Nonsteroidal anti-inflammatory drugs have an important role in ocular therapeutics. Topically, orally, and parenterally administered NSAIDs have the ability to suppress prostaglandin-mediated anterior uveitis.1–10 The NSAIDs act by inhibiting COX, the enzyme required for prostaglandin synthesis. Prostaglandins are lipids derived from fatty acids. They are synthesized locally within tissue cells and are released through the prostaglandin transporter on the cell's plasma membrane. Prostaglandins are mediators found in virtually all tissues and organs; they have a variety of strong physiologic effects and a short half-life. Prostaglandins have a wide array of actions, but most cause muscular constriction and mediate inflammation. This is particularly evident in the eyes, where prostaglandins (particularly PGE2) induce miosis and increase permeability of the anterior uveal vasculature, which causes an influx of cells, protein, and fibrin into the aqueous humor.5,11–13 Experimentally, evaluation of PGE2 concentrations in the aqueous humor has been used as a method for assessing anterior uveitis in dogs.1,14,a–f In one of those studies,e investigators found that evaluation of PGE2 concentrations in the aqueous humor was a much more reliable method for assessing the inflammatory response, compared with evaluation of protein concentrations in aqueous humor, because there was less variability in results for control and treated dogs.
Prostaglandin-mediated anterior uveitis is a typical sequela to cataract surgery. Veterinary ophthalmologists routinely pretreat cataract patients by topical, oral, or parenteral administration of an NSAID to help inhibit intraoperative and postoperative inflammation. Orally administered NSAIDs are frequently used after surgery for pain management and control of postoperative anterior uveitis. In recent years, there has been a surge of new NSAIDs entering the market, but few studies have evaluated their effect on anterior uveitis. The NSAIDs are often marketed on the basis of their preference or selectivity for COX-1 or COX-2. In general, COX-1 is responsible for production of the baseline concentrations of prostaglandins required for normal tissue homeostasis, such as gastric cytoprotection, renal blood flow regulation, and platelet function. In contrast, COX-2 produces prostaglandins primarily at sites of inflammation, although it does have a smaller role in homeostasis of the CNS, kidneys, reproductive tract, and vascular endothelium, and it is required for repair of gastric ulcers.15,16
Selectivity of NSAIDs is expressed as the IC50. The COX-1:COX-2 IC50 ratios provide a means of comparing the selectivity of various NSAIDs. A value > 1 for the ratio of COX-1 to COX-2 indicates greater drug inhibition of COX-2, whereas a ratio < 1 indicates greater drug inhibition of COX-1. The NSAIDs introduced for use in dogs have been compared on the basis of preference or selectivity for COX-1 and COX-2 on the presumption that a higher selectivity for COX-2 would result in fewer adverse effects on the gastrointestinal tract, renal system, or platelets but still provide anti-inflammatory and analgesic effects. Recently, this reasoning has been questioned because the role of COX-2 in homeostasis has been better defined. Both COX-1 and COX-2 have been identified in normal, unstimulated iris and ciliary body tissue of rabbits, which suggests that both enzymes may share roles in the maintenance of the physiologic status of the eyes and in the development of ocular inflammation.17 The purpose of the study reported here was to compare the effects of 3 orally administered NSAIDs (tepoxalin, COX-1 preferential; carprofen, COX-2 selective; and meloxicam, COX-2 preferential) for the control of aqueocentesis-induced anterior uveitis in dogs, as measured by assessment of PGE2 concentrations in the aqueous humor.
Materials and Methods
Animals—Thirty-eight adult mixed-breed dogs weighing 16 to 26 kg that were undergoing a terminal surgery were enrolled in the study. All dogs had an ophthalmic examination, including biomicroscopy, indirect ophthalmoscopy, applanation tonometry, and fluorescein staining, performed the day before inclusion in the study. The study protocol was approved by the Oklahoma State University Institutional Animal Care and Use Committee.
