In vivo effects of carprofen, deracoxib, and etodolac on prostanoid production in blood, gastric mucosa, and synovial fluid in dogs with chronic osteoarthritis

OBJECTIVE: To evaluate in vivo activity of carprofen, deracoxib, and etodolac on prostanoid production in several target tissues in dogs with chronic osteoarthritis. ANIMALS: 8 dogs with chronic unilateral osteoarthritis of the stifle joint. PROCEDURE: Each dog received carprofen, deracoxib, or etodolac for 10 days with a 30- to 60-day washout period between treatments. On days 0, 3, and 10, prostaglandin (PG) E2 concentrations were measured in lipopolysaccharide-stimulated blood, synovial fluid, and gastric mucosal biopsy specimens; PGE1 concentrations were measured in gastric mucosal biopsy specimens; and thromboxane B2 (TXB2) was evaluated in blood. RESULTS: Carprofen and deracoxib significantly suppressed PGE2 concentrations in blood at days 3 and 10, compared with baseline, whereas etodolac did not. None of the drugs significantly suppressed TXB2 concentrations in blood or gastric PGE1 synthesis at any time point. All 3 drugs significantly decreased gastric synthesis of PGE2 at day 3 but not day 10 of each treatment period. All 3 drugs decreased synovial fluid PGE2 concentrations in the affected and unaffected stifle joints at days 3 and 10. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicate that carprofen and deracoxib act in vivo on target tissues as COX-1-sparing drugs by sparing gastric PGE1 and PGE2 synthesis and production of TXB2 by platelets. Etodolac also appears to be COX-1 sparing but may have variable effects on COX-2 depending on the tissue. In gastric mucosa and synovial fluid, there were no significant differences in PG production between compounds at recommended concentrations.     

Changes in platelet function, hemostasis, and prostaglandin expression after treatment with nonsteroidal anti-inflammatory drugs with various cyclooxygenase selectivities in dogs

OBJECTIVE: To determine the effects of nonsteroidal anti-inflammatory drugs of various cyclooxygenase selectivities on hemostasis and prostaglandin expression in dogs. ANIMALS: 8 client-owned dogs with clinical signs of osteoarthritis. PROCEDURES: Dogs received aspirin (5 mg/kg, PO, q 12 h), carprofen (4 mg/kg, PO, q 24 h), deracoxib (2 mg/kg, PO, q 24 h), and meloxicam (0.1 mg/kg, PO, q 24 h) for 10 days each, with an interval of at least 14 days between treatments. On days 0 and 10, blood was collected for platelet aggregation assays, thrombelastography, and measurement of lipopolysaccharide-stimulated prostaglandin E(2), platelet thromboxane B(2) (TXB(2)), and free serum TXB(2) and 6-keto-prostaglandin F (PGF)-1alpha concentrations. RESULTS: Platelet aggregation decreased after treatment with aspirin and carprofen, whereas significant changes from baseline were not detected for the other drugs tested. Thrombelastograms obtained after treatment with carprofen revealed decreased maximum amplitude and alpha-angle, suggesting hypocoagulability. Maximum amplitude and coagulation index increased after treatment with deracoxib. Plasma concentrations of prostaglandin E(2) decreased after treatment with carprofen or deracoxib, and platelet TXB(2) production increased after treatment with aspirin. Serum concentrations of the prostacyclin metabolite 6-keto-PGF-1alpha did not change significantly after treatment with any of the drugs, although the ratio of free TXB(2) to 6-keto-PGF-1alpha decreased slightly after treatment with carprofen and increased slightly after treatment with deracoxib. CONCLUSIONS AND CLINICAL RELEVANCE: At the dosages tested, treatment with meloxicam affected platelet function minimally in dogs with osteoarthritis. Treatment with carprofen decreased clot strength and platelet aggregation. Clot strength was increased after treatment with deracoxib.     

