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Reliable blood pressure measurements with an external telemetry system (JET) in conscious, freely moving monkeys (M. fascicularis) in comparison to a fully implanted system
Abstracts / Toxicology Letters 205S (2011) S180–S300
P2087 A rodent model for visceral obesity development evaluated by MRI M. Rönn 1 , P.M. Lind 1,∗ , L. Lind 2 , F. Ortiz-Nieto 3 , H. Karlsson 4 , J. Kullberg 3 1 Occupational and Environmental Medicine, Uppsala University, Uppsala, Sweden, 2 Acute and Internal Medicine, Department of Medicine, Uppsala University, Uppsala, Sweden, 3 Division of Radiology, Department of Ros (Radiology, Oncology and Radiation Science), Uppsala University, Uppsala, Sweden, 4 Linkoping University Hospital, Occupational and Environmental Medicine, Linköpings University, Uppsala, Sweden
Purpose: To study possible effects of environmental contaminants on obesity development, a rodent model was developed by which a modest increase in fat adipose tissue in an environment of caloric excess could be induced. Since visceral adiposity is more dangerous than subcutaneous adiposity, magnetic resonance imaging (MRI) was used for fat quantification. Methods: Twenty-four 4-week-old female Fischer rats were divided into 2 groups. The exposed group was given drinking water containing fructose (5% for 7 weeks, then 20% for 3 weeks). At sacrifice, whole body MRI was performed to determine fat and lean mass. An intra-abdominal fat pad and the liver were dissected and weighed. Proteins were analyzed by Western Blot. Results: Rats given fructose gained 5 g more in weight during exposure than the control rats (p < 0.05). At sacrifice, their total body fat mass was modestly increased (28 cm3 vs. 24 cm3 , p < 0.05), while the weights of the fat pad (0.85 g vs. 0.67 g, p < 0.0001) and liver (5.2 g vs. 4.6 g, p = 0.001) were increased to a larger extent. Regarding the lipids, the most pronounced effects were seen for serum triglycerides (1.5 mmol/l vs. 1.0 mmol/l, p < 0.0001) and an increase of plasma apo A-I (p < 0.005) in fructose exposed rats. Conclusion: The model, based on modest fructose feeding evaluated by MRI, induced modest visceral obesity and hypertriglyceridemia, making it suitable for the study of cases where environmental contaminants further exaggerate the obesity development following modest excess caloric intake. doi:10.1016/j.toxlet.2011.05.711
P2088 Reliable blood pressure measurements with an external telemetry system (JET) in conscious, freely moving monkeys (M. fascicularis) in comparison to a fully implanted system B. Niggemann ∗ , M. Niehoff, J. Sternberg, G.F. Weinbauer Covance Laboratories GmbH, Muenster, Germany Purpose: This investigation reports results of blood pressure (BP) measurements recorded by an external telemetry system (JETTM ) in comparison to a fully implanted telemetry system. Intra animal and inter run precision were determined using both systems. In addition, hyper- and hypotensive compounds were investigated with the JET system. Methods: For the intra and inter run precision, two male monkeys carrying a fully implanted Koenigsberg telemetry implant (T27F-2B) were equipped with an additional miniature DSI BP transmitter (PA-C10-TOX-SA) for continuous blood pressure measurements. The animals carried a jacket including the JET equipment during the recordings. Systolic, diastolic, and mean arterial blood pressure was measured three times on day 1 and on 3 consecutive days for a period of at least 10 min. For manipulation of BP, twelve female monkeys were implanted with the
S207
DSI BP transmitter and distributed into 3 groups (n = 4) receiving either vehicle (water), or 1 or 10 mg/kg of etilefrine (Effortil® ) or 4 and 10 mg/kg of dihydralazine (Nepresol® ). Data were recorded for 1 h predose and 22 h post dose. Results: The coefficient of variation (CV) for intra- and inter-run precision was below 10% for the systolic, diastolic, and mean arterial BP for both techniques used. There was a significant increase in the systolic BP after dosing of 10 mg/kg of Effortil® and a significant decrease in the diastolic pressure post dose of 1 and 4 mg/kg Nepresol® . The data demonstrate that external telemetry provides a valid tool for BP monitoring in freely moving cynomolgus monkeys. doi:10.1016/j.toxlet.2011.05.712
