title: 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 1.0 microg/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 0.1microg/kg BW LPS i.v. Blood was sampled to measure interleukin 6 (IL-6) and tumor necrosis factor-alpha, C-reactive protein, prednisolone and cortisol concentrations. In accordance with human endotoxemia, LPS substantially and dose-dependently increased IL-6 and TNF-alpha several 1000-fold. Prednisolone significantly attenuated the LPS-induced IL-6 and TNF-alpha responses by a maximum of 96 percent (p less than 0.03 for all treatment groups) and significantly reduced peak cortisol concentrations in a dose-dependent way (p less than 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.
authors.affiliation: Boehringer Ingelheim Vetmedica GmbH, Ingelheim, Germany.
authors.forename: F
authors.initials: F
authors.lastname: De Vries
authors.affiliation: LPT Laboratory of Pharmacology and Toxicology GmbH and CoKG, Hamburg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Leuschner
authors.affiliation: Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: B
authors.initials: B
authors.lastname: Jilma
authors.affiliation: Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: U
authors.initials: U
authors.lastname: Derhaschnig
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D002097:C-Reactive Protein / Q000032:analysis; D004195:Disease Models, Animal; D004285:Dogs; D019446:Endotoxemia / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D006854:Hydrocortisone / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D011239:Prednisolone / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D000893:Anti-Inflammatory Agents; D015850:Interleukin-6; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D002097:C-Reactive Protein; D011239:Prednisolone; D006854:Hydrocortisone