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Aims: Low blood concentrations of the naturally occurring amino acid L-homoarginine (L-hArg) are related to impaired cardiovascular outcome and mortality in humans and animals. L-hArg is a weak substrate of nitric oxide synthase and an inhibitor of arginases in vitro. The aim of our study was to obtain kinetic and dynamic data after oral L-hArg supplementation., Methods: In a double-blind, randomized, placebo-controlled crossover study, 20 young volunteers received 125 mg L-hArg once daily for 4 weeks. Kinetic parameters (C max , T max and AUC 0-24h ) were calculated after ingestion of single and multiple doses of oral supplementation as primary endpoint. Secondary endpoints that were evaluated were routine laboratory, L-arginine, asymmetric dimethylarginine (ADMA), pulse wave velocity (PWV), augmentation index (AIx), flow-mediated vasodilatation (FMD), corticospinal excitability, i.e. motor threshold (MT), and cortical excitability, i.e. intracortical inhibition (ICI) and facilitation (ICF)., Results: One hour after ingestion (T max ), L-hArg increased the baseline L-hArg plasma concentration (2.87 ± 0.91 μmol l -1 , mean ± SD) by 8.74 ± 4.46 [95% confidence intervals 6.65; 10.9] and 17.3 ± 4.97 [14.9; 19.6] μmol l -1 (C max ), after single and multiple doses, respectively. Once-only and 4 weeks of supplementation resulted in AUCs 0-24h of 63.5 ± 28.8 [50.0; 76.9] and 225 ± 78.5 [188; 2624] μmol l -1 *h, for single and multiple doses, respectively. Routine laboratory parameters, L-arginine, ADMA, PWV, AIx, FMD, MT, ICI and ICF did not change by L-hArg supplementation compared to baseline., Conclusion: Once daily orally applied 125 mg L-hArg raises plasma L-hArg four- and sevenfold after single dose and 4 weeks of supplementation, respectively, and is safe and well tolerated in young volunteers., (© 2016 The British Pharmacological Society.)

Background: Medication reviews and medication management are being used more and more around the world to improve medication safety. Both of these tools were originally conceived as pharmaceutical care activities and have recently been developed into interdisciplinary approaches. We studied the efficacy of interprofessional medication management for multimorbid patients that takes their medical conditions, but also their general living situation into account., Methods: A comprehensive medication management was performed, which involved the collection of information on the drugs each patient took, the way they were stored, the patient's drug intake and handling, and any problems that arose with pharmacotherapy. The interventional approach was evaluated over a period of 15 months in a cluster-randomized controlled trial with a stepped wedge design. The primary endpoint was the quality of pharmacotherapy, as assessed with the Medication Appropriateness Index (MAI). A mixed model was used to analyze efficacy., Results: 162 patients were enrolled in the study; 142 were included in the intention-to-treat analysis (53.3% women, mean age 76.8 ± 6.3 years). The mean total MAI score decreased significantly (p ≤ 0.001) from the control phase (29.21, 95% CI [26.09; 32.33]) to the intervention phase (22.27 [19.00; 25.54]), with an effect strength (Cohen's d) of -0.24 [-0.36; -0.13]. The number of drug-related problems declined as well., Conclusion: In this study, interprofessional collaboration increased medication safety. Working across disciplinary boundaries allowed for a decrease in drugrelated problems and brought up aspects outside the purview of the primary care physician.

Foci of altered hepatocytes (FAH) were induced in fetal turkey liver (FTL) by diethyl nitrosamine. FAH in FTL were resistant to iron overload similar to FAH in humans and rodents. The mitotic index was significantly higher in FAH (6.2 mitosis in 1000 hepatocytes) than in extrafocal liver tissue (1.8 mitosis in 1000 hepatocytes). The calculation of the net growth rate based on both cell proliferation (mitosis) and cell death (TUNEL positive) revealed a threefold growth advantage of the FAH over the surrounding liver. Two well established anti-tumor substances from different chemical classes, different modes of action and with different clinical use in the treatment of hepatocellular carcinoma (HCC) were used to study their effect on FAH. Sorafenib is the only approved drug for systemic pharmacological treatment of HCC; cisplatin has been used for many years in hepatic arterial infusion. Cisplatin had no clear effect on number of size of FAH, cell proliferation (mitosis) or cell loss (TUNEL positive). Sorafenib enhanced the development of FAH. Morphometric quantification revealed a sorafenib-induced 2-3-fold increase in number (FAH per cm 2 and FAH per cm 3 ), size and volume fraction of FAH. This unexpected finding was confirmed in two experiments. The effect was driven by an increased cell proliferation in the FAH, resulting in an increased, 5.4-fold growth advantage of FAH versus the surrounding liver in sorafenib-treated FTL. In this model, sorafenib has a promoting effect on preneoplastic FAH. This might be of relevance for the treatment of patients with long term survival perspective, e.g. in an adjuvant setting.