P2089 An effective way to deliver drugs at the endotracheal/endobronchial level in the cynomolgus monkey P.A. Colombo ∗ , F. Carù, B. Rosa, S. Zanoncelli, U. Bonfanti Preclinical Development, Accelera Srl, Nerviano, Milano, Italy An increased interest for non-standard administration routes has led preclinical contract research organizations (CROs) to develop delivery systems able to administer compounds at the intratracheal or intrabronchial level. Such a procedure is useful not only for test items intended to act at this level (e.g. antiinflammatory drugs) but also for the study of intrapulmonary delivery (e.g. vectors) and its associated systemic distribution. While some companies in both the pharma and CRO industries have in-house capabilities to perform such tests in rodent species (e.g. mouse, rat, guinea pig), only a very limited number use the same approach in more complex and relevant species, such as the Non-Human Primate (NHP). Delivery into the respiratory apparatus can be considered a stand-alone technology useful to reach proofof-concept for a new drug, or perhaps as a first step before the use of dedicated inhalation systems. Often it allows investigators to estimate pharmacokinetic properties and/or pharmacodynamic endpoints (i.e. biomarkers), rather then a simple evaluation of tolerability. The possibility to perform these assays in NHPs may be crucial in mimicking the clinical scenario in a relevant species, especially in case of new biological entities (NBE). Either solutions/suspensions or dry powder can be administered at different levels of the respiratory system, applying different liquid flow-rates and aerosol particle-size according to experimental needs. Specific issues and challenges associated with this technique are presented here through an example of delivery of an NBE including corresponding target modulation/biomarker alteration. doi:10.1016/j.toxlet.2011.05.713
P2090 Focused expression screening by TRAC in predictive toxicology J. Rautio ∗ , O. Rechardt, L. Mattinen, H. Söderlund R&d, PlexPress, Helsinki, Finland Purpose: Gene expression analysis touches many areas within pre-clinical safety from early phase cell culture based compound screening to later stage animal studies. Wide range of test models and need for high-throughput is a challenge for conventional methods in toxicology testing as they are expensive, laborious, and often use models with poor predictivity of toxic effects in humans. As a consequence toxicology testing is moving towards earlier and
P2087 A rodent model for visceral obesity development evaluated by MRI M. Rönn 1 , P.M. Lind 1,∗ , L. Lind 2 , F. Ortiz-Nieto 3 , H. Karlsson 4 , J. Kullberg 3 1 Occupational and Environmental Medicine, Uppsala University, Uppsala, Sweden, 2 Acute and Internal Medicine, Department of Medicine, Uppsala University, Uppsala, Sweden, 3 Division of Radiology, Department of Ros (Radiology, Oncology and Radiation Science), Uppsala University, Uppsala, Sweden, 4 Linkoping University Hospital, Occupational and Environmental Medicine, Linköpings University, Uppsala, Sweden
Purpose: To study possible effects of environmental contaminants on obesity development, a rodent model was developed by which a modest increase in fat adipose tissue in an environment of caloric excess could be induced. Since visceral adiposity is more dangerous than subcutaneous adiposity, magnetic resonance imaging (MRI) was used for fat quantification. Methods: Twenty-four 4-week-old female Fischer rats were divided into 2 groups. The exposed group was given drinking water containing fructose (5% for 7 weeks, then 20% for 3 weeks). At sacrifice, whole body MRI was performed to determine fat and lean mass. An intra-abdominal fat pad and the liver were dissected and weighed. Proteins were analyzed by Western Blot. Results: Rats given fructose gained 5 g more in weight during exposure than the control rats (p < 0.05). At sacrifice, their total body fat mass was modestly increased (28 cm3 vs. 24 cm3 , p < 0.05), while the weights of the fat pad (0.85 g vs. 0.67 g, p < 0.0001) and liver (5.2 g vs. 4.6 g, p = 0.001) were increased to a larger extent. Regarding the lipids, the most pronounced effects were seen for serum triglycerides (1.5 mmol/l vs. 1.0 mmol/l, p < 0.0001) and an increase of plasma apo A-I (p < 0.005) in fructose exposed rats. Conclusion: The model, based on modest fructose feeding evaluated by MRI, induced modest visceral obesity and hypertriglyceridemia, making it suitable for the study of cases where environmental contaminants further exaggerate the obesity development following modest excess caloric intake. doi:10.1016/j.toxlet.2011.05.711
