Uveitis is a common and clinically important ophthalmic disorder in domestic cats, and the cause often is not determined. Complications of uveitis include secondary glaucoma,1 synechia, lens luxation,2 cataract formation,1 phthisis bulbi, and blindness. Topical and systemic administration of anti-inflammatory medications is commonly used in the treatment of uveitis in veterinary medicine. Anti-inflammatory drugs are used in conjunction with an antimicrobial agent when an infectious organism is identified. The route of administration of the anti-inflammatory medication is determined on the basis of the severity of inflammation and the location of inflammation within the eye. The goals of anti-inflammatory treatment are to decrease inflammatory mediators, reduce discomfort, and prevent complications associated with intraocular inflammation. In general, topical anti-inflammatory medications are indicated for treatment of inflammation in the anterior segment of the eye. Topical administration of anti-inflammatory medications does not result in therapeutic concentrations in the posterior segment of the eye. Systemic anti-inflammatory medications are generally recommended for the treatment of inflammation in the posterior segment of the eye or as an adjunctive treatment for anterior uveitis.
Anti-inflammatory treatment includes the use of corticosteroids and NSAIDs. Corticosteroids bind to specific receptors in the cytoplasm of cells in the iris, choroid, sclera, cornea, conjunctiva, and retina3,4 and inhibit phospholipase A2 activity on phospholipids, which in turn prevents the biosynthesis of arachidonic acid and subsequent formation of prostacyclin, thromboxane A, PGs, and leukotrienes.5,6 Glucocorticoids can also decrease PG synthesis at the level of the COX pathway,7 and they may induce local expression of somatostatin, a hormone with anti-inflammatory properties.8
Cats appear to be more resistant to the adverse effects of systemically administered glucocorticoids, compared with results in dogs, and reportedly have up to 50% fewer corticosteroid receptors than do dogs.9 In dogs, there is rapid hepatic conversion of prednisone to the active metabolite, prednisolone, which allows both prednisone and prednisolone to be used interchangeably at equivalent dosages. However, in cats, the pharmacokinetics of prednisone are inferior to those of prednisolone,10 and prednisolone is generally recommended over prednisone in cats.
Nonsteroidal anti-inflammatory drugs inhibit PG synthesis by competing with arachidonate for binding to the COX-active site of PG endoperoxide synthase. Prostaglandin endoperoxide synthase, also known as COX, is the enzyme that converts arachidonic acid to PGs (PGE2, PGD2, PGF2α, and PGI2) and thromboxane A2.11 Two main isoforms of COX (COX-1 and COX-2) have been identified; in general, COX-1 is responsible for production of PGs that are required for tissue homeostasis, such as gastric cytoprotection, regulation of renal blood flow, and platelet function.12 In contrast, COX-2 is responsible for production of PGs primarily at sites of inflammation by cells that have been stimulated by cytokines and other inflammatory mediators, although COX-2 can be found in low amounts in physiologically normal tissues.12
The toxic effects of NSAIDs are thought to result primarily from inhibition of COX-1. Cyclooxygenase selectivity is typically expressed as a ratio of the concentrations at which a specific drug inhibits each isoenzyme by 50%. Nonsteroidal anti-inflammatory drugs have been classified on the basis of their selectivity for COX-1 and COX-2 on the assumption that greater selectivity for COX-2 would result in fewer adverse effects but still provide anti-inflammatory and analgesic effects. In general, acetylsalicylic acid is considered to be a nonselective COX inhibitor, indicating that it inhibits both COX-1 and COX-2, whereas meloxicam is classified as a selective COX-2 inhibitor. Cats have a reduced ability for glucuronide conjugation that results in prolonged action of many drugs, including most NSAIDs. Therefore, cats may have an increased risk of complications associated with the use of systemically administered NSAIDs, particularly given that little is known about COX selectivity of various NSAIDs in cats.
Although several ophthalmic studies13–18,a,b have been conducted to evaluate the efficacy of orally administered anti-inflammatory agents in dogs, the authors are not aware of any such reports for cats. Because of species differences in stability of the BAB and differences in the metabolism of drugs, it is clinically relevant to evaluate the efficacy of anti-inflammatory medications in each species. The purpose of the study reported here was to assess the inhibitory effects of 4 orally administered anti-inflammatory medications on paracentesis-induced intraocular inflammation in clinically normal cats via fluorophotometry.