Background: Variable chemotherapy exposure may cause toxicity or lack of efficacy. This study was initiated to validate pharmacokinetically (PK)-guided paclitaxel dosing in patients with advanced non-small-cell lung cancer (NSCLC) to avoid supra- or subtherapeutic exposure., Patients and Methods: Patients with newly diagnosed, advanced NSCLC were randomly assigned to receive up to 6 cycles of 3-weekly carboplatin AUC 6 or cisplatin 80 mg/m(2) either with standard paclitaxel at 200 mg/m(2) (arm A) or PK-guided dosing of paclitaxel (arm B). In arm B, initial paclitaxel dose was adjusted to body surface area, age, sex, and subsequent doses were guided by neutropenia and previous-cycle paclitaxel exposure [time above a plasma concentration of 0.05 µM (Tc>0.05)] determined from a single blood sample on day 2. The primary end point was grade 4 neutropenia; secondary end points included neuropathy, radiological response, progression-free survival (PFS) and overall survival (OS)., Results: Among 365 patients randomly assigned, grade 4 neutropenia was similar in both arms (19% versus 16%; P = 0.10). Neuropathy grade ≥2 (38% versus 23%, P < 0.001) and grade ≥3 (9% versus 2%, P < 0.001) was significantly lower in arm B, independent of the platinum drug used. The median final paclitaxel dose was significantly lower in arm B (199 versus 150 mg/m(2), P < 0.001). Response rate was similar in arms A and B (31% versus 27%, P = 0.405), as was adjusted median PFS [5.5 versus 4.9 months, hazard ratio (HR) 1.16, 95% confidence interval (CI) 0.91-1.49, P = 0.228] and OS (10.1 versus 9.5 months, HR 1.05, 95% CI 0.81-1.37, P = 0.682)., Conclusion: PK-guided dosing of paclitaxel does not improve severe neutropenia, but reduces paclitaxel-associated neuropathy and thereby improves the benefit-risk profile in patients with advanced NSCLC., Clinical Trial Information: NCT01326767 (https://clinicaltrials.gov/ct2/show/NCT01326767)., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Medication reviews are recognized services to increase quality of therapy and reduce medication risks. The selection of eligible patients with potential to receive a major benefit is based on assumptions rather than on factual data. Acceptance of interprofessional collaboration is crucial to increase the quality of medication therapy., Objective: The research question was to identify and prioritize eligible patients for a medication review and to provide evidence-based criteria for patient selection. Acceptance of the prescribing general practitioner to implement pharmaceutical recommendations was measured and factors influencing physicians' acceptance were explored to obtain an impression on the extent of collaboration in medication review in an ambulatory care setting., Methods: Based on data of a cluster-randomized controlled study (WestGem-study), the correlation between patient parameters and the individual performance in a medication review was calculated in a multiple logistic regression model. Physician's acceptance of the suggested intervention was assessed using feedback forms. Influential factors were analyzed., Results: The number of drugs in use (p = 0.001), discrepancies between prescribed and used medicines (p = 0.014), the baseline Medication Appropriateness Index score (p<0.001) and the duration of the intervention (p = 0.006) could be identified as influential factors for a major benefit from a medication review, whereas morbidity (p>0.05) and a low kidney function (p>0.05) do not predetermine the outcome. Longitudinal patient care with repeated reviews showed higher interprofessional acceptance and superior patient benefit. A total of 54.9% of the recommendations in a medication review on drug therapy were accepted for implementation., Conclusions: The number of drugs in use and medication reconciliation could be a first rational step in patient selection for a medication review. Most elderly, multimorbid patients with polymedication experience a similar chance of receiving a benefit from a medication review. Longitudinal patient care should be preferred over confined medication reviews. The acceptance of medication reviews by physicians supports further implementation into health care systems., Trial Registration: ISRCTN ISRCTN41595373.

