Matthias Schwab

Universitätsklinikum Tübingen, Tübingen, Baden-Württemberg, Germany

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Publications (335)1915.07 Total impact

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    ABSTRACT: In addition to its well-characterized role in the regulation of drug metabolism and transport by xenobiotics, pregnane X receptor (PXR) critically impacts on lipid homeostasis. In mice, both ligand-dependent activation and knockout of PXR were previously shown to promote hepatic steatosis. To elucidate the respective pathways in human liver, we generated clones of human hepatoma HepG2 cells exhibiting different PXR protein levels, and analyzed effects of PXR activation and knockdown on steatosis and expression of lipogenic genes. Ligand-dependent activation as well as knockdown of PXR resulted in increased steatosis in HepG2 cells. Activation of PXR induced the sterol regulatory element-binding protein (SREBP) 1-dependent lipogenic pathway via PXR-dependent induction of SREBP1a, which was confirmed in primary human hepatocytes. Inhibiting SREBP1 activity by blocking the cleavage-dependent maturation of SREBP1 protein impaired the induction of lipogenic SREBP1 target genes and triglyceride accumulation by PXR activation. On the other hand, PXR knockdown resulted in up-regulation of aldo-keto reductase (AKR) 1B10, which enhanced the acetyl-CoA carboxylase (ACC)-catalyzed reaction step of de novo lipogenesis. In a cohort of human liver samples histologically classified for non-alcoholic fatty liver disease, AKR1B10, SREBP1a and SREBP1 lipogenic target genes proved to be up-regulated in steatohepatitis, while PXR protein was reduced. In summary, our data suggest that activation and knockdown of PXR in human hepatic cells promote de novo lipogenesis and steatosis by induction of the SREBP1 pathway and AKR1B10-mediated increase of ACC activity, respectively, thus providing mechanistic explanations for a putative dual role of PXR in the pathogenesis of steatohepatitis.
    Archives of toxicology. 09/2014;
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    ABSTRACT: Tamoxifen is the standard-of-care treatment for estrogen receptor-positive premenopausal breast cancer. We examined tamoxifen metabolism via blood metabolite concentrations and germline variations of CYP3A5, CYP2C9, CYP2C19 and CYP2D6 in 587 premenopausal patients (Asians, Middle Eastern Arabs, Caucasian-UK; median age 39 years) and clinical outcome in 306 patients. N-desmethyltamoxifen (DM-Tam)/(Z)-endoxifen and CYP2D6 phenotype significantly correlated across ethnicities (R(2): 53%, P<10(-77)). CYP2C19 and CYP2C9 correlated with norendoxifen and (Z)-4-hydroxytamoxifen concentrations, respectively (P<0.001). DM-Tam was influenced by body mass index (P<0.001). Improved distant relapse-free survival (DRFS) was associated with decreasing DM-Tam/(Z)-endoxifen (P=0.036) and increasing CYP2D6 activity score (hazard ratio (HR)=0.62; 95% confidence interval (CI), 0.43-0.91; P=0.013). Low (<14 nM) compared with high (>35 nM) endoxifen concentrations were associated with shorter DRFS (univariate P=0.03; multivariate HR=1.94; 95% CI, 1.04-4.14; P=0.064). Our data indicate that endoxifen formation in premenopausal women depends on CYP2D6 irrespective of ethnicity. Low endoxifen concentration/formation and decreased CYP2D6 activity predict shorter DRFS.The Pharmacogenomics Journal advance online publication, 5 August 2014; doi:10.1038/tpj.2014.34.
    The pharmacogenomics journal. 08/2014;
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    ABSTRACT: Wnt signaling regulates small intestinal stem cell maintenance and Paneth cell differentiation. In patients with ileal Crohn's disease (CD) a decrease of Paneth cell α-defensins has been observed which is partially caused by impaired TCF-4 and LRP6 function. Here we show reduced expression of the Wnt signaling effector TCF-1 (also known as TCF7) in patients with ileal CD. Reporter gene assays and in vitro promoter binding analysis revealed that TCF-1 activates α-defensin HD-5 and HD-6 transcription in cooperation with β-catenin and that activation is mediated by three distinct TCF binding sites. EMSA analysis showed binding of TCF-1 to the respective motifs. In ileal CD patients, TCF-1 mRNA expression levels were significantly reduced. Moreover we found specifically reduced expression of active TCF-1 mRNA isoforms. Tcf-1 knockout mice exhibited reduced cryptdin expression in the jejunum, which was not constistently seen at other small intestinal locations. Our data provide evidence that TCF-1 mediated Wnt signaling is disturbed in small intestinal Crohn's disease which might contribute to the observed barrier dysfunction in the disease.
