Carprofen-induced oxidative stress in mitochondria of the colonic mucosa of the dog

The purpose of the study was to compare the conductance and mannitol permeability of canine colonic mucosa in response to carprofen or 2,4-dinitrophenol (DNP) with or without tempol pretreatment. Ten colonic mucosa sections per dog were mounted in Ussing chambers. Treatments were done in duplicate. Mucosa was exposed to carprofen (200 μg/mL) or DNP (0.25 mM), both with and without tempol (1 mM) pretreatment. Conductance was calculated every 15 min for 240 min. Mannitol flux was calculated over 3 consecutive 60-minute periods. Histology or electron microscopy was done after exposure. Conductance over time, mannitol flux, frequency of histologic categories, and electron microscopic changes were analyzed for treatment effects. The mean ± standard deviation (SD) conductance over time for carprofen or DNP-treated colons was not significantly different from control regardless of tempol pretreatment. Period 3 mannitol fluxes for carprofen and DNP-treated colon were not significantly different, but were greater than control. Period 3 mannitol flux for tempol + carprofen was significantly less than tempol + DNP-treated colon. Sloughing of cells and erosions were seen in the mucosa of carprofen-treated colon. Mitochondrial damage was seen more often in carprofen-treated than DNP-treated or control colon. Tempol pretreatment resulted in more ruptured mitochondria in the carprofen-treated colon; however, other mitochondrial changes were not significantly affected by tempol pretreatment in either carprofen or DNP treated colon. Treatment with carprofen or DNP increased the mannitol flux, but pretreatment with tempol mitigated the carprofen effect. It is apparent that structural mitochondrial damage occurs in the canine colonic mucosa after carprofen and DNP exposure.     

Evaluation of adverse effects of long-term orally administered carprofen in dogs

OBJECTIVE: To evaluate the adverse effects of carprofen in dogs after oral administration for 2 months. DESIGN: Prospective, randomized, blinded, placebo-controlled clinical trial. ANIMALS: 22 dogs with osteoarthritis in the hip or elbow joint. PROCEDURE: 13 dogs received orally administered carprofen daily for 2 months, and 9 dogs received a placebo for 2 months. Dogs were weighed, and serum and urine samples were collected before initiation of treatment and 4 and 8 weeks after initiation of treatment. Serum concentrations of total protein, albumin, urea, and creatinine and serum activities of alkaline phosphatase (ALP) and alanine aminotransferase (ALT) were measured. Urinary ALP-to-creatinine, gamma-glutamyltransferase (GGT)-to-creatinine, and protein-to-creatinine ratios were calculated. Dogs were observed by owners for adverse effects. RESULTS: Serum protein and albumin concentrations were lower in treated dogs than in those that received placebo at 4 weeks, but not at 8 weeks. No changes were observed in serum urea or creatinine concentrations; ALP or ALT activity; or urinary ALP-to-creatinine, GGT-to-creatinine, or protein-to-creatinine ratios. Dogs' weights did not change. Severity of vomiting, diarrhea, and skin reactions did not differ between groups, but appetite was better in dogs receiving carprofen than in dogs in the placebo group. CONCLUSIONS AND CLINICAL RELEVANCE: It is possible that the transient decreases in serum protein and albumin concentrations in dogs that received carprofen were caused by altered mucosal permeability of the gastrointestinal tract because no indications of renal or hepatic toxicity were observed. Carprofen appeared to be well tolerated by dogs after 2 months of administration.     

Acute effects of carprofen and meloxicam on canine gastrointestinal permeability and mucosal absorptive capacity

