Establishment of a Low Dose Canine Endotoxemia Model to Test Anti-Inflammatory Drugs: Effects of Prednisolone

Abstract

Infusion of low doses of lipopolysaccharide (LPS) in human volunteers provides a standardised model to study novel anti-inflammatory drugs. However, low dose endotoxemia is not well characterised in animals larger than rodents and trials with immunomodulating substances are scarce. We conducted a dose-finding study to establish a canine endotoxemia model combining optimal cytokine response with minimal burden for the animals. We thereafter evaluated the pharmacodynamics and pharmacokinetics (PK) of prednisolone. For dose-finding, dogs randomly received a single bolus of 0.03, 0.1 or 1.0μg/kg BW LPS i.v. The second part was a randomised, placebo controlled trial with 4 parallel groups. Either 0.25, 0.5 or 5mg/kgBW prednisolone or placebo were given for 3 days. On day 3, all animals received 0.1μg/kg BW LPS i.v. Blood was sampled to measure interleukin 6 (IL-6) and tumor necrosis factor (TNF)-α, C-reactive protein, prednisolone and cortisol concentrations. In accordance with human endotoxemia, LPS substantially and dose-dependently increased IL-6 and TNF-α several 1000-fold. Prednisolone significantly attenuated the LPS-induced IL-6 and TNF-α responses by a maximum of 96% (p<0.03 for all treatment groups) and significantly reduced peak cortisol concentrations in a dose-dependent way (p<0.004 for all treatment groups). PK showed a non-linear kinetic. In conclusion, this dog model could provide a reliable setting to test experimental drugs for canine or human use.