Steven C. Budsberg

Cyclooxygenase selectivity of nonsteroidal anti-inflammatory drugs in canine blood

OBJECTIVE To evaluate cyclooxygenase (COX) selectivity of several nonsteroidal anti-inflammatory drugs (NSAID) in canine blood in vitro. ANIMALS 11 healthy adult male hound crosses. PROCEDURE 9 NSAID were studied at 5 concentrations. Thromboxane B2 (TxB2) was assayed as a measure of COX-1 activity in clotted blood. Prostaglandin E2 (PGE2) was assayed as a measure of COX-2 activity in heparinized, lipopolysaccharide (LPS)-stimulated blood. All assays were competitive ELISA tests. Cyclooxygenase selectivity was expressed as a ratio of the concentration of an NSAID that inhibited 50% of the activity (IC50) of COX-1 to the IC50 of COX-2. A separate ratio of the concentration that inhibited 80% of COX activity (IC80) was also determined. A ratio of < 1.0 indicated selectivity for COX-1, whereas a ratio of > 1.0 indicated COX-2 selectivity. RESULTS Ketoprofen, aspirin, and etodolac were COX-1 selective. Piroxicam, meloxicam, and carprofen had COX-2 selectivity. The IC50 and IC80 values were similar for most NSAID. CONCLUSIONS This methodology provides repeatable data from individual dogs and is comparable to results of previous in vitro and ex vivo models. Findings are also consistent with those of canine studies performed in vivo, suggesting that this is a viable in vitro assessment of the COX selectivity of NSAID in dogs.

Nonsteroidal Anti-Inflammatory Drugs and Corticosteroids for The Management of Canine Osteoarthritis

Anti-inflammatory medications have long been prescribed for relief of the pain and discomfort associated with OA. This occurs despite the recognized side effects associated with use of NSAIDs and corticosteroids. Available evidence suggests that NSAIDs provide this relief through a combination of central and peripheral actions. Recent discovery of two isoforms of cyclooxygenase has increased our understanding of NSAID activity and may result in identification of drugs that potentially will have fewer side effects. A review of NSAIDs used in veterinary medicine indicates that relatively little is known regarding their role in treating OA, although controlled studies involving carprofen and etodolac have increased our knowledge of the efficacy of specific NSAIDs used for this purpose.

Pharmacodynamic and pharmacokinetic evaluation of clopidogrel and the carboxylic acid metabolite SR 26334 in healthy dogs

OBJECTIVE To determine pharmacodynamic and pharmacokinetic properties of clopidogrel and the metabolite SR 26334 in dogs. ANIMALS 9 mixed-breed dogs. PROCEDURES 8 dogs received clopidogrel (mean +/- SD 1.13 +/- 0.17 mg/kg, PO, q 24 h) for 3 days; 5 of these dogs subsequently received a lower dose of clopidogrel (0.5 +/- 0.18 mg/kg, PO, q 24 h) for 3 days. Later, 5 dogs received clopidogrel (1.09 +/- 0.12 mg/kg, PO, q 24 h) for 5 days. Blood samples were collected for optical platelet aggregometry, citrated native and platelet mapping thrombelastography (TEG), and measurement of plasma drug concentrations. Impedance aggregometry was performed on samples from 3 dogs in each 3-day treatment group. RESULTS ADP-induced platelet aggregation decreased (mean +/- SD 93 +/- 6% and 80 +/- 22% of baseline values, respectively) after 72 hours in dogs in both 3-day treatment groups; duration of effect ranged from > 3 to > 7 days. Platelet mapping TEG and impedance aggregometry yielded similar results. Citrated native TEG was not different among groups. Clopidogrel was not detected in any samples; in dogs given 1.13 +/- 0.17 mg/kg, maximum concentration of SR 26334 (mean +/- SD, 0.206 +/- 0.2 microg/mL) was detected 1 hour after administration. CONCLUSIONS AND CLINICAL RELEVANCE Clopidogrel inhibited ADP-induced platelet aggregation in healthy dogs and may be a viable antiplatelet agent for use in dogs. Impact for Human Medicine-Pharmacodynamic effects of clopidogrel in dogs were similar to effects reported in humans; clopidogrel may be useful in studies involving dogs used to investigate human disease.

