Frank Dörje

In vivo imaging using fluorescent antibodies to tumor necrosis factor predicts therapeutic response in Crohn's disease

As antibodies to tumor necrosis factor (TNF) suppress immune responses in Crohns disease by binding to membrane-bound TNF (mTNF), we created a fluorescent antibody for molecular mTNF imaging in this disease. Topical antibody administration in 25 patients with Crohns disease led to detection of intestinal mTNF+ immune cells during confocal laser endomicroscopy. Patients with high numbers of mTNF+ cells showed significantly higher short-term response rates (92%) at week 12 upon subsequent anti-TNF therapy as compared to patients with low amounts of mTNF+ cells (15%). This clinical response in the former patients was sustained over a follow-up period of 1 year and was associated with mucosal healing observed in follow-up endoscopy. These data indicate that molecular imaging with fluorescent antibodies has the potential to predict therapeutic responses to biological treatment and can be used for personalized medicine in Crohns disease and autoimmune or inflammatory disorders.

The Influence of Macrolide Antibiotics on the Uptake of Organic Anions and Drugs Mediated by OATP1B1 and OATP1B3

Macrolides may cause severe drug interactions due to the inhibition of metabolizing enzymes. Transporter-mediated uptake of drugs into cells [e.g., by members of the human organic anion transporting polypeptide (OATP) family] is a determinant of drug disposition and a prerequisite for subsequent metabolism. However whether macrolides are also inhibitors of uptake transporters, thereby providing an additional mechanism of drug interactions, has not been systematically studied. The human OATP family members OATP1B1 and OATP1B3 mediate the uptake of endogenous substances and drugs such as antibiotics and HMG-CoA reductase inhibitors (statins) into hepatocytes. In this study we investigated the potential role of these uptake transporters on macrolide-induced drug interactions. By using sulfobromophthalein (BSP) and the HMG-CoA reductase inhibitor pravastatin as substrates, the effects of the macrolides azithromycin, clarithromycin, erythromycin, and roxithromycin and of the ketolide telithromycin on the OATP1B1- and OATP1B3-mediated uptake were analyzed. These experiments demonstrated that the OATP1B1- and OATP1B3-mediated uptake of BSP and pravastatin can be inhibited by increasing concentrations of all macrolides except azithromycin. The IC50 values for the inhibition of OATP1B3-mediated BSP uptake were 11 μM for telithromycin, 32 μM for clarithromycin, 34 μM for erythromycin, and 37 μM for roxithromycin. These IC50 values were lower than the IC50 values for inhibition of OATP1B1-mediated BSP uptake (96–217 μM). These macrolides also inhibited in a concentration-dependent manner the OATP1B1- and OATP1B3-mediated uptake of pravastatin. In summary, these results indicate that alterations of uptake transporter function by certain macrolides/ketolides have to be considered as a potential additional mechanism underlying drug-drug interactions.

Role of P-Glycoprotein Inhibition for Drug Interactions : Evidence from In Vitro and Pharmacoepidemiological Studies

ObjectivesWe determined in vitro the potency of macrolides as P-glycoprotein inhibitors and tested in hospitalised patients whether coadministration of P-glycoprotein inhibitors leads to increased serum concentrations of the P-glycoprotein substrates digoxin and digitoxin.MethodsIn vitro, the effect of macrolides on polarised P-glycoprotein-mediated digoxin transport was investigated in Caco-2 cells. In a pharmacoepidemiological study, we analysed the serum digoxin and digitoxin concentrations with and without coadministration of P-glycoprotein inhibitors in hospitalised patients.ResultsAll macrolides inhibited P-glycoprotein-mediated digoxin transport, with concentrations producing 50% inhibition (IC50) values of 1.8, 4.1, 15.4, 21.8 and 22.7 μmol/L for telithromycin, clarithromycin, roxithromycin, azithromycin and erythromycin, respectively. Coadministration of P-glycoprotein inhibitors was associated with increased serum concentrations of digoxin (1.3 ± 0.6 vs 0.9 ± 0.5 ng/mL, p < 0.01). Moreover, patients receiving macrolides had higher serum concentrations of cardiac glycosides (p < 0.05).ConclusionMacrolides are potent inhibitors of P-glycoprotein. Drug interactions between P-glycoprotein inhibitors and substrates are likely to occur during hospitalisation.

