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QT shift method in guinea pig
Abstracts
demonstrated immunosuppressive effects in animals; however, the cardiovascular liability remains unknown. These studies were designed to test both C-A and C-B on heart rate (HR) and blood pressure (BP) in conscious telemetrized rats and mice. Seven groups were studied in rats: vehicle, C-A at 0.3 and 5 mg/kg, C-B at 0.5, 5, 25, and 75 mg/kg. The C-A increased BP and decreased HR at doses of 0.3 and 5 mg/kg, respectively. C-B increased BP and decreased HR at doses of 25 and 75 mg/kg, but had no effect at 0.5 and 5 mg/kg. The hemodynamic effects observed with high doses of C-B may occur due to a lack of RX1 selectivity at high concentrations. To test this hypothesis, 8 groups of mice were studied: vehicle in wild type (WT) and knockout (KO) mice, C-A 10 mg/kg in WT and KO mice, and C-B at doses of 15 and 25 mg/kg in WT and KO mice. C-A increased BP and decreased HR in WT mice, but not in KO mice. These results suggest that the hemodynamic effects with C-A are directly linked to activation of RX2. C-B increased BP and decreased HR at a dose of 25 mg/kg in WT mice, but not in KO mice. These results suggest that the hemodynamic effects of high dose C-B in rats may be due to RX2 activation. The present study demonstrates that mouse telemetry is a valuable investigative model for safety studies. Selectivity for RX1 may have reduced liability compared to nonselective agonists.
doi:10.1016/j.vascn.2012.08.148
QT shift method in guinea pig Pascal Champeroux, Sebastien Jude, Eric Martel, Anne Maurin, Delphine Bouard, Aurore Contamine, Serge Richard Centre de Recherches Biologiques, CERB, Baugy, France QT interval prolongation constitutes a critical issue in the development of a new drug-candidate. A recent methodological refinement in nonclinical safety pharmacology telemetry studies designed to detect drug-induced QT prolongation is the probabilistic method we use in our laboratory in association with the QT shift method. In the present study, we have developed in Guinea pigs, the methodology routinely applied in large animals. For that purpose, Guinea pigs were instrumented with telemetric transmitters and subcutaneous ECG electrodes were placed in Lead II. The individual QT/RR relationships were built from 24-hour treatment free periods using the probabilistic method. The robustness of the QT shift method was tested using several reference drugs such as sotalol, thioridazine, dofetilide, terfenadine, haloperidol, cisapride and moxifloxacine. The results showed a very high sensitivity of the QT shift method in this species. Indeed, the statistical sensitivity threshold for detection of QT prolongation according to a standard study design including 6 Guinea pigs, 3 males and 3 females, was 3–4 ms. In conclusion, the QT shift method applied in Guinea pigs provides a reliable and precise assessment of drug-induced QT interval prolongation that can be particularly helpful in the early phase of development of a new drug-candidate.
doi:10.1016/j.vascn.2012.08.149
Assessing methods for the detection of pharmacologically induced myocardial ischemia in the conscious rat Philip H. Millikena, Tom Le Rueza, Andrew H. Tennanta, Gemma L. Warda, Malcolm J. Yorkb, Nick C. McMahona, James B. Louttita, Bela A. Patela a
GlaxoSmithKline, Safety Pharmacology, Ware, United Kingdom Clinical Pathology, Ware, United Kingdom
b
201
There are limited methods for assessing early preclinical drug induced myocardial effects from data generated in functional Safety Pharmacology studies. Here we examined the effects of both Isoprenaline (Iso) and Dobutamine (Dob) as positive controls, to assess markers of myocardial ischemia in the rat. Telemetered rats received 1 h intravenous infusions of vehicle (0.9% w/v aqueous NaCl), 360 and 720 μg/kg Dob, or 0.6, 1.8 and 3.6 μg/kg Iso. Blood pressures and heart rates were collected allowing analysis of Rate Pressure Product (RPP, index of myocardial oxygen consumption); ECG signals were analysed for several parameters including R-T amplitude, and T-amplitude. Blood samples were also taken for measurement of cardiac troponin I (cTnI, biomarker of myocardial damage). Systolic blood pressure was decreased by Dob (up to 14 mm Hg) and Iso (up to 19 mm Hg), with peak heart rate increases of 90 and 129 bpm, respectively. Dob increased RPP by up to 12%, and 31% following Iso, although Iso displayed more variability. T-amplitude was increased by both Dob and Iso, which was again more variable following Iso treatment. R-T amplitude was elevated by Iso (33%), but decreased by Dob. Serum cTnI levels were raised by both treatments at the high dose. cTnI remains an efficient marker of myocardial damage, with effects on RPP also being identified. Several additional parameters (R-T amplitude, T-amplitude) were modified, although variability was evident between treatments, but these could contribute to enhanced analysis in identifying myocardial risk.
