissues. During the last two decades, microdialysis has become increasingly popular for preclinical and clinical pharmacokinetic studies. The advantage of in vivo microdialysis over traditional methods relates to its ability to continuously sample the unbound drug fraction in the interstitial space fluid (ISF). This is of particular importance because the ISF may be regarded as the actual target compartment for many drugs, e.g. antimicrobial agents or other drugs mediating their action through surface receptors. In contrast, plasma concentrations are increasingly recognised as inadequately predicting tissue drug concentrations and therapeutic success in many patient populations. Thus, the minimally invasive microdialysis technique has evolved into an important tool for the direct assessment of drug concentrations at the site of drug delivery in virtually all tissues. In particular, concentrations of transdermally applied drugs, neurotransmitters, antibacterials, cytotoxic agents, hormones, large molecules such as cytokines and proteins, and many other compounds were described by means of microdialysis. The combined use of microdialysis with non-invasive imaging methods such as positron emission tomography and single photon emission tomography opened the window to exactly explore and describe the fate and pharmacokinetics of a drug in the body. Linking pharmacokinetic data from the ISF to pharmacodynamic information appears to be a straightforward approach to predicting drug action and therapeutic success, and may be used for decision making for adequate drug administration and dosing regimens. Hence, microdialysis is nowadays used in clinical studies to test new drug candidates that are in the pharmaceutical industry drug development pipeline.

Animals↗

PubMed2005

Expression levels of the EZH2 polycomb transcriptional repressor correlate with aggressiveness and invasive potential of bladder carcinomas.

The polycomb group protein enhancer of zeste 2 (EZH2) is a transcriptional repressor involved in the control of cellular proliferation and oncogenesis. The aim of the present study was to quantify EZH2 expression in bladder carcinomas and to correlate the data with clinicopathological findings. EZH2 mRNA expression was measured by real-time reverse transcription-polymerase chain reaction in tumor tissue specimens obtained from 37 patients with urothelial carcinomas of the bladder and in four bladder cancer cell lines. EZH2 levels were normalized to expression of the housekeeping porphobilinogen deaminase gene. EZH2 transcripts were commonly detected in tumor tissue. Transcript levels correlated significantly with the invasiveness of bladder tumors (p = 0.029) with elevated EZH2 mRNA expression measured in invasive bladder carcinomas (median value, 38.92) compared with non-invasive tumors (15.51). In addition, levels of expression were significantly higher in high-grade (G3) than in low-grade (G1/2) lesions (p < 0.001). EZH2 mRNA levels in bladder carcinoma cell lines were within the range of high-grade invasive bladder cancers. In conclusion, expression levels of EZH2 are elevated in aggressive and invasive urothelial carcinomas, suggesting that deregulated EZH2 expression may be involved in the progression of bladder tumors.

Aged↗

PubMed2005

Combined PET and microdialysis for in vivo assessment of intracellular drug pharmacokinetics in humans.

UNLABELLED: Because many drugs possess an intracellular site of action, the knowledge of intracellular concentration-time profiles is desirable. In the present study, PET, which measures total (i.e., intracellular, extracellular, and intravascular) concentrations of radiolabeled drugs in tissue, and microdialysis, which determines unbound drug concentrations in the extracellular space fluid of tissue, were combined to describe the intracellular pharmacokinetics of a model compound--that is, the (18)F-labeled antibiotic (18)F-ciprofloxacin--in vivo in humans. METHODS: Ten healthy male volunteers received a mixture of 687 +/- 50 MBq of (18)F-ciprofloxacin and 200 mg of unlabeled ciprofloxacin as an intravenous bolus infusion over 10 min. The pharmacokinetics of ciprofloxacin in skeletal muscle tissue were assessed by means of combined PET and in vivo microdialysis for 5 h after drug administration. A 3-compartment pharmacokinetic model was fitted to the tissue concentration-time profiles of ciprofloxacin measured by PET to estimate the rate constants of ciprofloxacin uptake and transport. RESULTS: In muscle tissue, mean total and extracellular peak concentration (C(max)) values of ciprofloxacin of 1.8 +/- 0.4 microg/mL and 0.7 +/- 0.2 microg/mL were attained at 95 +/- 34 min and 48 +/- 20 min after drug administration, respectively. The extracellular-to-intracellular exchange appeared to be very fast, with an estimated rate constant k(3) of 1.69 +/- 0.25 min(-1). An intracellular-to-extracellular concentration ratio (C(intra)/C(extra)) of 3.2 +/- 0.8 was reached at 110 min after injection and followed by sustained intracellular retention of the antibiotic for the remainder of the experiment. The predicted extracellular concentration-time profiles from the compartmental modeling were in good agreement with the measured microdialysis data. CONCLUSION: The results obtained in the present study were in accordance with previous in vitro data describing cellular ciprofloxacin uptake and retention. The presently used PET/microdialysis combination might be useful during research and development of new drugs, for which knowledge of intracellular concentrations is of interest.