    American journal of physiology. Gastrointestinal and liver physiology. 07/2014;
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    ABSTRACT: Background: The well-characterized tubular-type of breast tumors is classified as low-risk breast cancer. Patients and Methods: We report on the results of a retrospective analysis on clinical and biological features of 248 tubular breast tumors including follow-up and treatment data from two German series of 21,065 breast cancer cases. The majority of tumors were stage I or stage II, ER- and PR-positive and c-erbB2-negative with a 5-year survival-rate of 96.3%. 51.3% of patients received hormonal treatment, 75.5% had post-operative radiotherapy and 11.8% were treated with a chemotherapeutical regimen. Conclusion: Our retrospective analysis showed no treatment benefit for either anti-hormonal or chemotherapeutical regimens. Post-operative radiotherapy, however, improved the survival rate of patients with tubular carcinoma (log-rank=5, p=0.025). Our data suggest that post-operative radiotherapy is an important treatment to prolong survival for patients suffering from tubular breast cancer.
    Anticancer research 07/2014; 34(7):3647-56. · 1.71 Impact Factor
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    ABSTRACT: Individualized Medicine aims at providing optimal treatment for an individual patient at a given time based on his specific genetic and molecular characteristics. This requires excellent clinical stratification of patients as well as the availability of genomic data and biomarkers as prerequisites for the development of novel diagnostic tools and therapeutic strategies. The University Medicine Greifswald, Germany, has launched the "Greifswald Approach to Individualized Medicine" (GANI_MED) project to address major challenges of Individualized Medicine. Herein, we describe the implementation of the scientific and clinical infrastructure that allows future translation of findings relevant to Individualized Medicine into clinical practice.Methods/design: Clinical patient cohorts (N > 5,000) with an emphasis on metabolic and cardiovascular diseases are being established following a standardized protocol for the assessment of medical history, laboratory biomarkers, and the collection of various biosamples for bio-banking purposes. A multi-omics based biomarker assessment including genome-wide genotyping, transcriptome, metabolome, and proteome analyses complements the multi-level approach of GANI_MED. Comparisons with the general background population as characterized by our Study of Health in Pomerania (SHIP) are performed. A central data management structure has been implemented to capture and integrate all relevant clinical data for research purposes. Ethical research projects on informed consent procedures, reporting of incidental findings, and economic evaluations were launched in parallel.
    Journal of translational medicine. 05/2014; 12(1):144.
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    ABSTRACT: Background: Artesunate (AS) is a water soluble hemi-succinate derivative of artemisinin, which can easily be used in formulations for parenteral treatment of severe malaria. AS is rapidly hydrolysed in vivo to the active metabolite dihydroartemisinin (DHA) and primarily eliminated into bile after glucuronidation. Very recently, delayed hemolytic anemia has been observed as a relatively frequent complication after treatment of severe malaria with AS. It has been suggested that interindividual variability in pharmacokinetic profiles of antimalarial drugs might be responsible for variations in drug response or toxicity. While CYP2A6 was identified as responsible isoenzyme for AS hydrolysis, glucuronidation is catalysed predominately by the uridine diphosphate (UDP)-glucuronosyltransferases (UGT) UGT1A9 and UGT2B7 showing both a broad range of genetic variants. To elucidate systematically the impact of AS metabolism and pharmacokinetics on drug response and adverse effects the plasma concentrations of the parent drug and its two metabolites have to be determined. Methods: We established a novel LC-MS/MS method for simultaneous quantification of AS and its metabolites DHA and DHA glucuronide (DHAG) in human plasma. Sample preparation was performed with only 50 µL plasma by high-throughput solid phase extraction (SPE) in the 96-well plate format. Separation of the analytes was achieved on a Poroshell 120 EC-C18 column (Agilent Technologies, Waldbronn, Germany 50*2.1 mm, 2.7 µm). We used stable isotope-labelled analogues as internal standards. The method was validated according to the FDA guidelines. Results: The method was accurate and precise within a linear calibration range from 1 to 2,500 nM, 165 to 16,500 nM and 4 to 10,000 nM for AS, DHA and DHAG, respectively. Furthermore the method passed the tests on analyte stability during bench-top and autosampler storage, after 3 freeze/thaw cycles and during long term storage. The method was applied to plasma samples from patients under AS treatment. Conclusion: Our novel LC-MS/MS method provides a validated and highly sensitive tool for the simultaneous quantification of AS, DHA and DHAG in plasma samples. The required sample volume could be kept very low (50 µL). Using the SPE 96-well plate format permits preparation of 100 samples in only 2 h to minimize possible degradation of AS and DHA and qualifies this method to monitor pharmacokinetics and bioequivalence of large patients cohorts. Supported by the Robert Bosch Foundation (Stuttgart, Germany), the European and Developing Countries Clinical Trials Partnership (EDCTP) grant #2004.01.M.d2, the BMBF (Germany) grant 01KA1011, the Deutsche Forschungsgemeinschaft (Germany) grant KE 1629/1-1, and the IZEPHA grant 10-0-0.