Effects of carprofen, meloxicam and deracoxib on platelet function in dogs

ObjectiveTo determine effects of anti-inflammatory doses of COX-2 selective NSAIDs carprofen, meloxicam, and deracoxib on platelet function in dogs and urine 11-dehydro-thromboxane B2.Study designRandomized, blocked, crossover design with a 14-day washout period.AnimalsHealthy intact female Walker Hounds aged 1–6 years and weighing 20.5–24.2 kg.MethodsDogs were given NSAIDs for 7 days at recommended doses: carprofen (2.2 mg kg^?1, PO, every 12 hours), carprofen (4.4 mg kg^?1, PO, every 24 hours), meloxicam (0.2 mg kg^?1, PO, on the 1st day then 0.1 mg kg^?1, PO, every 24 hours), and deracoxib (2 mg kg^?1, PO, every 24 hours). Collagen/epinephrine and collagen/ADP PFA-100 cartridges were used to evaluate platelet function before and during and every other day after administration of each drug. Urine 11-dehydro-thromboxane B₂ was also measured before and during administration of each drug.ResultsAll NSAIDs significantly prolonged PFA-100 closure times when measured with collagen/epinephrine cartridges, but not with collagen/ADP cartridges. The average duration from drug cessation until return of closure times (collagen/epinephrine cartridges) to baseline values was 11.6, 10.6, 11 and 10.6 days for carprofen (2.2 mg kg^?1 every 12 hours), carprofen (4.4 mg kg^?1 every 24 hours), meloxicam and deracoxib, respectively.Conclusions and clinical relevanceOral administration of some COX-2 selective NSAIDs causes detectable alterations in platelet function in dogs. As in humans, PFA-100 collagen/ADP cartridges do not reliably detect COX-mediated platelet dysfunction in dogs. Individual assessment of platelet function is advised when administering these drugs prior to surgery, particularly in the presence of other risk factors for bleeding.     

Effects of firocoxib, meloxicam, and tepoxalin on prostanoid and leukotriene production by duodenal mucosa and other tissues of osteoarthritic dogs

OBJECTIVE: To evaluate the in vivo effects of firocoxib, meloxicam, and tepoxalin on prostaglandin (PG) and leukotriene production in duodenal mucosa and other target tissues in dogs with chronic osteoarthritis (OA). ANIMALS: 8 dogs with chronic, unilateral OA of the stifle joint. PROCEDURES: In a crossover design, each dog received placebo (no treatment), firocoxib, meloxicam, or tepoxalin for 7 days, followed by a 21-day washout period. On the first day of treatment (day 0; baseline) and days 2, 4, and 7, samples of whole blood, synovial fluid, and gastric and duodenal mucosae were collected. Prostaglandin E2 concentrations were measured in synovial fluid of the stifle joint and after ex vivo stimulation of whole blood samples. Synthesis of PGE1 and PGE2 was measured in samples of gastric and duodenal mucosae. Concentrations of thromboxane B2 (TxB2) were measured in whole blood samples. Leukotriene B4 (LTB4) concentrations were measured in samples of whole blood (ex vivo stimulation) and gastric and duodenal mucosae. RESULTS: Firocoxib, meloxicam, and tepoxalin significantly suppressed whole blood concentrations of PGE2, compared with baseline and placebo concentrations, at days 2, 4, and 7. Tepoxalin significantly suppressed serum TxB2 concentrations, compared with baseline, firocoxib, meloxicam, and placebo, at all 3 time points. Production of PGE1 and PGE2 was significantly lower in duodenal versus gastric mucosa. Tepoxalin significantly decreased rates of PGE1 and PGE2 in duodenal and gastric mucosae, compared with baseline rates. CONCLUSIONS AND CLINICAL RELEVANCE: PG production was lower in the duodenum than in the stomach. Firocoxib had a COX-1-sparing effect in vivo.     

