Ulrich Jaehde

University of Bonn, Bonn, North Rhine-Westphalia, Germany

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Publications (174)433.41 Total impact

  • Medizinische Monatsschrift für Pharmazeuten 09/2015; 38(4):135-40.
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    ABSTRACT: Intracellular binding of cisplatin to non-DNA partners, such as proteins, has received increasing attention as an additional mode of action and as mechanism of resistance. We investigated two cisplatin-interacting isoforms of protein disulfide isomerase regarding their contribution to acquired cisplatin resistance using sensitive and resistant A2780/A2780cis ovarian cancer cells. Cisplatin cytotoxicity was assessed after knockdown of either protein disulfide isomerase family A member 1 (PDIA1) or protein disulfide isomerase family A member 3 (PDIA3). Whereas PDIA1 knockdown led to increased cytotoxicity in resistant A2780cis cells, PDIA3 knockdown showed no influence on cytotoxicity. Coincubation with propynoic acid carbamoyl methyl amide 31 (PACMA31), a PDIA1 inhibitor, resensitized A2780cis cells to cisplatin treatment. Determination of the combination index revealed that the combination of cisplatin and PACMA31 acts synergistically. Our results warrant further evaluation of PDIA1 as promising target for chemotherapy, and its inhibition by PACMA31 as a new therapeutic approach.
    Journal of inorganic biochemistry 09/2015; DOI:10.1016/j.jinorgbio.2015.08.028 · 3.44 Impact Factor
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    ABSTRACT: Treatment with erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor used for treating non-small-cell lung cancer (NSCLC) and other cancers, is frequently associated with adverse events (AE). We present a modeling and simulation framework for the most common erlotinib-induced AE, rash, and diarrhea, providing insights into erlotinib toxicity. We used the framework to investigate the safety of high-dose erlotinib pulses proposed to limit acquired resistance while treating NSCLC. Continuous-time Markov models were developed using rash and diarrhea AE data from 39 NSCLC patients treated with erlotinib (150 mg/day). Exposure and different covariates were investigated as predictors of variability. Rash was also tested as a survival predictor. Models developed were used in a simulation analysis to compare the toxicities of different regimens, including the previously mentioned pulsed strategy. Probabilities of experiencing rash or diarrhea were found to be highest early during treatment. Rash, but not diarrhea, was positively correlated with erlotinib exposure. In contrast with some common understandings, radiotherapy decreased transitioning to higher rash grades by 81% (p < 0.01), and experiencing rash was not correlated with positive survival outcomes. Model simulations predicted that the proposed pulsed regimen (1600 mg/week + 50 mg/day remaining week days) results in a maximum of 20% of the patients suffering from severe rash throughout the treatment course in comparison to 12% when treated with standard dosing (150 mg/day). In conclusion, the framework demonstrated that radiotherapy attenuates erlotinib-induced rash, providing an opportunity to use radiotherapy and erlotinib together, and demonstrated the tolerability of high-dose pulses intended to address acquired resistance to erlotinib.
    The AAPS Journal 08/2015; DOI:10.1208/s12248-015-9815-8 · 3.80 Impact Factor
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    ABSTRACT: Cisplatin is one of the most widely used anticancer agents, but a major problem for successful chemotherapy is the development of drug resistance of tumour cells against cisplatin. Resistance to cisplatin is a multifactorial problem. A method to detect and identify intracellular cisplatin-protein adducts was developed using a fluorescent cisplatin analogue (CFDA-cisplatin), two-dimensional electrophoresis and electrospray ionization tandem mass spectrometry (ESI-MS/MS). We identified several CFDA-cisplatin-protein adducts including members of the protein disulfide isomerase family (PDI). These are the first results of the detection of intracellular CFDA-cisplatin-protein adducts, which may help to understand the resistance mechanism of cisplatin. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Electrophoresis 08/2015; DOI:10.1002/elps.201500188 · 3.03 Impact Factor
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    ABSTRACT: Neutropenia is a frequent and severe adverse event in patients receiving paclitaxel chemotherapy. The time above a paclitaxel threshold concentration of 0.05 μmol/L (Tc>0.05µmol/L) is a strong predictor for paclitaxel-associated neutropenia and has been proposed as a target pharmacokinetic (PK) parameter for paclitaxel therapeutic drug monitoring and dose adaptation. Up to now, individual Tc>0.05µmol/L values are estimated based on a published PK model of paclitaxel by using the software NONMEM. Since many clinicians are not familiar with the use of NONMEM, an Excel-based dosing tool was developed to allow calculation of paclitaxel Tc>0.05µmol/L and give clinicians an easy-to-use tool. Population PK parameters of paclitaxel were taken from a published PK model. An Alglib VBA code was implemented in Excel 2007 to compute differential equations for the paclitaxel PK model. Maximum a-posteriori (MAP) Bayesian estimates of the PK parameters were determined with the Excel Solver using individual drug concentrations. Concentrations from 250 patients were simulated receiving one cycle of paclitaxel chemotherapy. Predictions of paclitaxel Tc>0.05µmol/L as calculated by the Excel tool were compared with NONMEM, whereby MAP Bayesian estimates were obtained using the POSTHOC function. There was a good concordance and comparable predictive performance between Excel and NONMEM with regards to predicted paclitaxel plasma concentrations and Tc>0.05µmol/L values. Tc>0.05µmol/L had a maximum bias of 3% and an error on precision of <12%. The median relative deviation of the estimated Tc>0.05µmol/L values between both programs was 1%. The Excel-based tool can estimate the time above a paclitaxel threshold concentration of 0.05 μmol/L with acceptable accuracy and precision. The presented Excel tool allows reliable calculation of paclitaxel Tc>0.05µmol/L and thus allows target concentration intervention in order to improve the benefit-risk ratio of the drug. The easy use facilitates TDM in clinical routine.
