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A novel implantable blood pressure telemetry device; Comparison between data sciences and telemetry research systems
Abstracts / Journal of Pharmacological and Toxicological Methods 60 (2009) 210–258
Currently, approaches for accurate blood pressure determination rely predominantly on invasive techniques. This holds particularly true for safety pharmacology studies. The present work evaluates the novel High Definition Oscillometry (HDO) technique as non-invasive approach for accurate blood pressure recordings (systolic and diastolic blood pressure; mean arterial pressure (MAP); pulses/min) in monkeys. Marmoset and cynomolgus monkeys were divided into 3 groups: 6 male C. jacchus (0.38 kg, mean body weight), 6 male (7.3 kg) and 6 female (3.8 kg) M. fascicularis. For each animal 15 measurements were performed in every session which was repeated on three consecutive days. On average, these measurements required 9 min per animal. After procedural habituation, mean MAP in conscious animals was 94.9 ±4.3 (SD) mmHg in group 1; 96.2 ±3.4 mmHg in group 2 and 86.9±3.0 mmHg in group 3. These data correspond to data reported for invasive techniques. The intraindividual SD per session ranged between 9.0 and 1.2 irrespective of group and session. The data gained by HDO provide a clear advantage over standard oscillometry in terms of precision and accuracy. Also, HDO — when compared to telemetry as reference — detected drug related cardiovascular changes as a decreasing blood pressure was documented by both systems during a continuous monitoring before and during Ketamine/Xylazine anaesthesia. In conclusion, HDO provides a new and accurate non-invasive approach for blood pressure determination even in conscious animals applicable to Old World and New World monkeys.
doi:10.1016/j.vascn.2009.04.109
A cardiovascular safety assessment paradigm for the early identification of proarrhythmic and torsadagenic compounds Dinah L. Misnera,⁎, C. Frantza, E. Meierhenrya, M. Fieldena, L. Guob, J. Lya, H. Uppala, D. Rotsteina, M. Gralinskic, P. Senesec, M. Albassama, Sushmita Chandaa, Stefan Platza, K. Kolajaa a Roche Palo Alto, Palo Alto, CA, United States b Hoffman La-Roche Inc., Nutley, NJ, United States c CorDynamics Inc., Chicago, IL, United States The early identification of potential cardiovascular effects is critical, however, there currently are few in vitro or in vivo assays that can determine if a compound that blocks hERG currents will induce arrhythmias/torsades de pointes. Here we describe the identification of a torsadagenic compound during the initial pre-clinical testing and the approach used to identify proarrhythmic effects early. A lead compound was found to prolong QTc, increase QRS, and induce tachycardia, and myocardial degeneration at plasma exposure levels ∼100–200× the estimated Ceff. During a subsequent repeat-dose cardiovascular study the compound induced multiple instances of arrhythmias, including torsades de pointes with subsequent ventricular fibrillation in some instances. Microscopic effects were not observed upon histopathological evaluation, and no evidence of mitochondrial and direct cardiovascular toxicity was seen. Moderate potency against sodium channels was observed and the compound caused instability, effects on action potential duration, triangulation, increased QRS duration/AV block, and ventricular ectopic contractions in the guinea pig Langendorff heart model. It was concluded that the effects on cardiovascular conduction preceded and likely induced the myocardial degeneration. In order to identify the effects at an earlier stage in the development process we tested compounds against hERG and sodium channels followed by the isolated heart, and then in a dedicated repeat dose in vivo cardiovascular study prior to conducting repeat dose toxicology studies.