Effect of short-term sequential administration of nonsteroidal anti-inflammatory drugs on the stomach and proximal portion of the duodenum in healthy dogs

OBJECTIVE: To evaluate effects of injection with a nonsteroidal anti-inflammatory drug (NSAID) followed by oral administration of an NSAID on the gastrointestinal tract (GIT) of healthy dogs. ANIMALS: 6 healthy Walker Hounds. PROCEDURES: In a randomized, crossover design, dogs were administered 4 treatments consisting of an SC injection of an NSAID or control solution (day 0), followed by oral administration of an NSAID or inert substance for 4 days (days 1 through 4). Treatment regimens included carprofen (4 mg/kg) followed by inert substance; saline (0.9% NaCl) solution followed by deracoxib (4 mg/kg); carprofen (4 mg/kg) followed by carprofen (4 mg/kg); and carprofen (4 mg/kg) followed by deracoxib (4 mg/kg). Hematologic, serum biochemical, and fecal evaluations were conducted weekly, and clinical scores were obtained daily. Endoscopy of the GIT was performed before and on days 1, 2, and 5 for each treatment. Lesions were scored by use of a 6-point scale. RESULTS: No significant differences existed for clinical data, clinicopathologic data, or lesion scores in the esophagus, cardia, or duodenum. For the gastric fundus, antrum, and lesser curvature, an effect of time was observed for all treatments, with lesions worsening from before to day 2 of treatments but improving by day 5. CONCLUSIONS AND CLINICAL RELEVANCE: Sequential administration of NSAIDs in this experiment did not result in clinically important gastroduodenal ulcers. A larger study to investigate the effect of sequential administration of NSAIDs for longer durations and in dogs with signs of acute and chronic pain is essential to substantiate these findings.     

Colloid oncotic pressure and total protein changes in horses during anesthesia fluid therapy

It is unknown whether overlapping or sequential use of nonsteroidal anti‐inflammatory (NSAIDs) results in an increased risk for gastrointestinal (GI) ulceration. The purpose of this pilot study was to evaluate the GI effects of various combinations of an injectable NSAID followed by an oral NSAID, a scenario often employed clinically for management of the pre‐ and post‐operative canine patient. Six healthy Walker hounds received four treatment regimens in a randomized, cross‐over design with a 2 week washout period between each treatment week: carprofen (4 mg kg^–1, SQ) followed by placebo (PO, q24 × 4 days); placebo (SQ) followed by deracoxib (3–4 mg kg^–1, PO, q24 × 4 days); carprofen (4 mg kg^–1, SQ) followed by carprofen (4 mg kg^–1, PO, q24 × 4 days); carprofen (4 mg kg^–1, SQ) followed by deracoxib (3–4 mg kg^–1, PO, q24 ×4 days). Weekly bloodwork (CBC, biochemistry panel, fecal evaluation, fecal occult blood) and daily clinical scoring (TPR, vomiting, diarrhea, appetite) were obtained. GI endoscopy was performed on days –2, 1, 2, 5, and 11 days post treatment of each treatment period and lesions scored using a previously reported 6‐point scale. Data was analyzed using a mixed anova for repeated measures. There were no significant differences in clinical or clinicopathologic data between groups. Within the carprofen‐carprofen and carprofen‐deracoxib groups, lesions worsened by Day 5 (1 day after last oral dose) for the fundic and antral regions (p < 0.05). Fundic, antral and lesser curvature lesions improved by Day 5 in the carprofen‐placebo group and lesser curvature lesions improved in the placebo‐deracoxib group (p < 0.05). No significant within‐group differences were noted for the esophagus, cardia or duodenum. The small number of dogs precludes general conclusions about the safety of sequential NSAID use, but these results suggest that a larger scale study is warranted.     

