OBJECTIVE To compare the ability of acetaminophen-codeine (AC; 15.5 to 18.5 mg/kg and 1.6 to 2.0 mg/kg, respectively) or carprofen (4.2 to 4.5 mg/kg) administered PO to attenuate experimentally induced lameness in dogs. ANIMALS 7 purpose-bred dogs. PROCEDURES A blinded crossover study was performed. Dogs were randomly assigned to receive AC or carprofen treatment first and then the alternate treatment a minimum of 21 days later. Synovitis was induced in 1 stifle joint during each treatment by intra-articular injection of sodium urate (SU). Ground reaction forces were assessed, and clinical lameness was scored at baseline (before lameness induction) and 3, 6, 9, 12, 24, 36, and 48 hours after SU injection. Plasma concentrations of acetaminophen, carprofen, codeine, and morphine were measured at various points. Data were compared between and within treatments by repeated-measures ANOVA. RESULTS During AC treatment, dogs had significantly higher lameness scores than during carprofen treatment at 3, 6, and 9 hours after SU injection. Peak vertical force and vertical impulse during AC treatment were significantly lower than values during carprofen treatment at 3, 6, and 9 hours. Plasma concentrations of carprofen (R)- and (S)-enantiomers ranged from 2.5 to 19.2 μg/mL and 4.6 to 25.0 μg/mL, respectively, over a 24-hour period. Plasma acetaminophen concentrations ranged from 0.14 to 4.6 μg/mL and codeine concentrations from 7.0 to 26.8 ng/mL, whereas plasma morphine concentrations ranged from 4.0 to 58.6 ng/mL. CONCLUSIONS AND CLINICAL RELEVANCE Carprofen as administered was more effective than AC at attenuating SU-induced lameness in dogs.

OBJECTIVE To investigate the ability of a proprietary antagonist of E-type prostanoid receptor (EP) 4, grapiprant, and carprofen to attenuate lameness attributable to urate-induced synovitis in dogs. ANIMALS 5 purpose-bred hound-cross dogs. PROCEDURES A blinded, 3-way crossover study was performed. Dogs received each of 3 treatments (L-766, a proprietary antagonist of EP4; 4.0 mg/kg), grapiprant (an antagonist of EP4; 2.0 mg/kg), and carprofen (4.4 mg/kg); dogs received 4 doses of each treatment (14 and 2 hours before and 22 and 46 hours after urate injection). Synovitis was induced by intra-articular injection of sodium urate. Measurements (vertical ground reaction forces and clinical lameness scores) were obtained immediately before (0 hours; baseline) and 6, 12, 24, 36, and 48 hours after sodium urate injection. All data were analyzed with repeated-measures ANOVA. RESULTS Lameness scores at 6 hours were significantly higher than baseline lameness scores for all treatments. Lameness scores for the grapiprant treatment remained significantly higher at 12 and 24 hours, compared with baseline lameness scores. Lameness scores for the carprofen treatment were significantly lower than lameness scores for the grapiprant treatment at 6, 12, and 24 hours. Analysis of peak vertical force and vertical impulse data revealed a pattern similar to that for lameness scores. Treatment with L-766 resulted in a significantly higher vertical impulse at 48 hours than did treatment with carprofen or grapiprant. CONCLUSIONS AND CLINICAL RELEVANCE In these dogs, carprofen was the most effective treatment for attenuating lameness induced by injection of sodium urate, and grapiprant was the least effective treatment.

OBJECTIVE To evaluate lameness and morphological changes associated with an osteochondral fragment–groove procedure as a means of experimental induction of metacarpophalangeal (MCP) joint osteoarthritis within an 11-week period in horses. ANIMALS 6 nonlame adult warmbloods. PROCEDURES The right MCP joint of each horse underwent an osteochondral fragment–groove procedure (day 0). After 1 week of stall rest (ie, starting day 7), each horse was trained daily on a treadmill. Weekly, horses underwent visual and inertial sensor-based assessments of lameness. Both MCP joints were assessed radiographically on days 0 (before surgery), 1, 35, and 77. A synovial fluid sample was collected from the right MCP joint on days 0 (before surgery), 35, 36, 49, 63, and 77 for cytologic and biomarker analyses. On day 77, each horse was euthanized; both MCP joints were evaluated macroscopically and histologically. RESULTS Right forelimb lameness was detected visually and by the inertial sensor system when horses were moving on a straight line after distal forelimb flexion or circling left on days 14 to 77. Compared with presurgical values, synovial fluid interleukin-6, prostaglandin E2, hyaluronic acid, and interleukin-1 receptor antagonist protein concentrations were increased at 2 or 3 time points, whereas tumor necrosis factor-α and interleukin-10 concentrations were decreased at 1 time point. Gross examination of all right MCP joints revealed synovitis and wear lines; synovitis was confirmed histologically. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that a combined osteochondral fragment–groove procedure can be used to induce clinically and grossly observable early MCP joint osteoarthritis during an 11-week period in horses.

