title: Paw inflammation model in dogs for preclinical pharmacokinetic/pharmacodynamic investigations of nonsteroidal anti-inflammatory drugs.
abstract: The goal of the present study was to develop and validate a new canine model of inflammation. The motivation was to make available a scientifically appropriate and ethically acceptable model to conduct pharmacokinetic/pharmacodynamic investigations for testing nonsteroidal anti-inflammatory drugs in dogs. A kaolin-induce paw inflammation model previously developed in cats was adapted to the dog. The paw inflammation developed within a few hours, reached maximum values 24 h and up to 3 days after kaolin administration, and then progressively resolved over 2 months. Five end points of clinical interest (body temperature, creeping time under a tunnel, paw withdrawal latency to a standardized thermal stimulus, lameness score, and vertical force developed during walking on a force plate) were measured regularly over the next 24 h and beyond to characterize the time development of the inflammation either in control conditions (placebo period) or after the administration of meloxicam (test period) according to a crossover design. Pharmacodynamic data were modeled using an indirect response pharmacokinetic/pharmacodynamic model. This model described three effects of meloxicam, namely, classic anti-inflammatory, analgesic, and antipyretic effects. The mean plasma meloxicam IC(50) values were 210 ng/ml for the antipyretic effect, 390 ng/ml for the analgesic effect, and 546 ng/ml for the vertical force exerted by the paw on the ground as measured by force plates. These in vivo IC(50) values require approximately 80 (antipyretic effect) to 90% (all other effects) cyclooxygenase-2 inhibition as calculated ex vivo whole-blood assay data.
authors.affiliation: TOXALIM, Institut National de la Recherche Agronomique, Toulouse, France.
authors.forename: E C
authors.initials: EC
authors.lastname: Jeunesse
authors.forename: I A
authors.initials: IA
authors.lastname: Bargues
authors.forename: C E
authors.initials: CE
authors.lastname: Toutain
authors.forename: M Z
authors.initials: MZ
authors.lastname: Lacroix
authors.forename: I M
authors.initials: IM
authors.lastname: Letellier
authors.forename: J M
authors.initials: JM
authors.lastname: Giraudel
authors.forename: P L
authors.initials: PL
authors.lastname: Toutain
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004285:Dogs; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D005528:Foot / Q000473:pathology; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D007794:Lameness, Animal / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D000077239:Meloxicam; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D011897:Random Allocation; D015203:Reproducibility of Results; D013843:Thiazines / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D013844:Thiazoles / Q000493:pharmacokinetics* / Q000627:therapeutic use*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D013843:Thiazines; D013844:Thiazoles; D000077239:Meloxicam