doi:10.1016/j.vascn.2009.04.110
235
A novel implantable blood pressure telemetry device; Comparison between data sciences and telemetry research systems Simon Malpas Telemetry Research Ltd., Auckland, New Zealand The expiry of a Data Sciences (DSI) patent in the area of blood pressure telemetry permits the development of alternative technologies. A key aspect in providing new telemetry systems is a comparison to existing technology. Important aspects include stability of the calibration over time and the ability to capture the pulsitile blood pressure waveform. In a group of 8 rats and 8 rabbits DSI blood pressure transmitters (C40 or D70 models) were implanted in conjunction with Telemetry Research (TR) transmitters. Both systems incorporate a fluid filled catheter of similar dimensions with a biocompatible gel in the tip. The blood pressure waveform was collected via telemetry for up to 6 months after implantation. The signal was sampled at 500 Hz and digitally transmitted to a receiver up to 5 m away. The battery of TR transmitter was recharged within the rat using inductive power transfer technology. TR Transmitters permitted 24 h operation even during recharging in rats for up to 1 year. The pulsitile waveform associated with each heart beat was reflected similarly in all cases although the frequency response of DSI telemeters was limited to ∼ 40 Hz (−3 dB rolloff point). The calibrated offset level between the two transmitters was not more than 5 mmHg at all times over a 2 month period. Inductive power recharging did not cause heating effects. We propose that the Telemetry Research blood pressure transmitters offer comparable performance to existing technology, but with extra design advantages (rechargeable, co-housing of animals, greater range).
doi:10.1016/j.vascn.2009.04.111
Normal prevalence of cardiac arrhythmias in 24 h ECG recordings of chronically telemetered, healthy, freely moving beagle dogs Frank Cools⁎, David Gallacher Johnson & Johnson PRD, Beerse, Belgium In the in vivo pre-clinical cardiovascular safety evaluation there is increasing interest in proper scanning for drug induced ECG abnormalities in addition to electrophysiological/QT evaluation. The prevalence of abnormal cardiac arrhythmias and conduction disturbances in normal telemetered dogs is well known from industry experience, however it is under published. Consequently, for many scientists it will be difficult to differentiate normal ‘physiological’ variation from test compound effects in this model. In this study, we visually scanned 24 h control ECG recordings of 20 telemetered beagle dogs (ITS T27F-11 implant on average10 months after implant). Subsequently at an average of 10 months later, we again scanned 24 h ECG recording in the same dogs under the same conditions. The data show only marginal differences between the 1st and 2nd 24 h ECG scanning results.
#dogs/20 Single junctional complexes Runs of junctional complexes Single ventricular complexes Runs of ventricular complexes Periods of ventricular tachycardia Non-conducted P-waves Sinus pauses
1st analysis
2nd analysis
Day
Night
Day
Night
13 5 11 2 0 2 1
14 5 10 2 2 2 3
12 8 14 2 2 4 3
16 7 12 4 4 5 3
Currently, approaches for accurate blood pressure determination rely predominantly on invasive techniques. This holds particularly true for safety pharmacology studies. The present work evaluates the novel High Definition Oscillometry (HDO) technique as non-invasive approach for accurate blood pressure recordings (systolic and diastolic blood pressure; mean arterial pressure (MAP); pulses/min) in monkeys. Marmoset and cynomolgus monkeys were divided into 3 groups: 6 male C. jacchus (0.38 kg, mean body weight), 6 male (7.3 kg) and 6 female (3.8 kg) M. fascicularis. For each animal 15 measurements were performed in every session which was repeated on three consecutive days. On average, these measurements required 9 min per animal. After procedural habituation, mean MAP in conscious animals was 94.9 ±4.3 (SD) mmHg in group 1; 96.2 ±3.4 mmHg in group 2 and 86.9±3.0 mmHg in group 3. These data correspond to data reported for invasive techniques. The intraindividual SD per session ranged between 9.0 and 1.2 irrespective of group and session. The data gained by HDO provide a clear advantage over standard oscillometry in terms of precision and accuracy. Also, HDO — when compared to telemetry as reference — detected drug related cardiovascular changes as a decreasing blood pressure was documented by both systems during a continuous monitoring before and during Ketamine/Xylazine anaesthesia. In conclusion, HDO provides a new and accurate non-invasive approach for blood pressure determination even in conscious animals applicable to Old World and New World monkeys.
