[Generic drugs--medical progress at a moderate price].
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Austria↗
Biomedical subjects
Markus Müller
Publications and source records attributed to Markus Müller.
Single- and multiple-dose pharmacokinetics of oral creatine.
Supplementation with exogenous creatine (Cr) has shown physiological benefits in humans, but little is known about the pharmacokinetics of Cr in humans. Six healthy males completed an open-label study consisting of a full pharmacokinetic analysis following a single oral dose of Cr monohydrate (71 mg kg-1) and at steady-state after 6 days of Cr administration (71 mg kg-1 qid). After the single oral dose, the clearance (CL/F) was 0.20 +/- 0.066 L h-1 kg-1, tmax was 1.9 +/- 0.88 hours, and Cmax = 102.1 +/- 11.2 mg h L-1. At steady-state, CL/F decreased to 0.12 +/- 0.016 L h-1 kg-1, tmax did not change, and Cmax increased to 162.2 +/- 30.0 mg L-1. Penetration (AUCMUSCLE/AUCPLASMA) of Cr into the interstitial muscle space, as determined by microdialysis, was 0.47 +/- 0.09 and 0.37 +/- 0.27 for the single dose and at steady-state, respectively. Plasma and muscle data were simultaneously fitted with a model incorporating a saturable absorption and first-order elimination process. In conclusion, repeated dosing of Cr caused a reduction in clearance that could result from saturation of the skeletal muscle pool of Cr.
Administration, Oral↗
The differentiation status of primary gonadal germ cell tumors correlates inversely with telomerase activity and the expression level of the gene encoding the catalytic subunit of telomerase.
BACKGROUND: The activity of the ribonucleoprotein enzyme telomerase is detectable in germ, stem and tumor cells. One major component of telomerase is human telomerase reverse transcriptase (hTERT), which encodes the catalytic subunit of telomerase. Here we investigate the correlation of telomerase activity and hTERT gene expression and the differentiation status of primary testicular germ cell tumors (TGCT). METHODS: Telomerase activity (TA) was detected by a quantitative telomerase PCR ELISA, and hTERT mRNA expression was quantified by online RT-PCR in 42 primary testicular germ cell tumors. The control group consisted of benign testicular biopsies from infertile patients. RESULTS: High levels of telomerase activity and hTERT expression were detected in all examined undifferentiated TGCTs and in the benign testicular tissue specimens with germ cell content. In contrast, differentiated teratomas and testicular control tissue without germ cells (Sertoli-cell-only syndrome) showed no telomerase activity and only minimal hTERT expression. CONCLUSIONS: These findings demonstrate an inverse relationship between the level of telomerase activity and hTERT mRNA expression and the differentiation state of germ cell tumors. Quantification of telomerase activity and hTERT mRNA expression enables a new molecular-diagnostic subclassification of germ cell tumors that describes their proliferation potential and differentiation status.
Catalytic Domain↗
Microdialysis: an in vivo approach for measuring drug delivery in oncology.
Microdialysis (MD) is a catheter-based sampling method that provides the opportunity to directly study tumor drug exposure and metabolism in a minimally invasive way. Tumor drug exposure, which is directly linked to clinical outcome, may be substantially reduced due to diffusion barriers in solid tumors. Therefore plasma drug profiles are frequently inappropriate for predicting outcome in oncology. This contribution focuses on the application of MD in preclinical and clinical oncological research and presents an overview of the current literature. It is concluded that MD, in combination with pharmacokinetic/pharmacodynamic modeling, has the potential to contribute to the design of optimal treatment schedules and to select appropriate drug candidates, doses, and dosing intervals for established and new anticancer drugs.
Animals↗
Science, medicine, and the future: Microdialysis.
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Blood Glucose↗
Telomerase: its clinical relevance in the diagnosis of bladder cancer.
More than 50 years ago, Papanicolaou recognized the importance of a non-invasive technique for the diagnosis and follow-up of patients with carcinoma of the urinary bladder. Cystoscopy, however, has remained the 'gold standard' since no currently available non-invasive method can compete with cystoscopy's sensitivity and specificity. The detection of the ribonucleoprotein telomerase or the telomerase subunits human telomerase RNA (hTR) and human telomerase reverse transcriptase (hTERT) in urine samples offer new diagnostic perspectives. The present article presents a review of publications in the literature and evaluates their clinical relevance. The experimental studies reported to date are very promising and show that telomerase exactly fulfils the requirements for a good diagnostic marker for carcinoma of the urinary bladder. The diagnostic application remains in an experimental stage and telomerase is still several steps away for routine use as a clinical parameter. The remaining steps leading to its routine clinical application will be discussed.
