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Evaluation of cardiac conduction disturbances using Jacketed External Telemetry (JET) in conscious Non-Human Primates (NHP)
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Abstracts
the feasibility of using JET for ECG recording over 7 months and develop a jacket acclimation procedure for long-term use. In this study, two groups of 6 male cynomolgus monkeys were equipped with JET for recording: Group 1-ECG recordings at 1 and 4 months and Group 2-ECG recordings at 1 and 7 months. All NHP were acclimated to JET prior to the 1 month study (3 jacketings/2 weeks), then were re-acclimated to JET after 4 (Group 1) or 7 months (Group 2). All animals were previously implanted with PCT telemetry implants, thus changes in blood pressures (BP) and HR were used to assess stress-associated with repeated JET use. In Groups 1 and 2, a total of 15 and 11 jacketing sessions were conducted, respectively. For each session, NHP wore jacket for 36 hrs and JET and PCT-derived BP/ HR data were recorded and analyzed for 24 hrs. Initial jacketing was associated with higher systolic (SBP) and diastolic (DBP) blood pressures that subsided and reached steady-state with repeated acclimations. Nocturnal SBP (? = 15 ± 3 mmHg) and DBP (? = 10 ± 2 mmHg) were also higher than diurnal SBP (? = 10 ± 2 mmHg) and DBP (? = 6±2 mmHg), when compared to PCT values. At 4- (Days 134, 137, 142) and 7- (Days 231, 234, 239) months, re-jacketing had no no effect on BP and HR values relative to PCT values. From these findings, a total of three jacketing sessions within a two week period was needed to acclimate the NHP to JET, and restore physiological BP diurnal and nocturnal rhythms, while only one session is required for HR. In long-term tox evaluations, such beneficial effects could persist for 7 months. doi:10.1016/j.vascn.2011.03.159
Poster No: 154 Evaluation of cardiac conduction disturbances using Jacketed External Telemetry (JET) in conscious Non-Human Primates (NHP) Kathy Derakhchan, Ray W. Chui, Hugo M. Vargas Investigative Toxicology, Amgen Inc., Thousand Oaks, CA, USA Previously, we demonstrated the ability of the JET system to detect drug-induced QTc prolongation in awake NHP (Vargas and Derakhchan, SPS 2009), which showed that this non-invasive method could be used to detect ECG changes in toxicology study paradigms. This study addressed whether the JET system can detect cardiac conduction disturbances, specifically drug-induced PR and QRS prolongation, when compared to PCT implants. A parallel study was designed with 12 telemetered male Cynomolgus monkeys in two groups. Group 1 (n = 6, JET + PCT) and group 2 (n = 6, PCT) were dosed orally with 0, 1, 5 and 10 mg/kg of flecainide, in escalating manner (one dose/ week). Using a continuous data analysis approach, flecainide at 5 and 10 mg/kg caused significant prolongation of PR (8–22 msec) and QTc (15–40 msec). Prolongation of QRS (4–20 msec) was observed with substantial interanimal variability. At some time points, QRS morphology was consistent with right bundle branch block, large and deep S waves with a negative QRS vector. JET-derived PR and QRS intervals showed good trend agreement compared to implants, though there were some minor discrepancies due to potential morphological differences in waveforms obtained from the different leads. QT and heart rate values from JET and implants showed minimal discrepancy. Most importantly, JET was capable of detecting dose-related prolongation of PR, QRS and QTc with flecainide. Blood samples were collected from satellite animals (group 3; n = 6) for toxicokinetic evaluations. Tmax values were ranging from 1–3 hours and mean Cmax values (±SD) increased dose-dependently and were 51 ± 23; 513 ± 62; and 1290 ± 149 ng/mL for animals given 1, 5, or 10 mg/kg of flecainide, respectively.
In conclusion, JET is a valid method for long-term ECG monitoring and able to detect PR and QRS prolongation in awake and unrestrained NHP toxicology studies.