Development of a lauric acid/albumin hybrid iron oxide nanoparticle system with improved biocompatibility

The promising potential of superparamagnetic iron oxide nanoparticles (SPIONs) in various nanomedical applications has been frequently reported. However, although many different synthesis methods, coatings, and functionalization techniques have been described, not many core-shell SPION drug delivery systems are available for clinicians at the moment. Here, bovine serum albumin was adsorbed onto lauric acid-stabilized SPIONs. The agglomeration behavior, zeta potential, and their dependence on the synthesis conditions were characterized with dynamic light scattering. The existence and composition of the core-shell-matrix structure was investigated by transmission electron microscopy, Fourier transform infrared spectroscopy, and zeta potential measurements. We showed that the iron oxide cores form agglomerates in the range of 80 nm. Moreover, despite their remarkably low tendency to aggregate even in a complex media like whole blood, the SPIONs still maintained their magnetic properties and were well attractable with a magnet. The magnetic properties were quantified by vibrating sample magnetometry and a superconducting quantum interference device. Using flow cytometry, we further investigated the effects of the different types of nanoparticle coating on morphology, viability, and DNA integrity of Jurkat cells. We showed that by addition of bovine serum albumin, the toxicity of nanoparticles is greatly reduced. We also investigated the effect of the particles on the growth of primary human endothelial cells to further demonstrate the biocompatibility of the particles. As proof of principle, we showed that the hybrid-coated particles are able to carry payloads of up to 800 μg/mL of the cytostatic drug mitoxantrone while still staying colloidally stable. The drug-loaded system exhibited excellent therapeutic potential in vitro, exceeding that of free mitoxantrone. In conclusion, we have synthesized a biocompatible ferrofluid that shows great potential for clinical application. The synthesis is straightforward and reproducible and thus easily translatable into a good manufacturing practice environment.

Hospital use of systemic antifungal drugs

BackgroundSales data indicate a major increase in the prescription of antifungal drugs in the last two decades. Many new agents for systemic use that only recently have become available are likely to be prescribed intensively in acute care hospitals. Sales data do not adequately describe the developments of drug use density. Given the concerns about the potential emergence of antifungal drug resistance, data on drug use density, however, may be valuable and are needed for analyses of the relationship between drug use and antifungal resistance.MethodsHospital pharmacy records for the years 2001 to 2003 were evaluated, and the number of prescribed daily doses (PDD, defined according to locally used doses) per 100 patient days were calculated to compare systemic antifungal drug use density in different medical and surgical service areas between five state university hospitals.ResultsThe 3-year averages in recent antifungal drug use for the five hospitals ranged between 8.6 and 29.3 PDD/100 patient days in the medical services (including subspecialties and intensive care), and between 1.1 and 4.0 PDD/100 patient days in the surgical services, respectively. In all five hospitals, systemic antifungal drug use was higher in the hematology-oncology service areas (mean, 48.4, range, 24 to 101 PDD/100 patient days, data for the year 2003) than in the medical intensive care units (mean, 18.3, range, 10 to 33 PDD/100) or in the surgical intensive care units (mean, 10.7, range, 6 to 18 PDD/100). Fluconazole was the most prescribed antifungal drug in all areas. In 2003, amphotericin B consumption had declined to 3 PDD/100 in the hematology-oncology areas while voriconazole use had increased to 10 PDD/100 in 2003.ConclusionHematology-oncology services are intense antifungal drug prescribing areas. Fluconazole and other azol antifungal drugs are the most prescribed drugs in all patient care areas while amphotericin B use has considerably decreased. The data may be useful as a benchmark for focused interventions to improve prescribing quality.

