Matthias Schwab

Universitätsklinikum Tübingen, Tübingen, Baden-Württemberg, Germany

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Publications (361)1969.56 Total impact

  • David Zakim, Matthias Schwab
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    ABSTRACT: Basic life science research holds the promise of personalizing medical care. However, translation steps from the laboratory to the bedside are not trivial. Results from clinical research are difficult to replicate in part because study cohorts are poorly defined phenotypically. Here, we discuss how computer technology can improve the collection of clinical data to enable translation of insights from basic science to validated clinical guidelines. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Trends in Pharmacological Sciences 12/2014; · 9.25 Impact Factor
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    ABSTRACT: The incidence of acid-base disorders (ABDs) is high, especially in hospitalized patients. ABDs are often indicators for severe systemic disorders. In everyday clinical practice, analysis of ABDs must be performed in a standardized manner. Highly sensitive diagnostic tools to distinguish the various ABDs include the anion gap and the serum osmolar gap. Drug-induced ABDs can be classified into five different categories in terms of their pathophysiology: (1) metabolic acidosis caused by acid overload, which may occur through accumulation of acids by endogenous (e.g., lactic acidosis by biguanides, propofol-related syndrome) or exogenous (e.g., glycol-dependant drugs, such as diazepam or salicylates) mechanisms or by decreased renal acid excretion (e.g., distal renal tubular acidosis by amphotericin B, nonsteroidal anti-inflammatory drugs, vitamin D); (2) base loss: proximal renal tubular acidosis by drugs (e.g., ifosfamide, aminoglycosides, carbonic anhydrase inhibitors, antiretrovirals, oxaliplatin or cisplatin) in the context of Fanconi syndrome; (3) alkalosis resulting from acid and/or chloride loss by renal (e.g., diuretics, penicillins, aminoglycosides) or extrarenal (e.g., laxative drugs) mechanisms; (4) exogenous bicarbonate loads: milk-alkali syndrome, overshoot alkalosis after bicarbonate therapy or citrate administration; and (5) respiratory acidosis or alkalosis resulting from drug-induced depression of the respiratory center or neuromuscular impairment (e.g., anesthetics, sedatives) or hyperventilation (e.g., salicylates, epinephrine, nicotine).
    Pediatric nephrology (Berlin, Germany). 11/2014;
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    ABSTRACT: At present the global diabetes epidemic is affecting 347 million individuals, 90% of whom are diagnosed with type II diabetes mellitus (T2DM). T2DM is commonly treated with more than one type of therapy, including oral antidiabetic drugs (OADs) and agents used in the treatment of diabetic complications. Several pharmacological classes of OADs are currently available for the treatment of T2DM, of which insulin secretagogues (i.e. sulphonylureas and meglitinides), insulin sensitizers (thiazolidinediones) and biguanides are the most commonly prescribed. Although many of these OADs have been used for more than half a century in the treatment of T2DM, the pharmacogenomic characteristics of these compounds have only recently been investigated, primarily in retrospective studies. Recent advances in pharmacogenomics have led to the identification of polymorphisms that affect the expression and function of drug-metabolizing enzymes and drug transporters, as well as drug targets and receptors. These polymorphisms have been shown to affect the therapeutic response to and side effects associated with OADs. The aim of this review was to provide an up-to-date summary of some of the pharmacogenomic data obtained from studies of T2DM treatment, with a focus on polymorphisms in genes affecting pharmacokinetics, pharmacodynamics and treatment outcome of the most commonly prescribed OADs. In addition, the implications of pharmacogenomics in the use of the OAD metformin in cancer will be briefly discussed. Finally, we will focus on recent advances in novel ‘omics’ technologies and discuss how these might aid in the personalized management of T2DM.This article is protected by copyright. All rights reserved.