    20th International Symposium on Microsomes and Drug Oxidations, Stuttgart; 05/2014
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    ABSTRACT: Only limited data exist about the role of point of care CYP2C19 testing in the acute setting in the early phase of acute coronary syndromes (ACS). Therefore, the present study was designed to investigate the impact of CYP2C19 loss-of-function point-of-care (POC) genotyping in patients presenting with acute coronary syndromes (ACS) and treated with dual antiplatelet therapy in the emergency setting.
    Thrombosis Research 05/2014; · 3.13 Impact Factor
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    ABSTRACT: Artesunate (AS), a hemisuccinate derivative of artemisinin, is readily soluble in water and can easily be used in formulations for parenteral treatment of severe malaria. AS is rapidly hydrolyzed to the active metabolite dihydroartemisinin (DHA) and primarily eliminated by biliary excretion after glucuronidation. To investigate systematically the AS metabolism and pharmacokinetics, a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous quantification of AS and its metabolites DHA and DHA glucuronide (DHAG) in human plasma samples was developed. Compared to previous methods, our method includes for the first time the quantification of the glucuronide metabolite using a newly synthesized stable isotope-labeled analogue as internal standard. Sample preparation was performed with only 50 μL plasma by high-throughput solid-phase extraction in the 96-well plate format. Separation of the analytes was achieved on a Poroshell 120 EC-C18 column (50*2.1 mm, 2.7 μm, Agilent Technologies, Waldbronn, Germany). The method was validated according to FDA guidelines. Calibration curves were linear over the entire range from 1 to 2,500 nM (0.4-961.1 ng/mL), 165 to 16,500 nM (46.9-4,691.8 ng/mL), and 4 to 10,000 nM (1.8-4,604.7 ng/mL) for AS, DHA, and DHAG, respectively. Intra- and interbatch accuracy, determined as a deviation between nominal and measured values, ranged from -5.7 to 3.5 % and from 2.7 to 5.8 %, respectively. The assay variability ranged from 1.5 to 10.9 % for intra- and interbatch approaches. All analytes showed extraction recoveries above 85 %. The method was successfully applied to plasma samples from patients under AS treatment.
    Analytical and Bioanalytical Chemistry 04/2014; · 3.66 Impact Factor
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    ABSTRACT: Fluourouracil (FU) is a mainstay of chemotherapy, although toxicities are common. Genetic biomarkers have been used to predict these adverse events, but their utility is uncertain. We tested candidate polymorphisms identified from a systematic literature search for associations with capecitabine toxicity in 927 patients with colorectal cancer in the Quick and Simple and Reliable trial (QUASAR2). We then performed meta-analysis of QUASAR2 and 16 published studies (n = 4,855 patients) to examine the polymorphisms in various FU monotherapy and combination therapy regimens. Global capecitabine toxicity (grades 0/1/2 v grades 3/4/5) was associated with the rare, functional DPYD alleles 2846T>A and *2A (combined odds ratio, 5.51; P = .0013) and with the common TYMS polymorphisms 5`VNTR2R/3R and 3`UTR 6bp ins-del (combined odds ratio, 1.31; P = 9.4 × 10(-6)). There was weaker evidence that these polymorphisms predict toxicity from bolus and infusional FU monotherapy. No good evidence of association with toxicity was found for the remaining polymorphisms, including several currently included in predictive kits. No polymorphisms were associated with toxicity in combination regimens. A panel of genetic biomarkers for capecitabine monotherapy toxicity would currently comprise only the four DPYD and TYMS variants above. We estimate this test could provide 26% sensitivity, 86% specificity, and 49% positive predictive value-better than most available commercial kits, but suboptimal for clinical use. The test panel might be extended to include additional, rare DPYD variants functionally equivalent to *2A and 2846A, though insufficient evidence supports its use in bolus, infusional, or combination FU. There remains a need to identify further markers of FU toxicity for all regimens.
