The Irwin Test and Functional Observational Battery (FOB) for Assessing the Effects of Compounds on Behavior, Physiology, and Safety Pharmacology in Rodents

2018 ◽  
Vol 83 (1) ◽  
pp. e43 ◽  
Author(s):  
Joanne R. Mathiasen ◽  
Virginia C. Moser
Keyword(s):  
Safety Pharmacology ◽  
Functional Observational Battery

Use of a functional observational battery in the assessment of safety pharmacology endpoints in general toxicology studies in conscious cynomolgus monkey

2011 ◽  
Vol 205 ◽  
pp. S236
Author(s):  
A. Bétat ◽  
A. El Amrani ◽  
S. Loriot ◽  
R. Forster ◽  
J. Legrand
Keyword(s):  
Cynomolgus Monkey ◽  
Safety Pharmacology ◽  
Functional Observational Battery

A Functional Observational Battery for Use in Canine Toxicity Studies: Development and Validation

2003 ◽  
Vol 22 (6) ◽  
pp. 415-422 ◽  
Author(s):  
S. C. Gad ◽  
S. E. Gad
Keyword(s):  
Species Difference ◽  
Study Data ◽  
Prior Work ◽  
Safety Pharmacology ◽  
Wide Range ◽  
Standard Design ◽  
Repeat Exposure ◽  
Study Designs ◽  
Functional Observational Battery

The most commonly used nonrodent species in regulatory toxicity and safety assessment studies has been and remains the dog, with the beagle being the standard breed employed. Although a standard functional observational battery (FOB) or neurobehavioral screen for use in rodents (primarily rats) has been incorporated into rodent studies since the late 1980s, this is not the case in nonrodents. In the pharmaceutical area (where repeat exposure nonrodent studies are generally required to develop a drug for humans), some work has been previously conducted towards developing a similar screen in the dog but progress has been limited. Given both the differential metabolism and sensitivity of the dog compared to rodents and the extreme desirability of having as complete a set of toxicity and/or functionality measures in the same species (to simplify and improve the accuracy of dose/response metrics) as possible, the need for such a standardized and validated methodology is clear. Study data from prior work establish the susceptibility of dogs to a wide variety of neurotoxic agents, including 6-aminonicotinamide (ANA), methanol, lasalocid, metron-idazole, acrylamide, clinoquinol, organo tins, and mercury. Additionally, the dog is likewise well established as a sensitive model for a wide range of peripheral and central nervous system–active pharmacologic agents, as required by recent regulatory requirements for safety pharmacology evaluations. Here we report on a robust and yet sensitive noninvasive screening methodology for detecting and providing initial quantitation and characterization of such direct and indirect neurotoxic and neuropharmacologic effects that has been developed. Additionally, an analysis and interpretation component that allows differentiation of neurotoxic from neuropharmacologic activities has also been adapted from prior work by one of the authors. Comparative species difference in sensitivity to neuroactive agents are also discussed, as well as means for integrating this evaluation screen into existing standard design. Particularly, with the recent promulgation of safety pharmacology testing requirements (the in vivo cardiovascular component of which is performed in the dog), the availability of such an evaluation paradigm presents a valuable potential addition to existing study designs without increasing animal usage.

scholarly journals Development of a Functional Observational Battery in the Minipig for Regulatory Neurotoxicity Assessments

2017 ◽  
Vol 36 (2) ◽  
pp. 113-123 ◽  
Author(s):  
Miao Zhong ◽  
Catherine Shoemake ◽  
Amber Fuller ◽  
David White ◽  
Chris Hanks ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Home Cage ◽  
Mechanisms Of Action ◽  
Behavioral Effects ◽  
Neurologic Examination ◽  
Safety Pharmacology ◽  
And Behavior ◽  
Preclinical Safety ◽  
Cns Stimulant ◽  
Functional Observational Battery