Background: During the last decades, pharmaceutical care services have been developed and implemented to optimize drug therapies and ensure medication safety. To investigate the need for pharmaceutical care services, drug-related problems can be measured., Objective: Thus, the aim of this study was to analyse number, type and occurrence of drug-related problems in different clinical departments., Setting: A pharmaceutical care service was established on general wards in Urology, Neurology and Gastroenterology at the University Hospital RWTH Aachen, Germany., Method: For each of a total of 306 patients, a pharmacist conducted an extended medication history, performed medication reconciliation, conducted medication safety checks and if drug-related problems were discovered, gave valid recommendations to the attending healthcare team. Drug-related problems were classified using the APS-Doc system. For statistical analyses, SAS(®) 9.1.3, SAS Institute, Cary NC, USA was applied. The project was approved by the local ethics committee., Main Outcome Measure: Type, occurrence and frequency of DRP in different medical departments., Results: On average, 2.3 drug-related problems per patient were documented for all three departments. Drug-related problems were found in each category of the APS-Doc system. The most pronounced drug-related problems found were drug-drug interactions (34.6 %). 37 % of the identified drug-related problems occurred before hospital admission, 27 % during transitional care, and 36 % on the ward. Subgroup analysis revealed specific drug-related problem patterns for each clinical department. The number of drug-related problems was found to be associated with the number of drugs and age., Conclusion: Drug-related problems frequently occur in all investigated clinical departments. A holistic pharmaceutical care service could be an option to address this issue. In case of limited resources, individual drug-related problem patterns can be used as a basis for a tailored pharmaceutical care service. As number of drugs and age have been shown to be significant risk factors, it is crucial that the healthcare team including the pharmacist pays special attention to elderly patients and those with polymedication.

Doripenem is a broad-spectrum parenteral carbapenem with enhanced activity against Pseudomonas aeruginosa. While the initial dosing recommendation for renally competent patients and patients undergoing continuous renal replacement therapy (cRRT) was 500 mg every 8 h (q8h), the dose for renally competent patients was updated to 1 g q8h in June 2012. There are no updated data for the dosing of patients on continuous renal replacement therapy. The original dosing regimen for cRRT patients was based on nonseptic patients, while newer publications chose comparatively low target concentrations for a carbapenem. Thus, there is an urgent need for updated recommendations for dosing during cRRT. In the trial presented here, we included 13 oliguric septic patients undergoing cRRT in an intensive care setting. Five patients each were treated with hemodiafiltration or hemodialysis, while three patients received hemofiltration treatment. All patients received 1 g doripenem every 8 h. Doripenem concentrations in the plasma and ultrafiltrate were measured over 48 h. The mean hemofilter clearance was 36.53 ml/min, and the mean volume of distribution was 59.26 liters. The steady-state trough levels were found at 8.5 mg/liter, with no considerable accumulation. Based on pharmacokinetic and pharmacodynamic considerations, we propose a regimen of 1 g q8h, which may be combined with a loading dose of 1.5 to 2 g for critically ill patients. (This study has been registered with EudraCT under registration no. 2009-018010-18 and at ClinicalTrials.gov under registration no. NCT02018939.)., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Background: 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 > 0.05 μmol/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 > 0.05 μmol/L values are estimated based on a published PK model of paclitaxel by using the software NONMEM. Because many clinicians are not familiar with the use of NONMEM, an Excel-based dosing tool was developed to allow calculation of paclitaxel Tc > 0.05 μmol/L and give clinicians an easy-to-use tool., Methods: 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 Bayesian estimates of the PK parameters were determined with the Excel Solver using individual drug concentrations. Concentrations from 250 patients were simulated receiving 1 cycle of paclitaxel chemotherapy. Predictions of paclitaxel Tc > 0.05 μmol/L as calculated by the Excel tool were compared with NONMEM, whereby maximum a posteriori Bayesian estimates were obtained using the POSTHOC function., Results: There was a good concordance and comparable predictive performance between Excel and NONMEM regarding predicted paclitaxel plasma concentrations and Tc > 0.05 μmol/L values. Tc > 0.05 μmol/L had a maximum bias of 3% and an error on precision of <12%. The median relative deviation of the estimated Tc > 0.05 μmol/L values between both programs was 1%., Conclusions: 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 > 0.05 μmol/L and thus allows target concentration intervention to improve the benefit-risk ratio of the drug. The easy use facilitates therapeutic drug monitoring in clinical routine.