    Journal of Clinical Oncology 04/2014; 32(10):1031-9. · 18.04 Impact Factor
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    ABSTRACT: The identification of valid biomarkers for outcome prediction of diseases and improvement of drug response, as well as avoidance of side effects is an emerging field of interest in medicine. The concept of individualized therapy is becoming increasingly important in the treatment of patients with epilepsy, as predictive markers for disease prognosis and treatment outcome are still limited. Currently, the clinical decision process for selection of an antiepileptic drug (AED) is predominately based on the patient's epileptic syndrome and side effect profiles of the AEDs, but not on effectiveness data. Although standard dosages of AEDs are used, supplemented, in part, by therapeutic monitoring, the response of an individual patient to a specific AED is generally unpredictable, and the standard care of patients in antiepileptic treatment is more or less based on trial and error. Therefore, there is an urgent need for valid predictive biomarkers to guide patient-tailored individualized treatment strategies in epilepsy, a research area that is still in its infancy. This review focuses on genomic factors as part of an individual concept for AED therapy summarizing examples that influence the prognosis of the disease and the response to AEDs, including side effects.
    Journal of the American Society for Experimental NeuroTherapeutics 02/2014; · 5.38 Impact Factor
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    ABSTRACT: Statin-associated muscular adverse effects cover a wide range of symptoms, including asymptomatic increase of creatine kinase serum activity and life-threatening rhabdomyolysis. Different underlying pathomechanisms have been proposed. However, a unifying concept of the pathogenesis of statin-related muscular adverse effects has not emerged so far. In this review, we attempt to categorise these mechanisms along three levels. Firstly, among pharmacokinetic factors, it has been shown for some statins that inhibition of cytochrome P450-mediated hepatic biotransformation and hepatic uptake by transporter proteins contribute to an increase of systemic statin concentrations. Secondly, at the myocyte membrane level, cell membrane uptake transporters affect intracellular statin concentrations. Thirdly, at the intracellular level, inhibition of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase results in decreased intracellular levels of downstream metabolites (e.g. selenoproteins, ubiquinone, cholesterol) and alteration of gene expression (e.g. ryanodine receptor 3, glycine amidinotransferase). We also review current recommendations for prescribers.
    British Journal of Clinical Pharmacology 02/2014; · 3.58 Impact Factor
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    ABSTRACT: The approved dual-color fluorescence in situ hybridization (FISH) test for the detection of anaplastic lymphoma receptor tyrosine kinase (ALK) gene rearrangements in non-small-cell lung cancer (NSCLC) is complex and represents a low-throughput assay difficult to use in daily diagnostic practice. We devised a sensitive and robust routine diagnostic test for the detection of rearrangements and transcriptional up-regulation of ALK. We developed a quantitative reverse transcription polymerase chain reaction (qRT-PCR) assay adapted to RNA isolated from routine formalin-fixed, paraffin-embedded material and applied it to 652 NSCLC specimens. The reliability of this technique to detect ALK dysregulation was shown by comparison with FISH and immunohistochemistry. qRT-PCR analysis detected unbalanced ALK expression indicative of a gene rearrangement in 24 (4.6%) and full-length ALK transcript expression in six (1.1%) of 523 interpretable tumors. Among 182 tumors simultaneously analyzed by FISH and qRT-PCR, the latter accurately typed 97% of 19 rearranged and 158 nonrearranged tumors and identified ALK deregulation in two cases with insufficient FISH. Six tumors expressing full-length ALK transcripts did not show rearrangements of the gene. Immunohistochemistry detected ALK protein overexpression in tumors with gene fusions and transcriptional up-regulation, but did not distinguish between the two. One case with full-length ALK expression carried a heterozygous point mutation (S1220Y) within the kinase domain potentially interfering with kinase activity and/or inhibitor binding. Our qRT-PCR assay reliably identifies and distinguishes ALK rearrangements and full-length transcript expression in formalin-fixed, paraffin-embedded material. It is an easy-to-perform, cost-effective, and high-throughput tool for the diagnosis of ALK activation. The expression of full-length ALK transcripts may be relevant for ALK inhibitor therapy in NSCLC.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 02/2014; · 4.55 Impact Factor
