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Effects of fentanyl analgesia on electromechanical indices in conscious beagle dogs
188
Abstracts
0102 M-mode and 2D-speckle tracking echocardiography for the assessment of cardiac function in conscious dogs Kenta Watanabe, Akihiko Kiyoshi, Yasunori Katsura, Yuji Ogi, Tadashi Tsubouchi, Hitoshi Funabashi Sumitomo Dainippon Pharma Co., Ltd., Osaka, Japan Introduction: Echocardiography is a non-invasive imaging technique, which is considered to be useful for evaluation of cardiac function and morphology in safety studies for new drug development. Although M-mode is used for a simple method to measure cardiac function in the echocardiography, 2D-speckle tracking has been reported to be helpful for the further evaluation of the ventricle movement. In the present study, we assessed positive and negative inotropic effects of some drugs on cardiac contractility in conscious dogs by transthoracic echocardiography in M-mode as well as 2Dspeckle tracking. Method: Male conscious beagle dogs were intravenously administered with dobutamine (0.01–0.1 mg/kg), milrinone (0.01–0.1 mg/ kg) or atenolol (0.1, 0.3 mg/kg). Echocardiography was performed, using iE33 ultrasound system (Philips) equipped with 5 MHz transducer before and after administration. The right parasternal long- and short-axis views were obtained for M-mode and 2Dspeckle tracking analysis, respectively. Results: Dobutamine and milrinone increased Ejection Fraction (EF) by 15.4% and 19.2%, respectively (n = 3). To the contrary, atenolol decreased EF by 9.8% (n = 3). In addition, asynchrony in radial strain changes was found in a dog by means of 2D-speckle tracking, without change in EF by means of M-mode. Discussion: These data indicated that echocardiography can detect positive or negative inotropic effects of drugs in conscious dogs. In conclusion, echocardiography can be useful for the assessment of new drugs on the cardiac function in preclinical studies. Combined echocardiography with M-mode and 2D-speckle tracking helps further assessment of abnormal cardiac motions.
doi:10.1016/j.vascn.2015.08.101
0103 Effects of fentanyl analgesia on electromechanical indices in conscious beagle dogs Bradley Youngblooda, Carlos del Rioa, Sai Sutayatrama,c, Robert Hamlina,b, Bill Muira a
QTest Labs, Columbus, OH, USA The Ohio State University, Columbus, OH, USA c Chulalongkorn University, Bangkok, Thailand b
Fentanyl is an opiate analgesic commonly used in safety pharmacology studies. This study sought to determine the effects of fentanyl-analgesia on various electromechanical indices associated with cardiovascular liabilities; two fentanyl-preparations were studied, 1) a traditional continuous intravenous administration (IVF), and 2) a novel single-application transdermal solution (TDF, Elanco™). Healthy canine beagle dogs were instrumented for the recording of high-fidelity and telemetered left ventricular pressures (LVP), as well as for single-lead electrocardiogram (ECG) and aortic pressures. Electro-mechanical parameters were measured before and during fentanyl administration/application for up to 3 h; IVF was given at 5 μg/kg/h (with a 5 μg/kg loading bolus), while TDF was
given as labeled. On average, during the 3 hour observation period, fentanyl decreased heart rate (IVF: − 24%–TDF: −31%), while lengthening indices of repolarization (e.g., TPE, IVF: +37%–TDF: +16%). Fentanyl also shortened the electro-mechanical window (EMW, IVF: − 15%–TDF:-13%). Fentanyl had minimal effects on LV systolic pressures (IVF: − 2%–TDF: +2%), dP/dtmax (IVF: −4%–TDF: −10%) and the contractility index (CI, IVF: + 2%–TDF: −4%), however, it prolonged the time-constant of relaxation (IVF: + 20%– TDF: + 12%). The peak electromechanical effects of IVF (~ 30 min) and TDF (~180 min) differed. Taken together, these data support considerable electromechanical effects of fentanyl (when given at analgesic doses) in conscious beagle dogs, negatively affecting chronotropy, repolarization and lusitropy.