Safety and tolerability of 3-week and 6-month dosing of Deramaxx® (Deracoxib) chewable tablets in dogs

Although non-steroidal anti-inflammatory drugs (NSAIDs) are effective in reducing pain and inflammation, these agents have adverse effects. Selective inhibitors of COX-2 are an alternative to traditional NSAIDs. Deramaxx^® [Novartis Animal Health US, Inc. (NAH), Greensboro, NC, USA] contains the selective COX-2 inhibitor, deracoxib, and is approved for the relief of pain and inflammation associated with orthopedic surgery and osteoarthritis in dogs. The safety of Deramaxx was evaluated in two target animal safety studies: 40 dogs (four dogs/sex/group) received 0, 4, 6, 8, or 10 mg/kg/day deracoxib once daily for 21 days; and 60 dogs (five dogs/sex/group) received 0, 2, 4, 6, 8, or 10 mg/kg/day deracoxib once daily for 6 months. There was a dose-dependent trend towards increased blood urea nitrogen (BUN) in treated dogs, however mean BUN values remained within the reference range at the labeled doses. In both trials, histopathology revealed focal renal tubular degeneration/regeneration in some dogs receiving ≥6 mg/kg/day deracoxib. Focal renal papillary necrosis was seen in one dog treated with 8 mg/kg/day and in three dogs receiving 10 mg/kg/day deracoxib on the 6-month study. No other parameters of renal function were adversely affected for either study. Results show that Deramaxx is safe and well-tolerated in dogs when administered as directed.     

Effects of deracoxib and aspirin on serum concentrations of thyroxine, 3,5,3'-triiodothyronine, free thyroxine, and thyroid-stimulating hormone in healthy dogs

OBJECTIVE: To evaluate the effects of deracoxib and aspirin on serum concentrations of thyroxine (T4), 3,5,3'-triiodothyronine (T3), free thyroxine (fT4), and thyroid-stimulating hormone (TSH) in healthy dogs. ANIMALS: 24 dogs. PROCEDURE: Dogs were allocated to 1 of 3 groups of 8 dogs each. Dogs received the vehicle used for deracoxib tablets (PO, q 8 h; placebo), aspirin (23 to 25 mg/kg, PO, q 8 h), or deracoxib (1.25 to 1.8 mg/kg, PO, q 24 h) and placebo (PO, q 8 h) for 28 days. Measurement of serum concentrations of T4, T3, fT4, and TSH were performed 7 days before treatment (day -7), on days 14 and 28 of treatment, and 14 days after treatment was discontinued. Plasma total protein, albumin, and globulin concentrations were measured on days -7 and 28. RESULTS: Mean serum T4, fT4, and T3 concentrations decreased significantly from baseline on days 14 and 28 of treatment in dogs receiving aspirin, compared with those receiving placebo. Mean plasma total protein, albumin, and globulin concentrations on day 28 decreased significantly in dogs receiving aspirin, compared with those receiving placebo. Fourteen days after administration of aspirin was stopped, differences in hormone concentrations were no longer significant. Differences in serum TSH or the free fraction of T4 were not detected at any time. No significant difference in any of the analytes was detected at any time in dogs treated with deracoxib. CONCLUSIONS AND CLINICAL RELEVANCE: Aspirin had substantial suppressive effects on thyroid hormone concentrations in dogs. Treatment with high dosages of aspirin, but not deracoxib, should be discontinued prior to evaluation of thyroid function.     

Determination of expression of cyclooxygenase-1 and -2 isozymes in canine tissues and their differential sensitivity to nonsteroidal anti-inflammatory drugs

OBJECTIVE: To evaluate cyclooxygenase isozyme distribution in tissues from dogs and determine the differential sensitivity of canine cyclooxygenase (COX)-1 and -2 isozymes to nonsteroidal anti-inflammatory drugs (NSAIDs). SAMPLE POPULATION: Canine tissue samples (stomach, duodenum, ileum, jejunum, colon, spleen, cerebral cortex, lung, ovary, kidney, and liver) were obtained from 2 dogs for northern and western blot analyses, and blood for whole blood COX assays was obtained from 15 dogs. PROCEDURE: 11 NSAIDs were evaluated to determine their COX-2 selectivity in whole blood assays. The concentrations of the drug needed to inhibit 50% of enzyme activity (IC50) were then calculated for comparison. Expression and tissue distribution of COX isozymes were determined by northern and western blot analysis. RESULTS: Aspirin, diclofenac, indomethacin, ketoprofen, meclofenamic acid, and piroxicam had little selectivity toward COX isozymes, whereas NS398, carprofen, tolfenamic acid, nimesulide, and etodolac had more than 5 times greater preference for inhibiting COX-2 than COX-1. All canine tissues examined, including those from the gastrointestinal tract, coexpressed COX-1 and -2 mRNA, although protein expression was observed only for COX-1. CONCLUSIONS AND CLINICAL RELEVANCE: Canine COX-2 was selectively inhibited by etodolac, nimesulide, and NS398; tolfenamic acid and carprofen also appeared to be preferential COX-2 inhibitors in dogs. The roles of COX-1 as a constitutive housekeeping enzyme and COX-2 as a proinflammatory inducible enzyme (as determined in humans) appear to apply to dogs; therefore, COX-2-selective inhibitors should prove useful in reducing the adverse effects associated with nonselective NSAIDs.     