Adult↗

PubMed2005

EEG analysis with nonlinear excitable media.

The detection of patterns embedded within a complex, nonstationary, and noisy background activity is a crucial and important task in EEG analysis. The authors present a biologically inspired, analog approach to EEG analysis that is conceptually different from a variety of statistical approaches currently used. A nonlinear, excitable, spatially extended medium that is composed of diffusively coupled model neurons is considered. When EEG recordings are applied as local perturbations to such an excitable neural tissue, the induced transient changes in the dynamics of the perturbed system can be regarded as an instantaneous characterization of transient processes in the brain reflected by the EEG, e.g., in the form of a sequence of correlated dynamical events (patterns). Nonlinear excitable media can be implemented in form of an array of locally coupled integrated analog nonlinear electrical circuits called cellular neural networks, which represent a next evolutionary step in the parallel analog computer architecture. Using cellular neural networks, the authors show that the concept of signal-induced pattern generation allows an almost instantaneous and unsupervised detection of seizure onsets in EEG recordings. In addition, they show that a cellular neural network can be trained in a supervised way to approximate the degree of synchronization in EEG recordings. The resulting pattern-recognition device may be suitable for the prediction of epileptic seizures.

Animals↗

PubMed2004

Formation of the aureothin tetrahydrofuran ring by a bifunctional cytochrome p450 monooxygenase.

The polyketide antibiotic aureothin, produced by Streptomyces thioluteus, is equipped with a rare exomethylene-tetrahydrofuran moiety. Cloning, heterologous expression, and inactivation experiments reveal that AurH, a bifunctional cytochrome P450 monooxygenase, is required and sufficient for the stereoselective synthesis of the furan ring, involving the subsequent formation of two new C-O bonds.

Chromones↗

PubMed2004

The inhibitor of apoptosis (IAP) survivin is expressed in human testicular germ cell tumors and normal testes.

Deregulated apoptosis of germ cells may contribute to malignant transformation as well as male infertility. We analyzed expression of the inhibitor of apoptosis survivin by polymerase chain reaction (PCR) in testicular germ cell tumors (TGCTs, n=28), normal testes (n=19) and testes with defective spermatogenesis (n=22). In a subset of samples (n=35), survivin transcript levels were quantified using real-time PCR. While survivin mRNA was expressed at high levels in undifferentiated TGCTs and normal testes, it was lost in mature teratomas and germ cell aplasia. Survivin expression in both normal and transformed germ cells is in contrast to its sharp differential expression in other tissues. Survivin expression correlates with the differentiation state of TGCTs and may be relevant for their tumorigenesis and malignant potential.

Cell Transformation, Neoplastic↗

PubMed2004

Nonlinear dynamic conversion of analog signals into excitation patterns.

Local periodic perturbations induce frequency-dependent propagation waves in an excitable spatiotemporally chaotic system. We show how segments of noise-contaminated and chaotic perturbations induce characteristic sequences of excitations in the model system. Using a set of "tuned" excitable systems, it is possible to characterize signals by their spectral composition of excitation pattern. As an example, we analyze an epileptic "spike-and-wave" time series.

