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Analysis of sleep-wake sleep of marmosets (Callithrix jacchus) using a computer sleep-scoring algorithm
e20
Abstracts
THP, PCP and AMP, matching observations of sedation/stimulation. Effects not easily detected by eye; changes in mean/max intensity of paws, initial/final lateral placement or paw area/length/width may be more useful, suggesting altered gait, a change in toe spreading or toewalking. These effects were detected with PCP, BUS, 8-OH-DPAT, HARM, THP, YOH and SCOP. To conclude, gait analysis is a rapid, convenient method to detect motor dysfunction in rodents in the absence of adverse clinical observations, making it a useful addition within other studies. 1. Draper C et al. SPS Meeting 2009. doi:10.1016/j.vascn.2011.03.071
Poster No: 66 Analysis of sleep-wake sleep of marmosets (Callithrix jacchus) using a computer sleep-scoring algorithm Anne Maurin, Emmanuel Bracq, Eric Martel, Pascal Champeroux, Serge Richard CERB, Baugy, France Discovery of new drug candidates to fight insomnia is a major challenge in the future. Since any items have side effects on the sleep–wake cycle and it is important to evaluate them as early as possible during their development. The sleep architecture of rats (polyphasic sleep) is markedly different from that of Man, so we set out to determine if the sleep–wake cycle in marmosets would be closer to human. Two marmosets were implanted with DSI transmitters; cortical encephalogram, electromyogram and locomotor activity were recorded over the 12 h dark periods. Analysis of sleep phases was done using a computer sleep-scoring algorithm based on frequency bands ratios. The method was validated by testing zolpidem and caffeine. Marmoset sleep is organised in clear-cut cycles as in Man: the number over one night was between 15 and 20 cycles (mean duration: 50 min each); sleep percentage is greater than 90% and the basal architecture was as follows: light sleep (LS): 60–65%, deep sleep (DS): 15–20% and Rapid Eyes movements (REM): 9–14%. Zolpidem (3 mg/kg, po) induced an increase in DS: 35–45% and a decrease in its onset time. Caffeine (100 mg/kg, po) induced a marked increase in LS (80%) and a marked decrease in DS (less than 2%). No effect on REM was noted with these test items. In conclusion, these results show that since the sleep/awake cycles of Marmosets are closer to those of Human, the marmoset is a more appropriate model than rats for study of a drug candidate having the potential to interact with sleep activity in safety evaluation studies. doi:10.1016/j.vascn.2011.03.072
Poster No: 67 Streamlined functional measurements for early toxicology studies in rodents Will S. Redfern, Louise Marks, Claire Barnard, Des Cobey, Claire Grant, Katherine Greenwood, Lorna Ewart, Helen Prior, Jean-Pierre Valentin Safety Assessment UK, AstraZeneca R&D, Alderley Park, Macclesfield, SK10 4TG, UK Incorporation of functional endpoints into early Toxicology studies has the potential to flag adverse effects earlier in drug development. Here we evaluate whether condensed modified Irwin
screen, visual acuity and whole-body plethysmography (WBP) protocols can detect drug-induced changes in nervous, visual and respiratory system function in a standard Toxicology study format. Six (3 male and 3 female) Han Wistar rats received a single oral dose of theophylline (30 mg/kg), baclofen (10 mg/ kg), quinine (300 mg/kg) or vehicle. Post-dose assessments were split into two parallel sessions with a mix of vehicle and treated, male and female rats tested for Irwin/visual acuity then WBP, or WBP then Irwin/visual acuity. Assessments were performed at the compound's Tmax ± 1 h. For the Irwin, behavioural changes, body temperature and pupil diameter were recorded. For visual acuity, head tracking in response to a moving grating was recorded. WBP chambers were used for respiratory assessment (15 min settling and 30 min recording). Body weight was recorded 24 h post-dose. Baclofen decreased touch response, body temperature (P < 0.01) and body weight (P < 0.05) and also caused flattened body posture and sedation. Pupil size was increased (P < 0.05). Quinine reduced visual acuity (6/6 rats). Theophylline increased minute volume (P < 0.01) and respiratory rate (P < 0.001). In conclusion, streamlined modified Irwin screen, visual acuity and WBP protocols can detect changes in nervous, visual and respiratory system parameters and could be a valuable addition to early Toxicology studies. doi:10.1016/j.vascn.2011.03.073