Procedures—On day 0, dogs were randomly assigned to 1 of 4 groups consisting of a control group (n = 9 dogs) and 3 treatment groups (tepoxaling [10], carprofenh [9], and meloxicami [10]). Dogs in the control group received no medication. Dogs in each respective treatment group received an NSAID on days 0 and 1 (tepoxalin, 10 mg/kg, PO, q 24 h for 2 doses; carprofen, 2.2 mg/kg, PO, q 12 h for 3 doses; or meloxicam, 0.2 mg/kg, PO, q 24 h for 2 doses).
On day 1, dogs were anesthetized 3 to 6 hours after the last NSAID treatment and positioned in dorsal recumbency. Aqueocentesis was performed on both eyes of each dog by use of a 27-gauge needle inserted at the limbus and directed 1 mm through the corneal stroma into the anterior chamber. Then, 0.2 mL of aqueous humor was aspirated into a 1-mL syringe during a 30-second period. Anesthesia was maintained, and aqueocentesis was repeated on all eyes 1 hour later. Each controlled aqueocentesis was performed by the same investigator (MAG). Aqueocentesis was not performed on 2 dogs (4 eyes) because petrolatum ophthalmic ointment had been instilled in the eyes. Aqueous samples from eyes with traumatic aqueocentesis were excluded from the study (8 eyes). An aqueocentesis was deemed traumatic when visual observation of the anterior chamber and needle placement was compromised because of patient positioning, the syringe plunger did not withdraw smoothly, or the aqueous humor did not readily aspirate. Usable samples were obtained from 1 or both eyes of 10 dogs in the tepoxalin group (n = 16 eyes), 9 dogs in the meloxicam group (16 eyes), 9 dogs in the carprofen group (16 eyes), and 8 dogs in the control group (16 eyes).
The first aqueocentesis was used to collect samples for baseline measurement of PGE2 concentrations and to induce uveitis. The second aqueocentesis was used to collect samples for determining changes in PGE2 concentrations. Following completion of the terminal surgery, the anesthetized dogs were euthanatized by IV injection of a solutionj (combination of phenobarbital and phenytoin) administered at the recommended dosage of 1 mL/4.5 kg.
Measurement of PGE2 concentrations—Samples of aqueous humor were frozen at −80°C until assayed. Samples were thawed, and the PGE2 concentration was immediately measured by use of a commercial PGE2 monoclonal enzyme immunoassay kit.k All samples were measured in triplicate with no dilution. It was not possible to assay samples at multiple dilutions because of the limited volume of each sample. Mean highest calculated standard concentration for the assay plates was 2,044 pg/mL; therefore, the upper limit for the PGE2 concentration in samples was truncated at 2,000 pg/mL for statistical analysis of data.
Data analysis—Preexisting uveitis was assessed by evaluating the distribution of the PGE2 concentrations of the first samples of aqueous humor obtained from all dogs. Reference values for the sample population were arbitrarily defined as those that did not exceed an upper 5% limit (based on the value calculated as sample mean + [1.645 × SD]) because only increased concentrations (rather than low concentrations) would be exclusionary.18 Results were interpreted within the context of normal distribution theory.18 A paired t test was used to compare initial (first sample) PGE2 concentrations between right and left eyes. Expected increases in PGE2 concentration from first to second samples obtained from dogs in the control group were also evaluated by use of a paired t test to validate the experimental method for inducing uveitis and, consequently, production of PGE2.
Evaluation of the effect of oral administration of an NSAID on inhibition of PGE2 production was based on changes in PGE2 concentrations between first and second samples among the 4 groups of dogs. The mean value for samples obtained from the right and left eye was used to evaluate the effect of treatment. Preliminary evaluation of the data by use of the Levene test for homogeneity of variances revealed that there was a significant (P < 0.001) departure of sample variances from the assumption of equal population variances, which is required for parametric testing.19 Because of this finding, a Kruskal-Wallis test was used to determine whether values for 1 or more groups of dogs differed significantly from values for the others. Post hoc comparisons were performed by use of a Mann-Whitney test for each pairwise comparison and by use of the Holms stepdown procedure to adjust for an inflated type I error as a result of conducting multiple comparisons on the same set of data.19 For all statistical evaluations, values of P b 0.05 were considered significant. Commercially available softwarel,m was used for statistical analyses and to create charts.