Biomarkers, Tumor↗
Closed-chest microdialysis to measure antibiotic penetration into human lung tissue.
The majority of bacterial lung infections are localized to the interstitial space fluid, which is therefore an important target site for antimicrobial chemotherapy. Direct measurement of interstitial concentrations of antimicrobial agents in human lung tissue would allow for a more informed approach to appropriate dosing of antimicrobial agents, but until now this was beyond technical reach. In this exploratory pharmacokinetic study, we measured the time versus concentration profile of cefpirome after a single intravenous dose administration of 2 g in the lung interstitial fluid by flexible microdialysis catheters, which were implanted during lung surgery for pulmonary tumors in five patients. Cefpirome concentrations in lung interstitial fluid were 66% of corresponding plasma values within the first 240 min, and exceeded minimal inhibitory concentrations of most relevant bacteria. The experimental procedure was well tolerated by the patients and no adverse events were observed. The present study provides evidence for the first time that closed chest microdialysis of the human lung is a feasible and safe method to measure lung concentrations in patients in vivo. The present data also corroborate the use of cefpirome as a valuable agent in the treatment of lung infections with most extracellular bacteria.
Aged↗
Molecular scanner experiment with human plasma: improving protein identification by using intensity distributions of matching peptide masses.
The development of high throughput utilities to identify proteins is a major challenge in present research in the field of proteomics. One such utility, the molecular scanner, uses proteins separated by two-dimensional polyacrylamide gel electrophoresis that are digested in the gel and during transfer onto a collecting membrane. After adding a matrix, the membrane is inserted into a matrix-assisted laser desorption/ionization-time of flight mass spectrometer and a peptide mass fingerprint (PMF) is measured for every scanned site. Since the spacing between scanned sites is much smaller than the size of the most abundant protein spots, there is a certain redundancy in the data that was used in an earlier experiment with Escherichia coli [1] to improve mass calibration and PMF identification results. It was observed that the signal intensity of a peptide mass as a function of the position on the membrane showed similar patterns if peptides stemmed from the same protein. Taking account of these similarities a clustering algorithm was used to find lists of experimental masses with similar intensity distributions, which provided clearer identification of the corresponding proteins. Here, these methods are applied to a human plasma scan, where proteins were highly modified and less separated. The presence of very abundant proteins like albumin and immunoglobulins added another difficulty. The calibration of the initial PMFs was not satisfactory and masses had to be recalibrated. After discarding chemical noise, the membrane was partitioned into regions and for each region protein identification was carried out separately. A new scoring method was used, where the PMF score was multiplied by a factor that measures the similarity of matching peptides. This method proved to be more robust than the method developed in [1] if the region where a protein was found had an extended, nonspherical shape and strong overlap with regions of other proteins. Many proteins annotated on the SWISS-2D PAGE human plasma master gel could be clearly identified and many interesting properties were observed.
Algorithms↗
Methylation-specific PCR for detection of neoplastic DNA in biopsy washings.
Epigenetic DNA alterations such as promoter hypermethylation of glutathione S-transferase P1 (GSTP1) in prostatic adenocarcinoma frequently constitute tumour biomarkers. Neoplastic transformation was identified in washings of prostate biopsies by GSTP1 promoter hypermethylation, using methylation-specific PCR (MSP). Twenty-six patients undergoing sextant transrectal prostate biopsies for clinically suspected prostate cancer were enrolled. All ten patients diagnosed with adenocarcinoma (100%) and four of six patients with prostatic intraepithelial neoplasia (67%), but none of ten patients with benign hyperplasia (0%), exhibited GSTP1 promoter hypermethylation in at least one out of six biopsy washings. Since this approach is transferable to various cancer entities, a sensitive and specific DNA-based analysis of biopsy material seems generally feasible without impeding routine histopathological examination.
Adenocarcinoma↗
Some tumors of the bladder are polyclonal in origin.