Poster No: 68 Characterization of a functional observational battery in rodents and non human primates Philip J. Monroe, Michael A. Hawk, Glenn D. Ritchie, Kevin R. Hanjora, Craig R. Hassler Battelle Memorial Institute, Columbus, OH USA A Functional Observational Battery (FOB), consisting of approximately 40 homecage and open field tests, was developed at Battelle for rapid Central Nervous System (CNS) Safety Pharmacology screening in rats and mice. It was shown that the FOB could be used successfully to identify and differentiate the behavioral effects of amphetamine (AMPH), a stimulant, and chlorpromazine (CPZ), an antipsychotic and sedative agent. The FOB also clearly differentiated AMPH effects in male versus female animals. The testing paradigm is similar to the test battery developed previously by the EPA (Moser et al., 1988), and has been used in GLP studies assessing the safety of drug candidates. More recently, we have developed a similar FOB for drug screening in non-human primates (NHPs) that is based partially on a NHP test battery recently described in the literature (Gauvin and Baird, 2008). Consistent with what has been demonstrated in the rodent model, initial validation data from studies using female cynomolgous monkeys have shown an ability to discriminate the behavioral effects of CPZ and AMPH. (Studies examining the behavioral effects of AMPH and CPZ in male monkeys are in progress.) An NHP FOB testing paradigm may prove to be a more appropriate model for drug safety evaluation, especially in the case of biologic therapeutics. doi:10.1016/j.vascn.2011.03.074
Poster No: 69 Refinement of the CNS-FOB method via the use of automated noldus EthoVision® XT 7.0 video-tracking system in rats Tetsuya Yoshikawa, Amber Fyall, Jabin Green, Deborah Wilson, Tim Dawe, Russell Eyre, Hideshi Tsusaki, Frederick Sannajust
Abstracts
THP, PCP and AMP, matching observations of sedation/stimulation. Effects not easily detected by eye; changes in mean/max intensity of paws, initial/final lateral placement or paw area/length/width may be more useful, suggesting altered gait, a change in toe spreading or toewalking. These effects were detected with PCP, BUS, 8-OH-DPAT, HARM, THP, YOH and SCOP. To conclude, gait analysis is a rapid, convenient method to detect motor dysfunction in rodents in the absence of adverse clinical observations, making it a useful addition within other studies. 1. Draper C et al. SPS Meeting 2009. doi:10.1016/j.vascn.2011.03.071
Poster No: 66 Analysis of sleep-wake sleep of marmosets (Callithrix jacchus) using a computer sleep-scoring algorithm Anne Maurin, Emmanuel Bracq, Eric Martel, Pascal Champeroux, Serge Richard CERB, Baugy, France Discovery of new drug candidates to fight insomnia is a major challenge in the future. Since any items have side effects on the sleep–wake cycle and it is important to evaluate them as early as possible during their development. The sleep architecture of rats (polyphasic sleep) is markedly different from that of Man, so we set out to determine if the sleep–wake cycle in marmosets would be closer to human. Two marmosets were implanted with DSI transmitters; cortical encephalogram, electromyogram and locomotor activity were recorded over the 12 h dark periods. Analysis of sleep phases was done using a computer sleep-scoring algorithm based on frequency bands ratios. The method was validated by testing zolpidem and caffeine. Marmoset sleep is organised in clear-cut cycles as in Man: the number over one night was between 15 and 20 cycles (mean duration: 50 min each); sleep percentage is greater than 90% and the basal architecture was as follows: light sleep (LS): 60–65%, deep sleep (DS): 15–20% and Rapid Eyes movements (REM): 9–14%. Zolpidem (3 mg/kg, po) induced an increase in DS: 35–45% and a decrease in its onset time. Caffeine (100 mg/kg, po) induced a marked increase in LS (80%) and a marked decrease in DS (less than 2%). No effect on REM was noted with these test items. In conclusion, these results show that since the sleep/awake cycles of Marmosets are closer to those of Human, the marmoset is a more appropriate model than rats for study of a drug candidate having the potential to interact with sleep activity in safety evaluation studies. doi:10.1016/j.vascn.2011.03.072
