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Effect of chronic treatment of rosiglitazone and sitagliptin on cardiac function in genetic diabetic mice
Abstracts
Test Article X is a protein biologic with potential therapeutic indications in ocular disease. As part of the safety assessment program designed for this biotechnology-derived pharmaceutical, a comprehensive evaluation of relevant toxicological and safety pharmacology endpoints was conducted within a unified study design in the cynomolgus monkey. To facilitate the most appropriate assessment of administration route and local and systemic exposure levels and to permit sound characterization of potential safety concerns, four intravitreal and one intravenous dose groups were designated. At appropriate intervals relative to the course of dosing, groups 1–4 (IVT) were evaluated for clinical findings, food consumption, body weight, standard ophthalmoscopy, electroretinograms (ERG), electrocardiograms (ECG), clinical pathology, toxicokinetics, organ weights and standard macroscopic and microscopic examinations. Prior to study, group 5 (IV) animals were surgically implanted with telemetry transmitters (DSI-PCTR) capable of monitoring body temperature, electrocardiograms, blood pressure, heart rate, and respiratory mechanics (rate and volume), and were periodically assessed for these endpoints in addition to a battery of central nervous system tests and ECG morphology at appropriate intervals prior to and following the initiation of dosing. The chosen study design, with selected dose routes, telemetry instrumentation, and distribution of dependent measures allowed full characterization of the safety profile of Test Article X within an efficient model which also demonstrated accountability to animal use/ welfare (3Rs) concerns.
OF
The Safety Pharmacology Society (SPS) conducted an industry survey in 2012 in an attempt to define current industry practices as they relate to inclusion of safety pharmacology (SP) endpoints into Toxicology studies. The most frequent primary motivator for adding ICHS7 SP endpoints to regulatory toxicology studies was to generate additional data to allow for determination of an integrated risk assessment thereby testing Confidence in Safety (CIS) to better manage and/ or mitigate risk. Respondents suggest that such discussion could occur at the pre-IND meeting before the IND/CTA enabling program. A number of studies in which the respiratory and neurobehavioural assessments were included in the four-week repeated toxicology study in rats were reviewed from a CRO perspective. Different factors such as costs, efficiency and quality of data, added values or limitations were analyzed. Strategic considerations on the integration of SP endpoints in Toxicological studies are provided.
325
doi:10.1016/j.vascn.2014.03.056
CiToxLAB (Scantox) A/S, Lille Skensved, Denmark
doi:10.1016/j.vascn.2014.03.058
DP
Repeated measurements of motor activity in rats in long-term toxicity studies Valeria Golozoubova, Tina Brodersen, Signe Klastrup, Marjatta Oksama, Jeanet Loegsted, Andy Makin
RO
0052
0054
Effect of chronic treatment of rosiglitazone and sitagliptin on cardiac function in genetic diabetic mice Bianca Hemmeryckxa, Melissa Swinnena, Marc Hoylaertsa, David Gallacherb, Hua Rong Lub, Uwe Himmelreicha, Jan D´hoogea, H. Roger Lijnena
UN
CO
RR
EC
TE
Interpretation of the results of motor activity evaluation (open field test) repeatedly performed in the course of a long-term toxicity study is often complicated by time-dependent effects in the control group, which may differ between strains and gender. We compared the results of repeated open field test performed in both genders of Wistar and Sprague Dawley (SPRD) rats. All animals were examined in a standardised open field test before the start (Day-7), on Day 2, in Week 6 and in Week 13 of treatment with saline. Compared to naïve SPRD rats, naïve Wistar rats were more stressed when placed in the arena. In both strains, while average activity level on Day 2, in Week 6 and in Week 13 was comparable to that in the naïve animals, individual variation between animals in performance in the arena was higher at repeated measurements than in the start. This has a clear implication for decision on the group size in this type of studies. Three Wistar rats developed stereotypic behaviour in the home cage after 7 weeks. This was not observed in SPRD rats. In conclusion, due to individual variation, relatively large group of animals has to be tested in arena in order to obtain reliable data in the long term study. Male SPRD rats performed slightly better in the test in comparison to SPRD females and both genders of Wistar rats, as they showed less stress at initial exposure to the arena and slightly less variability in the results.
