Paw inflammation model in dogs for preclinical pharmacokinetic/pharmacodynamic investigations of nonsteroidal anti-inflammatory drugs.

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.

Use of a pharmacokinetic/pharmacodynamic approach in the cat to determine a dosage regimen for the COX-2 selective drug robenacoxib.

This study investigated the analgesic, anti-inflammatory and antipyretic efficacy of the new COX-2 selective inhibitor robenacoxib in the cat and established pharmacodynamic (PD) parameters for these effects. Robenacoxib, at a dosage of 2 mg/kg administered subcutaneously, was evaluated in a kaolin-induced paw inflammation model in 10 cats, using both clinically relevant endpoints (lameness scoring, locomotion tests) and other indicators of inflammation (body and skin temperature, thermal pain threshold) to establish its pharmacological profile. A pharmacokinetic/pharmacodynamic (PK/PD) modelling approach, based on indirect response models, was used to describe the time course and magnitude of the responses to robenacoxib. All endpoints demonstrated good responsiveness to robenacoxib administration and both the magnitude and time courses of responses were well described by the indirect pharmacodynamic response models. Pharmacokinetic and clinically relevant pharmacodynamic parameters were used to simulate dosage regimens that will assist the planning of clinical trials and the selection of an optimal dosage regimen for robenacoxib in the cat.

Effect of spironolactone on diuresis and urine sodium and potassium excretion in healthy dogs.

OBJECTIVES: To document the diuretic effect of different oral doses of spironolactone (SP) in healthy dogs. BACKGROUND: SP is currently mentioned as a diuretic agent in the dog. However, the recommended doses were empirically defined and their corresponding diuretic effect has never been documented in dogs. ANIMALS, MATERIALS AND METHODS: Eight adult Beagle dogs were used for two separate 2*2 cross-over designs. In the first cross-over, 4 dogs received SP orally for 8 days at 1 and 2mg/kg per day. In the second cross-over the 4 other dogs received SP similarly, but at 4 and 8 mg/kg per day. Dogs were weighed on the first and last day of each period. Plasma SP and canrenone (the main active metabolite of SP) were assayed by high performance liquid chromatography (HPLC). Daily water consumption, urine weight, urine specific gravity, and urine excretion of sodium and potassium were measured during the SP treatment. RESULTS: Two hours after SP administration, SP was metabolized into canrenone. A significant 14 and 22% decrease in urine potassium excretion was observed at 1 and 2mg/kg, respectively, but not at the two other dose levels. Daily water consumption, urine weight, urine specific gravity, and urine excretion of sodium were not significantly altered by the SP treatment regardless of dose. CONCLUSIONS: Repeated oral administration of SP at 1, 2, 4 or 8 mg/kg for 8 days had no effect on water and sodium diuresis in healthy dogs.