doi:10.1016/j.vascn.2012.08.150
Use of jacketed external telemetry in the conscious guinea-pig in early assessment of cardio-respiratory function Abdel-Ilah El Amrani, Anne-Marie Bétat, Stéphane Loriot, Roy Forster, Jean-Jacques Legrand CiTox-LAB, Evreux, France Because of the high predictive value of the guinea-pig in identifying QT lengthening potential and arrhythmias of drug candidates, this animal model is intensively used as an anesthetized or conscious model using implanted telemetry. Chronic implantation of telemetry devices in the guinea-pig requires surgical intervention that may be tedious, time-consuming and expensive. The purpose of the present study is to evaluate a jacketed external telemetry system in the freely moving guinea-pig. Placement of these animals in plethysmographs allows simultaneous recording of ECG and respiratory parameters. Female guinea-pigs have been equipped with external jacketed telemetry using DSI transmitters for ECG recording. Effects of sotalol (10 mg/kg) on ECG were investigated in 8 freely moving guinea-pigs per group. Effects of clonidine (5 mg/kg) and theophylline (10 mg/kg) on ECG and respiratory function have been investigated. All treatments were performed by oral route and all parameters were recorded for 1 h before and at least 4 h after treatment. Despite the low doses used in the study, increases in QT and QTb (Bazett) were observed with sotalol. Clonidine and theophylline produced bronchoconstriction and bronchodilatation, respectively. The present study demonstrates that the use of jacketed external telemetry in the freely moving guinea-pig may be considered as a valuable tool in the assessment of cardio-respiratory function in early drug development process.
doi:10.1016/j.vascn.2012.08.151
demonstrated immunosuppressive effects in animals; however, the cardiovascular liability remains unknown. These studies were designed to test both C-A and C-B on heart rate (HR) and blood pressure (BP) in conscious telemetrized rats and mice. Seven groups were studied in rats: vehicle, C-A at 0.3 and 5 mg/kg, C-B at 0.5, 5, 25, and 75 mg/kg. The C-A increased BP and decreased HR at doses of 0.3 and 5 mg/kg, respectively. C-B increased BP and decreased HR at doses of 25 and 75 mg/kg, but had no effect at 0.5 and 5 mg/kg. The hemodynamic effects observed with high doses of C-B may occur due to a lack of RX1 selectivity at high concentrations. To test this hypothesis, 8 groups of mice were studied: vehicle in wild type (WT) and knockout (KO) mice, C-A 10 mg/kg in WT and KO mice, and C-B at doses of 15 and 25 mg/kg in WT and KO mice. C-A increased BP and decreased HR in WT mice, but not in KO mice. These results suggest that the hemodynamic effects with C-A are directly linked to activation of RX2. C-B increased BP and decreased HR at a dose of 25 mg/kg in WT mice, but not in KO mice. These results suggest that the hemodynamic effects of high dose C-B in rats may be due to RX2 activation. The present study demonstrates that mouse telemetry is a valuable investigative model for safety studies. Selectivity for RX1 may have reduced liability compared to nonselective agonists.
doi:10.1016/j.vascn.2012.08.148
QT shift method in guinea pig Pascal Champeroux, Sebastien Jude, Eric Martel, Anne Maurin, Delphine Bouard, Aurore Contamine, Serge Richard Centre de Recherches Biologiques, CERB, Baugy, France QT interval prolongation constitutes a critical issue in the development of a new drug-candidate. A recent methodological refinement in nonclinical safety pharmacology telemetry studies designed to detect drug-induced QT prolongation is the probabilistic method we use in our laboratory in association with the QT shift method. In the present study, we have developed in Guinea pigs, the methodology routinely applied in large animals. For that purpose, Guinea pigs were instrumented with telemetric transmitters and subcutaneous ECG electrodes were placed in Lead II. The individual QT/RR relationships were built from 24-hour treatment free periods using the probabilistic method. The robustness of the QT shift method was tested using several reference drugs such as sotalol, thioridazine, dofetilide, terfenadine, haloperidol, cisapride and moxifloxacine. The results showed a very high sensitivity of the QT shift method in this species. Indeed, the statistical sensitivity threshold for detection of QT prolongation according to a standard study design including 6 Guinea pigs, 3 males and 3 females, was 3–4 ms. In conclusion, the QT shift method applied in Guinea pigs provides a reliable and precise assessment of drug-induced QT interval prolongation that can be particularly helpful in the early phase of development of a new drug-candidate.