Pharmaceutical formulation of HSA hybrid coated iron oxide nanoparticles for magnetic drug targeting

In this work we present a new formulation of superparamagnetic iron oxide nanoparticles (SPIONs) for magnetic drug targeting. The particles were reproducibly synthesized from current good manufacturing practice (cGMP) - grade substances. They were surface coated using fatty acids as anchoring molecules for human serum albumin. We comprehensively characterized the physicochemical core-shell structure of the particles using sophisticated methods. We investigated biocompatibility and cellular uptake of the particles using an established flow cytometric method in combination with microwave-plasma assisted atomic emission spectroscopy (MP-AES). The cytotoxic drug mitoxantrone was adsorbed on the protein shell and we showed that even in complex media it is slowly released with a close to zero order kinetics. We also describe an in vitro proof-of-concept assay in which we clearly showed that local enrichment of this SPION-drug conjugate with a magnet allows site-specific therapeutic effects.

[Antibiotic Use at German University Hospitals (Project INTERUNI-II). Results for Medical Intensive Care, Hematology-Oncology, and Other Medical Service Areas].

Zusammenfassung.Hintergrund:Intensiver Antibiotikaverbrauch fördert die bakterielle Resistenzentwicklung und -ausbreitung. Eine Korrelation von Antibiotikamengenverbrauch mit Resistenzraten in verschiedenen Kliniken könnte ein besseres Verständnis der komplexen Beziehung zwischen Antibiotikaeinsatz und bakterieller Resistenz ermöglichen. Der Antibiotikaverbrauch ist für deutsche Kliniken außerhalb kostenorientierter Marktforschungsanalysen jedoch nicht im Sinne von Anwendungsdichte quantifiziert.Methodik:Im Rahmen eines Pilotprojektes (INTERUNI-II) wurde der Antibiotikaverbrauch an acht Universitätskliniken retrospektiv für die Jahre 1998, 1999 und 2000 als Anwendungsdichte (Tagesdosen/100 Pflegetage) dargestellt. Die Definition von Tagesdosen erfolgte aufgrund der in den Kliniken üblicherweise bei Erwachsenen verordneten Dosis der entsprechenden Pharmaka („prescribed daily doses“ [PDD]). Dabei wurden im Bereich Innere Medizin Intensivstationen, hämatologisch-onkologische Stationen und sonstige internistische Stationen betrachtet.Ergebnisse:Die Antibiotikaanwendungsdichte in der Inneren Medizin betrug im 3-Jahres-Durchschnitt 55,2 PDD/100 Pflegetage. Die Werte schwankten zwischen 39,4 und 75,8 PDD/100 Pflegetage. In sieben der acht Kliniken kam es im Beobachtungszeitraum zu einem Anstieg der Anwendungsdichte. Im Intensivbereich wurden mehr Antibiotika eingesetzt (3-Jahres-Mittel 122,3, Schwankungsbereich 98–167 PDD/100 Pflegetage) als im Bereich hämatologisch-onkologischer (3-Jahres-Mittel 86,9, Schwankungsbereich 67,8–129,4 PDD/100 Pflegetage) und sonstiger internistischer Stationen (3-Jahres-Mittel 42,8, Schwankungsbereich 31,7–50,6 PDD/100 Pflegetage). In den meisten Bereichen nahmen oral verabreichte Antibiotika zu und machten außerhalb der Intensivstationen einen erheblichen Anteil am Gesamtverbrauch aus (Jahr 2000: Hämatologie-Onkologie 36–74%, sonstige Stationen 43–59%). β-Lactam- Antibiotika waren mit 22,6 PDD/100 Pflegetage (3-Jahres-Mittel über alle Kliniken) die am meisten verordneten Substanzen; zu 56% (Intensiv 49–82%, Hämatologie-Onkologie 61–89%, sonstige Stationen 24–58%) handelte es sich dabei um Breitspektrum-β-Lactam-Antibiotika. Zweitstärkste Gruppe waren Fluorochinolone (3-Jahres-Mittel, 13 PDD/100 Pflegetage), die vor allem im Bereich Hämatologie-Onkologie intensiv eingesetzt wurden (Intensiv 14,5, Hämatologie-Onkologie 26,5, sonstige Stationen 8,6 PDD/100 Pflegetage). Zwischen den beteiligten Kliniken wurden