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., (Copyright © 2015 Elsevier Inc. All rights reserved.)

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.

Cisplatin is one of the most widely used anticancer agents, but a major problem for successful chemotherapy is the development of drug resistance of tumor 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 carboxyfluorescein-diacetate-labeled cisplatin analogue (CFDA-cisplatin), 2DE, and 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., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background and Objectives: 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., Methods: 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., Results: 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 %., Conclusion: 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.

Purpose: 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., Methods: 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., Results: 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 %., Conclusions: 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.

Pt-based anticancer 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 noninnocent 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 h at nanomolar concentrations of CFDA-Pt by using CE-LIF. CE-MS enabled the online 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 5 min., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

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 100 mg/m(2). 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/m(2). The remaining five patients treated with 100 mg/m(2) tolerated their treatment well. The recommended phase II dose was established at 100 mg/m(2). 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 100 mg/m(2) 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/m(2). The results are encouraging to determine the efficacy of HIPEC as a complementary treatment in patients with EOC., (© 2014 UICC.)

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.

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.

Objective: To develop and evaluate a multiprofessional modular medication management to assure adherence to capecitabine., Methods: 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., Results: 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., Conclusions: 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.

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.

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 IC50 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., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Decreased cellular accumulation of cisplatin is a frequently observed mechanism of resistance to the drug. Beside passive diffusion, several cellular proteins using ATP hydrolysis as an energy source are assumed to be involved in cisplatin transport in and out of the cell. This investigation aimed at clarifying the contribution of intracellular ATP as an indicator of energy-dependent transport to cisplatin resistance using the A2780 human ovarian adenocarcinoma cell line and its cisplatin-resistant variant A2780cis. Depletion of intracellular ATP with oligomycin significantly decreased cellular platinum accumulation (measured by flameless atomic absorption spectrometry) in sensitive but not in resistant cells, and did not affect cisplatin efflux in both cell lines. Inhibition of Na(+),K(+)-ATPase with ouabain reduced platinum accumulation in A2780 cells but to a lesser extent compared with oligomycin. Western blot analysis revealed lower expression of Na(+),K(+)-ATPase α(1) subunit in resistant cells compared with sensitive counterparts. The basal intracellular ATP level (determined using a bioluminescence-based assay) was significantly higher in A2780cis cells than in A2780 cells. Our results highlight the importance of ATP-dependent transport, among other processes mediated by Na(+),K(+)-ATPase, for cisplatin influx in sensitive cells. Cellular platinum accumulation in resistant cells is reduced and less dependent on energy sources, which may partly result from Na(+),K(+)-ATPase downregulation. Our data suggest the involvement of other ATP-dependent processes beside those regulated by Na(+),K(+)-ATPase. Higher basal ATP level in cisplatin-resistant cells, which appears to be a consequence of enhanced mitochondrial ATP production, may represent a survival mechanism established during development of resistance.