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently prescribed to dogs for their analgesic, antipyretic, and anti-inflammatory properties. Their beneficial actions can be offset by gastrointestinal (GI) toxicosis. Endoscopy has traditionally been employed to detect GI lesions, but alterations in GI permeability precede the development of mucosal damage. HYPOTHESIS: Carprofen and meloxicam alter GI permeability and mucosal absorptive capacity of dogs. ANIMALS: Twenty adult dogs treated with an NSAID for >7 days were evaluated by permeability tests while receiving either carprofen (10 dogs) or meloxicam (10 dogs). METHODS: Prospective, longitudinal observational study. A 6-sugar permeability test (sucrose, lactulose, rhamnose, 3-O-methyl-D-glucose, D-xylose, and sucralose) was performed on the day before NSAID treatment, and after 3 and 8 days of treatment. RESULTS: There were no significant differences in the urinary recovery ratios of lactulose: rhamnose, D-xylose: 3-O-methyl-D-glucose, or sucralose recovery within either group at any time during the study. Sucrose permeability in the meloxicam group did not alter significantly over time. However, sucrose permeability in the carprofen group decreased significantly by day 3 (P = .049) and increased again by day 8 (P = .049), to a level that was not significantly different to permeability before treatment (P = .695). CONCLUSIONS AND CLINICAL IMPORTANCE: The absence of increased GI permeability and diminished mucosal absorptive capacity in this group of dogs does not support the development of acute GI toxicosis during treatment with either meloxicam or carprofen.     

Efficacy and Kinetics of Carprofen, Administered Preoperatively or Postoperatively, for the Prevention of Pain in Dogs Undergoing Ovariohysterectomy

Objective —To determine what effect the timing of carprofen administration has on the severity of postoperative pain in dogs undergoing ovariohysterectomy and to investigate the pharmacokinetics of carprofen under these conditions. Study Design —A prospective, randomized, double-blind, clinical trial. Animals —Sixty-two adult bitches weighing between 10 and 25 kgs, undergoing elective ovariohysterectomy. Methods —Examinations were performed for 20 hours postoperatively using subjective visual assessment scoring systems (DIVAS) and objective mechanical nociceptive threshold measurements. Forty dogs were assigned to one of three groups: (1) preoperative carprofen; (2) postoperative carprofen; and (3) no analgesics (saline injections). The dose of carprofen was 4.0 mg/kg subcutaneously. In another 22 bitches, the pharmacokinetics of carprofen given preoperatively or postoperatively at the same dose were examined. Results —The dogs given carprofen preoperatively had lower pain scores than the other groups, significantly so at 2 hours postextubation (P < .01 and P < .05, Kruskal-Wallis and post hoc Dunn's). Mechanical pain thresholds measured at the distal tibia showed the development of hyperalgesia at 12 and 20 hours postextubation; this was prevented by both the preoperative (P < .05 at 12 and 20 hours, Kruskal-Wallis) and postoperative (P <.05 at 20 hours, Kruskal-Wallis) administration of carprofen. Mechanical pain threshold testing at the wound showed a significant analgesic effect of carprofen. Plasma concentrations of carprofen were not directly related to analgesia; maximum plasma concentration, the area under the curve to the last data point, and area under the first moment curve up to the last data point were all significantly higher in the dogs given carprofen postoperatively (P < .05, Mann-Whitney). Conclusion—Preoperative administration of carprofen has a greater analgesic effect than postoperative administration in the early postoperative period in dogs undergoing ovariohysterectomy. Plasma levels of carprofen are not related to the degree of analgesia achieved. Clinical Relevance—Carprofen provides effective analgesia after canine ovariohysterectomy. The timing of analgesic administration is important to optimize the control of postoperative pain.     

Effect of carprofen, etodolac, meloxicam, or butorphanol in dogs with induced acute synovitis

