Derivatives of 8-hydroxyquinoline--antibacterial agents that target intra- and extracellular Gram-negative pathogens.

Small molecule screening identified 5-nitro-7-((4-phenylpiperazine-1-yl-)methyl)quinolin-8-ol INP1750 as a putative inhibitor of type III secretion (T3S) in the Gram-negative pathogen Yersinia pseudotuberculosis. In this study we report structure-activity relationships for inhibition of T3S and show that the most potent compounds target both the extracellular bacterium Y. pseudotuberculosis and the intracellular pathogen Chlamydia trachomatis in cell-based infection models.

Comparative Analysis of Stress Induced Gene Expression in Caenorhabditis elegans following Exposure to Environmental and Lab Reconstituted Complex Metal Mixture.

Metals are essential for many physiological processes and are ubiquitously present in the environment. However, high metal concentrations can be harmful to organisms and lead to physiological stress and diseases. The accumulation of transition metals in the environment due to either natural processes or anthropogenic activities such as mining results in the contamination of water and soil environments. The present study used Caenorhabditis elegans to evaluate gene expression as an indicator of physiological response, following exposure to water collected from three different locations downstream of a Swedish mining site and a lab reconstituted metal mixture. Our results indicated that the reconstituted metal mixture exerted a direct stress response in C. elegans whereas the environmental waters elicited either a diminished or abrogated response. This suggests that it is not sufficient to use the biological effects observed from laboratory mixtures to extrapolate the effects observed in complex aquatic environments and apply this to risk assessment and intervention.

A 24-hour continuous infusion study of bivalirudin in the rat.

The potential toxic effects of bivalirudin (an anticoagulant) were evaluated in this intravenous infusion study in Sprague-Dawley rats. Bivalirudin was administered over a 24-hour period by continuous intravenous infusion to six groups of rats. Dose levels of 100, 500, and 2000 mg/kg/24 h were selected for the low-, mid-, and high-dose groups. Three bivalirudin-treated groups of 12 males and 12 females each were designated for toxicology assessment. Six animals/sex/group were euthanized at the completion of 24-hour infusion, and the remaining animals were assigned to a 14-day recovery period. Three additional groups of 10 rats/sex/group were designated for toxicokinetic assessment. This study included a saline control group and a vehicle control group. No bivalirudin-related toxicity was noted. There were no treatment-related effects on clinical pathology parameters. No definitive test article-related macroscopic, organ weight, or microscopic changes were identified. Three animals in the 500-mg/kg/24 h group, and 7 animals in the 2000-mg/kg/24 h group in the toxicokinetic assessment phase of the study were found dead or euthanized in extremis (following blood sampling). The concurrent clinical signs suggest that the animals hemorrhaged, which is consistent with the pharmacological action of bivalirudin. The extent of systemic exposure was similar in male and female rats, indicating a lack of a sex-related difference. Plasma concentrations of bivalirudin appeared to be linear and dose independent. Based on the results of this study, the no-observed-adverse-effect level (NOAEL) for bivalirudin, administered to rats via intravenous infusion over a 24-hour period, was 2000 mg/kg/24 h. However, the known pharmacological properties of bivalirudin could result in hemorrhage in the presence of an appropriate challenge (e.g., blood collection).