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Assessment of drug induced hypertension and hypotension by non-invasive High Definition Oscillometry (HDO) in beagle dogs and cynomolgus monkeys
Abstracts
The “gold standard” or industry standard for accurate collection of systemic arterial blood pressure uses a catheter attached to a telemetry device that is surgically implanted into a branch of the arterial tree. This invasive procedure, coupled with ECG collection, allows for new chemical entities to be evaluated for cardiovascular effects in compliance with ICH S7A. Attempts to meet ICH S7A guidelines with non-invasive telemetry devices have been periodically used with varying degrees of success. Recently developed devices incorporate the data collection systems into ambulatory jacketed systems that have the capability to transmit the data, thus incorporating some of the advantages of the implantable telemetry systems without surgical invasion but are limited in the duration over which data can be continuously collected. The purpose of this study was to evaluate the functionality of a commercially available (EMKA) non-invasive telemetry jacket for collection of blood pressure in dogs. Four telemetered beagle dogs were instrumented with VAPs and acclimated to jackets prior to dosing. Dogs were intravenously dosed with an ambulatory infusion device with 1 of 3 treatments over 10 min with sufficient washout between doses; vehicle, prazosin and phenylephrine. The changes in blood pressure to each treatment were compared between the ambulatory oscillometric method and implantable telemetry in each animal. BP decreased after dosing with prazosin; increased, transiently, during dosing with phenylephrine; and did not change after dosing with vehicle. doi:10.1016/j.vascn.2011.03.169
Poster No: 165 Ambulatory non-invasive blood pressure recording in a freely moving cynomolgus monkey using High Definition Oscillometry (HDO) and Bluetooth technology Barthel Schmelting Covance, Muenster, Germany Avoidance of stress-associated blood pressure (BP) increases is crucial when evaluating drug related hemodynamic changes. In general, non-invasive BP assessment requires animal restraint and handling procedures, and allows only “snapshot” BP evaluation, especially in non-human primates (NHP). The HDO technique as a novel, non-invasive approach to record BP in animal models has demonstrated precision and sensitivity for BP measurement under restraint conditions. Now the feasibility of ambulatory (nonrestrained), non-invasive BP determination is possible in NHP using HDO combined with Bluetooth technology (HDO-BT). To evaluate HDO-BT, a male Macaca fascicularis (6.1 kg) implanted with a BP transmitter was used in this evaluation. The animal was fitted with a modified jacket with a prototype HDO-BT device (weight 325 g) and a tail cuff. After, the monkey was allowed free-movement in a cage with EU dimensions (cage size: 5.7 m³). Systolic (SYS), diastolic (DIA), mean arterial (MAP) BP and pulse rate derived by HDO-BT and implant telemetry were determined at 1 min intervals. Within 2 h, 15 valid HDO measurements, without artefacts, were made, with the following means (mm Hg ± SD): 130 ± 7 (SYS); 97 ± 7 (MAP), 78 ± 7 (DIA) and a pulse rate of 187. Mean time interval between the valid data was 8 min. This first attempt to conduct non-invasive, unrestrained, continuous BP recording by HDO-BT demonstrates the potential of this new technique for use in NHP toxicology studies. doi:10.1016/j.vascn.2011.03.170
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Poster No: 166 Assessment of drug induced hypertension and hypotension by non-invasive High Definition Oscillometry (HDO) in beagle dogs and cynomolgus monkeys Barthel Schmelting a, Jay Albretsen a, Dedhia Himanshu a, Kathy Derakhchan b, Hugo M. Vargas b a b
Covance, Chandler, USA Investigative Toxicology, Amgen Inc., Thousand Oaks, CA, USA