Purpose: Individualized patient care may help reduce the incidence of adverse drug events in systemic cancer therapy. This study was conducted to explore the feasibility and potential of additional pharmaceutical care for breast and ovarian cancer patients., Methods: The study was designed as a prospective, multicentered cohort study with a control group. Ninety-eight breast or ovarian cancer patients were recruited from outpatient oncology clinics and primary care oncologists: initially into the control group receiving standard care and after implementation of pharmaceutical care into the intervention group consisting of additional patient counseling on the management of treatment-associated adverse events and optimization of supportive medication. Primary outcome was the complete response to the antiemetic prophylaxis. Secondary endpoints were the severity of nausea, frequency of emesis, health-related quality of life, and patient satisfaction with information on cancer treatment education., Results: Forty-eight patients were included in the control group and 50 in the intervention group. Of the patients, 35.4% in the control group and 76.0% in the intervention group (p < 0.001) had a complete response to the antiemetic prophylaxis. The severity of acute and delayed nausea was not reduced. The global health scale and two symptom scales (nausea and vomiting, appetite loss) of the EORTC QLQ-C30 questionnaire were positively affected by pharmaceutical care. Patient satisfaction with information was significantly higher in the intervention group., Conclusions: Patients with breast and ovarian cancer seem to benefit from pharmaceutical care, as suggested by improved patient-reported outcomes such as emetic episodes, quality of life, and patient satisfaction after implementation.

Defects in intracellular accumulation of the antitumour drug cisplatin are a commonly observed feature in the cells selected for cisplatin resistance. Copper transporter 1 (CTR1) has been suggested to play an important role in drug uptake and resistance. Here, we describe a detailed investigation of the involvement of CTR1 in cisplatin uptake and its relevance for cisplatin resistance using a well characterised sensitive/cisplatin-resistant cell line pair: A2780 human ovarian carcinoma cell line and its cisplatin-resistant variant A2780cis. A2780cis cells showed decreased cisplatin accumulation and lower CTR1 expression compared to A2780 cells. Co-incubation with copper sulphate affected neither cisplatin accumulation (determined by flameless atomic absorption spectrometry) nor its cytotoxicity (determined using an MTT-assay, MTT=3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide). In both cell lines, CTR1 was localised near the nucleus as found using confocal fluorescence microscopy. The steady-state localisation of the protein in perinuclear region appears to involve its continuous endocytosis from cell surface. In contrast to copper, cisplatin exposure had no influence on the sub cellular localisation of CTR1. Co-localisation between CTR1 and a fluorescent cisplatin analogue labelled with carboxyfluorescein-diacetate could be observed in vesicular structures when continuous retrieval of the protein from cell membrane was inhibited. Our results strongly suggest that CTR1 mediates cisplatin uptake in the cell lines studied. Upon its transport across the plasma membrane by CTR1 the platinum drug is likely to be internalised along with the protein. Our findings imply that reduced CTR1 expression accounts for decreased cisplatin accumulation and represents one of the determinants of cisplatin resistance in A2780cis cell line., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Soluble VEGFR-3 (sVEGFR-3) is a potential biomarker for the anti-angiogenic activity of tyrosine kinase inhibitors. The aim of this investigation was the validation of an enzyme-linked immunosorbent assay (ELISA) to measure sVEGFR-3 in human plasma and the investigation of its applicability in clinical trials as first step of the biomarker validation process. General validation criteria were assessed based on current guidelines and recommendations for immunoassays. The ELISA was applied in two clinical trials including healthy volunteers and metastatic colorectal cancer (mCRC) patients receiving 50 or 37.5mg sunitinib per day, respectively. SVEGFR-3 was measured at predefined time points. Undiluted, inactivated fetal calf serum was identified as surrogate matrix to substitute for human plasma. Dilutional linearity and parallelism could be successfully confirmed. The analyte was measured in the study matrix with intra- and inter-run precision and accuracy ≤20%. Stability was proven over a period of at least 15 months as well as upon three freeze-thaw cycles. SVEGFR-3 concentrations decreased in response to sunitinib to 57% (IQR 50-88%) and 58% (IQR 47-80%) of the respective baseline concentrations in healthy volunteers and mCRC patients, respectively, with subsequent increase after stop of treatment. The ELISA for the quantification of sVEGFR-3 in human plasma was successfully validated. The applicability of the assay was demonstrated in two clinical trials., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The efficacy and mechanism of action of cisplatin and gemcitabine were investigated in a panel of neuroblastoma cell lines and multicellular tumor spheroids. In neuroblastoma spheroids, the combination of cisplatin and gemcitabine induced a complete cytostasis at clinical relevant concentrations. A synergistic effect was observed when cells were coincubated with both drugs or preincubated with gemcitabine first. These administration sequences resulted in NASS cells in decreased ERCC1 and XPA expression, two key proteins of the NER DNA repair system, and increased platinum adduct formation in DNA. Most of these phenomena were not observed in SJNB8 cells which might explain the lack of synergy between cisplatin and gemcitabine in SJNB8 cells. Our results showed favorable interactions between cisplatin and gemcitabine in 4 out of 5 cell lines. Therefore, we feel that inclusion of gemcitabine into cisplatin-containing regiments might be a promising new strategy for the treatment of neuroblastoma., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

