Effects of cyclooxygenase inhibitors flunixin and deracoxib on permeability of ischaemic-injured equine jejunum

REASONS FOR PERFORMING STUDY: Recent studies have shown that flunixin prevented recovery of equine jejunum post ischaemia. However, the use of a purported cyclooxygenase (COX)-2 preferential inhibitor, etodolac, also prevented recovery. These findings may have implications for the use of nonsteroidal anti-inflammatory drugs in colic patients. OBJECTIVE: To compare the effects of deracoxib, a highly selective canine COX-2 inhibitor, with flunixin on in vitro recovery of ischaemic-injured equine jejunum. METHODS: Six horses underwent 2 h jejunal ischaemia, after which mucosa was mounted in Ussing chambers and recovered for 240 mins. Transepithelial electrical resistance (TER) and mucosal-to-serosal fluxes of 3H-mannitol were monitored as indices of barrier function in the presence of flunixin or deracoxib. RESULTS: The TER of ischaemic-injured tissue recovered significantly over 240 mins in the presence of no treatment, but not in the presence of flunixin or deracoxib. In addition, flunixin-treated ischaemic jejunum was significantly more permeable to mannitol when compared with untreated tissue by the end of the recovery period, whereas deracoxib treatment did not increase permeability. Addition of the PGE1 analogue misoprostol to flunixin-treated tissue restored recovery of TER. CONCLUSIONS AND POTENTIAL RELEVANCE: Treatment of horses with ischaemic jejunal disease with flunixin may result in a prolonged permeability defect in recovering mucosa. Addition of misoprostol or replacement of flunixin with deracoxib may ameliorate effects of COX inhibitors on recovering mucosa.     

Effects of flunixin meglumine or etodolac treatment on mucosal recovery of equine jejunum after ischemia

OBJECTIVE: To examine the effects of flunixin meglumine and etodolac treatment on recovery of ischemic-injured equine jejunal mucosa after 18 hours of reperfusion. ANIMALS: 24 horses. PROCEDURE: Jejunum was exposed to 2 hours of ischemia during anesthesia. Horses received saline (0.9% NaCl) solution (12 mL, i.v., q 12 h), flunixin meglumine (1.1 mg/kg, i.v., q 12 h), or etodolac (23 mg/kg, i.v., q 12 h). Tissue specimens were obtained from ischemic-injured and nonischemic jejunum immediately after ischemia and 18 hours after recovery from ischemia. Transepithelial electric resistance (TER) and transepithelial flux of tritium-labeled mannitol measured mucosal permeability. Denuded villous surface area and mean epithelial neutrophil count per mm2 were calculated. Western blot analysis for cyclooxygenase (COX)-1 and -2 was performed. Pharmacokinetics of flunixin and etodolac and eicosanoid concentrations were determined. RESULTS: Ischemic-injured tissue from horses treated with flunixin and etodolac had significantly lower TER and increased permeability to mannitol, compared with that from horses treated with saline solution. Epithelial denudation after ischemia and 18 hours after recovery was not significantly different among treatments. Both COX-1 and -2 were expressed in ischemic-injured and nonischemic tissues. Ischemia caused significant upregulation of both COX isoforms. Eicosanoid concentrations were significantly lower in tissues from flunixin and etodolac-treated horses, compared with that from horses treated with saline solution. CONCLUSIONS AND CLINICAL RELEVANCE: Flunixin and etodolac treatment retarded recovery of intestinal barrier function in jejunal mucosa after 18 hours of reperfusion, whereas tissues from horses treated with saline solution recovered baseline values of TER and permeability to mannitol.     

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.     

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.     

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.     

Pharmacokinetics of etodolac in the horse following oral and intravenous administration

The purpose of this study was to determine the pharmacokinetics of etodolac following oral and intravenous administration to six horses. Additionally, in vitro cyclooxygenase (COX) selectivity assays were performed using equine whole blood. Using a randomized two-way crossover design, horses were administered etodolac (20 mg/kg) orally or intravenously, with a minimum 3-week washout period. Plasma samples were collected after administration for analysis using high pressure liquid chromatography with ultraviolet detection. Following intravenous administration, etodolac had a mean plasma half-life (t(1/2)) of 2.67 h, volume of distribution (Vd) of 0.29 L/kg and clearance (Cl) of 234.87 mL/h kg. Following oral administration, the average maximum plasma concentration (Cmax)) was 32.57 mug/mL with a t(1/2) of 3.02 h. Bioavailability was approximately 77.02%. Results of in vitro COX selectivity assays showed that etodolac was only slightly selective for COX-2 with a COX-1/COX-2 selectivity ratio effective concentration (EC)50 of 4.32 and for EC80 of 4.77. This study showed that etodolac is well absorbed in the horse after oral administration, and may offer a useful alternative for anti-inflammatory treatment of various conditions in the horse.     

