The Experts below are selected from a list of 204 Experts worldwide ranked by ideXlab platform
Roger D. Porsolt - One of the best experts on this subject based on the ideXlab platform.
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Central Nervous System (CNS) Safety Pharmacology Studies
Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays, 2013Co-Authors: V. Castagne, Christelle Froger-colléaux, Elise Esneault, Hernier Anne Marie, Martine Lemaire, Roger D. PorsoltAbstract:This section describes basic protocols satisfying ICH S7A recommendations for core battery CNS studies. Included are protocols for measuring general behavioral signs induced by Test substances (Irwin Test), effects on spontaneous locomotion (activity meter Test), effects on neuromuscular coordination (rotarod Test), effects on the convulsive threshold (electroconvulsive shock (ECS) threshold and PTZ seizure Tests), interaction with hypnotics (barbital interaction Test), and effects on the pain threshold (hot plate Test).
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Primary observation (Irwin) Test in rodents for assessing acute toxicity of a Test agent and its effects on behavior and physiological function.
Current protocols in pharmacology, 2005Co-Authors: Sylvain Roux, Evelyne Sable, Roger D. PorsoltAbstract:The Irwin observation Test is commonly used to evaluate the effects of a new substance on behavior and physiological function. The results of the Irwin Test are used to determine potential toxicity and to select doses for specific therapeutic activity. The Irwin Test can also be used in a safety approach for detecting untoward effects of a new compound on general behavior and for evaluating its acute neurotoxicity. In particular, data obtained in the Irwin Test can help to determine the dose range to be Tested in other safety Tests. Furthermore, the Irwin Test can furnish a first but pertinent orientation towards a specific therapeutic indication, a specific mechanism of action or a specific physiological function.
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primary observation Irwin Test in rodents for assessing acute toxicity of a Test agent and its effects on behavior and physiological function
Current protocols in pharmacology, 2004Co-Authors: Sylvain Roux, Evelyne Sable, Roger D. PorsoltAbstract:The Irwin observation Test is commonly used to evaluate the effects of a new substance on behavior and physiological function. The results of the Irwin Test are used to determine potential toxicity and to select doses for specific therapeutic activity. The Irwin Test can also be used in a safety approach for detecting untoward effects of a new compound on general behavior and for evaluating its acute neurotoxicity. In particular, data obtained in the Irwin Test can help to determine the dose range to be Tested in other safety Tests. Furthermore, the Irwin Test can furnish a first but pertinent orientation towards a specific therapeutic indication, a specific mechanism of action or a specific physiological function. Keywords: Irwin Test; general behavior; physiological function; safety pharmacology
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Current Protocols in Pharmacology - Primary observation (Irwin) Test in rodents for assessing acute toxicity of a Test agent and its effects on behavior and physiological function.
Current protocols in pharmacology, 2004Co-Authors: Sylvain Roux, Evelyne Sable, Roger D. PorsoltAbstract:The Irwin observation Test is commonly used to evaluate the effects of a new substance on behavior and physiological function. The results of the Irwin Test are used to determine potential toxicity and to select doses for specific therapeutic activity. The Irwin Test can also be used in a safety approach for detecting untoward effects of a new compound on general behavior and for evaluating its acute neurotoxicity. In particular, data obtained in the Irwin Test can help to determine the dose range to be Tested in other safety Tests. Furthermore, the Irwin Test can furnish a first but pertinent orientation towards a specific therapeutic indication, a specific mechanism of action or a specific physiological function. Keywords: Irwin Test; general behavior; physiological function; safety pharmacology
William S Redfern - One of the best experts on this subject based on the ideXlab platform.