Materials and Methods
Animals—Thirty domestic shorthair cats (14 neutered males and 16 sexually intact females) weighing between 2.5 and 5.4 kg were used in the study. The cats were 8 to 20 months old (mean ± SD, 11.9 ± 3.2 months). The cats were part of a research colony at the Kansas State University Department of Diagnostic Medicine/Pathobiology; following completion of the study, cats were returned to the colony for subsequent adoption. The study was approved by the Institutional Animal Care and Use Committee at Kansas State University.
An ophthalmic examination, including slit-lamp biomicroscopy,c fluorescein stainingd of the cornea, rebound tonometry,e and indirect ophthalmoscopy,f was performed on each cat prior to the study. Inclusion criteria for the study required cats to have no abnormal findings for ophthalmic and physical examinations. The cats were housed in a temperature-controlled environment and exposed to 12 hours of light and 12 hours of darkness (light phase from 7 am to 7 pm).
Anti-inflammatory medications—Cats were assigned via a randomization procedure (randomization was achieved by use of a table of random numbers) to a control group and 4 treatment groups (acetylsalicylic acid,g meloxicam,h prednisone,i and prednisolonej); there were 6 cats in each group. Cats in the control group received no medication. Cats in each respective treatment group received an anti-inflammatory medication orally once daily at 7 am (acetylsalicylic acid [40.5 mg/cat; mean ± SD, 12.8 ± 2.4 mg/kg], meloxicam [0.1 mg/kg], prednisone [5 mg/cat; mean ± SD, 1.6 ± 0.3 mg/kg], or prednisolone [5 mg/cat; mean ± SD, 1.4 ± 0.3 mg/kg]) beginning 2 days before paracentesis (ie, breakdown of the BAB) and continuing until 2 days after paracentesis (total of 5 doses). The cats received 3 doses of the anti-inflammatory medication prior to paracentesis. Investigators performing the fluorophotometry (AJR and WRC) were not aware of the group assignment of each cat.
Paracentesis of the anterior chamber—In each cat, paracentesis of the anterior chamber was performed in 1 eye (selected via flipping of a coin) to induce disruption of the BAB. Cats were sedated with medetomidinek (0.03 mg/kg, IV) and ketamine hydrochloridel (5 mg/kg, IV). Paracentesis of the anterior chamber was performed with a 30-gauge needle attached to a 1-mL syringe. The needle was introduced into the cornea at a point 1 to 2 mm anterior to the limbus. The needle was advanced into the center of the anterior chamber, and 100 μL of aqueous humor was slowly aspirated during a period of 3 to 5 seconds. Investigators were careful to ensure the iris and lens were not traumatized during paracentesis. The cats were monitored after paracentesis for signs of discomfort (lethargy, blepharospasm, or rubbing of the eye), conjunctival hyperemia, and ocular discharge. Cats with any signs of discomfort or ocular abnormalities were removed from the study and treated by a board-certified veterinary ophthalmologist.
Fluorophotometry—In each cat, anterior chamber fluorophotometry was performed via a computerized scanning fluorophotometerm with an anterior chamber adapter. A catheter was placed in a cephalic vein, and 10% fluoresceinn (20 mg/kg, IV) was administered 1 hour before each fluorophotometry reading. Cats were sedated with medetomidine (0.03 mg/kg, IV) and ketamine (5 mg/kg, IV) to allow proper positioning for fluorophotometry. Fluorophotometry was performed in both eyes of each cat (≤ 2 minutes elapsed between measurements on both eyes of each cat) immediately before paracentesis (ie, breakdown of the BAB; time 0) and 6, 24, and 48 hours after paracentesis. Disruption of the BAB was quantified by measurement of the fluorescein concentration in the central portion of the anterior chamber.