Gastrointestinal tract perforation in dogs treated with a selective cyclooxygenase-2 inhibitor: 29 cases (2002-2003)

OBJECTIVE: To identify factors associated with gastrointestinal tract perforation in dogs being treated with a selective cyclooxygenase-2 (COX-2) inhibitor (deracoxib). DESIGN: Retrospective study. ANIMALS: 29 dogs. PROCEDURE: The Novartis Animal Health pharmacovigilance database was searched for records of dogs treated with deracoxib in which gastrointestinal tract perforation was documented. Results-16 of the 29 (55%) dogs had received deracoxib at a dosage higher than that approved by the FDA for the particular indication being treated, with 25 (86%) dogs having received deracoxib at a dosage > 2 mg/kg/d (0.9 mg/lb/d). Seventeen (59%) dogs had received at least 1 other nonsteroidal anti-inflammatory drug (NSAID) or a corticosteroid in close temporal association (within 24 hours) with deracoxib administration (ie, immediately before or following). In all, 26 (90%) dogs had received deracoxib at a higher-than-approved dosage or had received at least 1 other NSAID or corticosteroid in close temporal association with deracoxib administration. Twenty dogs died or were euthanatized, and 9 survived. CONCLUSIONS AND CLINICAL RELEVANCE: In dogs with gastrointestinal tract perforation and that had been treated with deracoxib, perforation was most likely attributable to a number of factors. Deracoxib should only be used at approved dosages. Cortico-steroids and other less selective NSAIDs should not be administered in close temporal association with selective COX-2 inhibitors, including deracoxib. Further study is required to define this problem.     

Development of in vitro assays for the evaluation of cyclooxygenase inhibitors and predicting selectivity of nonsteroidal anti-inflammatory drugs in cats

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.     

Pyloric stenosis caused by hypertrophic gastritis in three dogs

Hypertrophic gastritis of the pyloric antrum is described in an 11-year-old female poodle, a 14-year-old male Maltese terrier and a 13-year-old male mongrel. The dogs suffered from chronic vomiting. Gastroscopic examination revealed mucosal proliferations in dogs 1 and 3. Radiographic examination showed signs of pyloric obstruction in all three dogs. Contrast studies demonstrated thickenings in the region of the pylorus in dogs 1 and 2. Laparotomy was done in all three dogs: in dog 1 a gastro-duodenostomy was performed and in dogs 2 and 3 the circularly thickened mucosa was resected. The mucosa of all three dogs showed hypertrophic gastritis, chiefly due to foveolar hyperplasia, and round cell infiltration, especially in the superficial layers. Herniation of mucosal glands through the muscularis mucosae was found in dog 1. Dogs 1 and 2 recovered well and vomiting ceased. Dog 3 continued to vomit because of a pyloric stenosis, mainly due to muscular hypertrophy.     