doi:10.1016/j.vascn.2015.08.102
0104 Assessment of sedative or stimulant effect of drugs using the thiopental-induced sleeping time test Delphine Parachou, Emilie Cayre, Anthony Déal, Manon Sauvagnat, Sabrina Guiffard, Christophe Drieu la Rochelle, Eric Delpy BIOTRIAL Pharmacology, Rennes, France The interaction with the sleep induced by barbiturates, such as hexobarbital, is a classic model used in safety pharmacology for the assessment of sedative or stimulant activity of new CNS-active drugs. Hexobarbital being no longer commercially available, the aim of the study was to validate the model using thiopental, a short acting barbiturate anesthetic which has been clinically proven. The loss of righting reflex is measured in male Wistar rats as a criterion for the duration of thiopental-induced sleeping time. Incidence and latency to sleep were also measured. Thiopental administered i.p. led to either a weak incidence at low doses or too long sleep duration at high doses (cut-off 60 min). Thiopental was therefore administered through the i.v. route (tail vein). Doses of 18, 22 and 25 mg/kg i.v. induced sleeping in 100% of the rats and sleep duration of 270, 550 and 890 s, respectively. Pharmacological validation was performed using a dose of thiopental of 25 mg/kg i.v. Diazepam (1, 2.5 and 5 mg/kg p.o.), Clonidine (0.1, 0.3 and 1 mg/kg p.o.) and Chlorpromazine (10 and 30 mg/kg p.o.) dose-dependently potentiated the thiopental-induced sleeping time. On the contrary, amphetamine (10 mg/kg p.o.), caffeine (100 mg/kg p.o.) and a new test compound (60 mg/kg p.o.) were able to decrease this parameter. In conclusion, these results demonstrate that intravenous administration of thiopental can be used to induce sleeping in rats and that this model could be used to assess potential sedative or stimulant activity of new CNS-active drugs.
doi:10.1016/j.vascn.2015.08.103
0105 Predictive validity of an integrated preclinical approach combining in vivo rat PK/PD and in vitro rat hippocampal brain slice assays to assess drug-induced seizure risk liability Ivy Garfinkel, Jin Zhai, Jeff Travis, Haoyu Zeng, Armando Lagrutta, Alysia Chaves, Ying-Ying Zhou, Frederick Sannajust Merck Research Laboratories, West Point, PA, USA
Abstracts
0102 M-mode and 2D-speckle tracking echocardiography for the assessment of cardiac function in conscious dogs Kenta Watanabe, Akihiko Kiyoshi, Yasunori Katsura, Yuji Ogi, Tadashi Tsubouchi, Hitoshi Funabashi Sumitomo Dainippon Pharma Co., Ltd., Osaka, Japan Introduction: Echocardiography is a non-invasive imaging technique, which is considered to be useful for evaluation of cardiac function and morphology in safety studies for new drug development. Although M-mode is used for a simple method to measure cardiac function in the echocardiography, 2D-speckle tracking has been reported to be helpful for the further evaluation of the ventricle movement. In the present study, we assessed positive and negative inotropic effects of some drugs on cardiac contractility in conscious dogs by transthoracic echocardiography in M-mode as well as 2Dspeckle tracking. Method: Male conscious beagle dogs were intravenously administered with dobutamine (0.01–0.1 mg/kg), milrinone (0.01–0.1 mg/ kg) or atenolol (0.1, 0.3 mg/kg). Echocardiography was performed, using iE33 ultrasound system (Philips) equipped with 5 MHz transducer before and after administration. The right parasternal long- and short-axis views were obtained for M-mode and 2Dspeckle tracking analysis, respectively. Results: Dobutamine and milrinone increased Ejection Fraction (EF) by 15.4% and 19.2%, respectively (n = 3). To the contrary, atenolol decreased EF by 9.8% (n = 3). In addition, asynchrony in radial strain changes was found in a dog by means of 2D-speckle tracking, without change in EF by means of M-mode. Discussion: These data indicated that echocardiography can detect positive or negative inotropic effects of drugs in conscious dogs. In conclusion, echocardiography can be useful for the assessment of new drugs on the cardiac function in preclinical studies. Combined echocardiography with M-mode and 2D-speckle tracking helps further assessment of abnormal cardiac motions.