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the functional observational battery and modified Irwin Test as global neurobehavioral assessments in the rat pharmacological validation data and a comparison of methods
Journal of Pharmacological and Toxicological Methods, 2019Co-Authors: William S Redfern, Angela Dymond, I Strang, Sharon Storey, Claire Grant, Louise Marks, Claire Barnard, Clive Heys, Katherine Moyser, Katherine GreenwoodAbstract:Abstract Background Evaluation of the effects of candidate drugs on the nervous system in preclinical safety pharmacology studies utilises a global neurobehavioral assessment, usually in the rat. This either takes the form of the functional observational battery (FOB) or modified Irwin Test, both of which evaluate effects across 4 functional domains: autonomic, neuromuscular, sensorimotor and behavioral. Although there is a great deal of overlap in the parameters they address, the two Tests approach the assessments slightly differently. We undertook a broad pharmacological validation of both the FOB and the Irwin Test, and compared the two outcomes. Methods Male rats (6 per treatment group) were used to assess each of 12 reference drugs alongside vehicle controls in separate FOB and Irwin studies. The drugs compared in the two study types were chlorpromazine, chlordiazepoxide, clonidine, baclofen, (+)-amphetamine, harmaline, 8-hydroxy-2-(di-n-propylamino)tetralin, buspirone, physostigmine, picrotoxin, yohimbine and atropine. There is a high degree of semantic equivalence in the parameters assessed in the autonomic domain between the two Tests, with a lower degree of equivalence for neuromuscular and behavioral domains, whereas sensorimotor reflex Testing in the FOB is far more extensive than in the Irwin Test. Results Across the set of reference drugs, concordance between the two Tests was generally good across the 4 functional domains at the ‘domain’ level (i.e., detecting ‘an effect’), whereas there was generally a poor concordance at the individual parameter level. However, this was partially explained by variability between repeated studies on a single reference drug using the same Test (FOB or Irwin). Conclusions Both Tests are ‘fit-for-purpose’ in detecting effects of candidate drugs on the nervous system. We would encourage the global safety pharmacology community to consider whether (a) the Tests could be combined into one industry standard; (b) candidate drugs could be triaged according to CNS penetration, with the level of scrutiny in the CNS core battery assessment adjusted accordingly and (c) whether new home cage technology could be applied to semi-automate the preclinical neurobehavioral assessment.
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pharmacological validation of individual animal locomotion temperature and behavioural analysis in group housed rats using a novel automated home cage analysis system a comparison with the modified Irwin Test
Journal of Pharmacological and Toxicological Methods, 2018Co-Authors: Rowland R Sillito, Claire Grant, Amy Keerie, Rachel Collier, Natasha A Karp, Cathy Vickers, Kathryn Chapman, Douglas J Armstrong, William S RedfernAbstract:Abstract Background The ActualHCA™ system continuously monitors the activity, temperature and behavior of group-housed rats without invasive surgery. The system was validated to detect the contrasting effects of sedative and stimulant Test agents (chlorpromazine, clonidine and amphetamine), and compared with the modified Irwin Test (mIT) with rectal temperature measurements. Methods Six male Han Wistar rats per group were used to assess each Test agent and vehicle controls in separate ActualHCA™ recordings and mIT. The mIT was undertaken at 15, 30 mins, 1, 2, 4 and 24 h post-dose. ActualHCA™ recorded continuously for 24 h post-dose under 3 experimental conditions: dosed during light phase, dark phase, and light phase with a scheduled cage change at the time of peak effects determined by mIT. Results ActualHCA™ detected an increase stimulated activity from the cage change at 1-2 h post-dose which was obliterated by chlorpromazine and clonidine. Amphetamine increased activity up to 4 h post-dose in all conditions. Temperature from ActualHCA™ was affected by all Test agents in all conditions. The mIT showed effects on all 3 Test agents up to 4 h post-dose, with maximal effects at 1-2 h post-dose. The maximal effects on temperature from ActualHCA™ differed from mIT. Delayed effects on activity were detected by ActualHCA™, but not on mIT. Conclusions Continuous monitoring has the advantage of capturing effects over time that may be missed with manual Tests using pre-determined time points. This automated behavioural system does not replace the need for conventional methods but could be implemented simultaneously to improve our understanding of behavioural pharmacology.
Brigitte Olympe Depelchin - One of the best experts on this subject based on the ideXlab platform.