doi:10.1016/j.vascn.2014.03.057
0053
Integrated toxicological and safety pharmacology evaluation of a novel monoclonal antibody therapy for ocular disease in the cynomolgus monkey Marci Hartera, Melissa Haskellb, Denis Schrierb, Theodore Bairda a
MPI Research, Mattawan, MI, USA Alexion Pharmaceuticals, Inc., Cambridge, MA, USA
b
a
KU Leuven, Leuven, Belgium Janssen Research and Development, Janssen Pharmaceutica NV, Beerse, Belgium
b
To investigate the chronic effect of rosiglitazone (RGZ) and sitagliptin (SIT) on cardiac function in genetic diabetic Akita mice, 10 weeks old Akita mice were either exposed for 4 months to a high fat and high cholesterol (HF–HC) diet, with or without 10 or 30 mg/kg/day RGZ, or 10 mg/kg/day SIT, or were fed for 3 months with the same diet with or without 50 mg/kg/day SIT. Analysis of the heart function of Akita mice kept on the HF–HC diet by electrocardiography suggested a tendency to heart failure through impairment of systolic function as evidenced by a decrease in ejection fraction (EF) and fractional shortening (FS). Treatment with 10 mg/kg/day RGZ, however, did not markedly affect FS or EF. A higher dose of RGZ (30 mg/kg/day) induced early signs of hypertrophy as evidenced by increases in the intraventricular septum thickness and in cardiac output, without a significant effect on FS or EF. Administration of 10 mg/kg/day of SIT for 4 months to Akita mice showed improvements in EF and FS, whereas SIT at 50 mg/kg/day had no significant effect on these parameters, but it induced left ventricular (LV) hypertrophy as evidenced by an enlarged LV internal diameter, volume and mass. Thus, in this diabetic Akita mouse model, SIT is cardioprotective at a low dose (10 mg/kg/day), whereas a higher dose of SIT (50 mg/kg/day) and RGZ (30 mg/kg/day) induced early signs of LV hypertrophic cardiomyopathy. This mouse model may thus be potentially useful to study efficacy and safety of anti-diabetic drugs. doi:10.1016/j.vascn.2014.03.059
Test Article X is a protein biologic with potential therapeutic indications in ocular disease. As part of the safety assessment program designed for this biotechnology-derived pharmaceutical, a comprehensive evaluation of relevant toxicological and safety pharmacology endpoints was conducted within a unified study design in the cynomolgus monkey. To facilitate the most appropriate assessment of administration route and local and systemic exposure levels and to permit sound characterization of potential safety concerns, four intravitreal and one intravenous dose groups were designated. At appropriate intervals relative to the course of dosing, groups 1–4 (IVT) were evaluated for clinical findings, food consumption, body weight, standard ophthalmoscopy, electroretinograms (ERG), electrocardiograms (ECG), clinical pathology, toxicokinetics, organ weights and standard macroscopic and microscopic examinations. Prior to study, group 5 (IV) animals were surgically implanted with telemetry transmitters (DSI-PCTR) capable of monitoring body temperature, electrocardiograms, blood pressure, heart rate, and respiratory mechanics (rate and volume), and were periodically assessed for these endpoints in addition to a battery of central nervous system tests and ECG morphology at appropriate intervals prior to and following the initiation of dosing. The chosen study design, with selected dose routes, telemetry instrumentation, and distribution of dependent measures allowed full characterization of the safety profile of Test Article X within an efficient model which also demonstrated accountability to animal use/ welfare (3Rs) concerns.
OF
The Safety Pharmacology Society (SPS) conducted an industry survey in 2012 in an attempt to define current industry practices as they relate to inclusion of safety pharmacology (SP) endpoints into Toxicology studies. The most frequent primary motivator for adding ICHS7 SP endpoints to regulatory toxicology studies was to generate additional data to allow for determination of an integrated risk assessment thereby testing Confidence in Safety (CIS) to better manage and/ or mitigate risk. Respondents suggest that such discussion could occur at the pre-IND meeting before the IND/CTA enabling program. A number of studies in which the respiratory and neurobehavioural assessments were included in the four-week repeated toxicology study in rats were reviewed from a CRO perspective. Different factors such as costs, efficiency and quality of data, added values or limitations were analyzed. Strategic considerations on the integration of SP endpoints in Toxicological studies are provided.
