Objective—To investigate effects of the anti-arthritic
agents hyaluronan and polysulfated glycosaminoglycan
(PSGAG) on inflammatory metabolism in cultured
Sample Population—Synoviocytes cultured from
samples obtained from the metacarpophalangeal
joints of 4 horses.
Procedure—Equine synoviocytes were grown in
monolayer culture. Synoviocytes were stimulated
with lipopolysaccharide (LPS) and simultaneously
treated with various concentrations of hyaluronan or
PSGAG for 48 hours. Three hyaluronan preparations
were compared. Prostaglandin E2 (PGE2) concentrations
in culture medium were measured, using
Results—The highest concentrations of hyaluronan
and PSGAG tested inhibited PGE2 production.
Conclusions and Clinical Relevance—Clinically
achievable concentrations of hyaluronan and PSGAG
inhibited PGE2 synthesis by cultured equine synoviocytes.
This anti-inflammatory action may be a mechanism
through which these agents exert anti-arthritic
effects. The effect was obtained at concentrations
that can be achieved by use of intra-articular, but not
systemic, administration of hyaluronan or PSGAG.
( Am J Vet Res 2000;61:499–505)
Objective—To determine the pharmacokinetics and
pharmacodynamics of danofloxacin in goats and the
concentrations required to induce bacteriostasis, bactericidal
activity, and bacterial elimination.
Animals—6 healthy British Saanen goats.
Procedure—Danofloxacin (1.25 mg/kg of body
weight) was administered IV and IM in a cross-over
design with 14 days between treatments. A tissue
cage was used for evaluation of drug distribution into
transudate and exudate. The ex vivo antibacterial
activity of danofloxacin in serum, exudate, and transudate
against a caprine isolate of Mannheimia
haemolytica was determined. Pharmacokinetic and
pharmacodynamic data were integrated to determine
the ratio of the area under the concentration versus
time curve to the minimum inhibitory concentration
of danofloxacin (AUIC).
Results—Elimination half-lives of danofloxacin in
serum were 4.67 and 4.41 hours after IV and IM
administration, respectively. Volume of distribution
was high after administration via either route, and
bioavailability was 100% after IM administration. Rate
of penetration into exudate and transudate was slow,
but elimination half-lives from both fluids were approximately
twice that from serum. Drug concentrations in
serum, exudate, and transudate for 9 to 12 hours after
administration induced marked ex vivo antibacterial
activity. For serum, AUIC24h values required for bacteriostasis,
bactericidal effect, and bacterial elimination
were 22.6, 29.6, and 52.4, respectively. Similar values
were obtained for exudate and transudate.
Conclusions and Clinical Relevance—Integration of
danofloxacin pharmacokinetic and pharmacodynamic
data obtained in goats may provide a new approach
on which to base recommendations for therapeutic
dosages. (Am J Vet Res 2001;62:1979–1989)
Objective—To develop and validate in cats suitable in
vitro assays for screening and ranking nonsteroidal antiinflammatory
drugs (NSAIDs) on the basis of their
inhibitory potencies for cyclooxygenase (COX)-1 and
Procedure—COX-1 and COX-2 activities in heparinized
whole blood samples were induced with calcium
ionophore and lipopolysaccharide, respectively. For the
COX-2 assay, blood was pretreated with aspirin. The
COX-1 and COX-2 assays were standardized, such that
time courses of incubation with the test compounds
and conditions of COX expression were as similar as
possible in the 2 assays. Inhibition of thromboxane B2
production, measured by use of a radioimmunoassay,
was taken as a marker of COX-1 and COX-2 activities.
These assays were used to test 10 to 12 concentrations
of a COX-1 selective drug (SC-560) and of 2
NSAIDs currently used in feline practice, meloxicam
and carprofen. Selectivities of these drugs were compared
by use of classic 50% and 80% inhibitory concentration
(ie, IC50 and IC80) ratios but also with alternative
indices that are more clinically relevant.
