• View in gallery

    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).

  • View in gallery

    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.

  • 1. Stiles J, Townsend W. Feline ophthalmology. In: Gelatt KN, ed. Veterinary ophthalmology. 4th ed. Ames, Iowa: Blackwell Publishing, 2007;10951164.

    • Search Google Scholar
    • Export Citation
  • 2. Olivero D, Riis R, Dutton A. Feline lens displacement. A retrospective analysis of 345 cases. Prog Vet Comp Ophthalmol 1991; 1: 239244.

    • Search Google Scholar
    • Export Citation
  • 3. Tchernitchin AN, Tchernitchin N. Gluococorticoid localization by radioautography in the rabbit eye following systemic administration of 3H-dexamethasone. Experientia 1981; 37: 11201121.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4. Hernandez M, Weng E, Weinstein B, et al. Corneal-conjunctival uptake of topical 3H-dexamethasone in the rabbit eye. Invest Ophthalmol Vis Sci 1981; 20: 120123.

    • Search Google Scholar
    • Export Citation
  • 5. Schleimer R. The mechanism of anti-inflammatory steroid action in allergic disease. Annu Rev Pharmacol 1985; 85: 381412.

  • 6. Flower RJ. Lipocortin and the mechanism of action of the glucocorticoids. Br J Ophthalmol 1988; 94: 9871015.

  • 7. Goppelt-Struebe M, Wolter D, Resch K. Glucocorticoids inhibit prostaglandin synthesis not only at the level of phospholipase A2 but also at the level of cyclo-oxygenase/PG isomerase. Br J Pharmacol 1989; 98: 12871295.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8. Karalis K, Mastorakos G, Sano H, et al. Somatostatin may participate in the antiinflammatory actions of glucocorticoids. Endocrinology 1995; 136: 41334138.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9. van den Broek AH, Stafford WL. Epidermal and hepatic glucocorticoid receptors in cats and dogs. Res Vet Sci 1992; 52: 312315.

  • 10. Graham-Mize C, Rosser E, Hauptman J. Absorption, bioavailability and activity of prednisone and prednisolone in cats. In: Hillier A, Foster A, Kwochka K, eds. Advances in veterinary dermatology. Vol 5. Ames, Iowa: Blackwell, 2005;152.

    • Search Google Scholar
    • Export Citation
  • 11. Vane J, Botting R. Overview: mechanisms of action of anti-inflammatory drugs. In: Vane J, Botting J, Botting R, eds. Improved non-steroid anti-inflammatory drugs: COX2 enzyme inhibitors. Dordrecht, The Netherlands: Kluwer Academic Publishers, 1995;127.

    • Search Google Scholar
    • Export Citation
  • 12. Vane J, Bakhle Y, Botting R. Cyclooxygenases 1 and 2. Annu Rev Pharmacol 1998; 38: 97120.

  • 13. Ward D, Ferguson D, Ward S, et al. Comparison of the blood-aqueous barrier stabilizing effects of steroidal and nonsteroidal anti-inflammatory agents in the dog. Prog Vet Comp Ophthalmol 1992; 2: 117124.

    • Search Google Scholar
    • Export Citation
  • 14. Dziezyc J, Millichamp N, Smith W. Effect of flurbiprofen and corticosteroids on the ocular irritative response in dogs. Vet Comp Ophthalmol 1995; 5: 4245.

    • Search Google Scholar
    • Export Citation
  • 15. Brightman A, Helper L, Hoffman W. Effect of aspirin on aqueous protein values in the dog. J Am Anim Hosp Assoc 1981; 178: 572573.

  • 16. Krohne S, Blair M, Bingaman D, et al. Carprofen inhibition of flare in the dog measured by laser flare photometry. Vet Ophthalmol 1998; 1: 8184.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17. Gilmour MA, Lehenbauer TW. Comparison of tepoxalin, carprofen, and meloxicam for reducing intraocular inflammation in dogs. Am J Vet Res 2009; 70: 902907.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18. Pinard CL, Gauvin D, Moreau M, et al. Measurements of canine aqueous humor inflammatory mediators and the effect of carprofen following anterior chamber paracentesis. Vet Ophthalmol 2011; 14: 296303.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19. Jampel H, Brown A, Robets A, et al. Effect of paracentesis upon the blood-aqueous barrier of cynomolgus monkeys. Invest Ophthalmol Vis Sci 1992; 33: 165171.

    • Search Google Scholar
    • Export Citation
  • 20. Ward DA, Ferguson DC, Kaswan RL, et al. Fluorophotometric evaluation of experimental blood-aqueous barrier disruption in dogs. Am J Vet Res 1991; 52: 14331437.