325
doi:10.1016/j.vascn.2014.03.056
CiToxLAB (Scantox) A/S, Lille Skensved, Denmark
doi:10.1016/j.vascn.2014.03.058
DP
Repeated measurements of motor activity in rats in long-term toxicity studies Valeria Golozoubova, Tina Brodersen, Signe Klastrup, Marjatta Oksama, Jeanet Loegsted, Andy Makin
RO
0052
0054
Effect of chronic treatment of rosiglitazone and sitagliptin on cardiac function in genetic diabetic mice Bianca Hemmeryckxa, Melissa Swinnena, Marc Hoylaertsa, David Gallacherb, Hua Rong Lub, Uwe Himmelreicha, Jan D´hoogea, H. Roger Lijnena
UN
CO
RR
EC
TE
Interpretation of the results of motor activity evaluation (open field test) repeatedly performed in the course of a long-term toxicity study is often complicated by time-dependent effects in the control group, which may differ between strains and gender. We compared the results of repeated open field test performed in both genders of Wistar and Sprague Dawley (SPRD) rats. All animals were examined in a standardised open field test before the start (Day-7), on Day 2, in Week 6 and in Week 13 of treatment with saline. Compared to naïve SPRD rats, naïve Wistar rats were more stressed when placed in the arena. In both strains, while average activity level on Day 2, in Week 6 and in Week 13 was comparable to that in the naïve animals, individual variation between animals in performance in the arena was higher at repeated measurements than in the start. This has a clear implication for decision on the group size in this type of studies. Three Wistar rats developed stereotypic behaviour in the home cage after 7 weeks. This was not observed in SPRD rats. In conclusion, due to individual variation, relatively large group of animals has to be tested in arena in order to obtain reliable data in the long term study. Male SPRD rats performed slightly better in the test in comparison to SPRD females and both genders of Wistar rats, as they showed less stress at initial exposure to the arena and slightly less variability in the results.
doi:10.1016/j.vascn.2014.03.057
0053
Integrated toxicological and safety pharmacology evaluation of a novel monoclonal antibody therapy for ocular disease in the cynomolgus monkey Marci Hartera, Melissa Haskellb, Denis Schrierb, Theodore Bairda a
MPI Research, Mattawan, MI, USA Alexion Pharmaceuticals, Inc., Cambridge, MA, USA
b
a
KU Leuven, Leuven, Belgium Janssen Research and Development, Janssen Pharmaceutica NV, Beerse, Belgium
b
To investigate the chronic effect of rosiglitazone (RGZ) and sitagliptin (SIT) on cardiac function in genetic diabetic Akita mice, 10 weeks old Akita mice were either exposed for 4 months to a high fat and high cholesterol (HF–HC) diet, with or without 10 or 30 mg/kg/day RGZ, or 10 mg/kg/day SIT, or were fed for 3 months with the same diet with or without 50 mg/kg/day SIT. Analysis of the heart function of Akita mice kept on the HF–HC diet by electrocardiography suggested a tendency to heart failure through impairment of systolic function as evidenced by a decrease in ejection fraction (EF) and fractional shortening (FS). Treatment with 10 mg/kg/day RGZ, however, did not markedly affect FS or EF. A higher dose of RGZ (30 mg/kg/day) induced early signs of hypertrophy as evidenced by increases in the intraventricular septum thickness and in cardiac output, without a significant effect on FS or EF. Administration of 10 mg/kg/day of SIT for 4 months to Akita mice showed improvements in EF and FS, whereas SIT at 50 mg/kg/day had no significant effect on these parameters, but it induced left ventricular (LV) hypertrophy as evidenced by an enlarged LV internal diameter, volume and mass. Thus, in this diabetic Akita mouse model, SIT is cardioprotective at a low dose (10 mg/kg/day), whereas a higher dose of SIT (50 mg/kg/day) and RGZ (30 mg/kg/day) induced early signs of LV hypertrophic cardiomyopathy. This mouse model may thus be potentially useful to study efficacy and safety of anti-diabetic drugs. doi:10.1016/j.vascn.2014.03.059