teilweise erhebliche Unterschiede in der Anwendungsdichte bestimmter Substanzklassen beobachtet.Schlussfolgerung:Die Antibiotikaanwendungsdichte in der Inneren Medizin deutscher Hochschulkliniken schwankte im Beobachtungszeitraum erheblich für verschiedene Bereiche und Substanzklassen. Unter der Voraussetzung eines raschen Erfassungssystems könnte eine prospektive Beobachtung in Modellkliniken die Effekte unterschiedlicher Anwendungsdichten und geänderter Therapieleitlinien auf die bakterielle Resistenzentwicklung im Klinikbereich abschätzen.Abstract.Background:Excessive antibiotic use increases the risk of development and dissemination of bacterial resistance. A comparative analysis of the correlation between hospital antibiotic consumption and rates of bacterial resistance is needed for a better understanding of the complex relationship between antibiotic use and resistance. Apart from economic and market research studies, estimates of antibiotic consumption in German hospitals, however, are not available.Methods:In a pilot project (INTERUNI-II), retrospective data from eight university hospital pharmacies covering the period 1998, 1999, and 2000 were collected to obtain estimates for the antibiotic use densities in the medical services of teaching hospitals. Antibiotic use densities were expressed as prescribed daily doses per 100 occupied bed days (PDD/100). The definition of prescribed daily doses was according to guidelines for antimicrobial therapy in adults with normal renal and hepatic function used in the participant hospitals. Means and ranges of antibiotic use densities were separately assessed for medical intensive care units (MICU), hematology-oncology services (HEMONC), and other medical services (OTHER MED).Results:Mean antibiotic use density in internal medicine was 55.2 PDD/100 overall, ranging between 39.4 and 75.8 PDD/100 in the eight participant hospitals. In seven hospitals antibiotic use density increased during the years of observation. Antibiotic use was higher in MICU areas (3-year average, 122.3; range, 98–167 PDD/100) than in HEMONC (3-year average, 86.9; range, 67.8–129.4 PDD/100) and OTHER MED areas (3-year average, 42.8; range, 31.7–50.6 PDD/100). There was an increasing use of oral antibiotics resulting in a substantial proportion of oral agents among all antibacterial drugs outside MICU areas (year 2000, HEMONC, range, 36–74% of all PDD; OTHER MED, range, 43–59% of all PDD). β-lactam antibiotics were the most frequently prescribed drugs (3-year average, 22.6 PDD/100). 56% of β-lactam PDD belonged to the class of broad-spectrum β-lactams (ranges, MICU, 49–82%; HEMONC, 61–89%; OTHER MED, 24–58%). Fluoroquinolones were the second most prescribed drug class (3-year average, 13 PDD/100). They were most frequently used in HEMONC (3-year average, MICU, 14.5; HEMONC 26.5; and OTHER MED 8.6 PDD/100, respectively). There was considerable variation between participant hospitals in the use of specific drug classes in given patient care areas.Conclusion:This retrospective study showed significant variation in overall and specific antibacterial drug class use between German teaching hospital medical services and defined patient care areas. Given the variation in the obtained estimates, targeted prospective hospital antibiotic use surveillance with fast data acquisition and analysis might offer an excellent opportunity to evaluate the impact of differences in antibiotic use and of revised therapy guidelines on the evolution of nosocomial bacterial resistance.

Palliative treatment of colorectal cancer with secondary metastasis resection in Germany - impact of the multidisciplinary treatment approach on prognosis and cost: the Northern Bavaria IVOPAK I Project.