    Therapeutic Drug Monitoring 03/2015; Publish Ahead of Print. DOI:10.1097/FTD.0000000000000206 · 2.38 Impact Factor
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    ABSTRACT: The present simulation study was initiated to develop a limited sampling strategy and pharmacokinetically based dosing algorithm of weekly paclitaxel based on pharmacokinetic (PK) and chemotherapy-induced peripheral neuropathy (CIPN) data from a large database. We used paclitaxel plasma concentrations from 200 patients with solid tumors receiving weekly paclitaxel infusions to build a population PK model and a proportional odds model on CIPN. Different limited sampling strategies were tested on their accuracy to estimate the individual paclitaxel time-above-threshold-concentration of 0.05 µmol/L (T c>0.05µM), which is a common threshold for paclitaxel. A dosing algorithm was developed based on the population distribution of paclitaxel T c>0.05µM and the correlation between paclitaxel T c>0.05µM and CIPN. A trial simulation based on paclitaxel PK and CIPN was performed using empirical Bayes estimations, applying the proposed dosing algorithm and a single 24-h paclitaxel PK sample. A single paclitaxel plasma concentration taken 18-30 h after the start of chemotherapy infusion adequately predicted T c>0.05µM. By using an empirical dosing algorithm to target an average paclitaxel T c>0.05µM between 10 and 14 h, Bayesian simulations of repetitive (adapted) dosing suggested a potential reduction of grade 2 CIPN from 9.6 to 4.4 %. This simulation study proposes a pharmacokinetically based dosing algorithm for weekly paclitaxel and shows potential improvement of the benefit/risk ratio by using empirical Bayesian models.
    Cancer Chemotherapy and Pharmacology 03/2015; 75(5). DOI:10.1007/s00280-015-2724-9 · 2.77 Impact Factor
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    ABSTRACT: Pt-based anti-cancer drugs, such as cisplatin, are known to undergo several (bio-) chemical transformation steps after administration. Hydrolysis and adduct formation with small nucleophiles and larger proteins are their most relevant reactions on the way to the final reaction site (DNA), but there are still many open questions regarding the identity and pharmacological relevance of various proposed adducts and intermediates. Furthermore, the role of buffer components or additives, which are inevitably added to samples during any type of analytical measurement, has been frequently neglected in previous studies. Here, we report on adduct formation reactions of the fluorescent cisplatin analogue carboxyfluorescein diacetate-platinum (CFDA-Pt) in commonly used buffers and cell culture medium. Our results indicate that chelation reactions with non-innocent buffers (e.g. Tris) and components of the cell culture / cell lysis medium must be taken into account when interpreting results. Adduct formation kinetics was followed up to 60 hours at nM concentrations of CFDA-Pt by using CE-LIF. CE-MS enabled the on-line identification of such unexpected adducts down to the nanomolar concentration range. By using an optimized sample preparation strategy, unwanted adducts can be avoided and several fluorescent adducts of CFDA-Pt are detectable in sensitive and cisplatin-resistant cancer cell lines. By processing samples rapidly after incubation, we could even identify the initial, but transient, Pt-species in the cells as deacetylated CFDA-Pt with unaltered complexing environment at Pt. Overall, the proposed procedure enables a very sensitive and accurate analysis of low-molecular-mass Pt-species in cancer cells, involving a fast CE-LIF detection within five minutes. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Electrophoresis 02/2015; 36(4). DOI:10.1002/elps.201400467 · 3.03 Impact Factor