Preferential and non-selective cyclooxygenase inhibitors reduce inflammation during lipopolysaccharide-induced synovitis

Synovitis in horses is frequently treated by administration of non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit cyclooxygenase isoforms (COX-1 and COX-2). Constitutively expressed COX-1 is involved in physiologic functions such as maintenance of gastric mucosal integrity, whereas COX-2 is up-regulated at sites of inflammation. Thus, COX-2 inhibitors reduce inflammation with reduced gastrointestinal side effects as compared to non-selective COX inhibitors. The objective of the present study was to compare the anti-inflammatory effects of the preferential COX-2 inhibitor etodolac with the non-selective COX inhibitor phenylbutazone in horses with lipopolysaccharide (LPS)-induced synovitis. Three groups of horses (n=6) received no treatment, phenylbutazone (4.4 mg/kg, IV, q12h), or etodolac (23 mg/kg, IV, q12h), respectively, 2-h following injection of LPS into one middle carpal joint. Synovial fluid was analyzed for white blood cell (WBC) count, and TXB2 and PGE2 levels. Phenylbutazone and etodolac significantly reduced WBC count 6 and 24-h following injection of LPS compared to untreated horses. In addition, both drugs significantly reduced PGE2 levels (P<0.05) 6-h following LPS injection, whereas the probable COX-1 prostanoid TXB2 was significantly reduced by phenylbutazone (P<0.05), but not etodolac. Etodolac may serve as a more selective anti-inflammatory agent than phenylbutazone for treatment of equine synovitis.     

Effect of deracoxib,a new COX-2 inhibitor,on the prevention of lameness induced by chemical synovitis in dogs

Twenty-four healthy, mixed-breed hound-type dogs were evenly and randomly assigned to a placebo control group, one of four dosages of deracoxib (0.3, 1, 3, or 10 mg/kg), or carprofen (2.2 mg/kg). Oral dosing of placebo, carprofen, or deracoxib was done 30 minutes before intraarticular injection of urate crystal suspension for induction of synovitis. Ground reaction forces, subjective clinical lameness scores, pain, joint effusion, and quantitative pain threshold responses were measured in a blinded fashion before induction of synovitis and 2, 4, 6, 8, 12, and 24 hours after injection. The medium and high dosages of deracoxib were effective in preventing lameness and pain associated with synovitis. Carprofen was also somewhat effective in attenuating the severity of urate-induced synovitis but to a lesser degree than the medium dose of deracoxib. Preemptive deracoxib treatment at dosages as low as 1 mg/kg reduced lameness and pain of synovitis associated with intraarticular administration of urate crystals.     

In vitro and ex vivo inhibition of canine cyclooxygenase isoforms by robenacoxib: A comparative study

In vitro whole blood canine assays were used to quantify the inhibitory actions of the novel non-steroidal anti-inflammatory drug (NSAID) robenacoxib on the cyclooxygenase (COX) isoenzymes, COX-1 and COX-2, in comparison with other drugs of the NSAID class. COX-1 activity was determined by measuring serum thromboxane (Tx)B₂ synthesis in blood samples allowed to clot at 37 °C for 1 h. COX-2 activity was determined by measuring prostaglandin (PG)E₂ synthesis in blood samples incubated at 37 °C for 24 h in the presence of lipopolysaccharide. The rank order of selectivity for inhibition of COX-2 versus COX-1 (IC₅₀ COX-1:IC₅₀ COX-2) for veterinary drugs was highest with robenacoxib (128.8) compared to deracoxib (48.5), nimesulide (29.2), S+ carprofen (17.6), meloxicam (7.3), etodolac (6.6), R? carprofen (5.8) and ketoprofen (0.88). Selectivity expressed as the clinically relevant ratio IC₂₀ COX-1:IC₈₀ COX-2 was highest for robenacoxib (19.8) compared to deracoxib (2.3), S+ carprofen (2.5), R? carprofen (2.1), nimesulide (1.8), etodolac (0.76), meloxicam (0.46) and ketoprofen (0.21).An in vivo pharmacokinetic ex vivo pharmacodynamic study in the dog established dosage and concentration–effect relationships for single oral doses of robenacoxib over the dosage range 0.5–8.0 mg/kg. Values of C_max and AUC were linearly related to dosage over the tested range. Robenacoxib did not inhibit serum TxB₂ synthesis (COX-1) ex vivo at dosages of 0.5–4.0 mg/kg and produced only transient inhibition (at the 1 h and 2 h sampling times) at the 8 mg/kg dosage. All dosages of robenacoxib (0.5–8 mg/kg) produced marked, significant and dose related inhibition of PGE₂ synthesis (COX-2) ex vivo.The data demonstrate that in the dog robenacoxib is a highly selective inhibitor of the COX-2 isoform of COX, and significantly inhibits COX-2 and spares COX-1 in vivo when administered orally over the dosage range 0.5–4.0 mg/kg.     