The purpose of this study was to systematically investigate the relationships between reactivity, cellular accumulation, and cytotoxicity of a panel of oxaliplatin analogues with different leaving groups in human carcinoma cells. The reactivity of the complexes towards the nucleotides 2'-deoxyguanosine 5'-monophosphate and 2'-deoxyadenosine 5'-monophosphate was studied using capillary electrophoresis. Cellular accumulation and cytotoxicity were measured in an oxaliplatin-sensitive and oxaliplatin-resistant ileocecal colorectal adenocarcinoma cell line pair (HCT-8/HCT-8ox). Platinum concentrations were determined by flameless atomic absorption spectrometry. The 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was used to assess cytotoxicity. Early cellular platinum accumulation was predominantly affected by lipophilicity. A relationship between reactivity and cellular accumulation was observed for three of four platinum complexes investigated, whereas the most lipophilic oxaliplatin analogue was an exception. Increased reactivity and reduced lipophilicity were associated with high cytotoxic activity. Resistance was influenced by lipophilicity but not by reactivity. The observed relationships may help in the design of analogues with high antitumoral activity in oxaliplatin-sensitive as well as oxaliplatin-resistant cells.

Fatigue is characterized by persistent tiredness or exhaustion and besides the anorexia-nausea-emesis syndrome one of the most frequent adverse events of cancer treatment. There is a large variety of causes and symptoms. Various non-pharmacologic and pharmacologic interventions can help to ameliorate the symptoms and to improve patient's quality of life. For the effective management of fatigue a systematic approach of the multiprofessional team is required. Last but not least, the pharmacist can contribute to support cancer patients suffering from fatigue.

Multimorbidity, polymedication and functional impairment together with diminished everyday competence and communication ability predispose nursing home residents to adverse drug events (ADE). The high number of psychiatric drug prescriptions is a characteristic feature. The project "Medication Safety in Nursing Homes", funded by the Federal Ministry of Health, found an incidence of approximately 8 ADEs per 100 nursing home resident-months. About one third of the ADEs had clinical consequences, notably hospital admissions and additional visits of general practitioners. Many ADEs are due to errors in the medication process, coupled with the effects of poor communication among health care professionals. Thus, structured interventions are intended to not only sensitize to these problems, but also to support and foster a multidisciplinary way of thinking and acting., (Copyright © 2012. Published by Elsevier GmbH.)

In the execution of their pharmacotherapy, many patients deviate from the prescribed treatment regimen. Reasons for noncompliance can be diverse and range from forgetfulness of the patient to attributes of the health care system. Besides increased health care costs, poor compliance causes both an endangerment to the patient and poor health outcomes. Therefore, it is crucial that compliance enhancement receives high priority. In the beginning of this process, noncompliance must be detected in daily practice. Moreover, various methods can provide valuable information about medication-taking behavior, time patterns, and reasons for noncompliance. Based on this assessment, appropriate measures to enhance compliance can be taken. In this article, the opportunities and limitations of compliance enhancement are discussed.

Elevated homocysteine concentrations have been associated with methotrexate-induced neurotoxicity. Based on methotrexate and homocysteine plasma concentrations of 494 children with acute lymphoblastic leukemia treated with high-dose methotrexate in the TOTAL XV study, a pharmacokinetic/pharmacodynamic (PK/PD) model was built with NONMEM. Several compartment and indirect response models were investigated. The pharmacokinetic disposition of methotrexate was best described by a two-compartment model. Homocysteine concentrations were included by an indirect response model where methotrexate inhibition of the homocysteine elimination rate was described by an E(max) model. The homocysteine baseline level was found to be age-dependent. Simulations revealed that folinate rescue therapy does not affect peak concentrations of homocysteine but leads to a modestly reduced homocysteine exposure. In conclusion, our PK/PD model describes the increase of methotrexate-induced HCY concentrations with satisfactory precision and can be applied to assess the effect of folinate regimens on the HCY concentration-time course.

