Comparison of the Tissue Distribution and Metabolism of AN1284, a Potent Anti-Inflammatory Agent, After Subcutaneous and Oral Administration in Mice

Purpose. To establish a liquid chromatography/mass spectrometry method to compare the tissue distribution and metabolism of AN1284 after subcutaneous and oral administration at doses causing maximal reductions in IL-6 in plasma and tissues of mice. Methods. Lipopolysaccharide activated RAW 264.7 macrophages were used to detect the anti-inflammatory activity of AN1284 and its metabolites. Mice were given AN1284 by injection or gavage, 15 min before lipopolysaccharide. The reduction of IL-6 measured after 4h. Results. AN1284 is metabolized to the indole (AN1422), a 7-OH derivative and its glucuronide. AN1422 had weaker anti-inflammatory activity than AN1284 in LPS-activated macrophages and in mice. Maximal reductions in IL-6 in plasma, brain and liver were seen after subcutaneous injection of (0.5 mg/kg). This dose was also most effective in reducing IL-6 in the liver after oral drug administration but 2.5 mg/kg was needed for the same reductions in plasma and brain. Peak concentrations after oral administration of AN1284 (2.5 mg/kg) were 5.5-fold higher in the liver but 7-, 11 and 19-fold lower in plasma, brain and kidneys than after injection of 0.5 mg/kg. Similar concentrations in the liver were achieved by AN1284 (1 mg/kg/day) administered in the drinking fluid, and 2.5 mg/kg/day, via subcutaneously-implanted mini-pumps. Although drug levels were only 12% of the peak seen after acute injection of 0.5 mg/kg, they significantly decreased hepatocellular damage, liver triglycerides and cholesterol in diabetic mice. Conclusion. AN1284 can be given orally to treat chronic liver disease and its preferential concentration in the liver should limit potential adverse effects.

Efficient mate finding in planktonic copepods swimming in turbulence

Zooplankton live in dynamic environments where turbulence may challenge their limited swimming abilities. How this interferes with fundamental behavioral processes remains elusive. We reconstruct simultaneously the trajectories of flow tracers and calanoid copepods and we quantify their ability to find mates when ambient flow imposes physical constrains on their motion and impairs their olfactory orientation. We show that copepods achieve high encounter rates in turbulence due to the contribution of advection and vigorous swimming. Males further convert encounters within the perception radius to contacts and then to mating via directed motion toward nearby organisms within the short time frame of the encounter. Inertial effects do not result in preferential concentration, reducing the geometric collision kernel to the clearance rate, which we model accurately by superposing turbulent velocity and organism motion. This behavioral and physical coupling mechanism may account for the ability of copepods to reproduce in turbulent environments.