Results
Animals—No relevant abnormalities were found during the ophthalmic examinations. Two dogs had a unilateral, focal corneal scar, and 1 dog had a focal hyperreflective scar in the tapetal fundus.
Concentrations of PGE2—Mean ± SD PGE2 concentrations for the first samples of aqueous humor were 9.30 ± 3.27 pg/mL for the right eyes and 11.22 ± 7.23 pg/mL for the left eyes (mean for both eyes was 10.24 ± 4.47 pg/mL). The mean concentration for left eyes was significantly greater than that for right eyes, although this difference was not considered clinically important. The calculated upper 5% limits for PGE2 concentrations for the sample population was 14.68 pg/mL for the right eyes and 23.11 pg/mL for the left eyes (mean for both eyes was 17.60 pg/mL). Analysis of the distribution of PGE2 concentrations for the first samples of aqueous humor did not reveal marked deviation from expected normal distributions (Figure 1). In the control group, the concentration for the right eye of 1 dog (16.71 pg/mL) and the left eye of another dog (41.99 pg/mL) exceeded the respective 5% upper limit for the left and right eyes; both of these dogs had a mean concentration for both eyes (18.04 and 25.92 pg/mL, respectively) that also exceeded the 5% upper limit. Furthermore, the dog with the high concentration for the left eye exceeded the upper 1% limits for the left eyes and the mean value for both eyes. Because of a lack of clinical signs indicative of current or prior anterior uveitis in these 2 dogs, the findings were considered to be compatible with the expected frequency of clinically normal dogs that might exceed such limits by chance, as determined in accordance with normal distribution theory. By comparison, the percentage of PGE2 concentrations for the second samples obtained from the dogs of all 4 groups that exceeded the 5% limits for the left and right eyes and the mean value for both eyes was 71%, 73%, and 69%, respectively.
Distribution of PGE2 concentrations in the first sample of aqueous humor obtained from the right (white bars) and left (black bars) eyes of 36 dogs in the study. Upper 5% limits for sample populations for the right eyes (triangles and dotted line) and left eyes (squares and solid line), as well as the mean of both eyes (circles and dotted-and-dashed line), were calculated as mean + (1.645 × SD).
Citation: American Journal of Veterinary Research 70, 7; 10.2460/ajvr.70.7.902
Distribution of PGE2 concentrations in the first sample of aqueous humor obtained from the right (white bars) and left (black bars) eyes of 36 dogs in the study. Upper 5% limits for sample populations for the right eyes (triangles and dotted line) and left eyes (squares and solid line), as well as the mean of both eyes (circles and dotted-and-dashed line), were calculated as mean + (1.645 × SD).
Citation: American Journal of Veterinary Research 70, 7; 10.2460/ajvr.70.7.902
Distribution of PGE2 concentrations in the first sample of aqueous humor obtained from the right (white bars) and left (black bars) eyes of 36 dogs in the study. Upper 5% limits for sample populations for the right eyes (triangles and dotted line) and left eyes (squares and solid line), as well as the mean of both eyes (circles and dotted-and-dashed line), were calculated as mean + (1.645 × SD).
Citation: American Journal of Veterinary Research 70, 7; 10.2460/ajvr.70.7.902
Comparison of changes in PGE2 concentrations between the first and second samples of aqueous humor obtained from the 8 control dogs confirmed that PGE2 production was induced. Mean paired differences for each of the comparisons among right eyes, left eyes, and the mean of both eyes ranged between 1,180 and 1,209 pg/mL and were significant (P = 0.01), which indicated that the aqueocentesis technique induced uveitis, as measured by PGE2 concentrations in the aqueous humor.