Sparing the gut: COX-2 inhibitors herald a new era for treatment of horses with surgical colic

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to manage a wide variety of conditions in horses, including management of colic. Flunixin meglumine is by far the most commonly used drug in the control of colic pain and inflammation and has become a go-to for not only veterinarians but also horse-owners and nonmedical equine professionals. NSAID use, however, has always been controversial in critical cases due to a high risk of adverse effects associated with their potent cyclo-oxygenase (COX) inhibition. There are two important COX isoenzymes: COX-1 is generally beneficial for normal renal and gastrointestinal functions and COX-2 is associated with the pain and inflammation of disease. Newer selective NSAIDs can target COX-2-driven pathology while sparing important COX-1-driven physiology, which is of critical importance in horses with severe gastrointestinal disease. Emerging research suggests that firocoxib, a COX-2-selective NSAID labelled for use in horses, may be preferable for use in colic cases in spite of the decades-long dogma that flunixin saves lives.     

In vitro and ex vivo pharmacodynamics of selected non-steroidal anti-inflammatory drugs in equine whole blood

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenases (COX), and the inhibition of COX-2 rather than COX-1 can limit the onset of NSAID-related adverse effects. The pharmacodynamic properties of eltenac, naproxen, tepoxalin, SC-560 and NS 398 in healthy horses were investigated using an in vitro whole blood assay. To predict COX selectivity in clinical use, eltenac and naproxen were also studied ex vivo after intravenous administration. SC-560 acted as a selective COX-1 inhibitor, tepoxalin as a dual inhibitor with potent activity against COX-1, and NS 398 as a preferential COX-2 inhibitor. Eltenac was a preferential COX-2 inhibitor in vitro but un-selective in the ex vivo study. Naproxen maintained its non-selectivity both in vitro and ex vivo. These findings have demonstrated that in vitro studies may not accurately predict in vivo NSAID selectivity for COX and should be confirmed using an ex vivo whole blood assay.     

Attenuation of ischaemic injury in the equine jejunum by administration of systemic lidocaine

REASONS FOR PERFORMING STUDY: Absorption of endotoxin across ischaemic-injured mucosa is a major cause of mortality after colic surgery. Recent studies have shown that flunixin meglumine retards mucosal repair. Systemic lidocaine has been used to treat post operative ileus, but it also has novel anti-inflammatory effects that could improve mucosal recovery after ischaemic injury. HYPOTHESIS: Systemic lidocaine ameliorates the deleterious negative effects of flunixin meglumine on recovery of mucosal barrier function. METHODS: Horses were treated i.v. immediately before anaesthesia with either 0.9% saline 1 ml/50 kg bwt, flunixin meglumine 1 mg/kg bwt every 12 h or lidocaine 1.3 mg/kg bwt loading dose followed by 0.05 mg/kg bwt/min constant rate infusion, or both flunixin meglumine and lidocaine, with 6 horses allocated randomly to each group. Two sections of jejunum were subjected to 2 h of ischaemia by temporary occlusion of the local blood supply, via a midline celiotomy. Horses were monitored with a behavioural pain score and were subjected to euthanasia 18 h after reversal of ischaemia. Ischaemic-injured and control jejunum was mounted in Ussing chambers for measurement of transepithelial electrical resistance (TER) and permeability to lipopolysaccharide (LPS). RESULTS: In ischaemic-injured jejunum TER was significantly higher in horses treated with saline, lidocaine or lidocaine and flunixin meglumine combined, compared to horses treated with flunixin meglumine. In ischaemic-injured jejunum LPS permeability was significantly increased in horses treated with flunixin meglumine alone. Behavioural pain scores did not increase significantly after surgery in horses treated with flunixin meglumine. CONCLUSIONS: Treatment with systemic lidocaine ameliorated the inhibitory effects of flunixin meglumine on recovery of the mucosal barrier from ischaemic injury, when the 2 treatments were combined. The mechanism of lidocaine in improving mucosal repair has not yet been elucidated.     