Purpose: The aim of this study was to evaluate the quality of care and interdisciplinary cooperation in the palliative treatment of colorectal cancer (CRC), including the associated costs. Patients and Methods: 103 patients were enrolled from 13 institutions to reflect the existing clinical treatment reality and costs of palliative CRC treatment. We present the clinical outcome of the patients and compare the results obtained in the 3 centers with double-figure recruitment numbers (centers A, B, and C). Results: First-line treatment with 5-fluorouracil monotherapy was applied in exceptional cases. The regular treatment method comprised either an irinotecan- (30%) or an oxaliplatin-based regimen (32%). Biological agents were added to the treatment of 33 patients (32%). The median overall survival (OS) of the total patient collective was 25 months. The OS differed significantly in 2 out of the 3 centers, ranging between 27 and 11 months. Secondary metastasis resections were performed in 26% of the total patient collective. The center with the most favorable outcome results also had the lowest costs for palliative treatment and care, including the lowest drug costs. Conclusion: A combined chemotherapy treatment was the rule. Concerning biological agents, a significant lack of their application in first-line treatment and the quality of interdisciplinary cooperation have to be addressed.

Evaluation of eight drug interaction databases commonly used in the German healthcare system

Objectives The aim of the study was to determine the best database regarding accuracy, comprehensiveness and user-friendliness out of eight German and International databases. Methods Accuracy, comprehensiveness and ease of use of ABDA-database (ABDA), MediQ, Pharmavista, MMI Pharmindex, AiDKlinik (AIK), Lexi-Interact (LI), Epocrates and drugs.com were evaluated using 50 clinically relevant and 50 non-relevant drug interaction pairs. Accuracy was determined investigating sensitivity, specificity and positive and negative predictive values. Comprehensiveness was rated according to monograph components. Ease of use was evaluated by the time needed to assess the management of 10 clinically relevant interactions. The main outcome measure was the Total Score (TS) (max. 312.5 points) obtained by adding the specifically weighted points for accuracy, comprehensiveness and ease of use. Results LI ranked first in TS (243/312.5 points), followed by AIK (229/312.5 points). All databases showed high sensitivity. However, they had difficulties in clearly classifying an interaction as non-relevant, reflected in a low specificity. ABDA ranked first in accuracy because it dealt best with this problem. LI provided the most detailed monographs, reflected in a high Comprehensiveness Score. Results for comprehensiveness varied greatly, as the databases are designed for different needs. This also applied to Ease of Use Score, where AIK performed best. Conclusions LI proved to be the most recommendable database in our evaluation due to its superior comprehensiveness. All databases scored rather well on accuracy, but showed a tendency towards over-alerting.

OHP-022 Advances in pharmacy education: evaluation of a ward-based clinical teaching course

Background The pharmacy profession is changing towards patient-centred care. To meet the new challenges but also to drive the profession forward it is necessary to provide students with clinical competencies. Clinical courses with teacher practitioners are part of the pharmacy curriculum in countries like the UK or USA and are increasingly being established within Europe.1 Purpose To systematically evaluate the benefits of clinical teaching in our country: a quasi-randomised teaching and learning study. Material and methods A clinical teaching course on a psychiatric ward was created for small student groups. Learning aims included: communication, drug histories, drug-related problems and counselling. The control group only participated in the theoretical part while the intervention group took part in the complete course. The effects were assessed by an objective structured clinical examination (OSCE) and a student questionnaire. Results The intervention group achieved a significantly better overall result in the OSCE assessment (46.4 ± 9.5 vs. 28.2 ± 9.0 of 90 points; p < 0.001) with the most positive effect in communications skills (27.4 ± 5.4 vs. 16.3 ± 6.0 of 40 points; p < 0.001). The performance in the theoretical tasks was improved but unsatisfactory in both groups considering the maximum score (12.1 ± 4.1 vs. 8.1 ± 3.2 of 30 points; p < 0.001). 93% of the students rated the course as practice-orientated and 90% felt better prepared for patient contact. Many students suggested an extension of the course in the free text field of the questionnaire. Conclusion The results suggest significant learning benefits from the ward-based course created. The overall satisfaction was high. Inclusion in the pharmacy curriculum should be considered. Further studies are required to optimise course structure. Reference Ramos RG. Eur J Hosp Pharm 2014;21:A119 This work was supported by Bayerische Akademie für Klinische Pharmazie/Dr. August und Dr. Anni Lesmüller-Stiftung, Munich, Germany. The authors are grateful for the expert advice of Dr. Freidank, Fulda Hospital, Germany and PD Dr. Frobenius, MME, Erlangen University Hospital, Germany. No conflict of interest.