Concentrations of PGE2 were determined for the first and second samples of aqueous humor obtained from each group (Table 1). The range of PGE2 concentrations varied considerably in the second samples of aqueous humor for dogs of all groups, except for dogs treated with tepoxalin. There were 7 samples for the control group, 3 samples for the meloxicam group, and 3 samples for the carprofen group that had concentrations of PGE2 > 2,000 pg/mL; none of the samples for the tepoxalin group exceeded 2,000 pg/mL.
Concentrations of PGE2 in samples of aqueous humor obtained during an initial aqueocentesis (first sample) and a second aqueocentesis performed 1 hour later (second sample) in dogs given no medications (control group) and dogs orally administered tepoxalin, carprofen, or meloxicam.
| Group | First sample | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Min | Percentile | Max | Min | Percentile | Max | |||||
| 25th | 50th | 75th | 25th | 50th | 75th | |||||
| Control (n = 8) | 6.32 | 7.15 | 10.44 | 16.87 | 25.92 | 36.25 | 370.08 | 1,424.34 | 2,000.00 | > 2,000.00 |
| Tepoxalin (n = 10) | 4.81 | 7.47 | 9.06 | 11.17 | 13.74 | 6.84 | 7.82 | 12.18 | 12.80 | 15.76 |
| Carprofen (n = 9) | 4.47 | 6.53 | 9.37 | 13.52 | 17.02 | 74.44 | 93.52 | 437.49 | 1542.54 | > 2,000.00 |
| Meloxicam (n = 9) | 4.69 | 5.95 | 9.53 | 12.50 | 16.93 | 13.08 | 69.04 | 317.25 | 1,646.74 | > 2,000.00 |
Values are reported in pg/mL.
n = Number of dogs. Min = Minimum. Max = Maximum.
Obvious differences were found for the effect of oral administration of an NSAID among the 4 groups (Figure 2). Dogs treated with tepoxalin had minimal changes in median PGE2 concentrations between the first and second samples of aqueous humor. This result for tepoxalin differed significantly (P < 0.001), compared with results for the control dogs and dogs treated with meloxicam or carprofen. Although the median value for dogs in the meloxicam and carprofen groups (306 pg/mL and 430 pg/mL, respectively) was smaller than the median value for the control dogs (1,412 pg/mL), these values did not differ significantly (P > 0.20). None of the significant differences changed when evaluations were limited to the values for only the right or only the left eyes. Median value for the change in PGE2 concentration between the first and second samples of aqueous humor was 1.97 pg/mL for dogs administered tepoxalin; the median value for dogs administered meloxicam (the group with the next closest value) was > 150 times higher. Median change for control dogs was > 700 times higher than the change for dogs treated with tepoxalin and > 3 times higher than the change for dogs treated with carprofen or meloxicam.
Box-and-whisker charts of change in PGE2 concentrations between the first and second samples of aqueous humor obtained from 10 dogs treated by administration of tepoxalin (A) and those 10 tepoxalin-treated dogs, 9 dogs treated by administration of meloxicam, 9 dogs treated by administration of carprofen, and 8 unmedicated control dogs (B). The mean value for both eyes in each dog was used for analysis. The lower and upper limits of each box represent the 25th and 75th percentiles, respectively. The horizontal bar in each box represents the median value (50th percentile). The lower and upper whiskers represent the 10th and 90th percentiles, respectively. Notice that the y-axis scale differs between panels. The group treated with tepoxalin had values that differed significantly (P < 0.001), compared with values for the other 3 groups. However, values did not differ significantly (P > 0.20) between the control group and the carprofen or meloxicam groups.
Citation: American Journal of Veterinary Research 70, 7; 10.2460/ajvr.70.7.902
Box-and-whisker charts of change in PGE2 concentrations between the first and second samples of aqueous humor obtained from 10 dogs treated by administration of tepoxalin (A) and those 10 tepoxalin-treated dogs, 9 dogs treated by administration of meloxicam, 9 dogs treated by administration of carprofen, and 8 unmedicated control dogs (B). The mean value for both eyes in each dog was used for analysis. The lower and upper limits of each box represent the 25th and 75th percentiles, respectively. The horizontal bar in each box represents the median value (50th percentile). The lower and upper whiskers represent the 10th and 90th percentiles, respectively. Notice that the y-axis scale differs between panels. The group treated with tepoxalin had values that differed significantly (P < 0.001), compared with values for the other 3 groups. However, values did not differ significantly (P > 0.20) between the control group and the carprofen or meloxicam groups.