Ex vivo COX-1 and COX-2 inhibition in equine blood by phenylbutazone,flunixin meglumine,meloxicam and firocoxib: Informing clinical NSAID selection

Newer cyclo-oxygenase-2 (COX-2) selective nonsteroidal anti-inflammatory drugs (NSAIDs), such as firocoxib, are proposed to reduce inhibition of cyclo-oxygenase-1 (COX-1) and avoid undesirable side effects, while continuing to inhibit inflammation associated with COX-2. However, COX selectivity is typically based on in vitro testing, which may not provide sufficient information critical for treatment selection. This study investigated the pharmacokinetics and ex vivo COX-1 and COX-2 inhibition of phenylbutazone, flunixin meglumine, meloxicam and firocoxib. Horses (n = 3) were administered one of the four drugs, in a randomised cross-over design, with 3-week washout periods. For each drug, three doses were given and sampling performed. Drug plasma concentrations, thromboxane B₂ (TXB₂) and prostaglandin E₂ (PGE₂) were determined. After one dose, TXB₂ and PGE₂ levels were significantly higher in horses administered firocoxib compared to flunixin meglumine. Following the third dose, TXB₂ levels in horses administered firocoxib and meloxicam were significantly higher compared to flunixin meglumine or phenylbutazone; all drugs reduced PGE₂ to a similar degree. The mean plasma half-lives were 5.97 ± 0.47, 4.74 ± 0.14, 8.24 ± 3.74 and 47.42 ± 7.41 h for phenylbutazone, flunixin meglumine, meloxicam and firocoxib, respectively. Firocoxib and meloxicam exhibited significantly less COX-1 inhibition compared to flunixin meglumine and phenylbutazone; all drugs inhibited COX-2. The plasma half-life of firocoxib was longer than the other NSAIDs, including meloxicam. Data from this study have important clinical relevance and should be used to inform practitioners’ drug selection of a COX-1 sparing or traditional NSAID and dose selection and to provide knowledge of the duration for the four NSAIDs studied.     

Bradykinin stimulates prostaglandin E2 production and cyclooxygenase activity in equine nonglandular and glandular gastric mucosa in vitro

REASONS FOR PERFORMING STUDY: There are few data available regarding regulation of prostaglandin (PG) generation by equine gastric mucosae and the role of the cyclooxygenase (COX) isoforms in their production. OBJECTIVES: To: 1) characterise and quantify PGE2 output in vitro; 2) examine the sensitivity of PGE2 production to exogenous bradykinin (BK) exposure; 3) determine the contribution of the COX-1 and COX-2 pathways to basal and BK-stimulated PGE2 production; and 4) measure if BK influences electrogenic ion transport in equine gastric mucosae in vitro. METHODS: Full thickness gastric sheets were obtained from horses at post mortem, stripped of muscle layers and mounted in Ussing chambers. Tissues were exposed to bradykinin (BK, 0.1 micromol/l) either alone, or following pretreatment with a selective COX-2 inhibitor (NS-398, 1 micromol/l) or a nonselective COX inhibitor (piroxicam, 1 micromol/l), or were untreated. RESULTS: BK administration increased PGE2 output from the basolateral but not the apical faces of both tissue types. Piroxicam, but not NS-398, reduced basolateral PGE2 release below control levels in both tissue types. Both piroxicam and NS-398 pretreatment inhibited BK-stimulated PGE2 release. In separate experiments, BK was without effect upon electrophysiological parameters of tissues mounted in Ussing chambers. CONCLUSIONS: PGE2 is produced by the nonglandular and glandular equine gastric mucosae in vitro. Significantly more PGE2 is released basolaterally than apically. BK stimulated the production of PGE2 from the basolateral side of both tissue types. These findings suggest that COX-1 is a significant pathway for basal PGE2 production from the basolateral faces of both nonglandular and glandular equine gastric mucosae in vitro.     

