title: CNS Adverse Effects: From Functional Observation Battery/Irwin Tests to Electrophysiology.
abstract: This chapter describes various approaches for the preclinical assessment of drug-induced central nervous system (CNS) adverse effects. Traditionally, methods to evaluate CNS effects have consisted of observing and scoring behavioral responses of animals after drug is administered. Among several behavioral testing paradigms, the Irwin and the functional observational battery (FOB) are the most commonly used assays for the assessment of CNS effects. The Irwin and FOB are considered good first-tier assays to satisfy the ICH S7A guidance for the preclinical evaluation of new chemical entities (NCE) intended for humans. However, experts have expressed concern about the subjectivity and lack of quantitation that is derived from behavioral testing. More importantly, it is difficult to gain insight into potential mechanisms of toxicity by assessing behavioral outcomes. As a complement to behavioral testing, we propose using electrophysiology-based assays, both in vivo and in vitro, such as electroencephalograms and brain slice field-potential recordings. To better illustrate these approaches, we discuss the implementation of electrophysiology-based techniques in drug-induced assessment of seizure risk, sleep disruption, and cognitive impairment.
authors.affiliation: Global Safety Pharmacology, AstraZeneca Pharmaceuticals LP, 35 Gatehouse Drive, Waltham, MA, 02451, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Fonck
authors.forename: Alison
authors.initials: A
authors.lastname: Easter
authors.forename: Mark R
authors.initials: MR
authors.lastname: Pietras
authors.forename: Russell A
authors.initials: RA
authors.lastname: Bialecki
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects* / Q000502:physiology; D003072:Cognition Disorders / Q000139:chemically induced; D004353:Drug Evaluation, Preclinical; D064420:Drug-Related Side Effects and Adverse Reactions; D004569:Electroencephalography; D004594:Electrophysiology; D005071:Evoked Potentials / Q000187:drug effects; D006801:Humans; D018570:Risk Assessment; D012890:Sleep / Q000187:drug effects