Hepatic toxicity is a key concern for novel pharmaceutical drugs since it is difficult to anticipate in preclinical models, and it can originate from pharmacologically unrelated drug effects, such as pathway interference, metabolism, and drug accumulation. Because liver toxicity still ranks among the top reasons for drug attrition, the reliable prediction of adverse hepatic effects is a substantial challenge in drug discovery and development. To this end, more effort needs to be focused on the development of improved predictive in-vitro and in-silico approaches. Current computational models often lack applicability to novel pharmaceutical candidates, typically due to insufficient coverage of the chemical space of interest, which is either imposed by size or diversity of the training data. Hence, there is an urgent need for better computational models to allow for the identification of safe drug candidates and to support experimental design. In this context, a large data set comprising 3712 compounds with liver related toxicity findings in humans and animals was collected from various sources. The complex pathology was clustered into 21 preclinical and human hepatotoxicity endpoints, which were organized into three levels of detail. Support vector machine models were trained for each endpoint, using optimized descriptor sets from chemometrics software. The optimized global human hepatotoxicity model has high sensitivity (68%) and excellent specificity (95%) in an internal validation set of 221 compounds. Models for preclinical endpoints performed similarly. To allow for reliable prediction of "truly external" novel compounds, all predictions are tagged with confidence parameters. These parameters are derived from a statistical analysis of the predictive probability densities. The whole approach was validated for an external validation set of 269 proprietary compounds. The models are fully integrated into our early safety in-silico workflow.

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A study of European brown hare syndrome (EBHS) was conducted in Poland (Czempin). From April 1993 until February 1994, 100 blood and 78 spleen samples of European brown hares (Lepus europaeus) were tested for prevalence of EBHS and rabbit hemorrhagic disease (RHDV) antibodies and EBHS virus antigen with two enzyme-linked immunosorbent assay (ELISA) test kits. Thirty-eight of 100 serum samples were positive for EBHS, and six (7.6%) of 78 of the spleen materials were-antigen positive for EBHS virus. Three (3%) of the sera were positive against RHDV, whereas two of these also were seropositive for EBHSV. European brown hare syndrome virus seropositive hares were most frequently found from April to September. Based on negative staining electron microscopy investigations of liver and spleen homogenates of all antigen-positive hares, we observed caliciviruses in only one animal. For histopathological investigations organ specimens were available from 98 hares. Histopathological findings corresponded with the clinical picture of chronic EBHS. A pathohistological picture consistent with EBHS was found in 22 (22%) of investigated hares and corresponded in 50% of the animals which reacted positively in the EBHSV antigen-ELISA and in 29% of the animals which reacted positively in the EBHSV antibody-ELISA. These results from western Poland are the first that caliciviruses are present in European brown hare population in Eastern Europe and may be one of the causes for increased mortality in the Polish hare population over the past 10 years.

Sarcocysts from the tongue muscle of a European badger (Meles meles) are reported for the first time and described by light and transmission electron microscopy. Judging from the ultrastructure of the cyst wall, the parasite is similar to the species Sarcocystis gracilis Rátz, 1909 sensu Erber, Boch & Barth (1978) from roe deer and possibly identical with it. This is noteworthy regarding the intermediate host specificity.

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