- Email: [email protected]
Comparison of four in silico models to predict cardiac action potential effects and proarrhythmia liability
350
Abstracts
0049 Comparison of four in silico models to predict cardiac action potential effects and proarrhythmia liability Annie Delaunois, Aurore Colomar, Jean-Pierre Valentin UCB Biopharma sprl, Braine-l'Alleud, Belgium The Comprehensive in vitro Proarrhythmia Assay (CiPA) is a novel safety screening proposal intended to replace the current regulatory strategy based on the S7B and E14 guidances. One of the three CiPA components consists of in silico simulation of cardiac action potential (AP) in ventricular cardiomyocytes by integrating ion channel dataset obtained in patch-clamp assays. Several AP in silico models have been developed over the last years, with various levels of complexity regarding the number of ion channels integrated in the model, the species used, and the number of generated parameters. We compared the simulation results generated by 4 in silico models from different providers using 3 UCB compounds for which a full dataset of cardiac ion currents, action potentials (AP) in dog or rabbit Purkinje fibers, and clinical data (for 2 compounds) were available. The selected models were based on published in silico models (O'Hara et al., 2011; Hund and Rudy, 2004; Benson et al.,2008: Shannon et al.,2004; Aslanadi et al., 2009). Only one model (isAP, developed from Hund and Rudy's and Benson's models) was able to predict for the 3 compounds the AP changes observed in the Purkinje fiber model, both qualitatively (AP duration change) and quantitatively (threshold concentration at which AP changes appear). It was concluded that although in silico modeling appears as a promising approach to reduce drug safety attrition and better design subsequent experiments, a careful evaluation and validation of the model selected are recommended before full implementation in cardiac safety screening strategy. doi:10.1016/j.vascn.2016.02.050
0050 Calcium channel blocker increases the anticancer activity of temozolomide by inhibiting autocrine VEGF signaling Farina Hanifa, Kahkashan Perveena, Saima Mahmood Malhib,c, Shabana Usman Simjeea,b a
Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Sindh, Pakistan b H.E.J Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Sindh, Pakistan c Dow University of Health Sciences, Karachi, Sindh, Pakistan Glioblastoma multiforme (GBM) is the most common and malignant primary brain tumor in adults. Median survival rates range from 12–15 months. Alkylating agents used for the treatment of GBM have severe side effects. The development of new therapeutic strategies for the management of gliomas is therefore crucial. The aim of the study was to examine the efficacy of calcium channel blocker Verapamil (VP) and standard chemotherapeutic drug for GBM i.e. Temozolomide (TMZ) in human glioblastoma cells, when used alone and in combination. MTT and TUNEL assays were used to detect the anti-proliferative and apoptotic activity. Synergy was assessed using combination Index method. The RT-PCR, immunocytochemistry and ELISA were used to determine the mRNA and protein expression of proliferation markers i.e. vascular endothelial growth factor (VEGF) and its transcription factor hypoxia
inducible factor-1 (HIF-1α). VEGF receptors are exclusively present on glioblastoma cells and upon VEGF binding stimulate proliferation and survival pathways. Results revealed that the combined administration of VP (0.2 mM) and TMZ (0.1 mM) synergistically inhibited the proliferation of glioblastoma cells. Furthermore RT-PCR, immunocytochemistry and data from ELISA experiments revealed that cooperative anti-proliferative activity is associated with inhibition of autocrine VEGF signaling. Our findings support that the combine administration of VP and TMZ may be therapeutically exploited for the management of GBM. doi:10.1016/j.vascn.2016.02.051
0051 Decreased ejection fraction induced by a MEK inhibitor in spontaneously hypertensive and Wistar rats: Reversibility following co-administration of lisinopril Haisong Jua, Shufang Zhaob, Lori Martina, Eileen Wolaka, Suzette Hahna, Neeta Shenoya, Sudeep Chandrab, Greg Friedrichsa, Stan Spencea a