A functional observational battery (FOB) is recommended as the first-tier neurotoxicity screening in the preclinical safety pharmacology testing guidelines. Minipigs have increasingly been used in regulatory toxicology studies; however, no current FOB protocol is available for neurotoxicity testing in these species. Hence, a minipig FOB instrument was developed. A complete crossover study with Sinclair minipigs was performed to evaluate physiologic, neurologic, and behavioral effects of amphetamine, ketamine, and diazepam. The treated minipigs were first observed in their home cage, were video-recorded for 10 minutes in an open field, and then went through a complete neurologic examination. Both ketamine and diazepam were shown to reduce the freezing and behavior shifts of treated minipigs, while increasing their exploratory behaviors. Both drugs also caused muscular and gait impairment. The effects of ketamine and diazepam were consistent with their roles as central nervous system (CNS) suppressants. Unique effects were also observed with ketamine and diazepam treatments, which may reflect their unique mechanisms of action. Consistent with its role as a CNS stimulant, amphetamine caused the treated minipigs to be hyperactive and to display increased freezing and behavior shifts and reduced exploring activities. These effects of amphetamine were opposite to those observed with ketamine and diazepam. Amphetamine also increased locomotion in the treated minipigs. The present effects of amphetamine, ketamine, and diazepam are in agreement with observations by others. In conclusion, the minipig is a suitable species for FOB evaluation of pharmaceuticals in preclinical safety pharmacology testing.

scholarly journals Improving drug safety predictions by reducing poor analytical practices

2020 ◽  
Vol 4 ◽  
pp. 239784732097863
Author(s):  
Stanley E Lazic ◽  
Dominic P Williams
Keyword(s):  
At Risk ◽  
Drug Discovery ◽  
Drug Safety ◽  
Prediction Models ◽  
Predictive Modelling ◽  
Equal Weight ◽  
Negative Consequences ◽  
Preclinical Data ◽  
Safety Pharmacology ◽  
Patients At Risk

Predicting the safety of a drug from preclinical data is a major challenge in drug discovery, and progressing an unsafe compound into the clinic puts patients at risk and wastes resources. In drug safety pharmacology and related fields, methods and analytical decisions known to provide poor predictions are common and include creating arbitrary thresholds, binning continuous values, giving all assays equal weight, and multiple reuse of information. In addition, the metrics used to evaluate models often omit important criteria and models’ performance on new data are often not assessed rigorously. Prediction models with these problems are unlikely to perform well, and published models suffer from many of these issues. We describe these problems in detail, demonstrate their negative consequences, and propose simple solutions that are standard in other disciplines where predictive modelling is used.

Safety Pharmacology assessment of drugs with biased 5-HT2B receptor agonism mediating cardiac valvulopathy

2014 ◽  
Vol 69 (2) ◽  
pp. 150-161 ◽  
Author(s):  
Icilio Cavero ◽  
Jean-Michel Guillon
Keyword(s):  
Safety Pharmacology

Assessment of sensitivity of three ECG recording methods used in dog toxicology and safety pharmacology studies

2010 ◽  
Vol 62 (2) ◽  
pp. e4
Author(s):  
Pierre Laine ◽  
Mark Deurink ◽  
Alan Bass ◽  
Jonathan Bright ◽  
Richard Briscoe ◽  
...  
Keyword(s):  
Safety Pharmacology

Characterization of db/db mice for efficacy/safety pharmacology assessment of antidiabetic drugs

2013 ◽  
Vol 68 (1) ◽  
pp. e50
Author(s):  
Clarisse Duval ◽  
Martine Lemaire ◽  
Philippe Guillaume ◽  
Daniel Provost ◽  
Guillaume Froget
Keyword(s):  
Antidiabetic Drugs ◽  
Safety Pharmacology

Respiratory safety pharmacology – Current practice and future directions

2014 ◽  
Vol 69 (1) ◽  
pp. 135-140 ◽  
Author(s):  
Dennis J. Murphy
Keyword(s):  
Current Practice ◽  
Future Directions ◽  
Safety Pharmacology
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