Naunyn-Schmiedeberg's Arch Pharmacol (2016) 389 (Suppl 1):S1–S104 DOI 10.1007/s00210-016 -1213 - y GERMAN PHARM-TOX SUMMIT 2016 Abstracts of the 82nd Annual Meeting of the German Society for Experimental and Clinical Pharmacology and Toxicology (DGPT) and the 18th Annual Meeting of the Network Clinical Pharmacology Germany (VKliPha) in cooperation with the Arbeitsgemeinschaft für Angewandte Humanpharmakologie e.V. (AGAH) 29th February – 03rd March 2016 Henry-Ford-Bau · Berlin This supplement was not sponsored by outside commercial interests. It was funded entirely by the publisher. S2 Structure IDs Oral presentations 001 – 081 In vitro systems and mechanistic investigations I 001 – 006 Heart 007 – 012 Immunology – inflammation – cancer 013 – 018 Individualized therapy and clinical implications 019 – 023 In vitro systems and mechanistic investigations II 024 – 027 DNA-damage and cancer 028 – 033 GPCR signaling 034 – 038 Cardiovascular pharmacology 039 – 043 Potential drug targets and pharmacotherapy 044 – 048 DNA-damage and –repair 049 – 054 GPCR receptor pharmacology 055 – 060 Ion channels 061 – 066 Organ- and neurotoxicity 067 – 072 Toxic substances, particles and food components 073 – 077 Clinical pharmacology and drug use 078 – 081 Poster presentations 082 – 421 Poster Session I Berlin-Brandenburger Forschungsplattform BB3R 082 – 094 Pharmacology – G-protein coupled receptors 095 – 116 Pharmacology – GTP-binding proteins 117 – 124 Pharmacology – Cyclic nucleotides 125 – 135 Pharmacology – Cardiovascular system 136 – 169 Pharmacology – Ion channels 170 – 187 Toxicology – Biotransformation and toxicokinetics 188 – 192 Toxicology – Organtoxicity (immunotoxicity, blood, and kidney) 193 – 195 Toxicology – Neurotoxicity, incl. neurodevelopment 196 – 200 Toxicology – Reproductive/developmental toxicity 201 – 202 Toxicology – Endocrine effects 203 – 207 Toxicology – Immunotoxicology 208 – 209 Toxicology – Nanomaterials 210 – 226 Toxicology – Exposure/effect monitoring 227 – 229 Toxicology – Biomarkers of exposure/Biomonitoring 230 – 236 Toxicology – External exposure 237 Toxicology – Food toxicology 238 – 246 Toxicology – Environmental toxicology/Ecotoxicology 247 – 252 Poster Session II Pharmacology – Membrane transporters 253 – 261 Pharmacology – Central nervous system 262 – 269 Pharmacology – Endocrine, immune and pulmonary pharmacology 270 – 280 Pharmacology – Gastrointestinal tract, NO, CO 281 – 290 Pharmacology – Cancer pharmacology 291 – 302 Pharmacology – Drug discovery 303 – 313 Pharmacology – Disease models 314 – 322 Pharmacology – Pharmacokinetics and clinical studies 323 – 335 Pharmacology – Education 336 – 340 Toxicology – Risk assessment 341 – 347 Toxicology – Methods 348 – 349 Toxicology – Substances and compound groups 350 Toxicology – Genotoxicity 351 – 361 Toxicology – Carcinogenesis 362 – 365 Toxicology – Non-animal testing 366 – 371 Toxicology – Non-animal testing in sicilco 372 – 378 Toxicology – Non-animal testing in vitro 379 – 394 Toxicology – Toxic pathway analysis/AOP 395 – 400 Clinical Pharmacology – Drug therapy in pregnancy 401 Clinical Pharmacology – Cardiovascular treatment 402 – 404 Clinical Pharmacology – Antineoplastic treatment 405 Clinical Pharmacology – Safety of drug therapy 406 – 407 Clinical Pharmacology – Personalized therapy 408 – 409 Clinical Pharmacology – Regulatory 410 Clinical Pharmacology – Others 411 – 416 Free topics 417 – 421 S3 Oral presentations Key results: Control IMA supported neurons, and protected them from neurotoxicants. Inflammatory activation reduced this protection, and prolonged exposure of co-cultures to CM triggered neurotoxicity. This neither involved direct effects of cytokines on In vitro systems and mechanistic investigations I neurons, nor secretion of nitric oxide from astrocytes, but it was prevented by the corticosteroid dexamethasone. The neurotoxicity-mediating effect of IMA was faithfully reproduced by human astrocytes. Moreover, glia-dependent toxicity was also observed, 001 when IMA cultures were stimulated with CM, and the culture medium was transferred to neurons. Such neurotoxicity was prevented when astrocytes were treated by p38 kinase Crosstalk between macrophages and monocytes: killing in trans inhibitors or dexamethasone, whereas such compounds had no effect, when added to V. Ponath1, B. Kaina1 neurons. Conversely, treatment of neurons with five different drugs, including resveratrol 1University Medical Center Mainz, Department of Toxicology, Mainz,Germany and CEP1347, prevented toxicity of astrocyte supernatants. Conclusion: The sequential IMA-LUHMES neuroinflammation model is suitable for Monocytes are mononuclear phagocytes that play an important role in the rapid separate profiling of both glial-directed and directly neuroprotective