OBJECTIVE: To compare the analgesic and anti-inflammatory effect of single doses of carprofen, etodolac, meloxicam, and butorphanol in dogs with induced acute synovitis (acute pain model) via kinetic gait analysis and orthopedic evaluation and examine measurement of serum C-reactive protein (CRP) concentration as an indicator of treatment efficacy. ANIMALS: 12 Beagles and 6 additional Beagles that were used only in serum CRP analyses. PROCEDURE: Acute synovitis was induced in right stifle joints of dogs via intra-articular injection of monosodium urate solution. Treatments included butorphanol (0.2 mg/kg, i.v.), carprofen (4 mg/kg, PO), etodolac (17 mg/kg, PO), or meloxicam (0.2 mg/kg, PO); control dogs received no treatment. The procedure was repeated (3-week intervals) until all dogs received all treatments including control treatment. Lameness was assessed on a biomechanical force platform and via orthopedic evaluations of the stifle joints; blood was collected to monitor serum CRP concentration. RESULTS: Compared with control dogs, treated dogs had significantly different vertical ground reaction forces and weight-bearing scores. Greatest improvement in lameness was observed in carprofen-treated dogs. Etodolac had the fastest onset of action. Compared with butorphanol treatment, only carprofen and etodolac were associated with significantly lower pain scores. An increase in serum CRP concentration was detected after intra-articular injection in all dogs; this change was similar among groups. CONCLUSIONS AND CLINICAL RELEVANCE: Carprofen, etodolac, and meloxicam had greater efficacy than butorphanol in relief of acute pain. Carprofen was most effective overall. In this acute pain model, serum CRP analysis was not useful to assess drug efficacy.     

In vitro evaluation of intraluminal factors that may alter intestinal permeability in ponies with carbohydrate-induced laminitis

OBJECTIVES: To study the in vitro effects of cecal contents incubated with corn starch on colonic permeability in horses. ANIMALS: 4 healthy adult ponies. PROCEDURE: Mucosal specimens were obtained from the right ventral colon and mounted in Ussing chambers. Changes in short circuit current, conductance, and large-molecule permeability in response to addition of cecal contents and cecal contents incubated with corn starch were evaluated for 120 minutes. RESULTS: Incubation of cecal contents with corn starch for 8 hours resulted in a decrease in cecal content pH and an increase in lactic acid concentration. These changes were similar to those reported in vivo for ponies given corn starch. Exposure of colonic mucosa to cecal contents incubated with corn starch resulted in an increase in tissue conductance and permeability of technetium Tc 99m pentetate, compared with mucosa exposed to cecal contents alone. CONCLUSIONS AND CLINICAL RELEVANCE: In vitro exposure of colonic mucosa to cecal contents incubated with starch resulted in increased paracellular permeability. Fermentation of excessive amounts of carbohydrate in the intestinal lumen of horses may directly induce increased intestinal permeability associated with carbohydrate-induced laminitis.     

Carprofen inhibition of flare in the dog measured by laser flare photometry

The purpose of this study was to determine whether oral carprofen (Rimadyl®) treatment in dogs could prevent or decrease the breakdown of the blood–aqueous barrier. The topical pilocarpine irritative model was used to induce breakdown and cause flare. Pilocarpine was instilled in both eyes of seven dogs at time zero and again 5 h later. At 7 h, laser flare photometry was used to measure the flare concentration in each eye using the Kowa FC-1000 laser flare cell meter. All treatments were then discontinued. Two days later, carprofen was administered to the same dogs for a total of three doses. After the last dose of carprofen, pilocarpine treatments and flare measurements were repeated. Carprofen pretreatment resulted in a 68% inhibition of flare, which was highly significant ( P < 0.01). The pilocarpine group had a mean of 16.1 photon counts per millisecond (PC ms⁻¹) ± 2.2 SE, and the carprofen group had a mean of 7.0 PC/ms ± 1.2 SE. These results compare favorably with previous studies measuring increased protein or fluorescein concentrations in the aqueous humor after blood–aqueous barrier breakdown in the dog. These results suggest that carprofen may be effectively used as a systemically administered ocular anti-inflammatory drug. Carprofen has the added benefit of fewer reported side effects.     

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.     

Effects of phenylbutazone, indomethacin, prostaglandin E2, butyrate, and glutamine on restitution of oxidant-injured right dorsal colon of horses in vitro