PURPOSE: Clonality assays can be used to address different questions of neoplasm development. The study of the X chromosome inactivation pattern in female patients provides a useful and most commonly used indirect approach to demonstrate the monoclonal status of a cell population. We used this approach to examine whether recurrent tumors of the bladder supposed to be of monoclonal origin derive from different, independently transformed cells or whether they arise from 1 primary tumor. MATERIALS AND METHODS: We analyzed 45 archival or fresh frozen bladder tumors from 27 female patients. We assessed the X inactivation status of each tumor by a polymerase chain reaction based method after HpaII digestion. RESULTS: Surprisingly 16 of the 45 tumors revealed a polyclonal pattern. The amount of undigested DNA far exceeded what was explained by contamination with normal cells, as determined on histological sections indicating that these tumors were in fact polyclonal. This polyclonal status was further confirmed by a comprehensive series of controls. CONCLUSIONS: Some bladder tumors are polyclonal in origin. Our findings are at variance with earlier observations and possibilities for explanation are proposed.
DNA Methylation↗
DNA alterations in body fluids as molecular tumor markers for urological malignancies.
OBJECTIVES: DNA-based tumor markers are characterized by unique specificity rendering them an attractive target for molecular diagnosis of cancer in body fluids like blood serum/plasma and urine. Both cell-free tumor DNA circulating in plasma/serum and cellular tumor DNA are detectable by minimally invasive measures. METHODS: Three main detection methods, microsatellite analysis, mutation analysis in genomic or mitochondrial DNA and gene promoter hypermethylation analysis are applied. Detection of gene promoter hypermethylation by methylation-specific PCR enables the best methodical sensitivity requiring a ratio of tumor DNA within normal DNA of less than 1:1000. RESULTS/CONCLUSIONS: Tumor DNA derived from renal cell carcinoma, bladder cancer or prostate cancer is detectable in considerably more than 50% of plasma/serum samples and more than 70% of urine samples from these patients. Because the targeted DNA alterations are absent or very rare in controls, the specificity of DNA-based tumor detection methods reaches almost 100%. Although the methodology currently is experimental, automatization will make it easier and less expensive. This review is focused on the potential clinical value of DNA-based analysis of body fluids for the initial diagnosis and the follow-up of urologic cancer patients.
Biomarkers, Tumor↗
Rational dosing of antibiotics: the use of plasma concentrations versus tissue concentrations.
At the moment, the most common pharmacokinetic/pharmacodynamic (PK/PD) approaches for anti-infective agents, such as time above MIC, C(max)/MIC and AUC(24)/MIC, rely on plasma concentration as the PK input value and minimum inhibitory concentration (MIC) as the PD input value. However, only the free tissue concentrations of antibiotics at the target site are responsible for the therapeutic effect. Using plasma concentrations frequently overestimates the target site concentrations and therefore clinical efficacy. Microdialysis is a new technique that allows direct measurement of unbound tissue concentrations. Furthermore, a better PD approach, bacterial time-kill curves, can offer more detailed information about the antibacterial activity as a function of time and antibiotic concentration than MICs.
Anti-Bacterial Agents↗
Visualization and analysis of molecular scanner peptide mass spectra.
The molecular scanner combines protein separation using gel electrophoresis with peptide mass fingerprinting (PMF) techniques to identify proteins in a highly automated manner. Proteins separated in a 2-dimensional polyacrylamide gel (2-D PAGE) are digested in parallel and transferred onto a membrane keeping their relative positions. The membrane is then sprayed with a matrix and inserted into a matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometer, which measures a peptide mass fingerprint at each site on the scanned grid. First, visualization of PMF data allows surveying all fingerprints at once and provides very useful information on the presence of chemical noise. Chemical noise is shown to be a potential source for erroneous identifications and is therefore purged from the mass fingerprints. Then, the correlation between neighboring spectra is used to recalibrate the peptide masses. Finally, a method that clusters peptide masses according to the similarity of the spatial distributions of their signal intensities is presented. This method allows discarding many of the false positives that usually go along with PMF identifications and allows identifying many weakly expressed proteins present in the gel.
Algorithms↗
Evaluation of the time window for Resovist-enhanced T2-weighted MRI of the liver.
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Contrast Media↗
Penetration of fosfomycin into the parenchyma of human brain: a case study in three patients.
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Adult↗
Quantification of cyclin A1 and glyceraldehyde-3-phosphate dehydrogenase expression in testicular biopsies of infertile patients by fluorescence real-time RT-PCR.