P2088 Reliable blood pressure measurements with an external telemetry system (JET) in conscious, freely moving monkeys (M. fascicularis) in comparison to a fully implanted system B. Niggemann ∗ , M. Niehoff, J. Sternberg, G.F. Weinbauer Covance Laboratories GmbH, Muenster, Germany Purpose: This investigation reports results of blood pressure (BP) measurements recorded by an external telemetry system (JETTM ) in comparison to a fully implanted telemetry system. Intra animal and inter run precision were determined using both systems. In addition, hyper- and hypotensive compounds were investigated with the JET system. Methods: For the intra and inter run precision, two male monkeys carrying a fully implanted Koenigsberg telemetry implant (T27F-2B) were equipped with an additional miniature DSI BP transmitter (PA-C10-TOX-SA) for continuous blood pressure measurements. The animals carried a jacket including the JET equipment during the recordings. Systolic, diastolic, and mean arterial blood pressure was measured three times on day 1 and on 3 consecutive days for a period of at least 10 min. For manipulation of BP, twelve female monkeys were implanted with the
S207
DSI BP transmitter and distributed into 3 groups (n = 4) receiving either vehicle (water), or 1 or 10 mg/kg of etilefrine (Effortil® ) or 4 and 10 mg/kg of dihydralazine (Nepresol® ). Data were recorded for 1 h predose and 22 h post dose. Results: The coefficient of variation (CV) for intra- and inter-run precision was below 10% for the systolic, diastolic, and mean arterial BP for both techniques used. There was a significant increase in the systolic BP after dosing of 10 mg/kg of Effortil® and a significant decrease in the diastolic pressure post dose of 1 and 4 mg/kg Nepresol® . The data demonstrate that external telemetry provides a valid tool for BP monitoring in freely moving cynomolgus monkeys. doi:10.1016/j.toxlet.2011.05.712
P2089 An effective way to deliver drugs at the endotracheal/endobronchial level in the cynomolgus monkey P.A. Colombo ∗ , F. Carù, B. Rosa, S. Zanoncelli, U. Bonfanti Preclinical Development, Accelera Srl, Nerviano, Milano, Italy An increased interest for non-standard administration routes has led preclinical contract research organizations (CROs) to develop delivery systems able to administer compounds at the intratracheal or intrabronchial level. Such a procedure is useful not only for test items intended to act at this level (e.g. antiinflammatory drugs) but also for the study of intrapulmonary delivery (e.g. vectors) and its associated systemic distribution. While some companies in both the pharma and CRO industries have in-house capabilities to perform such tests in rodent species (e.g. mouse, rat, guinea pig), only a very limited number use the same approach in more complex and relevant species, such as the Non-Human Primate (NHP). Delivery into the respiratory apparatus can be considered a stand-alone technology useful to reach proofof-concept for a new drug, or perhaps as a first step before the use of dedicated inhalation systems. Often it allows investigators to estimate pharmacokinetic properties and/or pharmacodynamic endpoints (i.e. biomarkers), rather then a simple evaluation of tolerability. The possibility to perform these assays in NHPs may be crucial in mimicking the clinical scenario in a relevant species, especially in case of new biological entities (NBE). Either solutions/suspensions or dry powder can be administered at different levels of the respiratory system, applying different liquid flow-rates and aerosol particle-size according to experimental needs. Specific issues and challenges associated with this technique are presented here through an example of delivery of an NBE including corresponding target modulation/biomarker alteration. doi:10.1016/j.toxlet.2011.05.713
P2090 Focused expression screening by TRAC in predictive toxicology J. Rautio ∗ , O. Rechardt, L. Mattinen, H. Söderlund R&d, PlexPress, Helsinki, Finland Purpose: Gene expression analysis touches many areas within pre-clinical safety from early phase cell culture based compound screening to later stage animal studies. Wide range of test models and need for high-throughput is a challenge for conventional methods in toxicology testing as they are expensive, laborious, and often use models with poor predictivity of toxic effects in humans. As a consequence toxicology testing is moving towards earlier and