The objective of this study was to evaluate the effect of a single joint lavage with 7.2% or 15% hypertonic saline solutions (HSS) on the tarsocrural joints of healthy calves. The tarsi of 10 calves were randomly lavaged with 7.2% HSS, 15% HSS, or isotonic saline. Synovial fluid samples were collected aseptically on days 1 (before joint lavage), 2, 3, 4, and 8 for complete cytological analysis. Lameness, joint swelling, and pain were recorded daily. Calves were euthanized on day 8 for gross and histological analyses of synovial membranes and articular cartilage. Synovitis was evaluated using a scoring system reflecting inflammatory changes in synovial membranes. Joints irrigated with HSS were more distended and painful compared with isotonic control joints. Swelling decreased consistently in the joints lavaged with 7.2% HSS, whereas it remained unchanged in joints lavaged with 15% HSS. Slight to moderate lameness was observed in the joints lavaged with 15% HSS. In comparison to isotonic saline joints, total protein concentration was significantly increased on day 2 and 3 for the joints lavaged with 7.2% HSS (P ≤ 0.01) and on days 2, 3, and 4 in the joints lavaged with 15% HSS (P ≤ 0.0006). Gross and histological findings revealed that synovitis was more severe in the joints lavaged with 15% HSS but variable in the joints lavaged with 7.2% HSS. No significant differences were observed for the articular cartilage. Fifteen percent HSS is not recommended for joint lavage. Although irrigation with 7.2% HSS may induce a variable synovitis, it was found appropriate for joint lavage. Its effects on septic joints remain undetermined.

Objective-To investigate the ability of ABT-116 (a proprietary antagonist of transient receptor potential vanilloid type 1) administered at 2 doses to attenuate lameness in dogs with experimentally induced urate synovitis. Animals-8 purpose-bred mixed-breed dogs. Procedures-n a 4-way crossover study, dogs orally received each of low-dose ABT-116 treatment (LDA; 10 mg/kg), high-dose ABT-116 treatment (HDA; 30 mg/kg), firocoxib (5 mg/kg), and no treatment (nontreatment) once a day for 2 days, in a randomly assigned order. Synovitis was induced on the second day of each treatment period by intra-articular injection of either stifle joint with sodium urate, alternating between joints for each treatment period, beginning with the left stifle joint. Ground reaction forces, clinical lameness scores, and rectal temperature were assessed before the injection (baseline) and at various points afterward. Results-Lameness scores at the 2-, 6-, and 12-hour assessment points were higher than baseline scores for HDA and nontreatment, whereas scores at the 2- and 6-hour points were higher than baseline scores for LDA. For firocoxib, there was no difference from baseline scores in lameness scores at any point. Compared with baseline values, peak vertical force and vertical impulse were lower at 2 and 6 hours for HDA and nontreatment and at 2 hours for LDA. No changes in these values were evident for firocoxib. The HDA or LDA resulted in higher rectal temperatures than did treatment with firocoxib or nothing, but those temperatures did not differ among treatments. Conclusions and Clinical Relevance-HDA had no apparent effect on sodium urate–induced lameness; LDA did attenuate the lameness but not as completely as firocoxib treatment. High rectal temperature is an adverse effect of oral ABT-116 administration that may be of clinical concern.

Objective-To compare plasma and synovial fluid endothelin-1 (ET-1) and nitric oxide (NO) concentrations in clinically normal horses and horses with joint disease. Animals-36 horses with joint disease, and 15 horses without joint disease. Procedure-Horses with joint disease were assigned to 1 of the 3 groups (ie, synovitis, degenerative joint disease [DJD], or joint sepsis groups) on the basis of findings on clinical and radiographic examination and synovial fluid analysis. Endothelin-1 and NO concentrations were measured in plasma from blood samples, collected from the jugular vein and ipsilateral cephalic or saphenous vein of the limb with an affected or unaffected joint, as well as in synovial fluid samples obtained via arthrocentesis from the involved joint. Results-Plasma ET-1 concentrations between affected and unaffected groups were not significantly different. Median concentration and concentration range of ET-1 in synovial fluid obtained from the joint sepsis group (35.830 pg/mL, 7.926 to 86.614 pg/mL; n = 7) were significantly greater than values from the synovitis (17.531 pg/mL, 0.01 to 46.908 pg/mL; 18), DJD (22.858 pg/mL, 0.01 to 49.990 pg/mL; 10), and unaffected (10.547 pg/mL, 0.01 to 35.927 pg/mL; 10) groups. Plasma and synovial fluid NO concentrations between affected and unaffected groups were not significantly different. Conclusions and Clinical Relevance-Endothelin-1 is locally synthesized in the joints of horses with various types of joint disease. Synovial fluid concentrations of ET-1 varied among horses with joint disease, with concentrations significantly higher in the synovial fluid of horses with joint sepsis. These results indicate that ET-1 may play a role in the pathophysiologic mechanism of joint disease in horses.