doi:10.1016/j.vascn.2012.08.149
Assessing methods for the detection of pharmacologically induced myocardial ischemia in the conscious rat Philip H. Millikena, Tom Le Rueza, Andrew H. Tennanta, Gemma L. Warda, Malcolm J. Yorkb, Nick C. McMahona, James B. Louttita, Bela A. Patela a
GlaxoSmithKline, Safety Pharmacology, Ware, United Kingdom Clinical Pathology, Ware, United Kingdom
b
201
There are limited methods for assessing early preclinical drug induced myocardial effects from data generated in functional Safety Pharmacology studies. Here we examined the effects of both Isoprenaline (Iso) and Dobutamine (Dob) as positive controls, to assess markers of myocardial ischemia in the rat. Telemetered rats received 1 h intravenous infusions of vehicle (0.9% w/v aqueous NaCl), 360 and 720 μg/kg Dob, or 0.6, 1.8 and 3.6 μg/kg Iso. Blood pressures and heart rates were collected allowing analysis of Rate Pressure Product (RPP, index of myocardial oxygen consumption); ECG signals were analysed for several parameters including R-T amplitude, and T-amplitude. Blood samples were also taken for measurement of cardiac troponin I (cTnI, biomarker of myocardial damage). Systolic blood pressure was decreased by Dob (up to 14 mm Hg) and Iso (up to 19 mm Hg), with peak heart rate increases of 90 and 129 bpm, respectively. Dob increased RPP by up to 12%, and 31% following Iso, although Iso displayed more variability. T-amplitude was increased by both Dob and Iso, which was again more variable following Iso treatment. R-T amplitude was elevated by Iso (33%), but decreased by Dob. Serum cTnI levels were raised by both treatments at the high dose. cTnI remains an efficient marker of myocardial damage, with effects on RPP also being identified. Several additional parameters (R-T amplitude, T-amplitude) were modified, although variability was evident between treatments, but these could contribute to enhanced analysis in identifying myocardial risk.
doi:10.1016/j.vascn.2012.08.150
Use of jacketed external telemetry in the conscious guinea-pig in early assessment of cardio-respiratory function Abdel-Ilah El Amrani, Anne-Marie Bétat, Stéphane Loriot, Roy Forster, Jean-Jacques Legrand CiTox-LAB, Evreux, France Because of the high predictive value of the guinea-pig in identifying QT lengthening potential and arrhythmias of drug candidates, this animal model is intensively used as an anesthetized or conscious model using implanted telemetry. Chronic implantation of telemetry devices in the guinea-pig requires surgical intervention that may be tedious, time-consuming and expensive. The purpose of the present study is to evaluate a jacketed external telemetry system in the freely moving guinea-pig. Placement of these animals in plethysmographs allows simultaneous recording of ECG and respiratory parameters. Female guinea-pigs have been equipped with external jacketed telemetry using DSI transmitters for ECG recording. Effects of sotalol (10 mg/kg) on ECG were investigated in 8 freely moving guinea-pigs per group. Effects of clonidine (5 mg/kg) and theophylline (10 mg/kg) on ECG and respiratory function have been investigated. All treatments were performed by oral route and all parameters were recorded for 1 h before and at least 4 h after treatment. Despite the low doses used in the study, increases in QT and QTb (Bazett) were observed with sotalol. Clonidine and theophylline produced bronchoconstriction and bronchodilatation, respectively. The present study demonstrates that the use of jacketed external telemetry in the freely moving guinea-pig may be considered as a valuable tool in the assessment of cardio-respiratory function in early drug development process.
doi:10.1016/j.vascn.2012.08.151