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advantageous safety profile of a dual selective alpha 2c agonist alpha 2a antagonist antinociceptive agent
Fundamental & Clinical Pharmacology, 2014Co-Authors: Annie Delaunois, Paul Dedoncker, Marieluce Rosseels, Miranda Cornet, Eric Jnoff, Etienne Hanon, Michel Guyaux, Brigitte Olympe DepelchinAbstract:: A selective α2C -adrenoceptor (AR) agonist was developed for the treatment of neuropathic pain. The objective was to dissociate analgesic activity from cardiovascular and sedative side effects commonly observed with nonselective agents. A 2-amino-oxazoline derivative (compound A), identified as a dual α2C -AR agonist/α2A -AR antagonist in in vitro-binding assays, exhibited in vivo efficacy in rodent pain models. Its safety profile was compared with that of clonidine in six different in vivo models. Contrary to clonidine, compound A did not induce hypotension in pentobarbital-anesthetized rats, in conscious spontaneous hypertensive rats, or in telemetered dogs. Both agents induced similar dose-dependent decreases in heart rate in dogs and rats. In anesthetized pithed rats, clonidine showed dose-dependent hypertension and inhibited electrical nerve stimulation-induced tachycardia at doses close to its efficacious doses in the mouse formalin Test, while compound A had much weaker vasoconstrictive and antichronotropic effects. Finally, in a mouse Irwin Test, no sedation was observed with compound A at 30-fold its ED50 in the mouse formalin Test, while sedative effects of clonidine started from three-fold its ED50 . These data confirm the advantageous safety profile of the new dual α2C -AR agonist/α2A -AR antagonist agent vs. the nonselective agonist clonidine.
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Advantageous safety profile of a dual selective alpha(2C) agonist/alpha(2A) antagonist antinociceptive agent.
Fundamental & Clinical Pharmacology, 2013Co-Authors: Annie Delaunois, Paul Dedoncker, Marieluce Rosseels, Miranda Cornet, Eric Jnoff, Etienne Hanon, Michel Guyaux, Brigitte Olympe DepelchinAbstract:: A selective α2C -adrenoceptor (AR) agonist was developed for the treatment of neuropathic pain. The objective was to dissociate analgesic activity from cardiovascular and sedative side effects commonly observed with nonselective agents. A 2-amino-oxazoline derivative (compound A), identified as a dual α2C -AR agonist/α2A -AR antagonist in in vitro-binding assays, exhibited in vivo efficacy in rodent pain models. Its safety profile was compared with that of clonidine in six different in vivo models. Contrary to clonidine, compound A did not induce hypotension in pentobarbital-anesthetized rats, in conscious spontaneous hypertensive rats, or in telemetered dogs. Both agents induced similar dose-dependent decreases in heart rate in dogs and rats. In anesthetized pithed rats, clonidine showed dose-dependent hypertension and inhibited electrical nerve stimulation-induced tachycardia at doses close to its efficacious doses in the mouse formalin Test, while compound A had much weaker vasoconstrictive and antichronotropic effects. Finally, in a mouse Irwin Test, no sedation was observed with compound A at 30-fold its ED50 in the mouse formalin Test, while sedative effects of clonidine started from three-fold its ED50 . These data confirm the advantageous safety profile of the new dual α2C -AR agonist/α2A -AR antagonist agent vs. the nonselective agonist clonidine.
Sylvain Roux - One of the best experts on this subject based on the ideXlab platform.
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Primary observation (Irwin) Test in rodents for assessing acute toxicity of a Test agent and its effects on behavior and physiological function.
Current protocols in pharmacology, 2005Co-Authors: Sylvain Roux, Evelyne Sable, Roger D. PorsoltAbstract:The Irwin observation Test is commonly used to evaluate the effects of a new substance on behavior and physiological function. The results of the Irwin Test are used to determine potential toxicity and to select doses for specific therapeutic activity. The Irwin Test can also be used in a safety approach for detecting untoward effects of a new compound on general behavior and for evaluating its acute neurotoxicity. In particular, data obtained in the Irwin Test can help to determine the dose range to be Tested in other safety Tests. Furthermore, the Irwin Test can furnish a first but pertinent orientation towards a specific therapeutic indication, a specific mechanism of action or a specific physiological function.
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primary observation Irwin Test in rodents for assessing acute toxicity of a Test agent and its effects on behavior and physiological function
Current protocols in pharmacology, 2004Co-Authors: Sylvain Roux, Evelyne Sable, Roger D. PorsoltAbstract:The Irwin observation Test is commonly used to evaluate the effects of a new substance on behavior and physiological function. The results of the Irwin Test are used to determine potential toxicity and to select doses for specific therapeutic activity. The Irwin Test can also be used in a safety approach for detecting untoward effects of a new compound on general behavior and for evaluating its acute neurotoxicity. In particular, data obtained in the Irwin Test can help to determine the dose range to be Tested in other safety Tests. Furthermore, the Irwin Test can furnish a first but pertinent orientation towards a specific therapeutic indication, a specific mechanism of action or a specific physiological function. Keywords: Irwin Test; general behavior; physiological function; safety pharmacology
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Current Protocols in Pharmacology - Primary observation (Irwin) Test in rodents for assessing acute toxicity of a Test agent and its effects on behavior and physiological function.