The novel HDO technique was evaluated as a potential noninvasive approach to record BP in beagle dogs and cynomolgus monkeys (NHP) during a three week dose-escalation study with: A) vehicle PO; B) hexamethonium, an antagonist of the ganglionic nicotinic acetylcholine receptor (20 mg/kg IV-dogs; 10 mg/kg IVNHP); and C) ephedrine, an agonist at α and β adrenergic receptors (10 mg/kg PO). Six animals (3M/3F) were used per group (N-18 per species). Once per week the animals were given one treatment, and HDO-BP measurements compared (pre-dose vs post-dose). There were no significant differences in BP in vehicle-treated dogs or NHP (group A) at any time point following dosing, compared to pre-dose values. Pharmacological effects could be determined at day 22 of study. In NHP, hexamethonium lowered systolic BP front a pre-dose baseline of 117 ± 25 mm Hg to 90 ± 8 mm Hg. In dogs given ephedrine, a significant increase in systolic BP could be detected (baseline: 142 ± 15 mm Hg; ephedrine: 176 ± 9 mm Hg; N = 6) when measured 2 h after dosing. A training/handling effect was obvious when predose BP data were compared on days 1, 8, 15 and 22 of the study. Acclimation of animals to the HDO method related to repeated handling may reduce overall physiological stress and reduce intraspecific group variability, which may facilitate detection of BP changes in ‘minimally-stressed’ animals. HDO appears to be a sensitive non-invasive method to assess BP in toxicology studies, but avoidance of stress-associated BP increases is crucial when evaluating drug-related hemodynamic changes. doi:10.1016/j.vascn.2011.03.171
Poster No: 167 The implications of handling, restraint, anesthesia, and kinetics on cardiac Troponin I analysis in rats when utilizing an ultrasensitive immunoassay Michael E. Dunn, Rachael Fernandes, Denise Coluccio, Rosemary Nicklaus, Gerard Hirkaler, Igor Mikaelian, Martin Sanders, Wanping Geng Roche, Nutley, New Jersey, USA Introduction: Recent advances in assay sensitivity have allowed for the quantification of cardiac Troponin I (cTnI) concentrations at previously undetectable levels. Here, we report the effects of restraint or anesthesia on baseline cTnI levels and the pharmacokinetic profile of cTnI in rats. Methods: Male rats were assigned to an event group (n = 12) entailing: no handling (NH), simulated tail vein injection (SI), or placement into an isoflurane/O2 anesthesia induction chamber (IF). Blood samples were collected via implanted femoral catheters at baseline, 6 and 48 h post-event. A separate 24-hr pharmacokinetics study consisting of a cTnI single bolus dose (0.005, 0.05, and 0.5 μg/kg purified rat cTnI) was performed on 18 additional rats (n = 6 per dose group). Serum cTnI was quantified using the Singulex Erenna® Ultrasensitive Immunoassay system.
The “gold standard” or industry standard for accurate collection of systemic arterial blood pressure uses a catheter attached to a telemetry device that is surgically implanted into a branch of the arterial tree. This invasive procedure, coupled with ECG collection, allows for new chemical entities to be evaluated for cardiovascular effects in compliance with ICH S7A. Attempts to meet ICH S7A guidelines with non-invasive telemetry devices have been periodically used with varying degrees of success. Recently developed devices incorporate the data collection systems into ambulatory jacketed systems that have the capability to transmit the data, thus incorporating some of the advantages of the implantable telemetry systems without surgical invasion but are limited in the duration over which data can be continuously collected. The purpose of this study was to evaluate the functionality of a commercially available (EMKA) non-invasive telemetry jacket for collection of blood pressure in dogs. Four telemetered beagle dogs were instrumented with VAPs and acclimated to jackets prior to dosing. Dogs were intravenously dosed with an ambulatory infusion device with 1 of 3 treatments over 10 min with sufficient washout between doses; vehicle, prazosin and phenylephrine. The changes in blood pressure to each treatment were compared between the ambulatory oscillometric method and implantable telemetry in each animal. BP decreased after dosing with prazosin; increased, transiently, during dosing with phenylephrine; and did not change after dosing with vehicle. doi:10.1016/j.vascn.2011.03.169