OBJECTIVE: To study the effects of phenylbutazone, indomethacin, prostaglandin E2 (PGE2), glutamine, and butyrate on restitution of oxidant-injured right dorsal colon of horses in vitro. SAMPLE POPULATION: Right dorsal colon from 9 adult horses euthanatized for reasons other than gastrointestinal tract disease. PROCEDURES: Mucosal segments from the right dorsal colon were injured via exposure to HOCl and incubated in Ussing chambers in solutions containing phenylbutazone, indomethacin, indomethacin and PGE2, glutamine, and butyrate. Transepithelial resistance and mucosal permeability to mannitol were measured, and all mucosal segments were examined histologically. RESULTS: The HOCl-injured mucosa had lower resistance and higher permeability to mannitol, compared with control tissue. Histologic changes were also evident. Resistance of HOCl-injured mucosa recovered partially during the incubation period, and glutamine improved recovery. Phenylbutazone and indomethacin increased resistance, but these increases were not significant. Butyrate and PGE2 had no effects, compared with nontreated HOCl-injured tissues. Mucosal permeability to mannitol was lower in glutamine-treated tissue, compared with nontreated tissue. Histologic changes reflected the resistance and permeability changes. CONCLUSIONS AND CLINICAL RELEVANCE: According to our findings, phenylbutazone and indomethacin do not seem to interfere with restitution of oxidant-injured mucosa of equine colon in vitro, and glutamine could facilitate mucosal restitution.     

Effects of acetylcysteine and migration of resident eosinophils in an in vitro model of mucosal injury and restitution in equine right dorsal colon

OBJECTIVES: To evaluate the in vitro protective effects of acetylcysteine and response of resident mucosal eosinophils in oxidant-induced injury to tissues of right dorsal colon of horses. ANIMALS: 9 adult horses. PROCEDURE: Gastrointestinal mucosa was damaged in vitro with 3 mM hypochlorous acid (HOCl), with and without prior exposure to 6mM acetylcysteine. Control tissues were not exposed to HOCl or acetylcysteine. Control and damaged tissues were incubated in Krebs-Ringer-bicarbonate solution and tissue resistance measured during 240 minutes. Tissue permeability to radiolabeled mannitol was also used to assess mucosal barrier integrity. Tissues were examined by light microscopy before and after HOCl exposure and during and after incubation. RESULTS: Exposure to HOCl caused tissue damage and decreased tissue resistance. Restitution did occur during the incubation period. Eosinophils were located near the muscularis mucosae in freshly harvested tissues and migrated towards the luminal surface in response to HOCl-induced injury. Compared with tissues treated with HOCl without acetylcysteine, pretreatment with acetylcysteine prevented HOCl-induced tissue damage, changes in resistance, and histologically detectable eosinophil migration. The permeability to mannitol increased to the same extent in tissues treated with HOCl alone or with acetylcysteine and HOCl. CONCLUSIONS AND CLINICAL RELEVANCE: Eosinophils migrated toward the mucosal surface in equine colon in response to oxidant-induced damage in vitro. This novel finding could be relevant to inflammation in equine colon and a pathophysiologic feature of many colonic diseases. Acetylcysteine protected the mucosa against oxidant-induced injury and may be useful as a treatment option for various gastrointestinal tract disorders in horses.     

Effect of carprofen on hemostatic variables in dogs

OBJECTIVE: To evaluate the effect of carprofen on hemostatic variables in clinically normal dogs. ANIMALS: 12 clinically normal Labrador Retrievers. PROCEDURE: 10 dogs (6 females, 4 males) received carprofen (2.2 mg/kg of body weight, PO, q 12 h) for 5 days. Two dogs (untreated control group; 1 female, 1 male) did not receive carprofen. Hemostatic variables (platelet count, activated partial thromboplastin time, prothrombin time, fibrinogen, platelet aggregation, and bleeding time) were assessed for all dogs prior to treatment, on day 5 of treatment, and 2 and 7 days after discontinuation of the drug (days 7 and 12). Serum biochemical variables and Hct were assessed prior to treatment and on days 5 and 12. RESULTS: In dogs receiving carprofen, platelet aggregation was significantly decreased, and onset of aggregation was significantly delayed on days 5, 7, and 12, compared with pretreatment values. Activated partial thromboplastin time was significantly increased on days 5, 7, and 12 over pretreatment values in treated dogs, but values remained within reference ranges. Significant differences were not detected in buccal mucosal bleeding time, other serum biochemical and hemostatic variables, or Hct, compared with pretreatment values and the internal control group. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of carprofen for 5 days causes minor but not clinically important alterations in hemostatic and serum biochemical variables in clinically normal Labrador Retrievers. Carprofen is commonly used to treat osteoarthritis and chronic pain in dogs, but prior to this study, its effect on platelet aggregation and hemostatic variables was unknown.     