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 Tukey's 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.     

Effects of deracoxib or buffered aspirin on the gastric mucosa of healthy dogs

BACKGROUND: Use of cyclo-oxygenase-2 specific nonsteroidal anti-inflammatory drugs such as deracoxib has been advocated because of their anti-inflammatory actions and apparently low incidence of gastrointestinal adverse effects. HYPOTHESIS: Deracoxib will cause less endoscopically detectable gastric injury in dogs than aspirin, a nonselective nonsteroidal anti-inflammatory drug. ANIMALS: Twenty-four random source healthy dogs. METHODS: A randomized, placebo-controlled trial compared gastroscopic findings of dogs receiving placebo (q8h), aspirin (25 mg/kg PO q8h), or deracoxib (1.5 mg/kg QD, placebo ql2h) for 28 days. Gastroscopy on days -7, 6, 14, and 28 evaluated 4 regions of the stomach separately and visible lesions were scored. Dogs were observed every 8 hours for vomiting and diarrhea. Median total scores for each group were compared each day of endoscopic examination and total dog-days of vomiting and diarrhea were compared. Significance was determined at P < .05. RESULTS: There were significant differences in total scores of the aspirin group and both the placebo and deracoxib groups on days 6, 14, and 28. No significant differences in total scores were found between placebo and deracoxib on days 6, 14, and 28. Significant differences in dog-days of vomiting were found between the aspirin and deracoxib groups whereas no significant differences were found between the deracoxib and placebo groups. There was no detectable effect of treatment on dog-days of diarrhea. CONCLUSIONS AND CLINICAL IMPORTANCE: Administration of deracoxib to healthy dogs resulted in significantly lower gastric lesion scores, and fewer days of vomiting compared to aspirin, indicating that deracoxib is better tolerated than aspirin in some dogs.     

Systematic Review of Nonsteroidal Anti‐Inflammatory Drug‐Induced Adverse Effects in Dogs

The aim of this systematic review was to identify, assess, and critically evaluate the quality of evidence of nonsteroidal anti‐inflammatory drug (NSAID)‐induced adverse effects in dogs. Original prospective studies published in peer‐reviewed journals in English (1990–2012) that reported data on the safety of NSAIDs administration in dogs were searched. For each study, design type (I, II, III, or IV) and assessment of quality (+, Ø, ?) were rated. For each drug, quantity and consistency rating (***, **, *) and strength of evidence (high, moderate, low, or extremely low) were identified and evaluated. The strength of evidence was defined in terms of how applicable and relevant the conclusions were to the target population. Sixty‐four studies met the inclusion criteria. Thirty‐five (55%) research studies and 29 (45%) clinical trials were identified. A high strength of evidence existed for carprofen, firocoxib, and meloxicam; moderate for deracoxib, ketoprofen, and robenacoxib; and low for etodolac. Quality and consistency rating were as follows: carprofen (***/***), deracoxib (**/***), etodolac (*/unable to rate), firocoxib (***/**), ketoprofen (**/***), meloxicam (***/***), and robenacoxib (**/**), respectively. Adverse effects were detected in 35 studies (55%) and commonly included vomiting, diarrhea, and anorexia. Three studies (5%) reported a power analysis related to adverse effects of ≥80%. In randomized, placebo‐controlled, blinded studies (n = 25, 39%), the incidence of adverse effects was not statistically different between treated and control dogs. Finally, most studies were not appropriately designed to determine the safety of NSAIDs, and involved a healthy nongeriatric population of research dogs.     