In vitro investigation of the effects of cyclooxygenase-2 inhibitors on contractile activity of the equine dorsal and ventral colon

OBJECTIVE: To evaluate the effect of 2 cyclooxygenase (COX)-2 inhibitors on contractile activity of the circular smooth muscle layer of the equine dorsal and ventral colon. SAMPLE POPULATION: Samples of the dorsal and ventral colon obtained from 10 healthy horses. PROCEDURE: Full-thickness tissue samples were collected from the dorsal colon in the area of the diaphragmatic flexure and the ventral colon in the area of the sternal flexure. Samples were cut into strips oriented along the fibers of the circular muscle layer and mounted in a tissue bath system for determination of contractile strength. Incremental amounts of etodolac, nabumetone, and indomethacin were added, and contractile activity was recorded. RESULTS: Response of the dorsal and ventral colon to nonsteroidal anti-inflammatory drugs (NSAIDs) was variable. Indomethacin induced the greatest reduction in contractile activity, followed by nabumetone. For etodolac, the difference from baseline values was only significantly reduced at the highest concentration used (1 X 10(5)M) for the ventral colon. CONCLUSIONS AND CLINICAL RELEVANCE: The NSAIDs that are designed to target the COX-2 isoform appeared to have variable effects on the contractile activity of the equine dorsal and ventral colon. Etodolac appeared to have the least effect on contractile activity, compared with the effects attributable to nabumetone, and would potentially have the fewest adverse effects relative to motility of the dorsal and ventral colon.     

Distribution of flunixin meglumine and firocoxib into aqueous humor of horses

Background: Nonsteroidal anti‐inflammatory drugs (NSAIDs) are commonly used systemically for the treatment of inflammatory ocular disease in horses. However, little information exists regarding the ocular penetration of this class of drugs in the horse. Objective: To determine the distribution of orally administered flunixin meglumine and firocoxib into the aqueous humor of horses. Animals: Fifteen healthy adult horses with no evidence of ophthalmic disease. Methods: Horses were randomly assigned to a control group and 2 treatment groups of equal sizes (n = 5). Horses assigned to the treatment groups received an NSAID (flunixin meglumine, 1.1 mg/kg PO q24h or firocoxib, 0.1 mg/kg PO q24h for 7 days). Horses in the control group received no medications. Concentrations of flunixin meglumine and firocoxib in serum and aqueous humor and prostaglandin (PG) E₂ in aqueous humor were determined on days 1, 3, and 5 and aqueous : serum ratios were calculated. Results: Firocoxib penetrated the aqueous humor to a significantly greater extent than did flunixin meglumine at days 3 and 5. Aqueous : serum ratios were 3.59 ± 3.32 and 11.99 ± 4.62% for flunixin meglumine and firocoxib, respectively. Ocular PGE₂ concentrations showed no differences at any time point among study groups. Conclusions and Clinical Importance: Both flunixin meglumine and firocoxib penetrated into the aqueous humor of horses. This study suggests that orally administered firocoxib penetrates the aqueous humor better than orally administered flunixin meglumine at label dosages in the absence of ocular inflammation. Firocoxib should be considered for the treatment of inflammatory ophthalmic lesions in horses at risk for the development of adverse effects associated with nonselective NSAID administration.     

Modulation of arachidonic acid metabolism in endotoxic horses: comparison of flunixin meglumine, phenylbutazone, and a selective thromboxane synthetase inhibitor

Two cyclooxygenase inhibitors (flunixin meglumine and phenylbutazone) and a selective thromboxane synthetase inhibitor were assessed in the management of experimental equine endotoxemia. Drugs or saline solution were administered to 16 horses 15 minutes before administration of a sublethal dose of endotoxin (Escherichia coli 055:B5). Plasma concentrations of thromboxane B2 (TxB2), prostacyclin (6-keto PGF1 alpha), plasma lactate, and hematologic values and clinical appearance were monitored for 3 hours after endotoxin administration. Pretreatment with flunixin meglumine (1 mg/kg of body weight) prevented most of the endotoxin-induced changes and correlated with a significant decrease in plasma TxB2 and 6-keto PGF1 alpha concentrations, compared with concentrations in nontreated horses (ie, pretreated with saline solution). Pretreatment with phenylbutazone (2 mg/kg) attenuated the effects of endotoxin and was associated with a brief, early, significant increase in plasma TxB2 concentrations, but not in plasma 6-keto PGF1 alpha concentrations. Pretreatment with the thromboxane synthetase inhibitor did not appear to clinically benefit the horses involved; however, arachidonic acid metabolism was redirected to prostacyclin production.     