    Journal of Internal Medicine 11/2014; · 6.46 Impact Factor
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    ABSTRACT: Background. Functional recovery and prognosis after acute coronary syndromes (ACS) are mainly driven by the extent of reperfusion injury and myocardial repair mechanisms. Transforming growth factor-beta 1 (TGF-β1) is critically involved in cardiac injury, repair and remodeling. In this study, we investigated the prognostic role of platelet TGF-β1 surface expression and circulating TGF-β1 levels in patients with coronary artery disease (CAD). Methods and results. Expression of TGF-β1 in platelets and circulating TGF-β1 levels were investigated by flow cytometry and ELISA, respectively, among patients with ACS and stable CAD undergoing percutaneous coronary intervention (PCI). In a cohort study, platelet and circulating TGF-β1 was measured in 299 patients with symptomatic CAD (stable CAD = 145, ACS = 154) at the time of PCI. The primary combined endpoint was defined as death and/or STEMI during 12-month follow-up. Platelets expressed TGF-β1 and circulating TGF-β1 showed a weak, but significant negative correlation. TGF-β1 surface expression was significantly elevated on platelets in ACS patients compared to patients with stable CAD (median MFI 13.4 vs. median MFI 11.7, p = 0.003). During follow-up, lower platelet expression of TGF-β1 was associated with all-cause mortality (median MFI 11.0 vs. median MFI 13.9, p = 0.011) as well as for the combined endpoint of death and/or STEMI, (median MFI 10.8 vs. median MFI 13.9, p = 0.006). In multivariate analysis platelet TGF-β1 expression was independently associated with the combined primary endpoint in the overall cohort (Hazard Ratio 0.31, 95% Confidence Interval 0.11-0.89, p = 0.029) and was strongly associated with prognosis in ACS patients. There was no significant association of circulating TGF-β1 levels neither with the presence of ACS nor the occurrence of the primary endpoint. Conclusion. These findings highlight a potential role of platelet expressed TGF-β1 in ACS and indicate a prognostic value of TGF-β1 on clinical outcomes in patients with acute coronary syndromes. Large scale studies are warranted to further evaluate the regulatory mechanisms of platelet TGF-β1 expression- and its prognostic impact in CAD. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
    Atherosclerosis 10/2014; 237(2):754-759. · 3.71 Impact Factor
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    ABSTRACT: Puumala virus (PUUV) is the most common species of hantavirus in Central Europe. Nephropathia epidemica (NE), caused by PUUV, is characterized by acute kidney injury (AKI) and thrombocytopenia. The major goals of this study were to provide a clear clinical phenotyping of AKI in patients with NE and to develop an easy prediction rule to identify patients, who are at lower risk to develop severe AKI.
    10/2014;
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    ABSTRACT: Malaria patients are frequently co-infected with HIV and mycobacteria causing tuberculosis, which increases the co-administration of drugs and thereby enhances the risk of pharmacokinetic drug-drug interactions. Activation of pregnane X receptor (PXR) by xenobiotics, including many drugs, induces drug metabolism and transport, thereby possibly resulting in attenuation or loss of the therapeutic response of drugs being co-administered. While several artemisinin-type antimalarial drugs have been shown to activate PXR, data on non-artemisinin-type antimalarials are still missing. Therefore this study aims to elucidate the potential of non-artemisinin antimalarial drugs and drug metabolites to activate PXR. The screening of 16 clinically used antimalarial drugs and six major drug metabolites for binding to PXR, using the two-hybrid PXR ligand binding domain assembly assay, identified carboxymefloquine, the major and pharmacological inactive metabolite of the antimalarial drug mefloquine, as a potential PXR ligand. Two-hybrid PXR-coactivator and -corepressor interaction assays, as well as PXR-dependent promoter reporter gene assays, confirmed carboxymefloquine as a novel PXR agonist, which specifically activated the human receptor. In the PXR-expressing intestinal LS174T cells and in primary human hepatocytes, carboxymefloquine induced the expression of drug metabolizing enzymes and transporters on the mRNA and protein level. The crucial role of PXR for carboxymefloquine-dependent induction of gene expression was confirmed by siRNA-mediated knock-down of the receptor. Thus, the clinical use of mefloquine may result in pharmacokinetic drug-drug interactions by means of its metabolite carboxymefloquine. Whether these in vitro finding are of in vivo relevance has to be addressed in future clinical drug-drug interaction studies.
