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Schettler V.,Nephrologisches Zentrum Gottingen GbR | Neumann C.L.,Nephrologisches Zentrum Gottingen GbR | Hagenah G.C.,Nephrologisches Zentrum Gottingen GbR | Schulz E.G.,Nephrologisches Zentrum Gottingen GbR | Wieland E.,Zentralinstitut For Klinische Chemie Und Laboratoriumsmedizin
Atherosclerosis Supplements

Background: Lipoprotein apheresis (LA) is used in hypercholesterolemic patients suffering from cardiovascular disease (CHD) if a modified diet and lipid-lowering drug regimens had failed. During the first LA treatments LDL-cholesterol (LDL-C) and lipoprotein (a) (Lp(a)) can be decreased very effectively when using generally accepted formulas for calculating plasma (PV) (e.g. Pearson) or blood volumes (BV) as a basis for calculating treatment volume (e.g. Nadler). With respect to LDL-C and Lp(a) levels after LA treatment not all treated patients on steady state with apheresis treatment procedures may achieve the desired target concentrations for LDL-C (<70 mg/dl) and Lp(a) (<30 mg/dl). Are there further ways to increase the effectiveness of LA? Methods: Over months or years of LA the treated volumes were stepwise increased in patients to achieve target cholesterol concentrations but not sufficiently in all cases. Therefore the patients' actual LA treatment volumes were compared to the calculated PV or BV. To possibly optimize the treatment capacity of LA procedures independent of calculated PV or BV the capacity threshold was determined in addition. During LA procedures every 20 min cholesterol, triglycerides, LDL-C, HDL-C and Lp(a) concentrations were determined and related to the hematocrit to exclude dilution effects. Results: In patients undergoing regular LA treated volumes vs. calculated volumes were different: for PV 28 ± 18% (n = 7); for BV 28 ± 20% (n = 6). The mean treated volumes were 1.3 fold larger than the calculated volumes to achieve cholesterol target levels in most LA treatments. With respect to the capacity threshold we observed in only 1 of 13 patients an ineffective long treatment time. No LA procedure failed due to exhausted capacity. Conclusions: Lipoprotein apheresis treatment is a very effective treatment procedure in lowering LDL-C and Lp(a). However, not in all procedures the optimal treatment volume for LA patients may be calculated. However calculations of PV and BV are more or less error-prone. An increase of 1.3 fold in the calculated volumes may be the first step in optimizing individual LA treatment options. In addition, to exclude an exhaustion of LA procedures the determination of the individual capacity threshold in every LA patient may be further helpful to adjust treatment volumes. To substantiate our demand on changed treatment volumes further data are necessary. © 2012 Elsevier Ireland Ltd. Source

Shipkova M.,Zentralinstitut For Klinische Chemie Und Laboratoriumsmedizin
Therapeutic Drug Monitoring

ABSTRACT:: In response to the urgent need for new, reliable biomarkers to complement the guidance of the immunosuppressive therapy a huge number of biomarker candidates to be implemented in clinical practice have been introduced to the transplant community. This includes a diverse range of molecules with very different molecular weights, chemical and physical properties, ex vivo stabilities, in vivo kinetic behaviors and levels of similarity to other molecules, etc. In addition a large body of different analytical techniques and assay protocols can be used to measure biomarkers. Sometimes a complex software-based data evaluation is a prerequisite for appropriate interpretation of the results and for their reporting. Although some analytical procedures are of great value for research purposes, they may be too complex for implementation in a clinical setting. Whereas the proof of “fitness for purpose” is appropriate for validation of biomarker assays used in exploratory drug development studies, a higher level of analytical validation must be achieved and eventually advanced analytical performance might be necessary before diagnostic application in transplantation medicine. A high level of consistency of results between-laboratories as well as between-methods (if applicable) should be obtained and maintained to make biomarkers effective instruments in support of therapeutic decisions.This overview focuses on pre-analytical and analytical aspects to be considered for the implementation of new biomarkers for adjusting immunosuppression in a clinical setting and highlights critical points to be addressed on the way to make them suitable as diagnostic tools. These include but are not limited to appropriate method validation, standardization, education, automation and commercialization. © 2015 Wolters Kluwer Health, Inc. All rights reserved. Source

Kirchherr H.,Medizinisches Labor Bremen | Shipkova M.,Zentralinstitut For Klinische Chemie Und Laboratoriumsmedizin | Ahsen N.V.,Medizinisches Labor Bremen
Therapeutic Drug Monitoring