Pharmacokinetics of meloxicam following intravenous and oral administration in green iguanas (Iguana iguana)

OBJECTIVE To determine pharmacokinetics of meloxicam in healthy green iguanas following PO and IV administration and assess potential toxicity. ANIMALS 21 healthy green iguanas (Iguana iguana). PROCEDURES To assess pharmacokinetics, 13 iguanas were administered a single dose (0.2 mg/kg) of meloxicam PO and, 14 days later, the same dose IV. To assess potential toxicity, 4 iguanas were given meloxicam at a dosage of 1 or 5 mg/kg, PO, every 24 hours for 12 days, and results of histologic examination were compared with results for another 4 iguanas given a single dose of meloxicam (0.2 mg/kg). RESULTS There were no significant differences between PO and IV administration with regard to terminal half-life (mean ± SD, 12.96 ± 8.05 hours and 9.93 ± 4.92 hours, respectively), mean area under the curve to the last measured concentration (5.08 ± 1.62 μg•h/mL and 5.83 ± 2.49 μg•h/mL), volume of distribution (745 ± 475 mL/kg and 487 ± 266 mL/kg), or clearance (40.17 ± 10.35 mL/kg/h and 37.17 ± 16.08 mL/kg/h). Maximum plasma concentration was significantly greater following IV (0.63 ± 0.17 μg/mL) versus PO (0.19 ± 0.07 μg/mL) administration. Time from administration to maximum plasma concentration and mean residence time were significantly longer following PO versus IV administration. Daily administration of high doses (1 or 5 mg/kg) for 12 days did not induce any histologic changes in gastric, hepatic, or renal tissues. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that administration of meloxicam at a dose of 0.2 mg/kg IV or PO in green iguanas would result in plasma concentrations > 0.1 μg/mL for approximately 24 hours.

Nonsurgical Management of Osteoarthritis in Dogs

Osteoarthritis (OA), although superficially considered to be deterioration of the joint associated with pain and dysfunction, is actually quite a complex condition. When considering treatment of OA, a multitude of biochemical, physical, and pathologic alterations must be recognized. This article presents a review of the published material regarding various nonsurgical treatments for OA. When there are no data regarding a specific treatment or when a statement is the opinion of the authors, such a deficiency is identified.

Effects of meloxicam on plasma iohexol clearance as a marker of glomerular filtration rate in conscious healthy cats

OBJECTIVE To investigate the effect of therapeutic dosages of meloxicam on the plasma clearance of iohexol in healthy, euvolemic, conscious cats fed a sodium-replete diet. ANIMALS 6 healthy adult neutered male cats. PROCEDURES For each treatment period in a masked, randomized, crossover study, cats were administered either no treatment or meloxicam. Iohexol clearance studies were performed before the treatment period began (baseline) and on the final day of the treatment period. Iohexol concentrations were determined by use of a high-performance liquid chromatography assay, and plasma iohexol clearance as a marker of glomerular filtration rate was calculated by use of a 1-compartment model. RESULTS No significant treatment effect was detected. Mean +/- SE iohexol clearance for cats administered meloxicam (3.31 +/- 0.27 mL/min/kg) was not significantly different from mean baseline value for the meloxicam treatment period (3.07 +/- 0.32 mL/min/kg). CONCLUSIONS AND CLINICAL RELEVANCE In this study, short-term meloxicam administration did not measurably alter the glomerular filtration rate as assessed via plasma clearance of iohexol. This suggests that renal prostaglandins in cats did not have a measurable effect on glomerular filtration rates in healthy, euvolemic, conscious states as determined on the basis of methods used in this study.

