Irwin Test

The present 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). 

The primary aim of the Irwin Test, first described in the mouse by Irwin (1968) but easily adapted to the rat, is to evaluate the qualitative effects of the test substance on behavior and physiological function, from the first doses that have observable effects up to doses which induce clear behavioral toxicity or even death. The Irwin Test also permits a reasonable estimate of the test substance s duration of action on the different parameters observed. 

Because most measures involve subjective assessment of different aspects of the animal s behavior, the test must be performed in a highly standardized manner by well trained observers to ensure reproducible findings on different occasions, or at different observation times on the same day. Indeed, because of systematic changes in the behavior and reactions of test animals over a test day, drug-treated animals are always evaluated with reference to a simultaneously treated group of vehicle controls under non-blind conditions to gauge whether an observed effect is truly a consequence of treatment with the test substance. 

Observations are performed 15, 30, 60, 120 and 180 minutes after administration of the test substance and also 24 and 48 hours later. The symptoms marked ( ) are observed continuously from 0 to 15 minutes after administration. 

The test substance is usually evaluated at 6 doses, administered p.o. immediately before the test. For safety pharmacology studies, the lowest dose is close 

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The Irwin Test serves at both ends of the drag discov-ery/development spectrum. 

At later stages of drug development (before Phase I), when the test substance has been more fully characterized, the Irwin Test provides a clear over-all index of the test substance s margin of safety. Furthermore, although the test is mainly behavioral, it can give global indications of drug effects on vital functions such as respiration or intestinal motility. On the other hand, the test provides little information about effects... 

Whereas many CNS safety tests evaluate multiple doses, we recommend the inclusion of just two doses for non-precipitated withdrawal studies. The low dose should be close to the dose inducing clear effects in the test predictive of the substance s therapeutic indication. The high dose should be the maximally tolerated dose as determined, for example, from an Irwin test. If it can be shown that the test substance can be repeatedly administered at a maximally tolerated dose under conditions where similar treatment with an appropriately chosen reference substance induces... 

Irwin test General assessment of effects on gross behavior and physiological state ... 

CNS Adverse Effects From Functional Observation Battery/Irwin Tests to Electrophysiology... 

Rats or mice of either sex can be used in the Irwin test. Various rat or mouse strains may be employed, but often it is necessary to revalidate assay parameters because some behavioral characteristics may differ between strains. For example, different rat strains that may differ in body weights may consequently display... 

Global neurobehavioural assessment Functional observational battery or Irwin test Rat mouse dog monkey... 

Therefore, in safety pharmacology, the first-tier test used is a neurobehavioural assessment, either in the format of the functional observational battery (FOB) or Irwin test (Moser 1989 LeBel and Foss 1996 Moser et al. 1997 Redfern et al. 2005 Roux et al. 2005 Redfern and Wakefield 2006). Similar assessments have been devised for dogs (Gad and Gad 2003 Tontodonati et al. 2007 Moscardo et al. 2009) and monkeys (Gauvin and Baird 2008 Moscardo et al. 2010 Froget et al. 2012). Where there is specific cause for concern arising from the knowledge of a compound, appropriate single-parameter tests can be incorporated into a repeat-dose toxicity study on a case-by-case basis to address the issue. Examples of suitable tests are listed in Table 3. 

Roux S, Sable E, Porsolt RD (2005) Primary observation (Irwin) test in rodents for assessing acute toxicity of a test agent and its effects on behaviOT and physiological function. Curr Protoc Pharmacol Chapter 10 Unit 10.10... 

Korte S, Fuchs A, Weinbauer GF et al (2007) Modified Irwin test as diagnostic tool to monitor neurobehavioral changes in monkeys. J Pharmacol Toxicol Methods 56 e47 Kurtz TW, Griffin KA, Bidani AK et al (2005) Recommendations for blood pressure measurement in humans and experimental animals. Hypertension 45 299-310 Lawler JV, Endy TP, Hensley LE et al (2006) Cynomolgus macaque as an animal model for severe acute respiratory syndrome. PLoS Med 3 el49... 

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