    Antimicrobial Agents and Chemotherapy 10/2014; · 4.57 Impact Factor
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    ABSTRACT: In view of the rapid preclinical development of cell-based therapies for neurodegenerative disorders, traumatic brain injury, and tumors, the safe and efficient delivery and targeting of therapeutic cells to the central nervous system is critical for maintaining therapeutic efficacy and safety in the respective disease models. Our previous data demonstrated therapeutically efficacious and targeted delivery of mesenchymal stem cells (MSCs) to the brain in the rat 6-hydroxydopamine model of Parkinson?s disease (PD). The present study examined delivery of bone marrow derived MSCs, macrophages, and microglia to the brain in a transgenic model of PD ((Thy1)-h[A30P] αS) and an APP/PS1 model of Alzheimer?s disease (AD) via intranasal application (INA). INA of microglia in na?ve BL/6 mice led to targeted and effective delivery of cells to the brain. Quantitative PCR analysis of eGFP DNA showed that the brain contained the highest amount of eGFP-microglia (up to 2.1x10(4)) after INA of 1x10(6) cells, while the total amount of cells detected in peripheral organs did not exceed 3.4x10(3). Seven days after INA, MSCs expressing eGFP were detected in the olfactory bulb (OB), cortex, amygdala, striatum, hippocampus, cerebellum, and brainstem of (Thy1)-h[A30P] αS transgenic mice, showing predominant distribution within the OB and brainstem. INA of eGFP-expressing macrophages in 13 month-old APP/PS1 mice led to delivery of cells to the OB, hippocampus, cortex, and cerebellum. Both, MSCs and macrophages contained Iba-1-positive population of small microglia-like cells and Iba-1-negative large rounded cells showing either intracellular Amyloid beta (macrophages in APP/PS1 model) or α-Synuclein (MSCs in (Thy1)-h[A30P] αS model) immunoreactivity. Here we show, for the first time, intranasal delivery of cells to the brain of transgenic PD and AD mouse models. Additional work is needed to determine the optimal dosage (single treatment regimen or repeated administrations) to achieve functional improvement in these mouse models with intranasal microglia/macrophages and MSCs. This manuscript is published as part of the International Association of Neurorestoratology (IANR) special issue of Cell Transplantation.
    Cell transplantation. 10/2014;
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    ABSTRACT: Objective: Monocyte infiltration is a critical step in the pathophysiology of plaque instability in coronary artery disease (CAD). Macrophage migration inhibitory factor (MIF) is involved in atherosclerotic plaque progression and instability leading to intracoronary thrombosis. Gremlin-1 (Grem1) has been recently identified as endogenous inhibitor of MIF. To date there are no data on the clinical impact of this interaction in cardiovascular patients. Methods and results: Plasma levels of MIF and Grem1 were determined by enzyme-linked immunoassay in patients with acute coronary syndromes (ACS, n = 120; stable CAD, n = 166 and healthy control subjects, n = 25). MIF levels were significantly increased in ACS compared to stable CAD and healthy control (ACS: median 2.85; IQR 3.52 ng/ml; versus SAP: median 1.22; IQR 2.99 ng/ml; versus healthy control: median 0.10; IQR 0.09 ng/ml, p < 0.001). Grem1 levels were significantly higher in ACS and stable CAD patients compared to healthy control (ACS: median 211.00; IQR 130.47 ng/ml; SAP: median 220.20; IQR 120.93 ng/ml, versus healthy control: median 90.57; IQR 97.68 ng/ml, p < 0.001). Grem1/MIF ratio was independently associated with ACS, whereas the single parameters were not associated with the presence of ACS. Furthermore, Grem1/MIF ratio was associated with angiographic signs of intracoronary thrombi and severity of thrombus burden. Conclusion: These novel findings suggest a potential role of Grem1/MIF ratio to indicate acuity of CAD and the grade of plaque stability. Prospective angiographic cohort studies involving plaque imaging techniques are warranted to further characterize the prognostic role of this novel risk marker in CAD patients. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
    Atherosclerosis 09/2014; 237(2):426-432. · 3.71 Impact Factor
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    ABSTRACT: Treatment of diabetics with metformin is associated with decreased breast cancer risk in observational studies, but it remains unclear if this drug has clinical antineoplastic activity. In a recent presurgical trial, we found a heterogeneous effect of metformin on breast cancer proliferation (ki-67) depending upon insulin resistance (HOMA index). Here, we determined the associations of additional serum biomarkers of insulin resistance, tumor subtype, and drug concentration with ki-67 response to metformin. Two-hundred non-diabetic women were randomly allocated to metformin (850 mg/bid) or placebo for 4 weeks prior to breast cancer surgery. The ki-67 response to metformin was assessed comparing data obtained from baseline biopsy (ki-67 and tumor subtype) and serum markers (HOMA index, C-peptide, IGF-I, IGFBP-1, IGFBP-3, free IGF-I, hs-CRP, adiponectin) with the same measurements at definitive surgery. For patients with a blood sample taken within 24 h from last drug intake, metformin level was measured. Compared with placebo, metformin significantly decreased ki-67 in women with HOMA > 2.8, those in the lowest IGFBP-1 quintile, those in the highest IGFBP-3 quartile, those with low free IGF-I, those in the top hs-CRP tertile, and those with HER2-positive tumors. In women with HOMA index > 2.8, drug levels were positively correlated with the ki-67 decrease, whereas no trend was noted in women with HOMA < 2.8 (p-interaction = 0.07). At conventional antidiabetic doses, the effect of metformin on tumor ki-67 of non-diabetic breast cancer patients varies with host and tumor characteristics. These findings are relevant to design breast cancer prevention and treatment trials with metformin.