Current protocols in pharmacology, 2004Co-Authors: Sylvain Roux, Evelyne Sable, Roger D. PorsoltAbstract:The Irwin observation Test is commonly used to evaluate the effects of a new substance on behavior and physiological function. The results of the Irwin Test are used to determine potential toxicity and to select doses for specific therapeutic activity. The Irwin Test can also be used in a safety approach for detecting untoward effects of a new compound on general behavior and for evaluating its acute neurotoxicity. In particular, data obtained in the Irwin Test can help to determine the dose range to be Tested in other safety Tests. Furthermore, the Irwin Test can furnish a first but pertinent orientation towards a specific therapeutic indication, a specific mechanism of action or a specific physiological function. Keywords: Irwin Test; general behavior; physiological function; safety pharmacology
Annie Delaunois - One of the best experts on this subject based on the ideXlab platform.
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advantageous safety profile of a dual selective alpha 2c agonist alpha 2a antagonist antinociceptive agent
Fundamental & Clinical Pharmacology, 2014Co-Authors: Annie Delaunois, Paul Dedoncker, Marieluce Rosseels, Miranda Cornet, Eric Jnoff, Etienne Hanon, Michel Guyaux, Brigitte Olympe DepelchinAbstract:: A selective α2C -adrenoceptor (AR) agonist was developed for the treatment of neuropathic pain. The objective was to dissociate analgesic activity from cardiovascular and sedative side effects commonly observed with nonselective agents. A 2-amino-oxazoline derivative (compound A), identified as a dual α2C -AR agonist/α2A -AR antagonist in in vitro-binding assays, exhibited in vivo efficacy in rodent pain models. Its safety profile was compared with that of clonidine in six different in vivo models. Contrary to clonidine, compound A did not induce hypotension in pentobarbital-anesthetized rats, in conscious spontaneous hypertensive rats, or in telemetered dogs. Both agents induced similar dose-dependent decreases in heart rate in dogs and rats. In anesthetized pithed rats, clonidine showed dose-dependent hypertension and inhibited electrical nerve stimulation-induced tachycardia at doses close to its efficacious doses in the mouse formalin Test, while compound A had much weaker vasoconstrictive and antichronotropic effects. Finally, in a mouse Irwin Test, no sedation was observed with compound A at 30-fold its ED50 in the mouse formalin Test, while sedative effects of clonidine started from three-fold its ED50 . These data confirm the advantageous safety profile of the new dual α2C -AR agonist/α2A -AR antagonist agent vs. the nonselective agonist clonidine.
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Advantageous safety profile of a dual selective alpha(2C) agonist/alpha(2A) antagonist antinociceptive agent.
Fundamental & Clinical Pharmacology, 2013Co-Authors: Annie Delaunois, Paul Dedoncker, Marieluce Rosseels, Miranda Cornet, Eric Jnoff, Etienne Hanon, Michel Guyaux, Brigitte Olympe DepelchinAbstract:: A selective α2C -adrenoceptor (AR) agonist was developed for the treatment of neuropathic pain. The objective was to dissociate analgesic activity from cardiovascular and sedative side effects commonly observed with nonselective agents. A 2-amino-oxazoline derivative (compound A), identified as a dual α2C -AR agonist/α2A -AR antagonist in in vitro-binding assays, exhibited in vivo efficacy in rodent pain models. Its safety profile was compared with that of clonidine in six different in vivo models. Contrary to clonidine, compound A did not induce hypotension in pentobarbital-anesthetized rats, in conscious spontaneous hypertensive rats, or in telemetered dogs. Both agents induced similar dose-dependent decreases in heart rate in dogs and rats. In anesthetized pithed rats, clonidine showed dose-dependent hypertension and inhibited electrical nerve stimulation-induced tachycardia at doses close to its efficacious doses in the mouse formalin Test, while compound A had much weaker vasoconstrictive and antichronotropic effects. Finally, in a mouse Irwin Test, no sedation was observed with compound A at 30-fold its ED50 in the mouse formalin Test, while sedative effects of clonidine started from three-fold its ED50 . These data confirm the advantageous safety profile of the new dual α2C -AR agonist/α2A -AR antagonist agent vs. the nonselective agonist clonidine.