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    ABSTRACT: The Clinical Pharmacogenetics Implementation Consortium (CPIC) publishes genotype-based drug guidelines to help clinicians understand how available genetic test results could be used to optimize drug therapy. CPIC has focused initially on well-known examples of pharmacogenomic associations that have been implemented in selected clinical settings, publishing nine to date. Each CPIC guideline adheres to a standardized format and includes a standard system for grading levels of evidence linking genotypes to phenotypes and assigning a level of strength to each prescribing recommendation. CPIC guidelines contain the necessary information to help clinicians translate patient-specific diplotypes for each gene into clinical phenotypes or drug dosing groups. This paper reviews the development process of the CPIC guidelines and compares this process to the Institute of Medicine's Standards for Developing Trustworthy Clinical Practice Guidelines.
    Current Drug Metabolism 01/2014; · 4.41 Impact Factor
  • Hiltrud Brauch, Matthias Schwab
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    ABSTRACT: We appreciate the opportunity to further clarify the issues raised by Damkier (1) related to our recent Correspondence (2) in which we summarized the available evidence of the prediction of tamoxifen outcome by genetic variation of CYP2D6 in post-menopausal women with early breast cancer for the purpose of rectifying current controversies. Damkier takes the position that we missed to discuss original findings by others, however we respectfully disagree that the quoted articles (3, 4) can have an impact on our conclusions.
    British Journal of Clinical Pharmacology 01/2014; · 3.58 Impact Factor
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    ABSTRACT: Introduction: The final excretion step of several drugs is facilitated by membrane transporters of the Solute carrier (SLC) family expressed in the proximal tubules of the kidney. Membrane transporters contribute substantially to the pharmacokinetic profile of drugs and play important roles in drug-induced nephrotoxicity. Different cell models have been applied as tools for the assessment of nephrotoxic effects caused by drugs. Areas covered: This review gives an overview over clinically relevant SLC transporters involved in the renal elimination of drug agents and their specific role in drug-induced nephrotoxicity. Most widely applied cell models are described and their advantages and limitations are outlined. Expert opinion: In vitro cell culture models (e.g., continuous and primary renal cell lines, polarized cell monolayers) represent valuable tools for early assessment of the nephrotoxic potential of drugs. Since SLC transporters contribute to drug excretion in a large part, in vitro cell culture models might be very helpful to study transport pathways and/or potential drug-drug interactions at an early stage of the drug development process to predict nephrotoxic effects.
    Expert Opinion on Drug Metabolism &amp Toxicology 01/2014; · 2.94 Impact Factor
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    ABSTRACT: To overcome cytochrome P450 2D6 (CYP2D6) mediated tamoxifen resistance in postmenopausal early breast cancer, CYP2D6 phenotype-adjusted tamoxifen dosing in patients with impaired CYP2D6 metabolism and/or the application of endoxifen, the most potent tamoxifen metabolite, are alternative treatment options. To elucidate both strategies comprehensively we used a physiologically-based pharmacokinetic (PBPK) modeling approach.
    SpringerPlus 01/2014; 3:285.