    • Search Google Scholar
    • Export Citation
  • 21. Stjernschantz J, Uusitalo R, Palkama A. The aqueous proteins of the rat in normal eye and after aqueous withdrawal. Exp Eye Res 1973; 16: 215221.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22. Unger W, Cole D, Hammond B. Disruption of the blood aqueous barrier following paracentesis in the rabbit. Exp Eye Res 1975; 20: 255270.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23. Rankin AJ, Krohne SG, Glickman NW, et al. Laser flaremetric evaluation of experimentally induced blood-aqueous barrier disruption in cats. Am J Vet Res 2002; 63: 750756.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24. Okisaka S. Effects of paracentesis on the blood-aqueous barrier: a light and electron microscopic study on cynomolgus monkey. Invest Ophthalmol Vis Sci 1976; 15: 824834.

    • Search Google Scholar
    • Export Citation
  • 25. Bartels S, Pederson J, Gaasterland D, et al. Sites of breakdown of the blood-aqueous barrier after paracentesis of the rhesus monkey eye. Invest Ophthalmol Vis Sci 1979; 18: 10501060.

    • Search Google Scholar
    • Export Citation
  • 26. Cole DF, Unger WG. Prostaglandins as mediators for the responses of the eye to trauma. Exp Eye Res 1973; 17: 357368.

  • 27. Neufeld A, Jampol L, Sears M. Aspirin prevents the disruption of the blood-aqueous barrier in the rabbit eye. Nature 1972; 238: 158159.

  • 28. Graff G, Brady MT, Gamache DA, et al. Transient loss of prostaglandin synthetic capacity in rabbit iris-ciliary body following anterior chamber paracentesis. Ocul Immunol Inflamm 1998; 6: 227238.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29. Eakins K. Prostaglandin and non-prostaglandin mediated breakdown of the blood-aqueous barrier. Exp Eye Res 1977; 25: 483493.

  • 30. Millichamp N, Dziezyc J. Mediators of ocular inflammation. Prog Vet Comp Ophthalmol 1991; 1: 4158.

  • 31. Dziezyc J, Millichamp NJ, Keller CB, et al. Effects of prostaglandin F and leukotriene D4 on pupil size, intraocular pressure, and blood-aqueous barrier in dogs. Am J Vet Res 1992; 53: 13021304.

    • Search Google Scholar
    • Export Citation
  • 32. Hayasaka Y, Hayasaka S, Zhang X, et al. Effects of topical corticosteroids and nonsteroidal anti-inflammatory drugs on prostaglandin E2-induced aqueous flare elevation in pigmented rabbits. Ophthalmic Res 2003; 35: 341344.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 33. Regnier A, Whitley RD, Bernard P, et al. Effect of flunixin meglumine on the breakdown of the blood-aqueous barrier following paracentesis in the canine eye. J Ocul Pharmacol 1986; 2: 165170.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 34. Ward DA. Comparative efficacy of topically applied flurbiprofen, diclofenac, tolmetin, and suprofen for the treatment of experimentally induced blood-aqueous barrier disruption in dogs. Am J Vet Res 1996; 57: 875878.

    • Search Google Scholar
    • Export Citation
  • 35. Colburn W, Sibley C, Buller R. Comparative serum prednisone and prednisolone concentrations following prednisone and prednisolone administration to Beagle dogs. J Pharm Sci 1976; 65: 9971001.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 36. Tse F, Welling P. Prednisolone bioavailability in the dog. J Pharm Sci 1977; 66: 17511754.

  • 37. Begg EJ, Atkinson HC, Gianarakis N. The pharmacokinetics of corticosteroid agents. Med J Aust 1987; 146: 3741.

  • 38. Ferry J, Horvath A, Berkersky I, et al. Relative and absolute bioavailability of prednisone and prednisolone after separate oral and intravenous doses. J Clin Pharmacol 1989; 28: 8187.

    • Search Google Scholar
    • Export Citation

Advertisement

Effects of oral administration of anti-inflammatory medications on inhibition of paracentesis-induced blood-aqueous barrier breakdown in clinically normal cats

View More View Less
  • 1 Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506.
  • | 2 Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506.
  • | 3 Department of Statistics, College of Arts and Sciences, Kansas State University, Manhattan, KS 66506.
  • | 4 Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506.
  • | 5 Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506.

Abstract

Objective—To assess inhibitory effects of orally administered anti-inflammatory medications on paracentesis-induced intraocular inflammation in clinically normal cats.