doi:10.1016/j.vascn.2009.04.109
A cardiovascular safety assessment paradigm for the early identification of proarrhythmic and torsadagenic compounds Dinah L. Misnera,⁎, C. Frantza, E. Meierhenrya, M. Fieldena, L. Guob, J. Lya, H. Uppala, D. Rotsteina, M. Gralinskic, P. Senesec, M. Albassama, Sushmita Chandaa, Stefan Platza, K. Kolajaa a Roche Palo Alto, Palo Alto, CA, United States b Hoffman La-Roche Inc., Nutley, NJ, United States c CorDynamics Inc., Chicago, IL, United States The early identification of potential cardiovascular effects is critical, however, there currently are few in vitro or in vivo assays that can determine if a compound that blocks hERG currents will induce arrhythmias/torsades de pointes. Here we describe the identification of a torsadagenic compound during the initial pre-clinical testing and the approach used to identify proarrhythmic effects early. A lead compound was found to prolong QTc, increase QRS, and induce tachycardia, and myocardial degeneration at plasma exposure levels ∼100–200× the estimated Ceff. During a subsequent repeat-dose cardiovascular study the compound induced multiple instances of arrhythmias, including torsades de pointes with subsequent ventricular fibrillation in some instances. Microscopic effects were not observed upon histopathological evaluation, and no evidence of mitochondrial and direct cardiovascular toxicity was seen. Moderate potency against sodium channels was observed and the compound caused instability, effects on action potential duration, triangulation, increased QRS duration/AV block, and ventricular ectopic contractions in the guinea pig Langendorff heart model. It was concluded that the effects on cardiovascular conduction preceded and likely induced the myocardial degeneration. In order to identify the effects at an earlier stage in the development process we tested compounds against hERG and sodium channels followed by the isolated heart, and then in a dedicated repeat dose in vivo cardiovascular study prior to conducting repeat dose toxicology studies.
doi:10.1016/j.vascn.2009.04.110
235
A novel implantable blood pressure telemetry device; Comparison between data sciences and telemetry research systems Simon Malpas Telemetry Research Ltd., Auckland, New Zealand The expiry of a Data Sciences (DSI) patent in the area of blood pressure telemetry permits the development of alternative technologies. A key aspect in providing new telemetry systems is a comparison to existing technology. Important aspects include stability of the calibration over time and the ability to capture the pulsitile blood pressure waveform. In a group of 8 rats and 8 rabbits DSI blood pressure transmitters (C40 or D70 models) were implanted in conjunction with Telemetry Research (TR) transmitters. Both systems incorporate a fluid filled catheter of similar dimensions with a biocompatible gel in the tip. The blood pressure waveform was collected via telemetry for up to 6 months after implantation. The signal was sampled at 500 Hz and digitally transmitted to a receiver up to 5 m away. The battery of TR transmitter was recharged within the rat using inductive power transfer technology. TR Transmitters permitted 24 h operation even during recharging in rats for up to 1 year. The pulsitile waveform associated with each heart beat was reflected similarly in all cases although the frequency response of DSI telemeters was limited to ∼ 40 Hz (−3 dB rolloff point). The calibrated offset level between the two transmitters was not more than 5 mmHg at all times over a 2 month period. Inductive power recharging did not cause heating effects. We propose that the Telemetry Research blood pressure transmitters offer comparable performance to existing technology, but with extra design advantages (rechargeable, co-housing of animals, greater range).
doi:10.1016/j.vascn.2009.04.111
Normal prevalence of cardiac arrhythmias in 24 h ECG recordings of chronically telemetered, healthy, freely moving beagle dogs Frank Cools⁎, David Gallacher Johnson & Johnson PRD, Beerse, Belgium In the in vivo pre-clinical cardiovascular safety evaluation there is increasing interest in proper scanning for drug induced ECG abnormalities in addition to electrophysiological/QT evaluation. The prevalence of abnormal cardiac arrhythmias and conduction disturbances in normal telemetered dogs is well known from industry experience, however it is under published. Consequently, for many scientists it will be difficult to differentiate normal ‘physiological’ variation from test compound effects in this model. In this study, we visually scanned 24 h control ECG recordings of 20 telemetered beagle dogs (ITS T27F-11 implant on average10 months after implant). Subsequently at an average of 10 months later, we again scanned 24 h ECG recording in the same dogs under the same conditions. The data show only marginal differences between the 1st and 2nd 24 h ECG scanning results.
#dogs/20 Single junctional complexes Runs of junctional complexes Single ventricular complexes Runs of ventricular complexes Periods of ventricular tachycardia Non-conducted P-waves Sinus pauses
1st analysis
2nd analysis
Day
Night
Day
Night
13 5 11 2 0 2 1
14 5 10 2 2 2 3
12 8 14 2 2 4 3
16 7 12 4 4 5 3