Citation: American Journal of Veterinary Research 70, 7; 10.2460/ajvr.70.7.902
Box-and-whisker charts of change in PGE2 concentrations between the first and second samples of aqueous humor obtained from 10 dogs treated by administration of tepoxalin (A) and those 10 tepoxalin-treated dogs, 9 dogs treated by administration of meloxicam, 9 dogs treated by administration of carprofen, and 8 unmedicated control dogs (B). The mean value for both eyes in each dog was used for analysis. The lower and upper limits of each box represent the 25th and 75th percentiles, respectively. The horizontal bar in each box represents the median value (50th percentile). The lower and upper whiskers represent the 10th and 90th percentiles, respectively. Notice that the y-axis scale differs between panels. The group treated with tepoxalin had values that differed significantly (P < 0.001), compared with values for the other 3 groups. However, values did not differ significantly (P > 0.20) between the control group and the carprofen or meloxicam groups.
Citation: American Journal of Veterinary Research 70, 7; 10.2460/ajvr.70.7.902
Discussion
The aqueocentesis technique for experimentally induced disruption of the blood-aqueous barrier has been used in several species of animals, including dogs.1–5,8,10,20–23 The difference in PGE2 concentrations between the first and second samples of aqueous humor for the control group in the study reported here confirmed that the technique was effective for increasing PGE2 concentrations in the aqueous humor.
Median changes in PGE2 concentrations for the meloxicam and carprofen groups were lower but not significantly different from the median change for the control group. Studies in which investigators have evaluated carprofen and meloxicam in patients with experimentally induced or naturally developing uveitis in which there is a breakdown of the blood-aqueous barrier are limited, and it is difficult to compare results because of differences in methods, routes of drug administration, and species. In 1 study,7 investigators used pilocarpine to induce breakdown of the blood-aqueous barrier and laser flare photometry to measure drug effects. In that study, dogs treated with carprofen had a significant reduction (68% inhibition) of aqueous flare. In another study,c investigators evaluated the effects of carprofen in samples obtained before and after cataract surgery in dogs with uveitis by measuring protein and PGE2 concentrations in the aqueous humor. No significant differences were found in results for normal, milduveitis, or severe-uveitis eyes between dogs receiving a single dose of carprofen (which was administered IV) and the untreated control dogs. In a third study,a investigators evaluated effects of carprofen administered by subconjunctival, topical, and SC routes in dogs with aqueocentesis-induced disruption of the blood-aqueous barrier. There was no significant difference in protein or PGE2 concentrations in the aqueous humor between any of the dogs treated with carprofen and the control dogs. In a studyf similar to that reported here, effects of orally administered carprofen were evaluated in 4 dogs by measurement of PGE2 concentrations in aqueous humor and investigators detected a significant difference between the dogs treated with carprofen and the control dogs. In rabbits, an irritant (3% croton oil) was topically applied to the eyes followed by topical ophthalmic administration of a 0.03% solution of meloxicam every 4 hours.24 In that study, eyes treated with meloxicam had a significant decrease in PGE2 concentrations in the aqueous humor at 24 and 72 hours after meloxicam application.
