Journal of pharmacological and toxicological methods
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J Pharmacol Toxicol Methods · Sep 2019
Variability of non-clinical behavioral CNS safety assessment: An intercompany comparison.
Irwin/FOB testing is routinely conducted to investigate the neurofunctional integrity of laboratory animals during preclinical development of new drugs, however, the study design frequently varies to meet specific needs. Representatives of several European-based pharmaceutical companies performed a "state-of-the-art" assessment of how they conduct their CNS safety evaluation using Irwin/FOB tests. ⋯ Our survey and intercompany test results demonstrate certain heterogeneity in design and conduct of Irwin/FOB tests by pharmaceutical companies. Although the general behavioral profiles for the reference compounds were consistently found, quantitative variability of results remained even under partially standardized conditions. This suggests the importance of a high level of standardization with regard to the Irwin/FOB test modification used, scoring system, and observer training, in order to achieve an improved intercompany comparability of Irwin/FOB results.
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J Pharmacol Toxicol Methods · Jul 2019
The functional observational battery and modified Irwin test as global neurobehavioral assessments in the rat: Pharmacological validation data and a comparison of methods.
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. ⋯ 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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There is a general sentiment in the nonclinical safety assessment literature and the proponents of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH), that the "Modified Irwin" and the Functional Observation Battery are distinct and unique assays for the nonclinical assessment of the central nervous system (CNS). We identify and defend the position that the Irwin screen was developed as an FOB and both terms refer to a single, unitary functional assay. In giving credit to one prominent contributor to any one significant discipline of science for a specific assay, orientation, or theory may have an exclusionary influence on the merits of other prominent contributors within the same research arena. ⋯ In 1968, Samuel Irwin established an operational method of analysis used for measuring drug effects in purpose bred laboratory animals. We present and defend the view that the behavioral screening assay developed by Irwin is, for all intents and purposes, a functional observational battery (FOB). We take the position that in standardizing nomenclature without "surnames" the FOB is simply the contemporary name for the data collection system in use under the harmonized safety pharmacology guidelines.
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J Pharmacol Toxicol Methods · Mar 2018
Development and validation of the experimental wound assessment tool (EWAT) for pressure ulcer in laboratory animals.
In studies with experimental models of pressure ulcer, until date, there is no validated instrument to assess the various visual aspects of the healing process. Measure of wound area is the most used method for this purpose. Thus, we aimed to develop and validate a visual assessment tool for the evaluation of healing in experimental models of pressure ulcer. ⋯ EWAT showed good/excellent results in all the validation tests, showing it to be a good tool to evaluate wound healing process in animal models of pressure ulcer and being recommended for assessment of wound healing in small experimental animals.
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J Pharmacol Toxicol Methods · Mar 2018
Transcutaneous glomerular filtration rate measurement in a canine animal model of chronic kidney disease.
Quantitative assessment of renal function by measurement of glomerular filtration rate (GFR) is an important part of safety and efficacy evaluation in preclinical drug development. Existing methods are often time consuming, imprecise and associated with animal burden. Here we describe the comparison between GFR determinations with sinistrin (PS-GFR) and fluorescence-labelled sinistrin-application and its transcutaneous detection (TD-GFR) in a large animal model of chronic kidney disease (CKD). ⋯ Renal function assessment using TD-GFR is a valid method to improve preclinical drug discovery and development. Furthermore, TD-GFR method offers advantages in terms of reduced need for blood sampling and thus decreasing animal burden compared to standard procedures.