In vitro effects of cyclooxygenase inhibitors in whole blood of horses, dogs, and cats.

OBJECTIVE: To determine potency and selectivity of nonsteroidal anti-inflammatory drugs (NSAID) and cyclooxygenase- (COX-) specific inhibitors in whole blood from horses, dogs, and cats. SAMPLE POPULATION: Blood samples from 30 healthy horses, 48 healthy dogs, and 9 healthy cats. PROCEDURE: Activities of COX-1 and COX-2 were determined by measuring coagulation-induced thromboxane and lipopolysaccharide-induced prostaglandin E2 concentrations, respectively, in whole blood with and without the addition of various concentrations of phenylbutazone, flunixin meglumine, ketoprofen, diclofenac, indomethacin, meloxicam, carprofen, 5-bromo-2[4-fluorophenyl]-3-14-methylsulfonylphenyl]-thiophene (DuP 697), 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl) phenyl-2(5H)-furan one (DFU), 3-(3,4-difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone (MF-tricyclic), and celecoxib. Potency of each test compound was determined by calculating the concentration that resulted in inhibition of 50% of COX activity (IC50). Selectivity was determined by calculating the ratio of IC50 for COX-1 to IC50 for COX-2 (COX-1/COX-2 ratio). RESULTS: The novel compound DFU was the most selective COX-2 inhibitor in equine, canine, and feline blood; COX-1/COX-2 ratios were 775, 74, and 69, respectively. Carprofen was the weakest inhibitor of COX-2, compared with the other COX-2 selective inhibitors, and did not inhibit COX-2 activity in equine blood. In contrast, NSAID such as phenylbutazone and flunixin meglumine were more potent inhibitors of COX-1 than COX-2 in canine and equine blood. CONCLUSIONS AND CLINICAL RELEVANCE: The novel COX-2 inhibitor DFU was more potent and selective in canine, equine, and feline blood, compared with phenylbutazone, flunixin meglumine, and carprofen. Compounds that specifically inhibit COX-2 may result in a lower incidence of adverse effects, compared with NSAID, when administered at therapeutic dosages to horses, dogs, and cats.     

The Gastroduodenal Effects of Buffered Aspirin, Carprofen, and Etodolac in Healthy Dogs

Twenty-four healthy mixed-breed dogs were divided into 4 groups. Group 1 received a placebo p.o. q12h, group 2 received an average of 16.5 (15.1-17.8) mg/kg buffered aspirin p.o. q12h, group 3 received an average of 2.2 (2.0-2.4) mg/kg carprofen p.o. q12h, and group 4 received an average of 12.8 (11.7-13.8) mg/kg etodolac p.o. q24h (with a placebo in the PM). All treatments continued for 28 consecutive days. Gastroduodenal endoscopy was performed on days -9, 0, 5, 14, and 28. Multiple gastric biopsies were obtained endoscopically on day -9 to determine each dog's Helicobacter infection status. Four regions in the stomach and 1 region in the proximal duodenum were evaluated endoscopically, and each was assigned a score from 1 to 11. Scores for each region then were summed to give a total score for each endoscopic evaluation. Erosions and submucosal hemorrhages were seen in all dogs receiving aspirin. Only minor gastric lesions were observed in the carprofen, etodolac, and control groups. No adverse clinical signs were noted in any dog given any treatment. Median total score on days 0, 5, 14, and 28, respectively, were as follows: group 1: 5.0, 5.0, 5.0, 5.0; group 2: 5.0, 27.0, 26.0, 27.5; group 3: 5.0, 5.0, 6.0, 5.0, group 4: 5.0, 7.0, 5.0, 5.0. There was no significant difference among dogs receiving carprofen, etodolac, or placebo. The administration of carprofen, etodolac, or placebo to healthy dogs resulted in significantly less gastroduodenal lesion development than in dogs receiving buffered aspirin.