A latent pharmacokinetic time profile to model dose-response survival data.

The accelerating rotarod test is a preclinical pharmacodynamic test to assess the effect of a treatment on an animal's motor coordination. Two models are proposed to analyze the dose-response time-to-event data that typically result from such experiments: (1) a linear regression model and (2) an E(max) model with latent drug concentration at the site of action. Both cope with the survival character of the data. The latter model allows a direct comparison of compounds, but raises the question of whether the study design would benefit from the inclusion of additional mice for plasma concentration sampling on the one hand or whether additional time-to-event data without plasma concentration sampling should be ascertained from these additional mice on the other hand. A simulation study explores the impact on operational characteristics of this change of study design.

The stress-induced hyperthermia paradigm as a physiological animal model for anxiety: a review of pharmacological and genetic studies in the mouse.

This paper reviews the function, brain mechanisms and pharmacology of stress-induced hyperthermia (SIH) in a broad context. Hyperthermia itself is induced by all stressful stimuli and can be found across numerous species, including humans. As a model for anxiety, the process of insertion of a rectal probe increases temperature ranging from about 0.5-1.5 degrees C in 10-15min is called SIH. This temperature increase can be blocked by anxiolytic drugs. The methodological as well as pharmacological aspects of the group- (G-SIH) and singly housed (SIH) version of the paradigm are described in detail. Also, an overview is presented about studies using the SIH procedure in genetically modified mice together with the potential interference with immunological induction of a febrile response. The paper also presents data that highlight some of the limitations of the SIH procedure for use of drugs like nicotine, which contain particular characteristics such as short in vivo half-life, and/or disturbance of thermoregulation. The advantages and disadvantages of the SIH procedure as a physiological model of anxiety are discussed.