strategies. Moreover, response against invading pathogens. They originate from progenitor cells in the bone direct evaluation in co-cultures of the same cells allows for testing of therapeutic marrow before they are released into the bloodstream. Circulating in the blood effectiveness in more complex settings, in which astrocytes affect pharmacological monocytes migrate into peripheral tissues where they differentiate into tissue-specific properties of neurons. macrophages or dendritic cells. Their recruitment to sites of inflammation and infection is crucial in the effective and controlled clearance of pathogens. However, monocytes also contribute to the pathogenesis of inflammatory diseases. Therefore, a mechanism to 004 maintain a healthy balance in the monocyte population is crucial for tissue homeostasis and controlled clearance of inflammatory sites. Previous studies in our lab showed an A human hepatic co-culture system for the analysis of cell-cell interactions in impaired DNA repair machinery in monocytes, affecting mainly base excision repair and vitro non-homologous end-joining, whereas macrophages (and dendritic cells) were DNA 1 2 3 3 1 repair competent. Based on these findings we studied the effect of reactive oxygen F. Wewering , J. Florent , D. K. Wissenbach , S. Gebauer , R. Pirow , M. von 2,3,4 2 1 1 species (ROS) generated by macrophages on DNA integrity, cell death and Bergen , S. Kalkhof , A. Luch , S. Zellmer 1 differentiation potential of monocytes. Here, we show that monocyte-derived Bundesinstitut für Risikobewertung, Chemikalien- und Produktsicherheit, Berlin, macrophages stimulated with phorbol 12-myristate 13-acetate (PMA) produce intra- and Germany 2 extracellular ROS. Co-cultured with activated macrophages monocytes displayed Helmholtz-Centre for Environmental Research, Department of Proteomics, Leipzig, oxidative DNA damage, i.e. 8-hydroxyguanosine and DNA single strand breaks, Germany 3 resulting in apoptosis. In addition, the surviving fraction of monocytes was severely Helmholtz-Centre for Environmental Research, Department of Metabolomics, Leipzig, impaired in its differentiation capacity and unable to give rise to new (healthy) Germany 4 macrophages. The data supports the hypothesis that the oxidative burst of macrophages Aalborg University, Department of Chemistry and Bioscience, Aalborg, Denmark not only kills pathogens, but also DNA repair defective monocytes in the target area, which could be a mechanism regulating the immune response. The demand of alternative test systems which closely mirror the in vivo situation is one of the main challenges in modern toxicity testing. The major goal is the development of in vitro systems that partly display the complexity of an organism and thus may mimick in vivo conditions. Despite great efforts in the past no adequate in vitro systems are 002 available yet. On the other hand, cell cultures from almost every organ are easily accessible and therefore may help to roughly assess the toxic potential of substances at Neuronal stress response following proteasomal inhibition, and its prevention by target structures. Nonetheless, the complex interactions which take place in vivo cannot astrocytic thiol supply be addressed in single cell cultures. In the liver, hepatocytes comprise 80% of the total S. Gutbier1, M. Leist1 liver volume while non-parenchymal cells – endothelial cells, stellate cells and Kupffer 1Universität Konstanz, Chair of In vitro toxicology and biomedicine, Konstanz, Germany cells (that is, liver resident macrophages) – contribute only 6.5% of the volume, but 40% of the total cell number (Kmiec 2001). It has been increasingly recognized that in the Introduction: The underlying mechanisms of neurodegenerative diseases such as liver neighboring non-parenchymal cells release molecules which contribute to the Parkinson’s disease (PD) are not completely understood. One key event in PD, amongst inflammatory damage and even aggravate it (Adams et al. 2010). others, is the disturbance of the ubiquitin proteasome system (UPS). The resulting In our project a human in vitro co-culture system was established by combining a misfolded and aggregated proteins have been discussed to induce cell death. Various hepatic and a monocytic cell line, the latter of which can be differentiated to a attempts in the past to treat these diseases and to slow down the progressive neuronal macrophage-like phenotype. In this system the hepatotoxicty of substances has been loss failed at different clinical stages. Most of these attempts followed the concept of analyzed, and the results were compared to single cultures and to published data from blocking specific stress pathways (e.g. caspase activation). An alternative therapeutic in vivo studies.