Use of mixed-effect models and tolerance limits to evaluate control cynomolgus monkey body weight change and variability during preclinical toxicology studies.

Cynomolgus monkeys are an important and widely used species in preclinical toxicology studies. During the in-life phase of study, body weight effects may be indicative of toxicity; however, trends in body weight and body weight variability are often difficult to interpret due to small sample size and/or inter- and intra-animal variability. The present analysis utilizes mixed-effect modelling, which incorporates random and fixed effects into linear regression models, to evaluate control monkey body weight trends and variability relative to baseline (initial) weight and study duration. The primary aim of this analysis is to evaluate whether mixed-effect model based tolerance limits can aide in determining whether apparent test article-related changes in body weight deviate more than the predicted variability defined by the model tolerance limits. The models for this study are based on vehicle control animal body weight data from the following studies: 1-month (20 studies, 198 animals), 3-month (19 studies, 180 animals), and 9-month (17 studies, 182 animals). The analysis presented herein provides the framework for evaluating control monkey body weight change in studies with small sample size, and anticipated control monkey body weight change relative to gender and study duration.

Activation of chloride secretion in cystic fibrosis cells and tissues by the substituted imidazole SRI 2931.

Recent interest in nucleotides and related agents as part of clinical trials in cystic fibrosis (CF) therapy have elicited efforts to identify novel compounds capable of activating transepithelial chloride (Cl(-)) transport in CF cells and tissues. From a library of nucleosides, bases, and other substituted heterocycles, 341 compounds were screened for their ability to activate anion transport in CF cells grown on permeable supports. One compound, SRI 2931, was found to confer prolonged and potent activity when administered to the apical surfaces of CF pancreatic epithelial cells, primary CF nasal epithelial cells, non-CF human colonic epithelial cells, and intact tissue taken from mouse models for CF. Concentrations of SRI 2931 (20 microM), which activated Cl(-) transport, had minimal effect on cell proliferation. SRI 2931 was not calcium (Ca(2+)) or cAMP dependent, suggesting important differences from conventional chloride secretagogues. The compound selectively released ATP from the apical, but not basolateral, surfaces of CF cells grown on permeable supports. The magnitude, longevity, and mechanism of action of the response provide a tool for dissecting pathways of epithelial ATP extracellular signaling and Cl(-) permeability.