Statistical analysis—Fluorescein concentration was evaluated with a general linear mixed model, assuming a Gaussian distribution. The linear predictor of the model included the fixed effects of treatment (control, acetylsalicylic acid, meloxicam, prednisone, and prednisolone), paracentesis (whereby there was 1 eye subjected to paracentesis eye and 1 eye not subjected to paracentesis), time (0, 6, 24, and 48 hours), and all 2- and 3-way interactions. Random effects were cat nested within treatment to recognize cat as the experimental unit for treatment and the blocking factor for paracentesis. The residual variance-covariance structure was modeled with a spatial power-type structure to account for repeated measures over uneven time intervals for the eye of each cat. Values of P ≤ 0.05 were considered significant.
Disruption of the BAB was expressed as the percentage increase in fluorescein concentration in the eye subjected to paracentesis versus that in the eye not subjected to paracentesis by use of the following equation:
where % Inc[Fl] is the percentage increase in fluorescein concentration, and [Fl] is the fluorescein concentration.
A general linear mixed model was fitted to the percentage increase in fluorescein concentration, assuming a Gaussian distribution. The linear predictor included the fixed effects of treatment (control, acetylsalicylic acid, meloxicam, prednisone, and prednisolone), time (0, 6, 24, and 48 hours), and their 2-way interaction as well as the covariate for concentration of fluorescein in the eye not subjected to paracentesis. Random effects were cat nested within treatment to recognize cat as the experimental unit for treatment. The residual variance-covariance structure was modeled with a spatial power-type structure to account for repeated measures over uneven time intervals for each cat.
For both modeling strategies, the Kenward-Roger procedure was used to estimate the degrees of freedom and to make the corresponding adjustments in estimated SEs. Models were fitted with statistical softwareo via the Newton-Raphson technique with ridging and the optimization technique. Model assumptions were considered to be appropriately met on the basis of diagnostic testing conducted on Studentized residuals. Estimated least squares means and corresponding SEs were reported. Relevant pairwise comparisons were conducted with Bonferroni adjustments to avoid inflation of the type I error rate attributable to multiple comparisons.
Results
Animals—Paracentesis and fluorophotometry procedures were tolerated well by all cats in the study. Results of the ophthalmic examinations at the end of the study were within anticipated limits and did not reveal any abnormalities.
Fluorescein concentrations—In the eyes not subjected to paracenteses, there was no evidence of significant (P > 0.900) treatment effects during the study. At time 0, there were no significant (P < 0.900) treatment effects in the eyes subsequently subjected to paracentesis.
At 24 and 48 hours after paracentesis, the concentration of fluorescein in the eyes subjected to paracentesis in the prednisolone-treated cats was significantly (P = 0.012 and 0.041, respectively) decreased, compared with the concentration in those same eyes of the control cats. At 48 hours, a significant (P = 0.041) decrease was also apparent in meloxicam-treated cats, compared with the concentration in the control cats. There was no evidence of a treatment effect for acetylsalicylic acid or prednisone on eyes subjected to paracentesis, compared with the concentration in the control cats, at any time point during the study (Figure 1).
Least squares mean and SE estimates of anterior chamber fluorescein concentrations in eyes subjected to paracentesis in control cats (n = 6) that received no medication (black bars) and cats (6/group) that received an anti-inflammatory medication orally once daily at 7 am (acetylsalicylic acid, 40.5 mg/cat [white bars]; meloxicam, 0.1 mg/kg [diagonal-striped bars]; prednisone, 5 mg/cat [gray bars]; or prednisolone, 5 mg/cat [horizontal-striped bars]). Fluorophotometry was performed immediately before paracentesis (ie, breakdown of the BAB; time 0) and 6, 24, and 48 hours after paracentesis. a–cWithin a time point, values with different letters differ significantly (P < 0.05).
Citation: American Journal of Veterinary Research 74, 2; 10.2460/ajvr.74.2.262
In comparing the effectiveness of the drugs, there was a significant (P = 0.031) difference at 6 hours after paracentesis between the meloxicam-treated and prednisolone-treated cats, with prednisolone-treated cats having lower fluorescein concentrations. Both at 6 and 24 hours after paracentesis, there were significant differences between the prednisolone-treated (P = 0.007) and prednisone-treated (P = 0.005) cats, with prednisolone-treated cats having lower fluorescein concentrations. At 48 hours after paracentesis, there was no significant difference among fluorescein concentrations in cats after treatment with any of the medications.