A morphometric study of the canine colon: comparison of control dogs and cases of colonic disease.

The microstructure of the canine colon was described morphometrically. The artifacts induced by administration of enemas and biopsy technique were studied by comparing biopsy specimens to tissues obtained at necropsy from 15 normal dogs. Biopsies from control dogs and clinical cases of colonic disease were then evaluated quantitatively, and histological abnormalities which might clarify mechanisms underlying large bowel dysfunction in the dog were sought. In control dogs, gland length and diameter, epithelial, goblet cell and mucosal mast cell numbers, and intraepithelial lymphocyte and mitotic indices were remarkably uniform throughout the colon. Minor variations were found in the proximal and distal regions of the colon. An apparent shortening of glands, and a reduction in mucous goblets and intraepithelial lymphocytes in biopsies were attributed to suboptimal orientation and irritation caused by enemas. The only significant difference from controls identified by morphometric analysis of biopsies from clinical cases was fewer epithelial cells lining longitudinal sections of glands. It was concluded that failure to identify morphometric variations in the colonic mucosa of clinical cases might reflect either a biased, homogeneously mild clinical syndrome in this group, or the possibility that in many of the clinical cases, a functional rather than physical abnormality was involved. The proprial inflammatory cell population was not examined quantitatively; further investigation of this component is merited.     

Cyclooxygenase expression and prostanoid production in pyloric and duodenal mucosae in dogs after administration of nonsteroidal anti-inflammatory drugs

OBJECTIVE: To assess cyclooxygenase (COX) expression and prostanoid concentrations in pyloric and duodenal mucosae of dogs after administration of nonsteroidal anti-inflammatory drugs (NSAIDs). ANIMALS: 8 healthy dogs. PROCEDURES: Each dog received carprofen (4.4 mg/kg, q 24 h), deracoxib (2 mg/kg, q 24 h), aspirin (10 mg/kg, q 12 h), and placebo (1 dog treat, q 24 h) orally for 3 days (4-week interval between treatments). Before study commencement (baseline) and on day 3 of each treatment, pyloric and duodenal mucosal appearance was assessed endoscopically and biopsy specimens were obtained for histologic examination. Cyclooxygenase-1 and COX-2 protein expressions were assessed via western blotting, and prostanoid concentrations were measured via ELISAs. An ANOVA was used to analyze data. RESULTS: Treatments had no effect on mucosal appearance and ulceration was not evident histologically. In pyloric and duodenal mucosae, COX-1 expression was unaffected by treatments. Cyclooxygenase-2 expression remained unchanged in pyloric mucosa; in duodenal mucosa, aspirin significantly increased COX-2 expression, compared with effects of deracoxib and carprofen. At baseline, total prostaglandin and thromboxane B2 concentrations in pyloric mucosa were significantly greater than those in duodenal mucosa. Aspirin significantly decreased both prostanoid concentrations in both mucosal tissues, compared with other treatments. In pyloric mucosa, carprofen administration significantly decreased total prostaglandin and thromboxane B2 concentrations, compared with deracoxib administration. CONCLUSIONS AND CLINICAL RELEVANCE: In dogs, prostanoid synthesis was greater in pyloric mucosa than it was in duodenal mucosa. Nonselective NSAIDs significantly decreased prostanoid concentrations in these mucosae, compared with the effects of a selective COX-2 NSAID.     