Poster No: 67 Streamlined functional measurements for early toxicology studies in rodents Will S. Redfern, Louise Marks, Claire Barnard, Des Cobey, Claire Grant, Katherine Greenwood, Lorna Ewart, Helen Prior, Jean-Pierre Valentin Safety Assessment UK, AstraZeneca R&D, Alderley Park, Macclesfield, SK10 4TG, UK Incorporation of functional endpoints into early Toxicology studies has the potential to flag adverse effects earlier in drug development. Here we evaluate whether condensed modified Irwin
screen, visual acuity and whole-body plethysmography (WBP) protocols can detect drug-induced changes in nervous, visual and respiratory system function in a standard Toxicology study format. Six (3 male and 3 female) Han Wistar rats received a single oral dose of theophylline (30 mg/kg), baclofen (10 mg/ kg), quinine (300 mg/kg) or vehicle. Post-dose assessments were split into two parallel sessions with a mix of vehicle and treated, male and female rats tested for Irwin/visual acuity then WBP, or WBP then Irwin/visual acuity. Assessments were performed at the compound's Tmax ± 1 h. For the Irwin, behavioural changes, body temperature and pupil diameter were recorded. For visual acuity, head tracking in response to a moving grating was recorded. WBP chambers were used for respiratory assessment (15 min settling and 30 min recording). Body weight was recorded 24 h post-dose. Baclofen decreased touch response, body temperature (P < 0.01) and body weight (P < 0.05) and also caused flattened body posture and sedation. Pupil size was increased (P < 0.05). Quinine reduced visual acuity (6/6 rats). Theophylline increased minute volume (P < 0.01) and respiratory rate (P < 0.001). In conclusion, streamlined modified Irwin screen, visual acuity and WBP protocols can detect changes in nervous, visual and respiratory system parameters and could be a valuable addition to early Toxicology studies. doi:10.1016/j.vascn.2011.03.073
Poster No: 68 Characterization of a functional observational battery in rodents and non human primates Philip J. Monroe, Michael A. Hawk, Glenn D. Ritchie, Kevin R. Hanjora, Craig R. Hassler Battelle Memorial Institute, Columbus, OH USA A Functional Observational Battery (FOB), consisting of approximately 40 homecage and open field tests, was developed at Battelle for rapid Central Nervous System (CNS) Safety Pharmacology screening in rats and mice. It was shown that the FOB could be used successfully to identify and differentiate the behavioral effects of amphetamine (AMPH), a stimulant, and chlorpromazine (CPZ), an antipsychotic and sedative agent. The FOB also clearly differentiated AMPH effects in male versus female animals. The testing paradigm is similar to the test battery developed previously by the EPA (Moser et al., 1988), and has been used in GLP studies assessing the safety of drug candidates. More recently, we have developed a similar FOB for drug screening in non-human primates (NHPs) that is based partially on a NHP test battery recently described in the literature (Gauvin and Baird, 2008). Consistent with what has been demonstrated in the rodent model, initial validation data from studies using female cynomolgous monkeys have shown an ability to discriminate the behavioral effects of CPZ and AMPH. (Studies examining the behavioral effects of AMPH and CPZ in male monkeys are in progress.) An NHP FOB testing paradigm may prove to be a more appropriate model for drug safety evaluation, especially in the case of biologic therapeutics. doi:10.1016/j.vascn.2011.03.074
Poster No: 69 Refinement of the CNS-FOB method via the use of automated noldus EthoVision® XT 7.0 video-tracking system in rats Tetsuya Yoshikawa, Amber Fyall, Jabin Green, Deborah Wilson, Tim Dawe, Russell Eyre, Hideshi Tsusaki, Frederick Sannajust