Percentage increase in fluorescein concentration—At time 0, there were no significant (P > 0.900) differences among the treatments for percentage increase in fluorescein concentration. However, at 6 hours after paracentesis, the prednisone-treated cats had a significantly (P = 0.004) greater percentage increase in fluorescein concentration, relative to results for the control cats. At 24 and 48 hours after paracentesis, the prednisolone-treated cats had a significantly (P < 0.001) smaller percentage increase in fluorescein concentration, compared with results for the control cats. The meloxicam-treated cats had a significantly (P = 0.002) smaller percentage increase in fluorescein concentration, compared with results for the control cats, at 24 and 48 hours after paracentesis. The acetylsalicylic acid–treated cats had no significant differences in the percentage increase in fluorescein concentration, compared with results for the control cats, at any time point (Figure 2).
Least squares mean and SE estimates of the percentage increase in fluorescein concentration for the same cats as in Figure 1 in samples of aqueous humor obtained before (time 0) and 6, 24, and 48 hours after paracentesis. See Figure 1 for remainder of key.
Citation: American Journal of Veterinary Research 74, 2; 10.2460/ajvr.74.2.262
Comparisons among treatments revealed that at 6 hours after paracentesis, the percentage increase in fluorescein concentration was significantly lower in the prednisolone-treated cats, compared with results for the meloxicam-treated (P = 0.046) and prednisone-treated (P < 0.001) cats. Cats treated with prednisone had a significantly higher percentage increase in fluorescein concentration than did cats treated with acetylsalicylic acid (P = 0.002) or meloxicam (P = 0.033). At 24 hours after paracentesis, prednisolone-treated cats had a significantly lower percentage increase in fluorescein concentration than did the acetylsalicylic acid–treated (P = 0.008) or prednisone-treated (P < 0.001) cats, and the meloxicam-treated cats had a significantly (P = 0.043) lower percentage increase in fluorescein concentration than did the prednisone-treated cats. At 48 hours after paracentesis, cats treated with prednisolone or meloxicam had a significantly (P < 0.001) lower percentage increase in fluorescein concentration than did cats treated with prednisone.
Discussion
In the study reported here, we used fluorophotometry to evaluate the ability of 4 orally administered anti-inflammatory medications to inhibit paracentesis-induced BAB disruption in clinically normal cats. Paracentesis-induced disruption of the BAB has been used experimentally in several species, including cats.19–23 The ciliary body epithelium in the anterior pars plicata is most likely the site of disruption of the BAB following paracentesis of the anterior chamber.22,24,25 Paracentesis-induced breakdown of the BAB is thought to be mediated primarily by PGs.17,22,26–29 Prostaglandins cause miosis, hypotony, and increased permeability of the anterior uveal vasculature.22,30–32 Inhibition of the breakdown of the BAB by prophylactic treatment with NSAIDs via topical ophthalmic or systemic administration in several studies13–15,17,27,33,34,p,q supports the role of PGs as mediators of ocular inflammation.
It is difficult to compare results of studies in which investigators evaluated the efficacy of orally administered medications for the control of intraocular inflammation because different methods of disrupting the BAB and of assessing the breakdown of the BAB have been used. These differences, along with variation in BAB stability and metabolism of drugs among species, highlight the clinical relevance of evaluating the efficacy of anti-inflammatory medications in each species.
In the present study, orally administered meloxicam significantly decreased the amount of fluorescein that entered the anterior chamber following paracentesis in clinically normal cats, compared with fluorescein concentrations in the control cats. These results are in accordance with those of a recent studyp in dogs that revealed IV administration of meloxicam was effective for the control of aqueocentesis-induced uveitis quantified on the basis of PGE2 concentrations in the aqueous humor. However, in another study,17 PGE2 concentrations in the aqueous humor were not significantly different between control dogs and dogs orally administered meloxicam prior to disruption of the BAB. In cats, meloxicam administered orally at a dose of 0.1 mg/kg followed by a daily dose of 0.05 mg/kg results in a maximum blood concentration 3.17 hours after administration, an elimination half-life of 28.72 hours, and steady-state concentrations after 2 days.q Meloxicam is licensed for oral use in cats in the United Kingdom and Canada as well as other countries, but it is currently approved only for SC injection in cats in the United States.