Tepoxalin was significantly more effective in controlling PGE2 production than was meloxicam or carprofen. In contrast to meloxicam and carprofen, tepoxalin is a COX-1 preferential inhibitor and inhibits 5-lipoxygenase in addition to COX. In the arachidonic acid cascade, 5-lipoxygenase is required for leukotriene synthesis. Leukotrienes are inflammatory mediators that promote chemotaxis of inflammatory cells and vasoconstriction. Results of studies14,20,25 suggest that the role of leukotrienes in uveitis of dogs may be minimal, although their role in various causes of clinical uveitis has not been established. Leukotriene B4 was detected in dogs with experimentally induced uveitis; however, the use of leukotriene inhibitors did not significantly reduce the signs of uveitis, compared with the effects achieved by the use of prostaglandin inhibitors.14 In 1 study,e concentrations of leukotriene B4 were extremely low (< 6 pg/mL) in control and tepoxalin-treated dogs with aqueocentesis-induced disruption of the blood-aqueous barrier. The significantly lower PGE2 concentrations in the tepoxalin-treated group of the study reported here indicated COX inhibition. Tepoxalin's preferential inhibition of COX-1, compared with meloxicam's preferential inhibition of COX-2 and carprofen's selective inhibition of COX-2, suggests that COX-1 may have a more important role in anterior uveitis than has been assumed. It may also explain the effects of flunixin meglumine (an older, nonselective NSAID) in the control of anterior uveitis in eyes of dogs and horses.1,6,22,26–28
The inability to measure PGE2 concentrations > 2,000 pg/mL was a limitation of the study reported here. Actual values may have revealed an even greater difference among treatment groups. For most of the samples, there was an insufficient quantity of aqueous humor to allow us to perform serial dilutions in triplicate. In the few samples for which dilutions were performed for comparison, the diluted values varied widely from the value for the undiluted sample. This may have been attributable to loss of PGE2 in the samples as a result of repeated thawing and freezing.
Oral administration of tepoxalin appeared to be more effective than oral administration of carprofen or meloxicam for controlling the production of PGE2 in dogs with experimentally induced uveitis. Therefore, tepoxalin may be an appropriate choice when treating dogs with anterior uveitis.
ABBREVIATIONS
| COX | Cyclooxygenase |
| IC50 | Concentration of drug necessary to inhibit activity by 50% |
| PGE2 | Prostaglandin E2 |
Laus JL, Ribeiro AP, Escobar A, et al. Effects of carprofen administered by different routes to control experimental uveitis in dogs (abstr), in Proceedings. 38th Annu Meet Am Coll Vet Ophthalmol 2007;26.
Pinard CL, Gauvin D, Moreau M, et al. Measurement of inflammatory mediators in aqueous humor following paracentesis of the anterior chamber in dogs (abstr), in Proceedings. 38th Annu Meet Am Coll Vet Ophthalmol 2007;81.
Fischer A. Carprofen in the aqueous humor of dogs and cats with uveitis. Dissertation, Freie University, Berlin, Gemany, 2000. Available at: library.vetmed.fu-berlin.de/diss-abstracts/115881. html. Accessed Apr 10, 2009.
Allgoewer I, Fischer A, Brunnberg L, et al. Concentration of carprofen in the aqueous humor of dogs with uveitis. Preliminary results (abstr), in Proceedings. 30th Annu Meet Am Coll Vet Ophthalmol 1999;16.
Gilmour MA, Lehenbauer TW. Effects of tepoxalin in reducing intraocular inflammation in the dog (abstr), in Proceedings. 37th Annu Meet Am Coll Vet Ophthalmol 2006;17.
Pinard CL, Moreau M, Martel-Pelletier J, et al. Effect of carprofen on aqueous humor levels of PGE2, NOx and TNF-A in an experimental canine uveitis model (abstr), in Proceedings. 37th Annu Meet Am Coll Vet Ophthalmol 2006;58.
Zubrin, Schering-Plough Animal Health, Summit, NJ.
Rimadyl, Pfizer Animal Health, Exton, Pa.
Metacam, Boehringer Ingelheim Vetmedica Inc, St Joseph, Mo.
Beuthanasia, Schering-Plough Animal Health, Union, NJ.
Prostaglandin E2 EIA kit—monoclonal, Cayman Chemical Co, Ann Arbor, Mich.
SPSS, version 15.0 for Windows, SPSS Inc, Chicago, Ill.
ProStat, version 4.8, Poly Software Int, Pearl River, NY.
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