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    ABSTRACT: Aims Only limited data exist about the role of point of care CYP2C19 testing in the acute setting in the early phase of acute coronary syndromes (ACS). Therefore, the present study was designed to investigate the impact of CYP2C19 loss-of–function point-of-care (POC) genotyping in patients presenting with acute coronary syndromes (ACS) and treated with dual antiplatelet therapy in the emergency setting. Methods and Results 137 subjects with ACS scheduled for percutaneous coronary intervention were consecutively enrolled. Pre- and on-treatment platelet aggregation was assessed by multiple electrode aggregometry (MEA) after stimulation with adenosine diphosphate (ADP). Patients were loaded according to current guideline adherent indications and contraindications for use of P2Y12 inhibitors in ACS. POC genotyping for CYP2C19*2 was performed in the emergency room after obtaining a buccal swab using the Spartan RX CYP2C19 system and obtaining patient’s informed consent. Prasugrel and ticagrelor treated patients had significantly lower PR compared to clopidogrel-treated patients. The benefits of prasugrel and ticagrelor compared to clopidogrel treated patients in terms of platelet inhibition were more pronounced in CYP2C19*2 carriers. Non-carriers showed similar inhibition regardless of particular P2Y12 inhibitor treatment. Statistical analyses adjusting for factors associated with response (e.g. smoking) revealed that CYP2C19*2 allele carrier status and loading with different type of P2Y12 receptor blockers were significant predictors of on-treatment platelet reactivity in the early phase of ACS. Conclusion The results of this pilot study of treatment of patients in the early phase of ACS indicate that CYP2C19*2 POC genotyping might help to identify patients at risk with poor response to clopidogrel treatment, thereby benefiting from reloading and switching to alternative P2Y12 receptor inhibition.
    Thrombosis Research 01/2014; · 3.13 Impact Factor
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    ABSTRACT: We show that, under in vitro conditions, the vulnerability of astroglia to hypoxia is reflected by alterations in endothelin (ET)-1 release and capacity of erythropoietin (EPO) to regulate ET-1 levels. Exposure of cells to 24 h hypoxia did not induce changes in ET-1 release, while 48-72 h hypoxia resulted in increase of ET-1 release from astrocytes that could be abolished by EPO. The endothelin receptor type A (ETA) antagonist BQ123 increased extracellular levels of ET-1 in human fetal astroglial cell line (SV-FHAS). The survival and proliferation of rat primary astrocytes, neural precursors, and neurons upon hypoxic conditions were increased upon administration of BQ123. Hypoxic injury and aging affected the interaction between the EPO and ET systems. Under hypoxia EPO decreased ET-1 release from astrocytes, while ETA receptor blockade enhanced the expression of EPO mRNA and EPO receptor in culture-aged rat astroglia. The blockade of ETA receptor can increase the availability of ET-1 to the ETB receptor and can potentiate the neuroprotective effects of EPO. Thus, the new therapeutic use of combined administration of EPO and ETA receptor antagonists during hypoxia-associated neurodegenerative disorders of the central nervous system (CNS) can be suggested.
    International Journal of Molecular Sciences 01/2014; 15(2):2858-75. · 2.46 Impact Factor
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    ABSTRACT: In addition to mutated BCR-ABL1 kinase, the organic cation transporter 1 (OCT1, encoded by SLC22A1) has been considered to contribute to imatinib resistance in patients with chronic myeloid leukemia (CML). Since data are conflicting as to whether OCT1 transports imatinib and may serve as clinical biomarker we used a combination of different approaches including animal experiments to elucidate comprehensively the impact of OCT1 on cellular imatinib uptake. Transport of imatinib was studied using OCT1-expressing Xenopus oocytes, mammalian cell lines (HEK293, MDCK, V79) stably expressing OCT1, human leukemic cells, and Oct1-knockout mice. OCT1 mRNA and protein expression were analyzed in leukemic cells from imatinib naïve CML patients as well as in cell lines. Transport and inhibition studies showed that overexpression of functional OCT1 protein in Xenopus oocytes or mammalian cell lines did not lead to an increased cellular accumulation of imatinib. The CML cell lines (K562, Meg-01, LAMA84) and leukemic cells from patients expressed neither OCT1 mRNA nor protein as demonstrated by immunoblotting and immunofluorescence microscopy, yet they showed a considerable imatinib uptake. Oct1 deficiency in mice had no influence on plasma and hepatic imatinib concentrations. These data clearly demonstrate that cellular uptake of imatinib is independent of OCT1 and therefore OCT1 is apparently not a valid biomarker for imatinib resistance.