Pyrimidine (imatinib, dasatinib, nilotinib and pazopanib), pyridine (sorafenib) and pyrrole (sunitinib) tyrosine kinase inhibitors (TKIs) are multi-targeted TKIs with high activity towards several families of receptor and non-receptor tyrosine kinases involved in angiogenesis, tumour growth and metastatic progression of cancer. These orally administered TKIs have quite diverse characteristics with regard to absorption from the gastrointestinal tract. Absolute bioavailability in humans has been investigated only for imatinib (almost 100%) and pazopanib (14-39%; n = 3). On the basis of human radioactivity data, dasatinib is considered to be well absorbed after oral administration (19% and 0.1% of the total radioactivity were excreted as unchanged dasatinib in the faeces and urine, respectively). Quite low absolute bioavailability under fasted conditions is assumed for nilotinib (31%), sorafenib (50%) and sunitinib (50%). Imatinib, dasatinib and sunitinib exhibit dose-proportional increases in their area under the plasma concentration-time curve values over their therapeutic dose ranges. Less than dose-proportional increases were observed for nilotinib at doses ≥400 mg/day and for sorafenib and pazopanib at doses ≥800 mg/day. At steady state, the accumulation ratios are 1.5-2.5 (unchanged imatinib), 2.0 (nilotinib once-daily dosing), 3.4 (nilotinib twice-daily dosing), 1.2-4.5 (pazopanib), 5.7-6.4 (sorafenib) and 3.0-4.5 (sunitinib). Concomitant intake of a high-fat meal does not alter exposure to imatinib, dasatinib and sunitinib but leads to considerably increased bioavailability of nilotinib and pazopanib and decreased bioavailability of sorafenib. With the exception of pazopanib, the TKIs described here have large apparent volumes of distribution, exceeding the volume of body water by at least 4-fold. Very low penetration into the central nervous system in humans has been reported for imatinib and dasatinib, but there are currently no published human data for nilotinib, pazopanib, sorafenib or sunitinib. All TKIs that have been described are more than 90% bound to the plasma proteins: α(1)-acid glycoprotein and/or albumin. They are metabolized primarily via cytochrome P450 (CYP) 3A4, the only exception being sorafenib, for which uridine diphosphate glucuronosyltransferase 1A9 is the other main enzyme involved. Active metabolites of imatinib and sunitinib contribute to their antitumour activity. Although some patient demographics have been identified as significant co-factors that partly explain interindividual variability in exposure to TKIs, these findings have not been regarded as sufficient to recommend age-, sex-, bodyweight- or ethnicity-specific dose adjustment. Systemic exposure to imatinib, sorafenib and pazopanib increases in patients with hepatic impairment, and reduction of the initial therapeutic dose is recommended in this subpopulation. The starting dose of imatinib should also be reduced in renally impaired subjects. Because the solubility of dasatinib is pH dependent, co-administration of histamine H(2)-receptor antagonists and proton pump inhibitors with dasatinib should be avoided. With the exception of sorafenib, systemic exposure to TKIs is significantly decreased/increased by co-administration of potent CYP3A4 inducers/inhibitors, and so it is strongly recommended that the TKI dose is adjusted or that such co-administration is avoided. Caution is also recommended for co-administration of CYP3A4 substrates with TKIs, especially for those with a narrow therapeutic index. However, current recommendations with regard to dose adjustment of TKIs need to be validated in clinical studies. Further investigations are needed to explain the large interindividual variability in the pharmacokinetics of these drugs and to assess theclinical relevance of their interaction potential and inhibitory effects on metabolizing enzymes and transporters.