Objectives: Thiopurine drugs (azathioprine, 6-mercaptopurine) show wide interindividual variability and a narrow therapeutic range thus making therapeutic monitoring of their active metabolite 6-thioguanine nucleotides (6-TGN) desirable. We improved the currently available laborious and complex methodology of therapeutic drug monitoring of 6-TGN and the metabolite 6-methylmercaptopurine (6-MMP) in washed erythrocytes (ery) based on a whole-blood method. Methods: The analytes were hydrolyzed and extracted from 25-mL ethylenediaminetetraacetic acid-Anticoagulated whole-blood spiked with isotope labeled 6-TG-13C2 15N and 6-MMP-d3 internal standards. Chromatography was performed in 5.1 minutes on a C18 reverse phase column followed by detection via electrospray interface- coupled API 4000 mass spectrometer set up in the positive multiple reaction monitoring mode. The hemoglobin concentration was measured in 20 mL of the original sample (AHD575 method), and the results were standardized to 120 g/L of hemoglobin. Results: Calibration curves were linear with r2 < 0.999 (6-TGN and 6-MMP up to 10,000 pmol/0.2 mL). The limit of quantification was 30 pmol/0.2 mL for 6-TGN and 6-MMP. Intraassay and interassay imprecision was >7.5% at 3 tested levels for 6-TGN and 6-MMP, respectively. Method comparisons were as follows: Ery 6-TGN: y = 1.3x 2 11 and ery 6-MMP y = 1.1x 2 124. Conclusions: The new method compares favorably with established ones, allowing for rapid single run determination of 6-TGN and 6-MMP from >50 mL of fresh or frozen whole blood. Linearity and limits of quantification cover the clinically relevant range. Variability during sample preparation and matrix effects are compensated by the use of isotope-labeled internal standards. The whole-blood method is hemoglobin standardized to avoid falsely low results in the case of anemia. The method correlates well with 6-TGN measured in washed erythrocytes, but it requires significantly less hands-on time. Preliminary therapeutic ranges for the most common indications of azathioprine and 6-MP are provided. © 2013 by Lippincott Williams and Wilkins. Source

Feichtiger H.,Zentralinstitut For Klinische Chemie Und Laboratoriumsmedizin | Wieland E.,Zentralinstitut For Klinische Chemie Und Laboratoriumsmedizin | Armstrong V.W.,University of Gottingen | Shipkova M.,Zentralinstitut For Klinische Chemie Und Laboratoriumsmedizin
Clinical Biochemistry

Objectives: The acyl glucuronide (AcMPAG) of mycophenolic acid (MPA) forms covalent protein adducts and possesses antiproliferative properties independent of IMPDH inhibition. The underlying mechanism is unknown. Disorganized tubulin polymerization prevents cell cycle progression. We investigated whether AcMPAG interacts with tubulin polymerization. Design and methods: AcMPAG (1.0-100 μM) was incubated with bovine tubulin in the presence of GTP. Polymerization was followed at 340 nm. The time until onset and the extent of polymerization were determined. MPA (100 μM), phenolic glucuronide MPAG (100 μM), and paclitaxel (10 μM) served as controls. Results: MPAG was without effect. The AcMPAG effect on tubulin polymerization was dose dependent and significantly stronger (about 2.5-fold) than that of MPA (n = 4; p < 0.05), but weaker than paclitaxel. Conclusions: MPA and AcMPAG can induce tubulin polymerization in the presence of GTP with AcMPAG being significantly stronger. This property of AcMPAG may contribute to its IMPDH independent antiproliferative effect. © 2009. Source

Seger C.,Risch Laboratories Group Schaan | Shipkova M.,Zentralinstitut For Klinische Chemie Und Laboratoriumsmedizin | Christians U.,University of Colorado at Denver | Billaud E.M.,University of Paris Descartes | And 10 more authors.
Therapeutic Drug Monitoring

Monitoring immunosuppressive drugs (ISDs) in blood or plasma is still a key therapeutic drug monitoring (TDM) application in clinical settings. Narrow target ranges and severe side effects at drug underexposure or overexposure make accurate and precise measurements a must. This overview prepared by the Immunosuppressive Drugs Scientific Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology is intended to serve as a summary and guidance document describing the current state-of-the-art in the TDM of ISDs. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Source

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