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Improvements in cardiac injury assessment via combined measurement modalities
Abstracts
intra-atrial valve (n = 6) deployed into the fossa ovalis. Shunt patency (Fick's method), mean atrial/pulmonary pressures, and LV function (echocardiography) were evaluated weekly. The valved-shunt acutely lowered left-atrial pressures (LAP, 15±1 to 11±1 mm Hg*) without increasing right-atrial/pulmonary-artery pressures (PAP: 18±1 to 17±1 mm Hg). Shunts were patent for the duration of the study (12 weeks; mean Qp/Qs: 1.4±0.1 vs. 0.7±0.1*). Post-implant, treated sheep had lower filling pressures (LAP: 11±1 vs. 18±1 mm Hg*) and preserved LV EF (40±3 vs. 22±1%*), resulting in improved survival (80% vs. 20%). [*: P b 0.05 vs. CTRL]. Left-heart unloading via an intra-atrial valved-shunt led to chronically reduced left-atrial pressures, preserved right-sided pressures, and improved LV function in a clinically-relevant chronic model of ischemic heart failure. doi:10.1016/j.vascn.2012.08.062
Evaluation of drug-induced cardiac conduction disturbance using conscious ferrets—An alternative small animal telemetry model Hugo M. Vargas, Kathy Derakhchan Safety and Exploratory Pharmacology, Amgen Inc., Thousand Oaks, CA, United States
177
contractility affected cardiac glucose uptake and/or left ventricular morphology utilizing PET/CT imaging. Battelle studied anesthetized dogs instrumented to measure blood pressure, left ventricular pressure and ECG after intravenous injection of a non-selective β-agonist (isoproterenol). PET, utilizing [18F]-FDG as a radiolabeled tracer for glucose, was used to determine changes in myocardial cellular metabolism, and CT was utilized to generate digital three-dimensional images of the heart. Heart rate increased 57 bpm, mean arterial pressure decreased 54 mm Hg and dP/dtmax increased 1581 mm Hg/s. Telemetry and PET/CT imaging correlated drug-induced functional and morphological changes with alterations in myocardial substrate used as an indicator of cardiac metabolism. In comparison to the ICH S7 cardiovascular assessment alone, when combined with PET/CT they collectively provide real-time vascular, anatomical and functional cardiac information. Thus, integrating non-invasive imaging into early cardiovascular safety studies allows for a more sensitive, predictive and robust assay. doi:10.1016/j.vascn.2012.08.064
A pharmacovigilance study in chest diseases outpatient clinic Coskun Usta, Aykut Çilli, Burcu Çelenk, Rusen Uzun Medi, Akdeniz Medical School, Antalya, Turkey
The ionic mechanisms of depolarization and repolarization in ferrets are similar to those in dogs, primates, and humans. Ferret can be a suitable alternative to dog for early screening, and due to their small size (1.4–2.2 kg), smaller amount of drug is required. Since flecainide and AMG1 cause PR/QRS widening in dogs and primates, we have evaluated the sensitivity of ferret to detect cardiac conduction delay in response to these NaV1.5 blockers. Male ferrets were implanted with transmitters (TL11M2-C5-PXT) to record ECG and arterial pressure. Two modified cross-over studies were designed with telemetered ferrets: group 1 (n = 6) was dosed with 0, 3, 10, and 15 mg/kg PO of flecainide, and group 2 (n = 6) with 0, 30, 100, and 200 mg/kg PO of AMG1 (1 dose/week). Using continuous data analysis approach, flecainide (10 and 15 mg/kg) caused significant prolongation of PR (18–29 ms), but QRS prolongation (7–10 ms) was observed at all doses. AMG1 caused significant prolongation of PR (12–23 ms), QRS (5–13 ms), and QTcF (27–43 ms) intervals and increased heart rate (69–81 bpm) at 100 and 200 mg/kg. The effects of flecainide and AMG1 were consistent with sodium channel blockade. Satellite ferrets (n = 6/agent) were used for toxicokinetics. For flecainide, Tmax was 1 h and mean Cmax (ng/ml) were 357, 1120, and 1320 at 3, 10, or 15 mg/kg, respectively. For AMG1, Tmax was 1 h and mean Cmax were 2040, 9510, and 32,000 at 30, 100, or 300 mg/kg, respectively. In conclusion, these findings suggest that telemeterized ferret is a useful model for assessment of cardiac conduction delay. doi:10.1016/j.vascn.2012.08.063