doi:10.1016/j.vascn.2011.03.160
Poster No: 156 Effects of pentamidine on QT interval and ether-a-go-go related gene expression in cynomolgus monkeys Koichi Kuwano, Junko Matsuo, Shinya Ohkuma, Masaaki Ban, Akiko Suzuki, Takeshi Kamenosono, Takayuki Sukamoto, Koichiro Fukuzaki, Ryoichi Nagata Shin Nippon Biomedical Laboratories, Ltd. (SNBL), Kagoshima, Japan Pentamidine, an antiprotozoal agent, has been known to induce QT prolongation and torsades de pointes in humans. It has also been reported that pentamidine inhibits human ether-a-go-go related gene (hERG) trafficking in-vitro, and that the trafficking defect has been implicated as a mechanism for pentamidine-induced QT prolongation. However, the effects of pentamidine on hERG trafficking in-vivo have not been fully elucidated. We investigated the QT prolongation effects of pentamidine in cynomolgus monkeys. Pentamidine (4 mg/ kg/day, i.m.) was administered repeatedly to n = 4 telemeterized male cynomolgus monkeys. ECG was measured continuously using a telemetry system. Cardiac tissues (papillary muscles and left ventricles) from pentamidine-treated animals were isolated. Action potential [AP (microelectrode recording technique)], the rapidly activating component of delayed rectifier potassium current (IKr) densities (patch clamp technique), and ERG channel protein expressions (western blot technique) were measured. Results: Pentamidine prolonged QT/QTc interval from 3 weeks after initiation of dosing in all 4 animals. In in-vitro assay using the cardiac tissues isolated from pentamidine-treated animals, APD90, APD30, and APD30-90 in papillary muscles were prolonged and IKr densities in single left ventricular myocytes were decreased. In addition, ERG channel protein expressions were decreased in left ventricles. Conclusion: These results demonstrated that pentamidine induced QT prolongation in cynomolgus monkeys due to defective ERG expression and function. doi:10.1016/j.vascn.2011.03.161
Poster No: 157 Telemetry use in infectious disease/biodefense: Biomarkers for model development and efficacy evaluation Robert C. Layton, William Mega, Frederick T. Koster Lovelace Respiratory Research Institute, Albuquerque, NM, USA Objective: The objective of these studies was to demonstrate the use of biomarkers in animal models of fatal infectious diseases for approval of vaccines, therapeutics, and other countermeasures through “the Animal Rule” (USFDA 21CFR). Methods: Chlorocebus aethiops (AGMs) were challenged with Yersinia pestis CO92 via head-only exposure apparatus using real-time plethysmography to determine challenge duration. Antibiotic treatment was initiated within six hours of fever. Treatment followed a “humanized” dosing regimen of alternating 8 mg/kg and 2 mg/kg 30minute intravenous infusions. Blood samples were obtained to determine bacteremia, clinical chemistries, and plasma antibiotic
Abstracts
the feasibility of using JET for ECG recording over 7 months and develop a jacket acclimation procedure for long-term use. In this study, two groups of 6 male cynomolgus monkeys were equipped with JET for recording: Group 1-ECG recordings at 1 and 4 months and Group 2-ECG recordings at 1 and 7 months. All NHP were acclimated to JET prior to the 1 month study (3 jacketings/2 weeks), then were re-acclimated to JET after 4 (Group 1) or 7 months (Group 2). All animals were previously implanted with PCT telemetry implants, thus changes in blood pressures (BP) and HR were used to assess stress-associated with repeated JET use. In Groups 1 and 2, a total of 15 and 11 jacketing sessions were conducted, respectively. For each session, NHP wore jacket for 36 hrs and JET and PCT-derived BP/ HR data were recorded and analyzed for 24 hrs. Initial jacketing was associated with higher systolic (SBP) and diastolic (DBP) blood pressures that subsided and reached steady-state with repeated acclimations. Nocturnal SBP (? = 15 ± 3 mmHg) and DBP (? = 10 ± 2 mmHg) were also higher than diurnal SBP (? = 10 ± 2 mmHg) and DBP (? = 6±2 mmHg), when compared to PCT values. At 4- (Days 134, 137, 142) and 7- (Days 231, 234, 239) months, re-jacketing had no no effect on BP and HR values relative to PCT values. From these findings, a total of three jacketing sessions within a two week period was needed to acclimate the NHP to JET, and restore physiological BP diurnal and nocturnal rhythms, while only one session is required for HR. In long-term tox evaluations, such beneficial effects could persist for 7 months. doi:10.1016/j.vascn.2011.03.159