Effects of Firocoxib and Tepoxalin on Healing in a Canine Gastric Mucosal Injury Model

BACKGROUND Little is known about the effect of dual cyclooxygenase (COX) and lipoxygenase inhibition on canine gastric mucosal healing. OBJECTIVE This study compares the effects of putative dual COX and 5-lipoxygenase inhibition with that of COX-2 selective inhibition on gastric mucosal lesion healing in dogs. ANIMALS Six normal adult mixed-breed research dogs. METHODS Gastric body and pyloric lesions were induced by endoscopic biopsy. Dogs were treated with tepoxalin, firocoxib, or placebo for 7 days in a randomized 3-way crossover study design. Healing was evaluated on days 2, 4, and 7 of treatment by endoscopic lesion scoring. Eicosanoid concentrations in plasma and at the lesion margins were determined on days 2, 4, and 7. Repeated measures analyses were performed. All hypothesis tests were 2-sided with P < .05. Multiple comparisons were adjusted using Tukeys test. RESULTS Significant treatment differences were noted in the pyloric lesion area measurements. Overall, the firocoxib group had larger lesions than the placebo (P= .0469) or tepoxalin (P= .0089) groups. Despite larger pyloric lesions in the firocoxib group, mucosal prostaglandin production did not differ significantly from placebo. In contrast, the tepoxalin group had significantly lower pyloric mucosal prostaglandin production compared with the firocoxib (P < .0001) or the placebo (P < .0001) groups but pyloric lesions were not significantly larger than those of the placebo group (P= .7829). CONCLUSION COX-2 inhibition by firocoxib slowed wound healing by a mechanism independent of prostaglandin synthesis. Suppression of mucosal prostaglandin production by tepoxalin did not alter mucosal lesion healing compared with placebo.

Comparison of Canine Stifle Kinematic Data Collected with Three Different Targeting Models

OBJECTIVE To model the kinematics of the canine stifle in 3 dimensions using the Joint Coordinate System (JCS) and compare the JCS method with linear and segmental models. STUDY DESIGN In vivo biomechanical study. ANIMALS Normal adult mixed breed dogs (n=6). METHODS Dogs had 10 retroreflective markers affixed to the skin on the right pelvic limb. Dogs were walked and trotted 5 times through the calibrated space and the procedure was repeated 5 days later. Sagittal flexion and extension angle waveforms acquired during each trial with all 3 models (JCS, Linear, and Segmental) were produced simultaneously during each gait. The JCS method provided additional internal/external and abduction/adduction angles. Comparison of sagittal flexion and extension angle waveforms was performed with generalized indicator function analysis (GIFA) and Fourier analysis. A normalization procedure was performed. RESULTS Each model provided consistent equivalent sagittal flexion-extension data. The JCS provided consistent additional internal/external and abduction/adduction. Sagittal waveform differences were found between methods and testing days for each dog at a walk and a trot with both GIFA and Fourier analysis. After normalization, differences were less with Fourier analysis and were unaltered with GIFA. CONCLUSIONS Whereas all methods produced similar flexion-extension waveforms, JCS provided additional valuable data. CLINICAL RELEVANCE The JCS model provided sagittal plane flexion/extension data as well as internal/external rotation and abduction/adduction data.

Evaluation of a three-dimensional kinematic model for canine gait analysis

OBJECTIVE To evaluate a 3-D kinematic model of the hind limb developed by use of a joint coordinate system in dogs. ANIMALS 6 clinically normal adult mixed-breed dogs. PROCEDURES 17 retroreflective markers were affixed to the skin on the right hind limb of each dog. Eight infrared cameras were arranged around a gait platform to record marker locations as dogs were recorded moving through the calibrated space 5 times during a walk and trot at velocities of 0.9 to 1.2 m/s and 1.7 to 2.1 m/s, respectively. Local and global coordinate systems were established, and a segmental rigid-body model of the canine hind limb was produced. Dynamic 3-D joint kinematic measurements were collected for the hip, stifle, and tarsal joints. RESULTS Sagittal (flexion-extension), transverse (internal-external rotation), and frontal (abduction-adduction) plane kinematic measurements were acquired during each trial for the hip, stifle, and tarsal joints. CONCLUSIONS AND CLINICAL RELEVANCE The joint coordinate system allowed acquisition of 3-D kinematic measurements of the hip, stifle, and tarsal joints of the canine hind limb. Methods were described to model 3-D joint motion of the canine hind limb.

Outcome Assessment in Clinical Trials Involving Medical Management of Osteoarthritis in Small Animals

The goal of any clinical trial involving modulation of osteoarthritis is to assess the efficacy of a proposed therapy. This article attempts to provide some insight into assessing the outcome of clinical trials involving the management of osteoarthritis and reviews select key areas within clinical trials that need to be evaluated during critical analysis of any proposed therapeutic product.