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Respiratory assessment in conscious, telemeterized cynomolgus monkeys
190
Abstracts
(PSD95), respectively. To analyze synapse response to toxicant exposure, we analyzed fixed images using algorithms to mask neurite regions demarked by expression of β-III tubulin and measured colocalized signals for the pre- and post-synaptic markers only in these functionally-relevant regions. Our HCS approach has enabled us to screen a library of EPA ToxCAST compounds, FDAapproved drugs (the NCC2 library), as well as other agents, such as glutamate and glycine, and Brefeldin A, known to modulate neuronal function. Additional information that may be related to the mechanism of action for chemicals that showed an effect in the assay included the amount of neurite outgrowth and alterations in nuclear texture. Using this approach we have developed a robust platform for large-scale screening of chemicals that affect synapse formation, the basic unit of neuronal function in humans. doi:10.1016/j.vascn.2015.08.107
0110 Safety and efficacy of antiepileptic drug therapy in pediatric population—New Delhi tertiary hospital study Sengottuvel Viswanathan, S.K. Bhattacharya, Anju Aggarwal
The growing number of biologics in development has resulted in an increasing need for assessment of the respiratory effects of test articles in nonhuman primates. This study evaluates the effects of diazepam in cynomolgus monkeys using respiratory rate and arterial blood gas values. Four conscious, freely moving males, previously implanted with telemetry transducers, received single IM doses of saline and diazepam (1 and 2.5 mg/kg) using an escalating dose design. Data collection concluded 24 h following dosing. Respiratory rate data derived from the blood pressure channel of DSI's D70-PCTR transmitters were compared against time-matched control data. Blood gas data was collected from vascular access ports at predose, 1 h, 5 h, and 24 h post-dose on all dose days. Data from the salinetreated group matched previous Xenometrics' historical data. Data from both the 1 and 2.5 mg/kg diazepam dose levels demonstrated decreases in respiratory rate of up to 23% starting immediately following dosing and returning to normal levels at approximately 4 1/2 to 5 h post-dose. Decreases in pH (~ 6%) were noted at 5 h postdose after 2.5 mg/kg diazepam. Increased PCO2 levels (~12%) were noted after both the 1 and 2.5 mg/kg dose levels at 1 h post-dose, and at 5 h post-dose at 2.5 mg/kg. In conclusion, expected respiratory parameter changes induced by moderate doses of diazepam were adequately assessed and detected with this method.
doi:10.1016/j.vascn.2015.08.109 UCMS and GTB Hospital, Delhi, India Background: Epilepsy is a chronic neurological morbidity in children. The treatment with antiepileptic drugs ( AEDs) at times fail to give complete seizure free interval and also cause various adverse drug reactions(ADRs). Objectives: In our drug utilization study we documented the treatment outcomes and the various adverse effect profiles of commonly prescribed AEDs among pediatric population. The study was conducted in a tertiary hospital set up in New Delhi India. Materials and methods: Patient characteristics such as age, sex, type of seizure and comorbid illness were noted. All 200 patients were followed up at 3 months for seizure control and ADRs. The ADRs were documented in WHO form. Results: Among the 200 children 87.5% received monotherapy and 12.5% combination therapy. Valproate was the commonly prescribed drug among 63.5% of the children followed by carbamazepine in 20.5%. Newer AEDs like oxcarbazepine and levetiracetam were prescribed in 1% of the children. Among the ADRs documented sedation was seen among 30%, irritability 34%, memory disturbances 14%, poor school performance 8%, weight gain 1%, and rashes 1% of the study population. Most of the ADRs seen were higher with combination therapy. The seizure control was significantly better with monotherapy compared to combination therapy. ADRs seen with valproate, carbamazepine and other AED combinations were documented. Conclusion: Our study results showed that monotherapy is more safe and effective as compared to combination therapy in pediatric population for the treatment of various types of seizures.
0112 Biovalidation of implantable impedance telemetry device Kenneth Kearney, Cory Appleby, Phil Atterson WIL Research, Ashland, OH, USA New chemical entities must be evaluated for changes in hemodynamic and respiratory function in accordance with the ICH S7A guidelines. The hemodynamic and electrocardiographic assessments are routinely conducted in large animal models (as mandated by the ICH S7B guidelines for assessing potential for delayed ventricular repolarization), while the respiratory evaluation has historically been conducted in the rodent as the species of choice. Enhancements in telemetry technology allow for the concurrent evaluation of hemodynamic, electrocardiographic and respiratory endpoints in large animal models within a single study. This design is gaining popularity for reasons of reduced test article demands, reduction of number of animals, and offering of a more robust safety assessment through concurrent evaluation of hemodynamic and respiratory endpoints. The current investigation was conducted to assess the reliability of the telemetric respiratory impedance through biovalidation with the use of positive control articles. The reliability of the system was further interrogated through assessment of drift in calibrations. The measure of drift was determined by comparing calibrations derived from multiple time points (pre- and post-dosing).