doi:10.1016/j.vascn.2015.08.101
0103 Effects of fentanyl analgesia on electromechanical indices in conscious beagle dogs Bradley Youngblooda, Carlos del Rioa, Sai Sutayatrama,c, Robert Hamlina,b, Bill Muira a
QTest Labs, Columbus, OH, USA The Ohio State University, Columbus, OH, USA c Chulalongkorn University, Bangkok, Thailand b
Fentanyl is an opiate analgesic commonly used in safety pharmacology studies. This study sought to determine the effects of fentanyl-analgesia on various electromechanical indices associated with cardiovascular liabilities; two fentanyl-preparations were studied, 1) a traditional continuous intravenous administration (IVF), and 2) a novel single-application transdermal solution (TDF, Elanco™). Healthy canine beagle dogs were instrumented for the recording of high-fidelity and telemetered left ventricular pressures (LVP), as well as for single-lead electrocardiogram (ECG) and aortic pressures. Electro-mechanical parameters were measured before and during fentanyl administration/application for up to 3 h; IVF was given at 5 μg/kg/h (with a 5 μg/kg loading bolus), while TDF was
given as labeled. On average, during the 3 hour observation period, fentanyl decreased heart rate (IVF: − 24%–TDF: −31%), while lengthening indices of repolarization (e.g., TPE, IVF: +37%–TDF: +16%). Fentanyl also shortened the electro-mechanical window (EMW, IVF: − 15%–TDF:-13%). Fentanyl had minimal effects on LV systolic pressures (IVF: − 2%–TDF: +2%), dP/dtmax (IVF: −4%–TDF: −10%) and the contractility index (CI, IVF: + 2%–TDF: −4%), however, it prolonged the time-constant of relaxation (IVF: + 20%– TDF: + 12%). The peak electromechanical effects of IVF (~ 30 min) and TDF (~180 min) differed. Taken together, these data support considerable electromechanical effects of fentanyl (when given at analgesic doses) in conscious beagle dogs, negatively affecting chronotropy, repolarization and lusitropy.
doi:10.1016/j.vascn.2015.08.102
0104 Assessment of sedative or stimulant effect of drugs using the thiopental-induced sleeping time test Delphine Parachou, Emilie Cayre, Anthony Déal, Manon Sauvagnat, Sabrina Guiffard, Christophe Drieu la Rochelle, Eric Delpy BIOTRIAL Pharmacology, Rennes, France The interaction with the sleep induced by barbiturates, such as hexobarbital, is a classic model used in safety pharmacology for the assessment of sedative or stimulant activity of new CNS-active drugs. Hexobarbital being no longer commercially available, the aim of the study was to validate the model using thiopental, a short acting barbiturate anesthetic which has been clinically proven. The loss of righting reflex is measured in male Wistar rats as a criterion for the duration of thiopental-induced sleeping time. Incidence and latency to sleep were also measured. Thiopental administered i.p. led to either a weak incidence at low doses or too long sleep duration at high doses (cut-off 60 min). Thiopental was therefore administered through the i.v. route (tail vein). Doses of 18, 22 and 25 mg/kg i.v. induced sleeping in 100% of the rats and sleep duration of 270, 550 and 890 s, respectively. Pharmacological validation was performed using a dose of thiopental of 25 mg/kg i.v. Diazepam (1, 2.5 and 5 mg/kg p.o.), Clonidine (0.1, 0.3 and 1 mg/kg p.o.) and Chlorpromazine (10 and 30 mg/kg p.o.) dose-dependently potentiated the thiopental-induced sleeping time. On the contrary, amphetamine (10 mg/kg p.o.), caffeine (100 mg/kg p.o.) and a new test compound (60 mg/kg p.o.) were able to decrease this parameter. In conclusion, these results demonstrate that intravenous administration of thiopental can be used to induce sleeping in rats and that this model could be used to assess potential sedative or stimulant activity of new CNS-active drugs.
doi:10.1016/j.vascn.2015.08.103
0105 Predictive validity of an integrated preclinical approach combining in vivo rat PK/PD and in vitro rat hippocampal brain slice assays to assess drug-induced seizure risk liability Ivy Garfinkel, Jin Zhai, Jeff Travis, Haoyu Zeng, Armando Lagrutta, Alysia Chaves, Ying-Ying Zhou, Frederick Sannajust Merck Research Laboratories, West Point, PA, USA