Results—These assay conditions provide a convenient
and robust method for the determination of NSAID
selectivity. The S(+) enantiomeric form of carprofen
was found to be COX-2 selective in cats, but meloxicam
was only slightly preferential for this isoenzyme.
Conclusions and Clinical Relevance—In vitro pharmacodynamic
and in vivo pharmacokinetic data predict
that the COX-2 selectivity of both drugs for cats
will be limited when used at the recommended
doses. This study provides new approaches to the
selection of COX inhibitors for subsequent clinical
testing. (Am J Vet Res 2005;66:700–709)
Objective—To establish pharmacokinetic and pharmacodynamic
properties of a racemic mixture and
individual R(–) and S(+) enantiomeric forms of ketoprofen
(KTP) in sheep and determine pharmacodynamic
variables of KTP by pharmacokinetic-pharmacodynamic
Animals—8 female Dorset crossbred sheep.
Procedure—A tissue cage model of inflammation
was used. Carrageenan was administered into tissue
cages. Time course of cyclooxygenase (COX)-2 inhibition
was determined in vivo by measurement of exudate
prostaglandin E2 (PGE2) concentrations. Time
course of COX-1 inhibition was determined ex vivo by
measurement of serum thromboxane B2 (TXB2) concentrations.
In addition, plasma concentration-time
course and penetration of KTP enantiomers into
inflammatory exudate and transudate (noninflamed
tissue cage fluid) were investigated. Four treatments
were compared: placebo, racemic mixture (rac-KTP [3
mg/kg of body weight, IV]), S(+) KTP (1.5 mg/kg,
IV),and R(–) KTP (1.5 mg/kg, IV).
Results—Both KTP enantiomers had elimination halflife
and mean residence time measurements that
were short and volume of the central compartment
and steady state volume of distribution that were low.
Clearance was rapid, particularly for R(–) KTP.
Elimination of both enantiomers from exudate was >
10 times slower than from plasma. Both rac-KTP and
the individual enantiomers significantly inhibited
serum TXB2 concentrations for 12 hours. Rac-KTP and
S(+) KTP, but not R(–) KTP, also significantly inhibited
PGE2 synthesis in exudate for 12 hours.
Conclusions and Clinical Relevance—Inhibition of
serum TXB2 concentration and exudate PGE2 synthesis
for similar time courses after S(+) KTP administration
indicates that it is a nonselective inhibitor of COX
in sheep. ( Am J Vet Res 2001;62:77–86)
Objective—To establish pharmacokinetics of robenacoxib after administration to cats via the IV, SC, and oral routes.
Procedures—In a crossover design, robenacoxib was administered IV, SC, and orally (experiment 1) and orally (experiment 2) to cats with different feeding regimens. Blood robenacoxib concentrations were assayed, with a lower limit of quantification of 3 ng/mL.
Results—In experiment 1, geometric mean pharmacokinetic values after IV administration of robenacoxib were as follows: blood clearance, 0.44 L/kg/h; plasma clearance, 0.29 L/kg/h; elimination half-life, 1.49 hours; and volume of distribution at steady state (determined from estimated plasma concentrations), 0.13 L/kg. Mean bioavailability was 69% and median time to maximum concentration (Cmax) was 1 hour for cats after SC administration of robenacoxib, whereas mean bioavailability was 49% and 10% and median time to Cmax was 1 hour and 30 minutes after oral administration to cats after food withholding and after cats were fed their entire ration, respectively. In experiment 2, geometric mean Cmax was 1,159, 1,201, and 692 ng/mL and area under the curve from 0 to infinity was 1,337, 1,383, and 1,069 ng × h/mL following oral administration to cats after food withholding, cats fed one-third of the daily ration, and cats fed the entire daily ration, respectively.
Conclusions and Clinical Relevance—For treatment of acute conditions in cats, it is recommended to administer robenacoxib by IV or SC injection, orally after food withholding, or orally with a small amount of food to obtain optimal bioavailability and Cmax.