Effects of preoperative administration of carprofen on renal function and hemostasis in dogs undergoing surgery for fracture repair

OBJECTIVE: To evaluate effects of preoperative administration of carprofen on renal function and hemostasis in dogs undergoing general anesthesia for fracture repair. ANIMALS: 26 client-owned dogs. PROCEDURE: Anesthesia was induced with levomethadone, diazepam, and propofol and maintained by administration of isoflurane in oxygen-nitrous oxide. Carprofen (4 mg/kg, SC) was administered 1 hour before induction to 13 dogs (group 1) and after extubation to the other 13 dogs (group 2). All dogs also received carprofen (4 mg/kg, SC, q 24 h) for the first 4 days after surgery. Renal function (glomerular filtration rate [GFR], urinary protein-to-urinary creatinine ratio [UP:UC], and results of urinalysis and biochemical analysis of plasma), hemostatic variables (bleeding time, platelet aggregation, prothrombin time [PT], activated partial thromboplastin time [APTT], and platelet count), and Hct were assessed before and at various time points after surgery. RESULTS: Analysis of results for renal function tests, most of the hemostatic and plasma biochemical variables, and Hct did not reveal significant differences between treatment groups. Values for GFR, UP:UC, PT, APTT, and platelet aggregation were outside reference ranges in many dogs before surgery and during the first 6 hours after surgery. In most dogs, these trauma-induced pathologic changes returned to within reference ranges during the 4-day period after surgery. CONCLUSIONS AND CLINICAL RELEVANCE: Carprofen did not cause clinically relevant adverse effects in dogs anesthetized for fracture repair after 5 days of treatment, even when it was administered before surgery or given to patients with trauma-induced alterations in renal function or hemostasis.     

Renal effects of carprofen administered to healthy dogs anesthetized with propofol and isoflurane

OBJECTIVE: To evaluate renal effects of carprofen in healthy dogs following general anesthesia. DESIGN: Randomized clinical trial. ANIMALS: 10 English hound dogs (6 females and 4 males). PROCEDURE: Dogs were randomly assigned to control (n = 5) or carprofen (5) groups. Anesthesia was induced with propofol (6 to 8 mg/kg [2.7 to 3.6 mg/lb] of body weight, i.v.) and maintained with isoflurane (end-tidal concentration, 2.0%). Each dog underwent two 60-minute anesthetic episodes with 1 week between episodes, and mean arterial blood pressure was maintained between 60 and 90 mm Hg during each episode. Dogs in the carprofen group received carprofen (2.2 mg/kg [1 mg/lb], p.o.) at 9:00 AM and 6:00 PM the day before and at 7:00 AM the day of the second anesthetic episode. Glomerular filtration rates (GFR) were determined during each anesthetic episode by use of renal scintigraphy. Serum creatinine and BUN concentrations and the urine gamma-glutamyltransferase-to-creatinine concentration (urine GGT:creatinine) ratio were determined daily for 2 days before and 5 days after general anesthesia. RESULTS: Significant differences were not detected in BUN and serum creatinine concentrations, urine GGT:creatinine ratio, and GFR either between or within treatment groups over time. CONCLUSIONS AND CLINICAL RELEVANCE: Carprofen did not significantly alter renal function in healthy dogs anesthetized with propofol and isoflurane. These results suggest that carprofen may be safe to use for preemptive perioperative analgesia, provided that normal cardiorespiratory function is maintained.     

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.     

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.     

Carprofen in veterinary medicine. I. Plasma disposition, milk excretion and tolerance in milk-producing cows

Carprofen, a non-steroidal anti-inflammatory drug (NSAID), was injected intravenously in six cows after calving, either as a single or a daily dose of 0.7 mg/kg for five days. Carprofen was well tolerated by the cows at this dose rate, the milk production and biochemical variables remaining within the normal ranges. The plasma elimination half-life of carprofen ranged from 44.5 to 64.6 h after repeated daily injections. These values are longer than those reported for other NSAIDs used in veterinary medicine, e.g. flunixin and phenylbutazone. The volume of distribution and the clearance values calculated after a single intravenous injection amounted to 0.09 l/kg and 9.0 ml/min. The concentration of carprofen in milk collected twice daily (morning and evening) was, in general, below the sensitivity limit of the analytical method (25 ng/ml) up to five days after the last carprofen injection; the concentration of carprofen reached about 30 ng/ml in only a few milk samples collected after the fourth or fifth injection. This indicates that carprofen is poorly excreted in the milk.     

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.