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    ABSTRACT: Linagliptin is a dipeptidyl peptidase (DPP)-4 inhibitor, used to treat type 2 diabetes mellitus (T2DM). Population pharmacokinetic and pharmacodynamic analyses were performed to characterize the impact of clinically relevant intrinsic/extrinsic factors (covariates) on linagliptin exposure and DPP-4 inhibition in patients with T2DM. Linagliptin plasma concentrations and DPP-4 activities were obtained from four studies (two phase 1, two phase 2b). Non-linear mixed-effects modelling techniques were implemented using NONMEM software. The covariates that were studied comprised demographic information and laboratory values, including liver enzyme levels and creatinine clearance, as well as study-related factors such as metformin co-treatment. Covariate effects on parameters describing the pharmacokinetics and pharmacokinetic/pharmacodynamic relationship were investigated using stepwise forward inclusion/backward elimination. The pharmacokinetic analysis included 6,907 measurements of plasma linagliptin concentrations from 462 patients; the pharmacokinetic/pharmacodynamic analysis included 9,674 measurements of plasma DPP-4 activity and linagliptin plasma concentrations from 607 patients. The non-linear pharmacokinetics were described by a target-mediated drug disposition model accounting for the concentration-dependent binding of linagliptin to its target, DPP-4. The difference in exposure between the 5th and 95th percentiles of the covariate distributions and median was <20 % for each single covariate. Likewise, the impact of the covariates on both the half-maximum effect (EC50) and the concentration leading to 80 % DPP-4 inhibition was <20 %. These analyses show that the investigated factors do not alter the pharmacokinetics and DPP-4 inhibitory activity of linagliptin to a clinically relevant extent and that dose adjustment is not necessary on the basis of factors including age, sex and weight.
    Clinical Pharmacokinetics 01/2015; 54(7). DOI:10.1007/s40262-014-0232-4 · 5.05 Impact Factor
  • S. Dilruba · G. V. Kalayda · U. Jaehde
    European Journal of Cancer 11/2014; 50. DOI:10.1016/S0959-8049(14)70218-7 · 5.42 Impact Factor
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    ABSTRACT: The World Health Organization initiated the project "High5s - Action on Patient Safety". The aim of the High5s project is to achieve a measurable, significant and sustained reduction in the occurrence of five serious patient safety problems within five years, in five countries. One of these patient safety issues is medication reconciliation - the process of assuring medication accuracy at transitions of care. In Germany, eleven hospitals are currently implementing medication reconciliation. Medication reconciliation represents the systematic comparison of the current patient's medication list with the medication list in hospital. For this purpose, Lead Technical Agencies of each participating country translated and adapted the standard operating procedure. This standard operating procedure describes the implementation and the procedure of the medication reconciliation process in detail. This process is divided into three parts. First, the best possible medication history is recorded. Second, based on those records, the responsible physician subsequently prescribes the medication. In the third step, the best possible medication history is compared with the medication orders at admission. During this process, it is likely that some discrepancies will occur. Such discrepancies are discussed with the responsible physician and clarified. A comprehensive acquisition of the best possible medication history is thus particularly important. It will be part of medical records throughout the patients' hospital stay. Thus it will be used as an additional source for comparison and adjustment of patients' medication in order to facilitate optimal drug treatment during the entire hospital stay. The practical implementation of medication reconciliation requires extensive change of the current prescription sheets or prescription software. Thus, this provides a great challenge for many hospitals. Nevertheless, in the Netherlands it has been shown that it is possible to prevent 90 % of unintentional discrepancies with medication reconciliation. A German hospital recently showed a reduction of discrepancies by about 77 %. The use of medication reconciliation to improve clinical endpoints is currently subject of further studies.