The objective of this study was to establish a classification of meiotic disorders by detection of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and cyclin A1 mRNA in patients presenting with non-obstructive azoospermia. GAPDH and cyclin A1 expression levels were detected in 37 histologically classified testicular tissue specimens by one-line RT-PCR. Levels of cyclin A1 expression (NCyclinA1) were high in tissue specimens with full spermatogenesis [3.519 +/- 3.141 (mean +/- SD)] but only minimal in those without haploid germ cells. A lack of cyclin A1 expression was seen in most sertoli-cell-only syndrome (SCOS) specimens. The criteria for an ideal internal standard were only partially met by GAPDH, as we detected decreased expression in tissue samples with maturation arrest [(268.2 +/- 106.2 relative gene expression (mean +/- SD)] and SCOS (201.7 +/- 95.2) compared to those with normal histological findings (325.1 +/- 129.3). It was concluded that the level of cyclin A1 mRNA expression predicts meiotic disorders during spermatogenesis. GAPDH is not an ideal internal standard for specific gene expression in testicular tissue specimens.
Adult↗
Cyclin A1 and gametogenesis in fertile and infertile patients: a potential new molecular diagnostic marker.
BACKGROUND: The study aim was to evaluate cyclin A1 mRNA expression levels as a potential molecular diagnostic parameter in the work-up of testicular tissue from fertile versus infertile patients. METHODS: Cyclin A1 expression was quantified in 55 cryopreserved testicular tissue specimens by fluorescence real-time RT-PCR. A conventional histological work-up was performed concomitantly in all tissue specimens with additional semi-thin sectioning in all cases of non-obstructive azoospermia (n = 12), maturation arrest (n = 17) and Sertoli cell-only syndrome (SCOS; n = 9). RESULTS: The mean (+/- SD) normalized cyclin A1 expression (N(CyclinA1)) was 3.82 +/- 2.23 relative gene expression (RGE) in tissue specimens with normal spermatogenesis, and 0.625 +/- 0.221 RGE in those with maturation arrest at the level of early spermatids. Only minimal N(CyclinA1) was detected in tissue specimens with spermatogonia only or maturation arrest at the level of primary spermatocytes (0.005 +/- 0.008). Cyclin A1 expression was absent in the majority of SCOS specimens (0.002 +/- 0.002). CONCLUSIONS: These investigations suggested that cyclin A1 expression is altered in cases of spermatogenic disorders. Moreover, the level of cyclin A1 mRNA expression correlates with gametogenic disorders and seems well suited for a molecular-diagnostic classification supplementing the histopathological evaluation of spermatogenic disorders.
Biomarkers↗
Interstitial tissue concentrations of cefpodoxime.
Microdialysis is a technique that allows the measurement of concentrations of free antibiotic in tissue. The free antibiotic concentration is responsible for the antibacterial effect at the target site. We used microdialysis in animal and human studies to investigate the tissue penetration of cefpodoxime. In the animal study, total plasma and free muscle and lung concentrations of cefpodoxime were measured after male Wistar rats had received either 10 mg/kg or 20 mg/kg i.v. cefpodoxime over 5 h or a continuous i.v. infusion of 260 microg/h cefpodoxime after a loading dose of 6 mg/kg. Free muscle concentrations of cefpodoxime were similar to free lung concentrations and therefore provided a surrogate measure of cefpodoxime concentrations at the pulmonary target site. In an open, randomized, two-way crossover, single-dose study in six healthy male volunteers, total plasma and free muscle concentrations were measured after a single oral dose of cefpodoxime 400 mg or cefixime 400 mg. The total plasma concentrations of each antibiotic were similar and higher than free muscle concentrations. The tissue penetration of cefpodoxime was, however, greater than that of cefixime, as shown by two-fold higher peak free muscle concentrations after dosing with cefpodoxime than with cefixime (2.1 mg/L versus 0.9 mg/L). In addition, the area under the curve for tissue (AUC(t)) of cefpodoxime (400 mg) was more than double that of cefixime (400 mg), based on free antibiotic concentrations (15.4 mg x h/L versus 7.3 mg x h/L). These findings indicate that, taking into account pharmacokinetic/pharmacodynamic considerations, cefpodoxime is likely to be more efficacious than cefixime, due to its greater tissue penetration.
Animals↗