Journal Article↗

PubMed2004

In vitro and in vivo evaluation of [18F]ciprofloxacin for the imaging of bacterial infections with PET.

PURPOSE: The suitability of the 18F-labelled fluoroquinolone antibiotic ciprofloxacin ([18F]ciprofloxacin) for imaging of bacterial infections with positron emission tomography (PET) was assessed in vitro and in vivo. METHODS: For the in vitro experiments, suspensions of various E. coli strains were incubated with different concentrations of [18F]ciprofloxacin (0.01-5.0 microg/ml) and radioactivity retention was measured in a gamma counter. For the in vivo experiments, 725 +/- 9 MBq [18F]ciprofloxacin was injected intravenously into four patients with microbiologically proven bacterial soft tissue infections of the lower extremities and time-radioactivity curves were recorded in infected and uninfected tissue for 5 h after tracer injection. RESULTS: Binding of [18F]ciprofloxacin to bacterial cells was rapid, non-saturable and readily reversible. Moreover, bacterial binding of the agent was similar in ciprofloxacin-resistant and ciprofloxacin-susceptible clinical isolates. These findings suggest that non-specific binding rather than specific binding to bacterial type II topoisomerase enzymes is the predominant mechanism of bacterial retention of the radiotracer. PET studies in the four patients with microbiologically proven bacterial soft tissue infections demonstrated locally increased radioactivity uptake in infected tissue, with peak ratios between infected and uninfected tissue ranging from 1.8 to 5.5. Radioactivity was not retained in infected tissue and appeared to wash out with a similar elimination half-life as in uninfected tissue, suggesting that the kinetics of [18F]ciprofloxacin in infected tissue are governed by increased blood flow and vascular permeability due to local infection rather than by a binding process. CONCLUSION: Taken together, our results indicate that [18F]ciprofloxacin is not suited as a bacteria-specific infection imaging agent for PET.

Aged↗

PubMed2004

Tacrolimus or cyclosporine: which is the better partner for mycophenolate mofetil in heart transplant recipients?

BACKGROUND: The aim of this single-center study was to investigate whether trough level adjusted mycophenolate mofetil (MMF) is more efficacious in combination with tacrolimus (TAC) or cyclosporine (CsA) and to evaluate the impact of either drug on MMF dosage. METHODS: Sixty patients (TAC, n = 30; CsA, n = 30) undergoing heart transplantation were randomized into a prospective, open-label, controlled trial. Immunosuppression consisted of TAC or CsA in combination with MMF and corticosteroids. Target blood trough levels of TAC, CsA, and mycophenolic acid (MPA) were in the range of 10 to 15 ng/mL, 100 to 300 ng/mL, and 1.5 to 4.0 microg/mL, respectively. Acute rejection episodes (ARE); survival data; and adverse events with a special emphasis on infections, diabetes, hypertension, hypercholesterolemia, and the development of graft vessel disease (GVD) were recorded. RESULTS: Baseline characteristics were well balanced. All patients were successfully withdrawn from corticosteroids within 6 months of transplant. Freedom from acute rejection was significantly higher (P = 0.0001) and the incidence of ARE per 100 patient days significantly lower in the TAC-MMF group than in the CsA-MMF group (0.03 vs. 0.15; P = 0.00007). Overall patient survival during follow-up was similar (93% vs. 90%). To achieve the targeted MPA blood levels, a significantly lower dose of MMF was required for TAC versus CsA patients. After a follow-up time of 2 years, the mean GVD score was 1.85 +/- 3.18 in the TAC-MMF group and 3.95 +/- 4.8 in the CsA-MMF group (P = 0.08). CONCLUSIONS: At the selected doses and target levels for TAC and CsA used in this study, trough level adjusted MMF was more efficacious in combination with TAC for prevention of ARE. Furthermore, CsA patients need significantly more MMF to achieve similar MPA levels.

Adult↗