In each of 4 horses, sterile synovitis was induced by intra-articular injection of 3 micrograms of Escherichia coli endotoxin (lipopolysaccharide, LPS) into one antebrachiocarpal joint; an equal volume (2 ml) of phosphate-buffered saline solution (PBSS) was injected into the opposite, control carpus. Blood and 1.5 ml of synovial fluid were obtained at postinjection hours (PIH) 0, 2, 4, 8, 12, 18, 42, 66, and 144. Synovial fluid sample collection was accomplished by use of an indwelling, intra-articular catheter through PIH 12, and by arthrocentesis subsequently. Joint fluid samples were analyzed for cell counts, protein concentration, cytologic variables, and tumor necrosis factor (TNF), interleukin 6 (IL-6), and prostaglandin E2 (PGE2) values. Tumor necrosis factor and IL-6 activities and WBC count were also measured in blood. To monitor local inflammation, skin temperature of each carpus was imaged, using a thermographic scanner prior to each sample collection time. Horses had minimal systemic effects. Mean (SEM) rectal temperature increased significantly to 39.02 +/- 0.15 C only at PIH 18 after intra-articular injection of LPS. One horse had signs of mild depression from PIH 7 to 18, but its vital signs did not change appreciably. Each horse had mild signs of discomfort in the LPS-injected limb from PIH 1 to 3 until PIH 8 to 10. Mean peak surface temperature of the LPS-injected carpi was significantly higher than that of control carpi from PIH 8 to 144 (P < 0.05). Mean synovial fluid WBC count in the LPS-injected and control carpi increased after injection and peaked by PIH 8 (193,125 +/- 8,528 cells/microliter, LPS-treated; 16,425 +/- 8,336 cells/microliter, controls). Mean values for LPS-treated (principal) joints were significantly greater than values for control joints from PIH 2 until after PIH 66 (P < 0.05). Mean synovial fluid protein concentration increased in the principal and control joints, with values for the principal joints remaining significantly greater than values for control joints from PIH to 144 (P < 0.05). Mean TNF activity in synovial fluid was maximal at PIH 2 (10,573 +/- 5,924 U/ml). Interleukin-6 activity increased more gradually and peaked at PIH 8 (1.78 +/- 0.71 X 10(6) U/ml). Tumor necrosis factor activity did not increase above the minimal detectable value of 6 U/ml in the control joints. Mean PGE2 concentration in the principal joints peaked by PIH 2 (3.6 +/- 0.37 ng/ml) and remained significantly (P < 0.05) greater than the value for control joints from PIH 2 through 66. These results indicate that a humane model of synovitis was created by intra-articular injection of LPS and can be used to establish the basic responses of synovial TNF, IL-6, and PGE, in horses with early inflammatory joint disease.

The pattern of vertical ground reaction force redistribution among limbs during episodes of acute synovitis of the stifle in 12 mixed-breed dogs was investigated as an adjunct to a blinded nonsteroidal anti-inflammatory drug efficacy study. Without regard to drug efficacy groupings, the redistribution of vertical forces before and during the acute synovitis episode was evaluated by analysis of gait, using a force platform. Acute synovitis was induced by intrasynovial injection of sodium urate crystals. Simultaneously, each dog was given 1 of 4 treatment regimens, including IV injection of sterile saline solution (as a negative control), phenylbutazone (as a positive control), or 1 of 2 proprietary nonsteroidal anti-inflammatory drugs. Postinjection analyses took place at 2, 4, 8, 12, 24, and 36 hours. The peak vertical force redistribution in the 3 untreated limbs of the dogs was described. The greatest redistribution sm observed 4 hours after substance injection when the synovitis was clinically at maximum. Thereafter, there was steady improvement and the dogs had a clinically normal gait 24 hours after substance injection. During synovitis, peak vertical force increased in the contralateral hind limb. During the more severe synovitis episodes, force was decreased in both forelimbs. There was good correlation between severity of lameness and peak vertical force response in the contralateral hind limb. Results of the study indicate that the untreated limbs of the same animal should not be used as a control during acute lameness studies.

In addition to its well-known physicochemical properties, hyaluronate (HA) has recently been shown to have important biological and pathophysiologic regulatory effects on granulocytes, monocytes, fibroblasts, and endothelial cells, as well as on the healing of wounds and various joint disorders. Many of these effects depend on or are reflected in the concentration and degree of polymerization of HA. Therefore, high-performance liquid chromatography with size-exclusion column was used to characterize the concentration and degree of polymerization of HA in equine synovial fluid (SF). The mean (+/-SD) HA concentration was 0.47 +/- 0.19 mg/ml and there was no difference between control joints and those with positive response to local anesthetic administration (0.61 +/- 0.20 mg/ml vs 0.42 +/-0.17 mg/ml), suggesting that in horses with acute traumatic synovitis causing lameness, HA concentration in SF cannot be used as a marker for the condition. High-performance liquid chromatograms disclosed considerable variation between horses in the degree of polymerization reflected in the peak area to height ratio (mean +/-SD, 3.207 +/- 0.447; range, 2.229 to 3.915), indicating differences in local synthesis, degradation, or mobilization into lymph of SF HA. In addition, the correlation between SF HA concentration and degree of polymerization was 0.760 (P < 0.01; linear regression analysis) suggesting that HA concentration and chain length are independently regulated.