Poster No: 165 Ambulatory non-invasive blood pressure recording in a freely moving cynomolgus monkey using High Definition Oscillometry (HDO) and Bluetooth technology Barthel Schmelting Covance, Muenster, Germany Avoidance of stress-associated blood pressure (BP) increases is crucial when evaluating drug related hemodynamic changes. In general, non-invasive BP assessment requires animal restraint and handling procedures, and allows only “snapshot” BP evaluation, especially in non-human primates (NHP). The HDO technique as a novel, non-invasive approach to record BP in animal models has demonstrated precision and sensitivity for BP measurement under restraint conditions. Now the feasibility of ambulatory (nonrestrained), non-invasive BP determination is possible in NHP using HDO combined with Bluetooth technology (HDO-BT). To evaluate HDO-BT, a male Macaca fascicularis (6.1 kg) implanted with a BP transmitter was used in this evaluation. The animal was fitted with a modified jacket with a prototype HDO-BT device (weight 325 g) and a tail cuff. After, the monkey was allowed free-movement in a cage with EU dimensions (cage size: 5.7 m³). Systolic (SYS), diastolic (DIA), mean arterial (MAP) BP and pulse rate derived by HDO-BT and implant telemetry were determined at 1 min intervals. Within 2 h, 15 valid HDO measurements, without artefacts, were made, with the following means (mm Hg ± SD): 130 ± 7 (SYS); 97 ± 7 (MAP), 78 ± 7 (DIA) and a pulse rate of 187. Mean time interval between the valid data was 8 min. This first attempt to conduct non-invasive, unrestrained, continuous BP recording by HDO-BT demonstrates the potential of this new technique for use in NHP toxicology studies. doi:10.1016/j.vascn.2011.03.170
e49
Poster No: 166 Assessment of drug induced hypertension and hypotension by non-invasive High Definition Oscillometry (HDO) in beagle dogs and cynomolgus monkeys Barthel Schmelting a, Jay Albretsen a, Dedhia Himanshu a, Kathy Derakhchan b, Hugo M. Vargas b a b
Covance, Chandler, USA Investigative Toxicology, Amgen Inc., Thousand Oaks, CA, USA
The novel HDO technique was evaluated as a potential noninvasive approach to record BP in beagle dogs and cynomolgus monkeys (NHP) during a three week dose-escalation study with: A) vehicle PO; B) hexamethonium, an antagonist of the ganglionic nicotinic acetylcholine receptor (20 mg/kg IV-dogs; 10 mg/kg IVNHP); and C) ephedrine, an agonist at α and β adrenergic receptors (10 mg/kg PO). Six animals (3M/3F) were used per group (N-18 per species). Once per week the animals were given one treatment, and HDO-BP measurements compared (pre-dose vs post-dose). There were no significant differences in BP in vehicle-treated dogs or NHP (group A) at any time point following dosing, compared to pre-dose values. Pharmacological effects could be determined at day 22 of study. In NHP, hexamethonium lowered systolic BP front a pre-dose baseline of 117 ± 25 mm Hg to 90 ± 8 mm Hg. In dogs given ephedrine, a significant increase in systolic BP could be detected (baseline: 142 ± 15 mm Hg; ephedrine: 176 ± 9 mm Hg; N = 6) when measured 2 h after dosing. A training/handling effect was obvious when predose BP data were compared on days 1, 8, 15 and 22 of the study. Acclimation of animals to the HDO method related to repeated handling may reduce overall physiological stress and reduce intraspecific group variability, which may facilitate detection of BP changes in ‘minimally-stressed’ animals. HDO appears to be a sensitive non-invasive method to assess BP in toxicology studies, but avoidance of stress-associated BP increases is crucial when evaluating drug-related hemodynamic changes. doi:10.1016/j.vascn.2011.03.171
Poster No: 167 The implications of handling, restraint, anesthesia, and kinetics on cardiac Troponin I analysis in rats when utilizing an ultrasensitive immunoassay Michael E. Dunn, Rachael Fernandes, Denise Coluccio, Rosemary Nicklaus, Gerard Hirkaler, Igor Mikaelian, Martin Sanders, Wanping Geng Roche, Nutley, New Jersey, USA Introduction: Recent advances in assay sensitivity have allowed for the quantification of cardiac Troponin I (cTnI) concentrations at previously undetectable levels. Here, we report the effects of restraint or anesthesia on baseline cTnI levels and the pharmacokinetic profile of cTnI in rats. Methods: Male rats were assigned to an event group (n = 12) entailing: no handling (NH), simulated tail vein injection (SI), or placement into an isoflurane/O2 anesthesia induction chamber (IF). Blood samples were collected via implanted femoral catheters at baseline, 6 and 48 h post-event. A separate 24-hr pharmacokinetics study consisting of a cTnI single bolus dose (0.005, 0.05, and 0.5 μg/kg purified rat cTnI) was performed on 18 additional rats (n = 6 per dose group). Serum cTnI was quantified using the Singulex Erenna® Ultrasensitive Immunoassay system.