Preclinical Safety, NIBR, East Hanover, NJ and Cambridge, MA, USA Translational Imaging, Transnational Medicine, NIBR, East Hanover, NJ and Cambridge, MA, USA
b
These studies were designed to assess cardiac function in SHR and Wistar rats administered a MEK inhibitor (MEKi) and to evaluate recovery in SHR upon co-administration of Lisinopril. Methods: BP and echocardiogram were measured weekly and 2D/M-mode ultrasound images recorded for the assessment of cardiac function under sedation. Exposure, cardiac biomarkers and histopathology were also assessed. Results: Within 7 days of treatment, marked decreases in EF (28%) were observed in SHR rats without clinical signs of toxicity. Following cessation of dosing, EF recovered within two weeks. In Wistar, a slight decrease (11%) in EF was observed at week 1, but took longer to progress (40% at week 3), compared to SHR. In surviving Wistar, full recovery of EF was seen within a week following cessation of dosing. There were no test article-related changes in BP in either strain. In a subsequent study in SHR, MEKi induced decreases in EF were reversed within two weeks upon coadministration with lisinopril. NTproBNP levels were also normalized upon treatment with lisinopril. No test article-related histopathological findings in the heart were observed. Conclusions: MEKi induced decreases in EF in both strains of rats; however, SHR rats were more sensitive. Decreased EF was not due to cardiomyocyte necrosis and was fully reversible after withdrawal of MEKi or coadministration of lisinopril. Collectively, these data imply that hypertension is a risk factor for the induction of cardiomyopathy seen with this class of compounds and that this toxicity may be mitigated by the co-administration of an ACE-inhibitor. doi:10.1016/j.vascn.2016.02.052
0054 Predicting drug-induced arrhythmia using afterdepolarisations Beth McMillan, David J. Gavaghan, Gary R. Mirams University of Oxford, Oxford, UK A novel simulated afterdepolarisation-based marker for the prediction of drug-induced arrhythmias was created using mathematical
Abstracts
0049 Comparison of four in silico models to predict cardiac action potential effects and proarrhythmia liability Annie Delaunois, Aurore Colomar, Jean-Pierre Valentin UCB Biopharma sprl, Braine-l'Alleud, Belgium The Comprehensive in vitro Proarrhythmia Assay (CiPA) is a novel safety screening proposal intended to replace the current regulatory strategy based on the S7B and E14 guidances. One of the three CiPA components consists of in silico simulation of cardiac action potential (AP) in ventricular cardiomyocytes by integrating ion channel dataset obtained in patch-clamp assays. Several AP in silico models have been developed over the last years, with various levels of complexity regarding the number of ion channels integrated in the model, the species used, and the number of generated parameters. We compared the simulation results generated by 4 in silico models from different providers using 3 UCB compounds for which a full dataset of cardiac ion currents, action potentials (AP) in dog or rabbit Purkinje fibers, and clinical data (for 2 compounds) were available. The selected models were based on published in silico models (O'Hara et al., 2011; Hund and Rudy, 2004; Benson et al.,2008: Shannon et al.,2004; Aslanadi et al., 2009). Only one model (isAP, developed from Hund and Rudy's and Benson's models) was able to predict for the 3 compounds the AP changes observed in the Purkinje fiber model, both qualitatively (AP duration change) and quantitatively (threshold concentration at which AP changes appear). It was concluded that although in silico modeling appears as a promising approach to reduce drug safety attrition and better design subsequent experiments, a careful evaluation and validation of the model selected are recommended before full implementation in cardiac safety screening strategy. doi:10.1016/j.vascn.2016.02.050
0050 Calcium channel blocker increases the anticancer activity of temozolomide by inhibiting autocrine VEGF signaling Farina Hanifa, Kahkashan Perveena, Saima Mahmood Malhib,c, Shabana Usman Simjeea,b a
Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Sindh, Pakistan b H.E.J Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Sindh, Pakistan c Dow University of Health Sciences, Karachi, Sindh, Pakistan Glioblastoma multiforme (GBM) is the most common and malignant primary brain tumor in adults. Median survival rates range from 12–15 months. Alkylating agents used for the treatment of GBM have severe side effects. The development of new therapeutic strategies for the management of gliomas is therefore crucial. The aim of the study was to examine the efficacy of calcium channel blocker Verapamil (VP) and standard chemotherapeutic drug for GBM i.e. Temozolomide (TMZ) in human glioblastoma cells, when used alone and in combination. MTT and TUNEL assays were used to detect the anti-proliferative and apoptotic activity. Synergy was assessed using combination Index method. The RT-PCR, immunocytochemistry and ELISA were used to determine the mRNA and protein expression of proliferation markers i.e. vascular endothelial growth factor (VEGF) and its transcription factor hypoxia
inducible factor-1 (HIF-1α). VEGF receptors are exclusively present on glioblastoma cells and upon VEGF binding stimulate proliferation and survival pathways. Results revealed that the combined administration of VP (0.2 mM) and TMZ (0.1 mM) synergistically inhibited the proliferation of glioblastoma cells. Furthermore RT-PCR, immunocytochemistry and data from ELISA experiments revealed that cooperative anti-proliferative activity is associated with inhibition of autocrine VEGF signaling. Our findings support that the combine administration of VP and TMZ may be therapeutically exploited for the management of GBM. doi:10.1016/j.vascn.2016.02.051
0051 Decreased ejection fraction induced by a MEK inhibitor in spontaneously hypertensive and Wistar rats: Reversibility following co-administration of lisinopril Haisong Jua, Shufang Zhaob, Lori Martina, Eileen Wolaka, Suzette Hahna, Neeta Shenoya, Sudeep Chandrab, Greg Friedrichsa, Stan Spencea a
Preclinical Safety, NIBR, East Hanover, NJ and Cambridge, MA, USA Translational Imaging, Transnational Medicine, NIBR, East Hanover, NJ and Cambridge, MA, USA
b
These studies were designed to assess cardiac function in SHR and Wistar rats administered a MEK inhibitor (MEKi) and to evaluate recovery in SHR upon co-administration of Lisinopril. Methods: BP and echocardiogram were measured weekly and 2D/M-mode ultrasound images recorded for the assessment of cardiac function under sedation. Exposure, cardiac biomarkers and histopathology were also assessed. Results: Within 7 days of treatment, marked decreases in EF (28%) were observed in SHR rats without clinical signs of toxicity. Following cessation of dosing, EF recovered within two weeks. In Wistar, a slight decrease (11%) in EF was observed at week 1, but took longer to progress (40% at week 3), compared to SHR. In surviving Wistar, full recovery of EF was seen within a week following cessation of dosing. There were no test article-related changes in BP in either strain. In a subsequent study in SHR, MEKi induced decreases in EF were reversed within two weeks upon coadministration with lisinopril. NTproBNP levels were also normalized upon treatment with lisinopril. No test article-related histopathological findings in the heart were observed. Conclusions: MEKi induced decreases in EF in both strains of rats; however, SHR rats were more sensitive. Decreased EF was not due to cardiomyocyte necrosis and was fully reversible after withdrawal of MEKi or coadministration of lisinopril. Collectively, these data imply that hypertension is a risk factor for the induction of cardiomyopathy seen with this class of compounds and that this toxicity may be mitigated by the co-administration of an ACE-inhibitor. doi:10.1016/j.vascn.2016.02.052
0054 Predicting drug-induced arrhythmia using afterdepolarisations Beth McMillan, David J. Gavaghan, Gary R. Mirams University of Oxford, Oxford, UK A novel simulated afterdepolarisation-based marker for the prediction of drug-induced arrhythmias was created using mathematical