Cyclooxygenase (COX) inhibitors and the intestine

Nonsteroidal anti-inflammatory drugs (NSAIDs) have long been used for the treatment of pain and inflammation because of their inhibitory effects on cyclooxygenase (COX). For almost as long as NSAIDs have been in use, multiple adverse effects have been noted. Assessment of many of these adverse effects have been complicated because of the discovery of multiple splice variants of the cox gene, and a greater array of COX inhibitors, especially the COX-2 selective inhibitors have become available. Some of these adverse effects cannot be readily explained by the effect of these drugs on COX. This has sparked a new field of investigation into the COX-independent effects of the COX inhibitors. The major noncyclooxygenase targets of the COX inhibitors of particular relevance to inflammation and the gastrointestinal tract are phosphatidylinositol 3'-kinase Akt signaling, uncoupling of oxidative phosphorylation, PPARgamma, nuclear factor KB, mitogen activated protein kinases, and heat shock proteins.     

Evaluation of adverse effects of long-term oral administration of carprofen, etodolac, flunixin meglumine, ketoprofen, and meloxicam in dogs

OBJECTIVE: To evaluate adverse effects of long-term oral administration of carprofen, etodolac, flunixin meglumine, ketoprofen, and meloxicam in dogs. ANIMALS: 36 adult dogs. PROCEDURES: Values for CBC, urinalysis, serum biochemical urinalyses, and occult blood in feces were investigated before and 7, 30, 60, and 90 days after daily oral administration (n = 6 dogs/group) of lactose (1 mg/kg, control treatment), etodolac (15 mg/kg), meloxicam (0.1 mg/kg), carprofen (4 mg/kg), and ketoprofen (2 mg/kg for 4 days, followed by 1 mg/kg daily thereafter) or flunixin (1 mg/kg for 3 days, with 4-day intervals). Gastroscopy was performed before and after the end of treatment. RESULTS: For serum gamma-glutamyltransferase activity, values were significantly increased at day 30 in dogs treated with lactose, etodolac, and meloxicam within groups. Bleeding time was significantly increased in dogs treated with carprofen at 30 and 90 days, compared with baseline. At 7 days, bleeding time was significantly longer in dogs treated with meloxicam, ketoprofen, and flunixin, compared with control dogs. Clotting time increased significantly in all groups except those treated with etodolac. At day 90, clotting time was significantly shorter in flunixin-treated dogs, compared with lactose-treated dogs. Gastric lesions were detected in all dogs treated with etodolac, ketoprofen, and flunixin, and 1 of 6 treated with carprofen. CONCLUSIONS AND CLINICAL RELEVANCE: Carprofen induced the lowest frequency of gastrointestinal adverse effects, followed by meloxicam. Monitoring for adverse effects should be considered when nonsteroidal anti-inflammatory drugs are used to treat dogs with chronic pain.     

Expression of the cyclooxygenase isoforms in the prodromal stage of black walnut-induced laminitis in horses

OBJECTIVE: To compare the levels of mRNA expression of cycooxygenase (COX)-1 and COX-2 in the digital laminae of normal horses and horses in the developmental stages of laminitis experimentally induced by administration of black walnut extract (BWE). SAMPLE POPULATION: Samples of mRNA extracted from the digital laminae of 5 control horses and 5 horses at the onset of leukopenia after administration of BWE. PROCEDURE: Specimens of laminae were collected from anesthetized horses prior to euthanasia. Expression of COX-1 and COX-2 mRNA in laminae of control and affected horses was evaluated via real-time quantitative polymerase chain reaction techniques. RESULTS: Expression of COX-2 mRNA was significantly increased in the BWE-treated group, compared with that in control horses. In contrast to COX-2 regulation, COX-1 mRNA expression was not significantly different between groups. Interestingly, despite consistent clinical signs such as leukopenia in all BWE-treated horses, distinct differences in COX-2 mRNA expression were detected among those 5 horses (compared with values for control horses, the increase in COX-2 mRNA expression ranged from no increase to a 30-fold increase). CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that there was a significant upregulation of COX-2 mRNA expression during the developmental stages of laminitis, with no significant change in expression of the COX-1 isoform. These data appear to provide support for aggressive use of nonsteroidal anti-inflammatory drugs in horses at risk for laminitis; further investigation into the clinical value of selective COX-2 inhibitors for treatment of laminitis in horses appears to be warranted.