    Breast Cancer Research and Treatment 09/2014; · 4.47 Impact Factor
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    ABSTRACT: Targeted chemotherapy for hepatocellular carcinoma (HCC) is impaired by intrinsic and/or acquired drug resistance. Since drugs used in HCC therapy (e.g. anthracyclines or the tyrosine kinase inhibitor sorafenib) are substrates of uptake and/or efflux transporters, variable expression of these transporters at the plasma membrane of tumor cells may contribute to drug resistance and subsequent clinical response. In this study, the variability of expression of uptake (OCT1, OCT3) and efflux transporters (MDR1/P-glycoprotein, MRP1, MRP2, BCRP), selected for their implication in transporting drugs used in HCC therapy, was investigated. HCC and corresponding non-tumor tissue samples were collected from 24 Japanese patients at time of surgery. Protein expression was determined by immunohistochemistry. Expression data were correlated with clinicopathological characteristics and patients' outcome (median follow-up 53 months). Generally, expression was highly variable among individual tumor samples. Yet, median expression of OCT1, OCT3 and MDR1 in HCC was significantly lower (1.4-, 2.7- and 2-fold, respectively) than in non-tumor tissue, while expression of MRP2 persisted and BCRP showed a trend of increased levels in HCC. Patients with low BCRP expression had a significantly shorter overall and recurrence-free survival time. Results suggest different expression patterns of drug transporters in HCC, which are only in part associated with clinicopathological characteristics. Detailed information of expression of drug transporters in HCC may be promising for individualization and optimization of drug therapy of liver cancer.
    Drug metabolism and disposition: the biological fate of chemicals 09/2014; · 3.74 Impact Factor
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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: Background:Metformin is an inhibitor of complex 1 in the respiratory chain, and is widely used to reduce insulin resistance. It has also been described to have pleotropic effects including via AMPK on inhibiting the mTOR kinase. Pre-clinical and epidemiological studies suggest an ability to modulate disease evolution in prostate cancer. In this study, we aimed to (i) demonstrate safety and tolerability of neoadjuvant metformin administration and (ii) document changes in proliferative (Ki67) and AMPK-related signalling indices between matching biopsies and prostatectomiesMethods:Men were treated in a single-arm 'window of opportunity' study between their decision to undergo radical prostatectomy and the operation itself. Forty patients were planned but only 24 patients were enrolled owing to slow accrual. Twenty-one patients were evaluable for pathological outcomes and 22 for serum metabolic indices. Metformin was given at doses to 500 mg t.i.d. Ki67 index was calculated using the Aperio-positive pixel count algorithm, whereas immunohistochemical measurements were by consensus H-Score. Comparative statistics were analysed by students t-tests and/or Wilcoxon matched pairs signed rank test.Results:Baseline characteristics included median PSA 6 ng ml(-1) (3.22-36.11 ng ml(-1)). Median duration of drug treatment was 41 days (18-81). Treatment was well tolerated with only three patients developing G3/4 toxicities. In a per patient and per tumour analyses, metformin reduced the Ki67 index by relative amounts of 29.5 and 28.6 % (P=0.0064 and P=0.0042) respectively. There was also a significant decrease in P-4EBP1 staining (P<0.001) but no change in P-AMPK or P-ACC. There were no correlations between any metabolic, morphometric or cancer-related serum indices. There was a trend towards PSA reduction (P=0.08). The study is limited by small patient numbers and tumour heterogeneity.Conclusions:Neoadjuvant metformin is well tolerated prior to radical prostatectomy. Data to date indicate promising effects on metabolic and tissue proliferation and signalling parameters.Prostate Cancer and Prostatic Disease advance online publication, 27 May 2014; doi:10.1038/pcan.2014.20.
    Prostate cancer and prostatic diseases. 05/2014;
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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

Publication Stats

10k Citations
1,969.56 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
  • 1997–2014
    • Institut für klinische Pharmakologie
      Stuttgart, 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
  • 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