Improvements in cardiac injury assessment via combined measurement modalities Brian M. Roche, Tom Vinci, Karen Elsass, Sarah McCullough, Susan Reed, Steve Behringer Battelle Memorial Institute, Columbus, OH, United States Combining traditional preclinical cardiovascular safety assessment methods with PET/CT imaging modalities provides standard data and unprecedented insight into the underlying mechanism of action of drug-induced cardiac injury. The specific objective of this study was to determine if drug-induced increases in left ventricular
Aim: Adverse drug reactions is an important healthcare issue, it causes excess morbidity and mortality. The aim of this study was to determine the adverse drug reactions in patients who admitted to the Outpatient Clinic of Respiratory Diseases and to improve some clinical strategies if they are preventable. Material and methods: This study is a prospective observational study which was performed to determine adverse drug reaction in patients who admitted to the Outpatient Clinic of Respiratory Diseases. Results: During the 15 months of study period a total of 114 adverse reactions were reported in 92 out of 18,163 patients. Most of the adverse reactions were related with gastrointestinal system, central nervous system and cardiovascular system. The most of the adverse events were associated with fixed inhaled formoterol– budesonide combination and inhaled tiotropium. The most frequently reported reactions were hoarseness, xerostomia, headache and dizziness. Poliuri and cough were less frequently reported reactions. Conclusion: Most of the adverse reactions were of limited intensity but some of these side effects might affect patient's compliance. Serious adverse events were not detected. doi:10.1016/j.vascn.2012.08.065
Influence of pharmaceutic promotion and advertisement on prescription habits and medicine intake Lina Maria Rodriguez, Lina Maria Martinez, Maria de los Angeles Rodriguez, Gloria Ines Martinez, Jonathan Cardona, Manuela Estrada, Edna Martinez, Diana Carolina Grajales Universidad Pontificia Bolivariana, Medellin, Colombia Background: Pharmaceutical advertising or “pharmaceutical marketing” has been part, for many decades now, of the daily life of healthcare providers. Objective: To determinate the influence of pharmaceutic promotion and advertisement on prescription habits and medicine intake. Methods: Cross-sectional, descriptive observational study with a population consisting of doctors (128) and the general population
intra-atrial valve (n = 6) deployed into the fossa ovalis. Shunt patency (Fick's method), mean atrial/pulmonary pressures, and LV function (echocardiography) were evaluated weekly. The valved-shunt acutely lowered left-atrial pressures (LAP, 15±1 to 11±1 mm Hg*) without increasing right-atrial/pulmonary-artery pressures (PAP: 18±1 to 17±1 mm Hg). Shunts were patent for the duration of the study (12 weeks; mean Qp/Qs: 1.4±0.1 vs. 0.7±0.1*). Post-implant, treated sheep had lower filling pressures (LAP: 11±1 vs. 18±1 mm Hg*) and preserved LV EF (40±3 vs. 22±1%*), resulting in improved survival (80% vs. 20%). [*: P b 0.05 vs. CTRL]. Left-heart unloading via an intra-atrial valved-shunt led to chronically reduced left-atrial pressures, preserved right-sided pressures, and improved LV function in a clinically-relevant chronic model of ischemic heart failure. doi:10.1016/j.vascn.2012.08.062
Evaluation of drug-induced cardiac conduction disturbance using conscious ferrets—An alternative small animal telemetry model Hugo M. Vargas, Kathy Derakhchan Safety and Exploratory Pharmacology, Amgen Inc., Thousand Oaks, CA, United States
177
contractility affected cardiac glucose uptake and/or left ventricular morphology utilizing PET/CT imaging. Battelle studied anesthetized dogs instrumented to measure blood pressure, left ventricular pressure and ECG after intravenous injection of a non-selective β-agonist (isoproterenol). PET, utilizing [18F]-FDG as a radiolabeled tracer for glucose, was used to determine changes in myocardial cellular metabolism, and CT was utilized to generate digital three-dimensional images of the heart. Heart rate increased 57 bpm, mean arterial pressure decreased 54 mm Hg and dP/dtmax increased 1581 mm Hg/s. Telemetry and PET/CT imaging correlated drug-induced functional and morphological changes with alterations in myocardial substrate used as an indicator of cardiac metabolism. In comparison to the ICH S7 cardiovascular assessment alone, when combined with PET/CT they collectively provide real-time vascular, anatomical and functional cardiac information. Thus, integrating non-invasive imaging into early cardiovascular safety studies allows for a more sensitive, predictive and robust assay. doi:10.1016/j.vascn.2012.08.064
