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Abstract

Objective—To investigate effects of the anti-arthritic agents hyaluronan and polysulfated glycosaminoglycan (PSGAG) on inflammatory metabolism in cultured equine synoviocytes.

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 radioimmunoassay.

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)

Full access
in American Journal of Veterinary Research

Abstract

Objective

To examine effects of carprofen (enantiomers and a racemic mixture) on the metabolism of equine chondrocytes.

Sample Population

Cartilage from clinically normal horses.

Procedure

Effects of carprofen on proteoglycan neosynthesis, glycosaminoglycan (GAG) release and prostaglandin (PG) E2 production by unstimulated chondrocyte monolayers and cartilage explants were examined, as were similar variables in monolayers and explants exposed to carprofen and recombinant human interleukin 1β (IL-1). Carprofen (enantiomers and racemic mixture) was used alone or along with IL-1 on monolayers and explant cultures. Medium was collected 48 to 96 hours later, and cartilage was digested. Proteoglycan synthesis was assessed as the amount of 35S-labeled proteoglycan in medium and digested cartilage. Total GAG content of the medium and digested cartilage was measured, and proteoglycan degradation was calculated. Radioimmunoassay was used to measure PGE2 production.

Results

Carprofen significantly decreased PGE2 production by unstimulated chondrocytes and antagonized an IL-1-induced increase in PGE2 production. Carprofen significantly increased proteoglycan synthesis in unstimulated monolayers and explants. Concurrently, there was a decrease in GAG release by explants. Use of IL-1 significantly decreased proteoglycan synthesis, but the highest concentrations of carprofen partially reversed this effect in chondrocyte monolayers.

Conclusions

Carprofen had a potentially beneficial effect on proteoglycan metabolism of equine chondrocytes. This effect was sufficiently strong at the highest concentrations to overcome inhibitory effects of IL-1 on proteoglycan synthesis. Carprofen also inhibited PGE2 production by unstimulated and IL-1-stimulated chondrocytes. Carprofen induced these enantiomer-specific effects.

Clinical Relevance

Use of carprofen in osteoarthritic horses may induce beneficial changes in articular cartilage matrix. (Am J Vet Res 1999;60:98–104)

Free access
in American Journal of Veterinary Research

Abstract

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)

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in American Journal of Veterinary Research

Abstract

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 modeling.

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)

Full access
in American Journal of Veterinary Research

Abstract

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 COX-2.

Animals—10 cats.

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)

Full access
in American Journal of Veterinary Research

SUMMARY

Carprofen (cpf) enantiomers and their glucuronide conjugates (gluc) were measured in plasma and bile of horses after iv administration of the racemic compound (0.7 mg/kg of body weight). The cpf was detectable in plasma for up to 72 hours after dosing, whereas gluc appeared early (time for maximal plasma concentration, 1 hour) and was measurable transiently at low concentration (maximal plasma concentration, 0.5 μg/ml). The enantiospecific plasma profiles indicated a clear predominance of R-cpf, whereas the stereoselectivity of the glucuronides favored S-gluc. At 1, 2, and 12 hours after administration of the drug, bile concentrations of gluc were high compared with those in plasma and enantioselectivity favored S-gluc. These data indicate that the higher body clearance observed for S-cpf is a consequence of the enantioselectivity in liver glucuronidation and subsequent biliary excretion of the S enantiomer of the drug.

Free access
in American Journal of Veterinary Research

Summary

Areas of skin vascularized by large axial vessels potentially suitable for microvascular anastomosis were investigated in 10 horse cadavers. Eleven such areas were dissected, and the skin over the flank region vascularized by the deep circumflex iliac artery was most suitable. The anatomy of this area was further defined, using angiography and latex injection studies on 10 cadavers.

Free access
in American Journal of Veterinary Research

Abstract

Objective—To establish pharmacokinetics of robenacoxib after administration to cats via the IV, SC, and oral routes.

Animals—24 cats.

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.

Full access
in American Journal of Veterinary Research