    Clinical Cancer Research 12/2013; · 7.84 Impact Factor
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    ABSTRACT: Mefloquine (MQ), a racemic mixture of (+)-(11S,12R)- and (-)-(11R,12S)-MQ, has been used for treatment and prophylaxis of malaria for almost 30 years. MQ is metabolized by the cytochrome P450 3A subfamily to 4-carboxymefloquine (CMQ), which shows no antimalarial activity in vitro. Highly stereospecific pharmacokinetics of MQ have been reported, although with contradictory results. This might be due to incorrect assignment of the absolute configuration as shown only recently. Gastrointestinal as well as neuropsychiatric adverse events were described after prophylaxis and treatment with MQ. Data are indicating that the tolerability of the enantiomers may vary considerably. An involvement of the main metabolite CMQ in the development of neuropsychiatric adverse events has also been supposed. Due to these inconsistent results we established a novel liquid chromatography/tandem mass spectrometry (LC-MS/MS) method for the simultaneous quantification of MQ enantiomers and the metabolite CMQ to investigate the attribution of efficacy and adverse effects to the single enantiomers as well as the main metabolite. Separation of the MQ enantiomers was achieved on a quinidine-based zwitterionic chiral stationary phase column, CHIRALPAK(®) ZWIX(-) (3.0×150mm, 3μm) in an isocratic run using a pre-mixed eluent consisting of methanol/acetonitrile/water (49:49:2 v/v) with 25mM formic acid and 12.5mM ammonium formate. We used stable isotope-labelled analogues as internal standards. The method was validated according to the FDA guidelines. With a linear calibration range from 5 to 2000nM for the MQ enantiomers and from 13 to 2600nM for CMQ respectively, the method was successfully applied to dried blood spot (DBS) samples from patients under prophylactic MQ treatment. The method was also applicable for plasma samples.
    Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 11/2013; · 2.78 Impact Factor

Publication Stats

10k Citations
1,915.07 Total Impact Points

Institutions

  • 2003–2014
    • Universitätsklinikum Tübingen
      • • Division of Clinical Pharmacology
      • • Division of Neurogastroenterology
      Tübingen, Baden-Württemberg, Germany
    • Humboldt-Universität zu Berlin
      • Department of Biology
      Berlín, Berlin, Germany
  • 2000–2014
    • University of Tuebingen
      • Institute for Physiology
      Tübingen, Baden-Württemberg, Germany
  • 2012–2013
    • Claude Bernard University Lyon 1
      Villeurbanne, Rhône-Alpes, France
    • Universität Basel
      Bâle, Basel-City, Switzerland
    • Binghamton University
      Binghamton, New York, United States
  • 2003–2013
    • University of Greifswald
      • Institute of Community Medicine
      Greifswald, Mecklenburg-Vorpommern, Germany
  • 1997–2013
    • Institut für klinische Pharmakologie
      Stuttgart, Baden-Württemberg, Germany
  • 2005–2012
    • Goethe-Universität Frankfurt am Main
      • Center for Internal Medicine
      Frankfurt, Hesse, Germany
    • Hannover Medical School
      • Department of Paediatric Haematology and Oncology
      Hannover, Lower Saxony, Germany
  • 2011
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France
  • 2001–2011
    • Robert-Bosch Krankenhaus
      Stuttgart, Baden-Württemberg, Germany
  • 2010
    • VU University Medical Center
      • Department of Clinical Pharmacology and Pharmacy
      Amsterdam, North Holland, Netherlands
  • 2009
    • Universität Ulm
      • Clinic of Internal Medicine I
      Ulm, Baden-Württemberg, Germany
    • University of Iowa Children's Hospital
      Iowa City, Iowa, United States
  • 2008
    • Universität Stuttgart
      Stuttgart, Baden-Württemberg, Germany
  • 2005–2008
    • Johannes Gutenberg-Universität Mainz
      • I. Department of Medicine
      Mayence, Rheinland-Pfalz, Germany
  • 2007
    • University of Lausanne
      • Department of Fundamental Microbiology (DMF)
      Lausanne, VD, Switzerland
  • 2005–2007
    • Medical University of Vienna
      • Klinische Abteilung für Gastroenterologie und Hepatologie
      Wien, Vienna, Austria
  • 2004–2007
    • Dr. Falk Pharma GmbH
      Freiburg, Baden-Württemberg, Germany
  • 2006
    • Government of the People's Republic of China
      Peping, Beijing, China
    • University of Bonn
      Bonn, North Rhine-Westphalia, Germany
  • 1999–2006
    • Philipps University of Marburg
      Marburg, Hesse, Germany
  • 2002
    • Universität Heidelberg
      • Department of Urology
      Heidelberg, Baden-Wuerttemberg, Germany