In the present study, we detected greater efficacy of prednisolone versus prednisone in cats. The percentage increase in fluorescein concentration for the prednisolone-treated cats was significantly (P < 0.001) lower than that for the prednisone-treated and control cats at both 24 and 48 hours after paracentesis. Prednisone must be converted to the active metabolite, prednisolone, in the liver by the enzyme 11β–hydroxydehydrogenase. The bioavailability for orally administered prednisone and prednisolone tablets does not appear to differ significantly between dogs35,36 and humans,37,38 and the drugs can be used at the same dosage interchangeably. However, prednisolone is generally preferred over prednisone for use in cats. It is unclear whether the inferior pharmacokinetics of prednisone in cats are the result of decreased gastrointestinal absorption or decreased hepatic conversion of the drug. The poor pharmacokinetics of orally administered prednisone in cats of the present study may be the reason that prednisone did not significantly decrease breakdown of the BAB, compared with results for the control cats.
Although previous studies13,15 have confirmed the efficacy of acetylsalicylic acid in controlling or reducing intraocular inflammation in dogs with experimentally induced uveitis, acetylsalicylic acid did not significantly reduce the breakdown of the BAB, compared with results for the control group, in the cats of the present study. Acetylsalicylic acid was effective in reducing protein concentrations in the aqueous humor of dogs, compared with results for control dogs, in a study15 in which investigators used aqueocentesis and reverse cyclodialysis–induced inflammation. In another study13 in dogs, acetylsalicylic acid was found to be moderately effective in stabilizing the BAB after aqueocentesis.
Oral administration of prednisolone and meloxicam appeared to be more effective than oral administration of acetylsalicylic acid or prednisone for reducing the breakdown of the BAB after paracentesis-induced intraocular inflammation in clinically normal cats, as evaluated via fluorophotometry. Orally administered prednisolone or meloxicam may be appropriate choices when treating feline patients with anterior uveitis. Although it was not evaluated in this study, it is possible that there may be greater penetration of orally administered anti-inflammatory medications, and therefore possibly greater efficacy, in cats with naturally occurring intraocular inflammation as a result of an increase in BAB disruption that may accompany severe inflammation.
ABBREVIATIONS
| BAB | Blood-aqueous barrier |
| COX | Cyclooxygenase |
| PG | Prostaglandin |
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.
Payen G, Pepin-Richard C, Bonnaire Y, et al. Evaluation of aqueous concentration and ocular effects of firocoxib following aqueocentesis-induced anterior uveitis in dogs (abstr), in Proceedings. 42nd Annu Meet Am Coll Vet Ophthalmol 2011;57.
SL-14 Biomicroscope, Kowa Co Ltd, Tokyo, Japan.
BioGlo, HUB Pharmaceuticals LLC, Rancho Cucamonga, Calif.
TonoVet, Tiolat Ltd, Helsinki, Finland.
HEINE Omega 180 ophthalmoscope, HEINE Optotechnik, Herrsching, Germany.
Aspirin, Perrigo, Allergan, Mich.
Metacam, Boehringer Ingelheim Vetmedica Inc, St Joseph, Mo.
Qualitest, Huntsville, Ala.
Lloyd Inc, Shenandoah, Iowa.
Domitor, Orion Corp, Espoo, Finland.
VetaKet, IVX Animal Health Inc, St Joseph, Mo.
FM-2 Fluorotron Master, OcuMetrics Inc, Mountain View, Calif.
AK-Fluor 10%, Akorn Inc, Lake Forest, Ill.
Proc GLIMMIX, SAS, version 9.2, SAS Institute Inc, Cary, NC.
McKinnon NJ, Wiechert S, Wang C, et al. Evaluation of intravenous meloxicam in controlling experimental intraocular inflammation (abstr), in Proceedings. 42nd Annu Meet Am Coll Vet Ophthalmol 2011;46.
Dammgen J. The use of metacam 0.5 mg/mL oral suspension in cats with osteoarthritis (abstr), in Proceedings. Metacam Symp Arthritic Dis Cats 2007;19–20.
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