doi:10.1016/j.vascn.2015.08.108 doi:10.1016/j.vascn.2015.08.110 0111 0113 Respiratory assessment in conscious, telemeterized cynomolgus monkeys Pamela Gayheart-Walsten, Ty Speece, Scott Hill, Joel Baublits, Sandra Love, Alfred Botchway
Development of methods for measuring ventilatory and arterial blood gas parameters in juvenile rats Loren Kohrs, Jon Renninger, Dennis Murphy
Xenometrics, Stilwell, KS, USA
GlaxoSmithKline, King of Prussia, PA, USA
Abstracts
(PSD95), respectively. To analyze synapse response to toxicant exposure, we analyzed fixed images using algorithms to mask neurite regions demarked by expression of β-III tubulin and measured colocalized signals for the pre- and post-synaptic markers only in these functionally-relevant regions. Our HCS approach has enabled us to screen a library of EPA ToxCAST compounds, FDAapproved drugs (the NCC2 library), as well as other agents, such as glutamate and glycine, and Brefeldin A, known to modulate neuronal function. Additional information that may be related to the mechanism of action for chemicals that showed an effect in the assay included the amount of neurite outgrowth and alterations in nuclear texture. Using this approach we have developed a robust platform for large-scale screening of chemicals that affect synapse formation, the basic unit of neuronal function in humans. doi:10.1016/j.vascn.2015.08.107
0110 Safety and efficacy of antiepileptic drug therapy in pediatric population—New Delhi tertiary hospital study Sengottuvel Viswanathan, S.K. Bhattacharya, Anju Aggarwal
The growing number of biologics in development has resulted in an increasing need for assessment of the respiratory effects of test articles in nonhuman primates. This study evaluates the effects of diazepam in cynomolgus monkeys using respiratory rate and arterial blood gas values. Four conscious, freely moving males, previously implanted with telemetry transducers, received single IM doses of saline and diazepam (1 and 2.5 mg/kg) using an escalating dose design. Data collection concluded 24 h following dosing. Respiratory rate data derived from the blood pressure channel of DSI's D70-PCTR transmitters were compared against time-matched control data. Blood gas data was collected from vascular access ports at predose, 1 h, 5 h, and 24 h post-dose on all dose days. Data from the salinetreated group matched previous Xenometrics' historical data. Data from both the 1 and 2.5 mg/kg diazepam dose levels demonstrated decreases in respiratory rate of up to 23% starting immediately following dosing and returning to normal levels at approximately 4 1/2 to 5 h post-dose. Decreases in pH (~ 6%) were noted at 5 h postdose after 2.5 mg/kg diazepam. Increased PCO2 levels (~12%) were noted after both the 1 and 2.5 mg/kg dose levels at 1 h post-dose, and at 5 h post-dose at 2.5 mg/kg. In conclusion, expected respiratory parameter changes induced by moderate doses of diazepam were adequately assessed and detected with this method.
doi:10.1016/j.vascn.2015.08.109 UCMS and GTB Hospital, Delhi, India Background: Epilepsy is a chronic neurological morbidity in children. The treatment with antiepileptic drugs ( AEDs) at times fail to give complete seizure free interval and also cause various adverse drug reactions(ADRs). Objectives: In our drug utilization study we documented the treatment outcomes and the various adverse effect profiles of commonly prescribed AEDs among pediatric population. The study was conducted in a tertiary hospital set up in New Delhi India. Materials and methods: Patient characteristics such as age, sex, type of seizure and comorbid illness were noted. All 200 patients were followed up at 3 months for seizure control and ADRs. The ADRs were documented in WHO form. Results: Among the 200 children 87.5% received monotherapy and 12.5% combination therapy. Valproate was the commonly prescribed drug among 63.5% of the children followed by carbamazepine in 20.5%. Newer AEDs like oxcarbazepine and levetiracetam were prescribed in 1% of the children. Among the ADRs documented sedation was seen among 30%, irritability 34%, memory disturbances 14%, poor school performance 8%, weight gain 1%, and rashes 1% of the study population. Most of the ADRs seen were higher with combination therapy. The seizure control was significantly better with monotherapy compared to combination therapy. ADRs seen with valproate, carbamazepine and other AED combinations were documented. Conclusion: Our study results showed that monotherapy is more safe and effective as compared to combination therapy in pediatric population for the treatment of various types of seizures.
0112 Biovalidation of implantable impedance telemetry device Kenneth Kearney, Cory Appleby, Phil Atterson WIL Research, Ashland, OH, USA New chemical entities must be evaluated for changes in hemodynamic and respiratory function in accordance with the ICH S7A guidelines. The hemodynamic and electrocardiographic assessments are routinely conducted in large animal models (as mandated by the ICH S7B guidelines for assessing potential for delayed ventricular repolarization), while the respiratory evaluation has historically been conducted in the rodent as the species of choice. Enhancements in telemetry technology allow for the concurrent evaluation of hemodynamic, electrocardiographic and respiratory endpoints in large animal models within a single study. This design is gaining popularity for reasons of reduced test article demands, reduction of number of animals, and offering of a more robust safety assessment through concurrent evaluation of hemodynamic and respiratory endpoints. The current investigation was conducted to assess the reliability of the telemetric respiratory impedance through biovalidation with the use of positive control articles. The reliability of the system was further interrogated through assessment of drift in calibrations. The measure of drift was determined by comparing calibrations derived from multiple time points (pre- and post-dosing).
doi:10.1016/j.vascn.2015.08.108 doi:10.1016/j.vascn.2015.08.110 0111 0113 Respiratory assessment in conscious, telemeterized cynomolgus monkeys Pamela Gayheart-Walsten, Ty Speece, Scott Hill, Joel Baublits, Sandra Love, Alfred Botchway
Development of methods for measuring ventilatory and arterial blood gas parameters in juvenile rats Loren Kohrs, Jon Renninger, Dennis Murphy
Xenometrics, Stilwell, KS, USA
GlaxoSmithKline, King of Prussia, PA, USA