Abstracts / Toxicology Letters 180S (2008) S32–S246
major feature of the model is trainability: user-defined experimental data may be added to extend its Applicability Domain without rebuilding the baseline model. The model is supplemented with a knowledge-based expert system that allows identification and visualization of hazardous substructures. The compiled set of 27 ‘genotoxicophores’ covers 90% of genotoxic compounds from the data set used in Ames test model development. doi:10.1016/j.toxlet.2008.06.335 P10 Trainable model of HERG channel inhibition prediction Liutauras Juska, Remigijus Didziapetris, Pranas Japertas ∗ Pharma Algorithms, Inc., Vilnius, Lithuania Cardiotoxicity of drug-like compounds associated with human ether-a-go-go (hERG) channel inhibition is a common cause of drug candidates’ attrition. Therefore, early computational prediction of hERG channel affinity of drug candidates is becoming increasingly important in the drug discovery process. Binary QSAR model with threshold values at IC(50) = 10 M was generated using binomial regression with 2-D fragmental descriptors. Model was trained on more than 600 binary data points mainly derived from the published hERG inhibition studies by patch-clamp method. For the full dataset, the accuracy of classification of hERG inhibitors was >85%, which meets prior classification models. Predictions of hERG inhibition probability are supported with estimations of Reliability Index. The novel similarity based methodology implemented in the model can be used to add new ‘in-house’ data on hERG inhibition to the existing training set, allowing for the straightforward expansion of the Model Applicability Domain to the specific classes of industrial compounds. doi:10.1016/j.toxlet.2008.06.336 P11 Comparative validation of repeated urinary bladder instillation in rat, guinea pig and beagle dog Raluca Banks
Kubaszky ∗ ,
Alyson Leyshon, David Esdaile, Christopher
LAB Research Ltd., Veszprem, Hungary Intravesical instillation has been extensively used in human urology, with a subsequent increase of the use of this route of administration in toxicology studies. Comparative validation of single or repeated intravesical administration in rat, guinea pig and dog was performed up to 8 weeks duration, from one to three times weekly. Parameters monitored were body weight, food consumption, clinical signs, and macroscopic and microscopic findings. Depending upon the species employed, various types of catheters or dosing solutions were tested, and the animals were conscious or anaesthetised. The duration of installation was 10 min to up to 1 h. Inflammation of the urethra and periurethral tissue, with thrombus formation, followed by urethral obstruction and secondary uraemia were described in the male rats as possible iatrogenic, traumatic complications of the intravesical administration. Orchitis and/or epididymitis occurred on occasion, but responded positively to local iodine applications and anti-inflammatory therapy. The number of animals afflicted was low (8.3%), and allowed the successful completion of the study. There were no significant clinical signs observed in the female rat, guinea pig or dog, nor were there any procedure-related, adverse effects on body weight or food con-
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sumption. Macro- and microscopic findings were limited to minor signs of inflammation of the urinary tract, which were considered expected changes associated with the dosing procedure. The maximal volume of dosing solution to be instilled in the urinary bladder was assessed for each of the species. doi:10.1016/j.toxlet.2008.06.337 P12 Acute, short-term, and subchronic oral toxicity of Boerhaavia erecta L. extract in rats Alicia Lagarto ∗ , Viviana Bueno, Isbel Micaela Couret, Yamile Vega
Guerra, Odalys
Valdes,
CIDEM, Havana, Cuba The objective of this investigation was to assess the acute, shortterm and subchronic oral toxicity of Boerhaavia erecta L. aqueous extract. In the acute study, female Wistar rats were gavaged with 2000 mg/kg of B. erecta extract and killed 14 days later. No acute effects were observed. Other both sexes Wistar rats received 1000 mg/kg/day for 28 days. Animals were sacrificed for hematological and biochemical evaluation. This dose regimen caused a decrease in glucose level in males, but no altered body weight and food consumption. For the subchronic study, both sexes Wistar rats were administered with 100, 300 and 1000 mg/kg/day of B. erecta extract by oral route 5 days/week for 90 days. The major toxicological endpoints examined included animal body weight, food intake, selected tissue weights, and histopathological examinations. In addition, we examined blood elements and blood chemistry. Glucose and alkaline phosphatase were affected in male animals, but these effects were reversible. Organs and tissues abnormalities were not observed in histopathological examination. In summary, 2000 mg/kg/day was the acute NOAEL and 1000 mg/kg/day the short-term and subchronic NOAEL for B. erecta extract, under the conditions of this investigation. doi:10.1016/j.toxlet.2008.06.338 P13 Centro de investigación y desarrollo de medicamentos UCTB control biológico Alicia Lagarto ∗ , Viviana Bueno, Micaela Couret, Odalys Valdes, Raissel Lopez, Isbel Guerra, Yamile Vega CIDEM, Havana, Cuba Morinda citrifolia L. (noni) is an evergreen or small tree that grows in many tropical regions of the world. The use of the noni leaves has not been so studied however; there are reports of its pharmacological benefits. The objective of this investigation was to assess the short-term and subchronic oral toxicity of M. citrifolia L leaves aqueous extract. For short-term toxicity, both sexes Wistar rats received 1000 mg/kg/day for 28 days. Animals were sacrificed for hematological and biochemical evaluation. This dose regimen resulted in absence of toxicity. For the subchronic study, both sexes Wistar rats were administered with 100, 300 and 1000 mg/kg/day of M. citrifolia extract by oral route for 90 days. The major toxicological endpoints examined included animal body weight, food intake, selected tissue weights, and histopathological examinations. In addition, we examined blood elements and blood chemistry. Treatment with 300 and 1000 mg/kg/day of M. citrifolia extract resulted in significantly decreased of hemoglobin and erythrocytes cells in male. Histology evaluation revealed treatment-related spleen abnormalities. This effect was characterized by red pulp congestion