Poster No: 154 Evaluation of cardiac conduction disturbances using Jacketed External Telemetry (JET) in conscious Non-Human Primates (NHP) Kathy Derakhchan, Ray W. Chui, Hugo M. Vargas Investigative Toxicology, Amgen Inc., Thousand Oaks, CA, USA Previously, we demonstrated the ability of the JET system to detect drug-induced QTc prolongation in awake NHP (Vargas and Derakhchan, SPS 2009), which showed that this non-invasive method could be used to detect ECG changes in toxicology study paradigms. This study addressed whether the JET system can detect cardiac conduction disturbances, specifically drug-induced PR and QRS prolongation, when compared to PCT implants. A parallel study was designed with 12 telemetered male Cynomolgus monkeys in two groups. Group 1 (n = 6, JET + PCT) and group 2 (n = 6, PCT) were dosed orally with 0, 1, 5 and 10 mg/kg of flecainide, in escalating manner (one dose/ week). Using a continuous data analysis approach, flecainide at 5 and 10 mg/kg caused significant prolongation of PR (8–22 msec) and QTc (15–40 msec). Prolongation of QRS (4–20 msec) was observed with substantial interanimal variability. At some time points, QRS morphology was consistent with right bundle branch block, large and deep S waves with a negative QRS vector. JET-derived PR and QRS intervals showed good trend agreement compared to implants, though there were some minor discrepancies due to potential morphological differences in waveforms obtained from the different leads. QT and heart rate values from JET and implants showed minimal discrepancy. Most importantly, JET was capable of detecting dose-related prolongation of PR, QRS and QTc with flecainide. Blood samples were collected from satellite animals (group 3; n = 6) for toxicokinetic evaluations. Tmax values were ranging from 1–3 hours and mean Cmax values (±SD) increased dose-dependently and were 51 ± 23; 513 ± 62; and 1290 ± 149 ng/mL for animals given 1, 5, or 10 mg/kg of flecainide, respectively.
In conclusion, JET is a valid method for long-term ECG monitoring and able to detect PR and QRS prolongation in awake and unrestrained NHP toxicology studies.
doi:10.1016/j.vascn.2011.03.160
Poster No: 156 Effects of pentamidine on QT interval and ether-a-go-go related gene expression in cynomolgus monkeys Koichi Kuwano, Junko Matsuo, Shinya Ohkuma, Masaaki Ban, Akiko Suzuki, Takeshi Kamenosono, Takayuki Sukamoto, Koichiro Fukuzaki, Ryoichi Nagata Shin Nippon Biomedical Laboratories, Ltd. (SNBL), Kagoshima, Japan Pentamidine, an antiprotozoal agent, has been known to induce QT prolongation and torsades de pointes in humans. It has also been reported that pentamidine inhibits human ether-a-go-go related gene (hERG) trafficking in-vitro, and that the trafficking defect has been implicated as a mechanism for pentamidine-induced QT prolongation. However, the effects of pentamidine on hERG trafficking in-vivo have not been fully elucidated. We investigated the QT prolongation effects of pentamidine in cynomolgus monkeys. Pentamidine (4 mg/ kg/day, i.m.) was administered repeatedly to n = 4 telemeterized male cynomolgus monkeys. ECG was measured continuously using a telemetry system. Cardiac tissues (papillary muscles and left ventricles) from pentamidine-treated animals were isolated. Action potential [AP (microelectrode recording technique)], the rapidly activating component of delayed rectifier potassium current (IKr) densities (patch clamp technique), and ERG channel protein expressions (western blot technique) were measured. Results: Pentamidine prolonged QT/QTc interval from 3 weeks after initiation of dosing in all 4 animals. In in-vitro assay using the cardiac tissues isolated from pentamidine-treated animals, APD90, APD30, and APD30-90 in papillary muscles were prolonged and IKr densities in single left ventricular myocytes were decreased. In addition, ERG channel protein expressions were decreased in left ventricles. Conclusion: These results demonstrated that pentamidine induced QT prolongation in cynomolgus monkeys due to defective ERG expression and function. doi:10.1016/j.vascn.2011.03.161
Poster No: 157 Telemetry use in infectious disease/biodefense: Biomarkers for model development and efficacy evaluation Robert C. Layton, William Mega, Frederick T. Koster Lovelace Respiratory Research Institute, Albuquerque, NM, USA Objective: The objective of these studies was to demonstrate the use of biomarkers in animal models of fatal infectious diseases for approval of vaccines, therapeutics, and other countermeasures through “the Animal Rule” (USFDA 21CFR). Methods: Chlorocebus aethiops (AGMs) were challenged with Yersinia pestis CO92 via head-only exposure apparatus using real-time plethysmography to determine challenge duration. Antibiotic treatment was initiated within six hours of fever. Treatment followed a “humanized” dosing regimen of alternating 8 mg/kg and 2 mg/kg 30minute intravenous infusions. Blood samples were obtained to determine bacteremia, clinical chemistries, and plasma antibiotic