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    ABSTRACT: This phase I study tested the safety, feasibility, pharmacokinetics and pharmacodynamics of cisplatin administered as hyperthermic intraoperative intraperitoneal chemoperfusion (HIPEC) in patients with platinum-sensitive recurrent epithelial ovarian cancer (EOC) undergoing secondary cytoreductive surgery followed by postoperative platinum-based intravenous chemotherapy. Twelve patients with operable, recurrent platinum-sensitive EOC (recurrence ≥6 months after first-line therapy) were included according to the classical 3+3 dose-escalation design at three dose levels—60, 80, and 100mg/m². After surgical cytoreduction, a single dose of cisplatin was administered via HIPEC for 90 min at 41-43°C. Postoperatively, all patients were treated with standard intravenous platinum-based combination chemotherapy. One of six patients experienced a dose-limiting toxicity (grade 3 renal toxicity) at a dose of 100 mg/m². The remaining five patients treated with 100mg/m² tolerated their treatment well. The recommended phase II dose was established at 100 mg/m². The mean peritoneal-to-plasma AUC ratio was 19·5 at the highest dose level. Cisplatin-induced DNA adducts were confirmed in tumor samples. Common postoperative grade 1-3 toxicities included fatigue, postoperative pain, nausea, and surgical site infection. The ability to administer standard intravenous platinum-based chemotherapy after HIPEC was uncompromised. Cisplatin administered as HIPEC at a dose of 100mg/m² has an acceptable safety profile in selected patients undergoing secondary cytoreductive surgery for platinum-sensitive recurrent EOC. Favorable pharmacokinetic and pharmacodynamic properties of HIPEC with cisplatin were confirmed at all dose levels, especially at 100 mg/m2. The results are encouraging to determine the efficacy of HIPEC as a complementary treatment in patients with EOC. © 2014 Wiley Periodicals, Inc.
    International Journal of Cancer 06/2014; 136(3). DOI:10.1002/ijc.29011 · 5.09 Impact Factor
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    ABSTRACT: Background: The aim of this study was the evaluation of pharmacokinetic parameters, biomarkers, clinical outcome, and imaging parameters in metastatic colorectal cancer (mCRC) patients treated with FOLFIRI plus sunitinib. Methods: mCRC patients with liver metastases were treated with FOLFIRI and sunitinib as 1st line therapy. At protocol-defined time points, multicontrast magnetic resonance imaging (MRI)measurements, computed tomography (CT) scans, pharmacokinetics (PK), and biomarker analyses were performed during the first and second treatment cycle. Thereafter, patients were treated until tumor progression, investigator’s decision due to toxicity, or patient withdrawal. Results: 28 patients were screened, 26 were included, and 23 received at least one study medication. Full safety analysis was performed in 23 patients. Full PK and biomarker analyses were performed in 21 patients. Strong responses in tumor size reduction forced a change from the original imaging timing scheme. This unforeseen change in the timing scheme resulted in subgroups too small for meaningful statistical analysis of most imaging parameters. Thus, only a descriptive analysis of the MRI data was possible. In 21/22 patients, MRI showeda decrease of the liver metastases. Best response was partial remission (PR) in 8/17 patients. Plasma concentrations of sVEGFR-2 and sVEGFR-3 decreased in all patients. The majority of the patients developed some kind of toxicity not always deducible to FOLFIRI or sunitinib. Conclusions: Due to the observed side effect profile, FOLFIRI plus sunitinib 37.5 mg per day cannot be recommended for previously untreated mCRC.
    International journal of clinical pharmacology and therapeutics 05/2014; 52(8). DOI:10.5414/CP202109 · 1.22 Impact Factor
  • Ulrich Jaehde · Hardy Müller
    Zeitschrift für Evidenz Fortbildung und Qualität im Gesundheitswesen 01/2014; 108(1). DOI:10.1016/j.zefq.2014.01.010
  • Ulrich Jaehde · Hardy Müller
    01/2014; 108(1):4-5.
  • International journal of clinical pharmacology and therapeutics 11/2013; 52(1). DOI:10.5414/CPXCES13EA08 · 1.22 Impact Factor
  • International journal of clinical pharmacology and therapeutics 11/2013; 52(1). DOI:10.5414/CPXCES13EA07 · 1.22 Impact Factor
  • Medizinische Monatsschrift für Pharmazeuten 08/2013; 36(8):299-304.
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    ABSTRACT: To develop and evaluate a multiprofessional modular medication management to assure adherence to capecitabine. The study was conducted as a prospective, multicentred observational cohort study. All participants received pharmaceutical care consisting of oral and written information. Daily adherence was defined as percentage of days with correctly administered capecitabine doses and assessed using medication event monitoring. According to their daily adherence during the first cycle, patients were identified as initially non-adherent (<90% adherence) or adherent (≥90% adherence). Initially non-adherent patients received additional adherence support. Seventy-three patients with various tumour entities were enrolled, 58 were initially adherent and 15 non-adherent. Median daily adherence of initially non-adherent patients increased from 85.7% to 97.6% during the observation period of six cycles. Throughout all cycles, median daily adherence of initially adherent patients was 100.0%. Daily adherence was not associated with sociodemographic and disease-related factors. No patient was non-persistent. An early adherence screening effectively distinguishes between patients adhering and non-adhering to capecitabine. The provision of specific adherence support is associated with enhanced adherence of initially non-adherent patients, whereas initially adherent patients remain adherent for at least six cycles without specific support. Our needs-based approach helps to use available resources for adherence management efficiently.