A pharmacovigilance study in chest diseases outpatient clinic Coskun Usta, Aykut Çilli, Burcu Çelenk, Rusen Uzun Medi, Akdeniz Medical School, Antalya, Turkey
The ionic mechanisms of depolarization and repolarization in ferrets are similar to those in dogs, primates, and humans. Ferret can be a suitable alternative to dog for early screening, and due to their small size (1.4–2.2 kg), smaller amount of drug is required. Since flecainide and AMG1 cause PR/QRS widening in dogs and primates, we have evaluated the sensitivity of ferret to detect cardiac conduction delay in response to these NaV1.5 blockers. Male ferrets were implanted with transmitters (TL11M2-C5-PXT) to record ECG and arterial pressure. Two modified cross-over studies were designed with telemetered ferrets: group 1 (n = 6) was dosed with 0, 3, 10, and 15 mg/kg PO of flecainide, and group 2 (n = 6) with 0, 30, 100, and 200 mg/kg PO of AMG1 (1 dose/week). Using continuous data analysis approach, flecainide (10 and 15 mg/kg) caused significant prolongation of PR (18–29 ms), but QRS prolongation (7–10 ms) was observed at all doses. AMG1 caused significant prolongation of PR (12–23 ms), QRS (5–13 ms), and QTcF (27–43 ms) intervals and increased heart rate (69–81 bpm) at 100 and 200 mg/kg. The effects of flecainide and AMG1 were consistent with sodium channel blockade. Satellite ferrets (n = 6/agent) were used for toxicokinetics. For flecainide, Tmax was 1 h and mean Cmax (ng/ml) were 357, 1120, and 1320 at 3, 10, or 15 mg/kg, respectively. For AMG1, Tmax was 1 h and mean Cmax were 2040, 9510, and 32,000 at 30, 100, or 300 mg/kg, respectively. In conclusion, these findings suggest that telemeterized ferret is a useful model for assessment of cardiac conduction delay. doi:10.1016/j.vascn.2012.08.063
Improvements in cardiac injury assessment via combined measurement modalities Brian M. Roche, Tom Vinci, Karen Elsass, Sarah McCullough, Susan Reed, Steve Behringer Battelle Memorial Institute, Columbus, OH, United States Combining traditional preclinical cardiovascular safety assessment methods with PET/CT imaging modalities provides standard data and unprecedented insight into the underlying mechanism of action of drug-induced cardiac injury. The specific objective of this study was to determine if drug-induced increases in left ventricular
Aim: Adverse drug reactions is an important healthcare issue, it causes excess morbidity and mortality. The aim of this study was to determine the adverse drug reactions in patients who admitted to the Outpatient Clinic of Respiratory Diseases and to improve some clinical strategies if they are preventable. Material and methods: This study is a prospective observational study which was performed to determine adverse drug reaction in patients who admitted to the Outpatient Clinic of Respiratory Diseases. Results: During the 15 months of study period a total of 114 adverse reactions were reported in 92 out of 18,163 patients. Most of the adverse reactions were related with gastrointestinal system, central nervous system and cardiovascular system. The most of the adverse events were associated with fixed inhaled formoterol– budesonide combination and inhaled tiotropium. The most frequently reported reactions were hoarseness, xerostomia, headache and dizziness. Poliuri and cough were less frequently reported reactions. Conclusion: Most of the adverse reactions were of limited intensity but some of these side effects might affect patient's compliance. Serious adverse events were not detected. doi:10.1016/j.vascn.2012.08.065
Influence of pharmaceutic promotion and advertisement on prescription habits and medicine intake Lina Maria Rodriguez, Lina Maria Martinez, Maria de los Angeles Rodriguez, Gloria Ines Martinez, Jonathan Cardona, Manuela Estrada, Edna Martinez, Diana Carolina Grajales Universidad Pontificia Bolivariana, Medellin, Colombia Background: Pharmaceutical advertising or “pharmaceutical marketing” has been part, for many decades now, of the daily life of healthcare providers. Objective: To determinate the influence of pharmaceutic promotion and advertisement on prescription habits and medicine intake. Methods: Cross-sectional, descriptive observational study with a population consisting of doctors (128) and the general population