Decreased influx represents one of the major resistance mechanisms of platinum complexes. In order to address the question if this mechanism of resistance can be overcome by enhancing the lipophilicity of platinum complexes, we investigated the influence of lipophilicity on cellular accumulation and cytotoxicity in a panel of oxaliplatin analogues with different carrier ligands. Cellular accumulation, DNA platination and cytotoxicity were measured in a cisplatin-sensitive and -resistant ovarian carcinoma (A2780/A2780cis) and in an oxaliplatin-sensitive and -resistant ileocecal colorectal adenocarcinoma (HCT-8/HCT-8ox) cell line pair. Platinum concentrations were determined by flameless atomic absorption spectrometry or adsorptive stripping voltammetry. Passive diffusion represented the main influx mechanism of oxaliplatin analogues during the first minutes of incubation as indicated by a correlation between lipophilicity and early influx rate. Afterwards, the predominant influx mechanism was lipophilicity-independent. More lipophilic complexes showed a reduced cytotoxic activity, although the early influx rate was increased. The resistance profiles of the two cell line pairs were found to be different: HCT-8ox cells were less resistant against more lipophilic complexes, whereas A2780cis cells exhibited a comparable degree of resistance against all investigated compounds. However, the reduction in resistance factor of HCT-8ox cells cannot be explained by increased influx suggesting that other resistance mechanisms are circumvented upon exposure to more lipophilic compounds. Though resistance against more lipophilic platinum complexes analogues is lower we conclude that enhancing lipophilicity is not a successful strategy to overcome platinum resistance as higher lipophilicity is also associated with lower cytotoxic activity., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background and Objectives: Linagliptin (BI 1356) is a highly specific inhibitor of dipeptidyl peptidase (DPP)-4, which is currently in phase III clinical development for the treatment of type 2 diabetes mellitus. Linagliptin exhibits nonlinear pharmacokinetics after oral administration, which are mainly related to concentration-dependent binding of linagliptin to its target, DPP-4. The objectives of the study were to investigate the pharmacokinetics and pharmacodynamics after intravenous administration of linagliptin and to determine its absolute bioavailability (F)., Subjects and Methods: This was a single rising-dose, randomized, four-group, placebo-controlled, single-blind (within dose groups) study. Thirty-six healthy men aged 18-50 years were enrolled and randomized into four sequential treatment groups. Group 1 received linagliptin 0.5 mg intravenously, group 2 received 2.5 mg intravenously and group 4 received 10 mg intravenously. In group 3, subjects underwent a two-way randomized crossover, receiving 5 mg intravenously and a 10 mg oral tablet. Linagliptin concentrations in plasma and urine, as well as plasma DPP-4 activity, were determined by validated assays. Noncompartmental analysis and population pharmacokinetic modelling were performed., Results: Linagliptin showed nonlinear pharmacokinetics after intravenous infusion of 0.5-10 mg, with a less than dose-proportional increase in exposure. Noncompartmental parameters were calculated on the basis of total (i.e. bound and unbound) plasma concentrations. The total clearance value was low and increased with dose from 2.51 to 14.3 L/h. The apparent steady-state volume of distribution (V(ss)) increased with dose from 380 to 1540 L. Renal excretion of the unchanged parent compound increased with increasing plasma concentrations from 2.72% in the 0.5 mg dose group to 23.0% in the 10 mg dose group. The terminal elimination half-life was comparable across dose groups (126-139 hours). Because of the nonlinear pharmacokinetics, the standard approach of comparing the area under the plasma concentration-time curve (AUC) after oral administration with the AUC after intravenous administration led to dose-dependent estimates of the absolute bioavailability. Therefore, a population pharmacokinetic model was developed, accounting for the concentration-dependent protein binding of linagliptin to its target enzyme, DPP-4. The model-derived estimates of the V(ss) and clearance of linagliptin not bound to DPP-4 were 402.2 L and 26.9 L/h, respectively. The absolute bioavailability was estimated to be about 30% for the linagliptin 10 mg tablet., Conclusion: The nonlinear pharmacokinetic characteristics and the pharmacokinetic/pharmacodynamic relationship of linagliptin were independent of the mode of administration (intravenous or oral). Because of the nonlinear pharmacokinetics, the standard approach of comparing the AUC after oral administration with the AUC after intravenous administration was inappropriate to determine the absolute bioavailability of linagliptin. By a modelling approach, the absolute bioavailability of the 10 mg linagliptin tablet was estimated to be about 30%.