    BMJ Open 07/2013; 3(7). DOI:10.1136/bmjopen-2013-003139 · 2.27 Impact Factor
  • C Mohn · H-G Häcker · R A Hilger · M Gütschow · U Jaehde
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    ABSTRACT: Albeit platinum complexes are widely used in cancer chemotherapy, their cellular processing has not been completely elucidated so far. In this study the effects of modulating multidrug resistance-associated protein (MRP)-mediated efflux and glutathione (GSH) depletion on the cytotoxicity of oxaliplatin were assessed in a human ileocecal colorectal adenocarcinoma cell line and its oxaliplatin-resistant variant. Upon oxaliplatin exposure, DNA platination was elevated by co-incubation with Gü83, a MRP1 and MRP2 inhibitor, but cytotoxicity was not increased. Addition of oxaliplatin did not alter the cellular GSH content. Following GSH depletion, platinum accumulation was unchanged but cytotoxicity was increased in oxaliplatin-sensitive cells. In conclusion, modulation of MRP-mediated efflux did not affect oxaliplatin cytotoxicity in the investigated cell lines. Intracellular GSH depletion seems to sensitize the cells but does not overcome resistance.
    Pharmazie 07/2013; 68(7):622-7. DOI:10.1691/ph.2013.6523 · 1.05 Impact Factor
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    ABSTRACT: Previously we reported that liposomal cisplatin (CDDP) overcomes CDDP resistance of ovarian A2780cis cancer cells (Krieger et al., Int. J. Pharm. 389, 2010, 10-17). Here we find that the cytotoxic activity of liposomal CDDP is not associated with detectable DNA platination in resistant ovarian cancer cells. This suggests that the mode of action of liposomal CDDP is different from the free drug. To gain insight into mechanisms of liposomal CDDP activity, we performed a transcriptome analysis of untreated A2780cis cells, and A2780cis cells in response to exposure with IC(50) values of free or liposomal CDDP. A process network analysis of upregulated genes showed that liposomal CDDP induced a highly different gene expression profile in comparison to the free drug. p53 was identified as a key player directing transcriptional responses to free or liposomal CDDP. The free drug induced expression of essential genes of the intrinsic (mitochondrial) apoptosis pathway (BAX, BID, CASP9) most likely through p38MAPK activation. In contrast, liposomal CDDP induced expression of genes from DNA damage pathways and several genes of the extrinsic pathway of apoptosis (TNFRSF10B-DR5, CD70-TNFSF7). It thus appears that liposomal CDDP overcomes CDDP resistance by inducing DNA damage and in consequence programmed cell death by the extrinsic pathway. Predictions from gene expression data with respect to apoptosis activation were confirmed at the protein level by an apoptosis antibody array. This sheds new light on liposomal drug carrier approaches in cancer and suggests liposomal CDDP as promising strategy for the treatment of CDDP resistant ovarian carcinomas.
    Biochemical pharmacology 02/2013; 85(8). DOI:10.1016/j.bcp.2013.01.028 · 5.01 Impact Factor

Publication Stats

2k Citations
433.41 Total Impact Points


  • 2000–2015
    • University of Bonn
      • • Pharmaceutical Institute
      • • Department of Pharmacy
      Bonn, North Rhine-Westphalia, Germany
  • 1987–2013
    • Freie Universität Berlin
      • • Division of Clinical Pharmacy
      • • Institute of Pharmacy
      Berlin, Land Berlin, Germany
  • 2009
    • Università degli Studi di Torino
      Torino, Piedmont, Italy
  • 2003–2007
    • University of Cologne
      • • Department of Pharmacology
      • • Institute of Pathology
      Köln, North Rhine-Westphalia, Germany
  • 2004
    • University of Strathclyde
      Glasgow, Scotland, United Kingdom
  • 2003–2004
    • Sana Klinikum Remscheid GmbH
      Remscheid, North Rhine-Westphalia, Germany
  • 2001
    • University Hospital Essen
      Essen, North Rhine-Westphalia, Germany
  • 1989–1994
    • Institute For Biomedical And Pharmaceutical Research
      Nuremberg, Bavaria, Germany