Animals—30 clinically normal domestic shorthair cats.

Procedures—Cats were randomly assigned to a control group and 4 treatment groups. Cats in the treatment groups received an anti-inflammatory medication orally once daily at 7 am (acetylsalicylic acid [40.5 mg/cat], meloxicam [0.1 mg/kg], prednisone [5 mg/cat], or prednisolone [5 mg/cat]) for 5 days beginning 2 days before paracentesis-induced breakdown of the blood-aqueous barrier (BAB) and continuing until 2 days after paracentesis. Paracentesis of the anterior chamber was performed in 1 randomly selected eye of each cat. Fluorophotometry was performed in both eyes of each cat immediately before (time 0) and 6, 24, and 48 hours after paracentesis.

Results—At 24 and 48 hours after paracentesis, fluorescein concentration in the eye subjected to paracentesis in the cats receiving prednisolone was decreased, compared with that in the control cats. At 48 hours, a decrease in the fluorescein concentration was also apparent in the eye subjected to paracentesis in the cats receiving meloxicam, compared with that in the control cats. There was no evidence of treatment effects for acetylsalicylic acid or prednisone. There was no evidence of treatment effects in eyes not subjected to paracentesis.

Conclusions and Clinical Relevance—Orally administered prednisolone and meloxicam significantly decreased intraocular inflammation in clinically normal cats with paracentesis-induced BAB breakdown. Oral administration of prednisolone or meloxicam may be an effective treatment for cats with uveitis.

Abstract

Objective—To assess inhibitory effects of orally administered anti-inflammatory medications on paracentesis-induced intraocular inflammation in clinically normal cats.

Animals—30 clinically normal domestic shorthair cats.

Procedures—Cats were randomly assigned to a control group and 4 treatment groups. Cats in the treatment groups received an anti-inflammatory medication orally once daily at 7 am (acetylsalicylic acid [40.5 mg/cat], meloxicam [0.1 mg/kg], prednisone [5 mg/cat], or prednisolone [5 mg/cat]) for 5 days beginning 2 days before paracentesis-induced breakdown of the blood-aqueous barrier (BAB) and continuing until 2 days after paracentesis. Paracentesis of the anterior chamber was performed in 1 randomly selected eye of each cat. Fluorophotometry was performed in both eyes of each cat immediately before (time 0) and 6, 24, and 48 hours after paracentesis.

Results—At 24 and 48 hours after paracentesis, fluorescein concentration in the eye subjected to paracentesis in the cats receiving prednisolone was decreased, compared with that in the control cats. At 48 hours, a decrease in the fluorescein concentration was also apparent in the eye subjected to paracentesis in the cats receiving meloxicam, compared with that in the control cats. There was no evidence of treatment effects for acetylsalicylic acid or prednisone. There was no evidence of treatment effects in eyes not subjected to paracentesis.

Conclusions and Clinical Relevance—Orally administered prednisolone and meloxicam significantly decreased intraocular inflammation in clinically normal cats with paracentesis-induced BAB breakdown. Oral administration of prednisolone or meloxicam may be an effective treatment for cats with uveitis.

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, PGF, 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:

article image

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).

Figure 1—
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).

Figure 2—
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

a.

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.

b.

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.

c.

SL-14 Biomicroscope, Kowa Co Ltd, Tokyo, Japan.

d.

BioGlo, HUB Pharmaceuticals LLC, Rancho Cucamonga, Calif.

e.

TonoVet, Tiolat Ltd, Helsinki, Finland.

f.

HEINE Omega 180 ophthalmoscope, HEINE Optotechnik, Herrsching, Germany.

g.

Aspirin, Perrigo, Allergan, Mich.

h.

Metacam, Boehringer Ingelheim Vetmedica Inc, St Joseph, Mo.

i.

Qualitest, Huntsville, Ala.

j.

Lloyd Inc, Shenandoah, Iowa.

k.

Domitor, Orion Corp, Espoo, Finland.

l.

VetaKet, IVX Animal Health Inc, St Joseph, Mo.

m.

FM-2 Fluorotron Master, OcuMetrics Inc, Mountain View, Calif.

n.

AK-Fluor 10%, Akorn Inc, Lake Forest, Ill.

o.

Proc GLIMMIX, SAS, version 9.2, SAS Institute Inc, Cary, NC.

p.

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.

q.

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.

References

  • 1. Stiles J, Townsend W. Feline ophthalmology. In: Gelatt KN, ed. Veterinary ophthalmology. 4th ed. Ames, Iowa: Blackwell Publishing, 2007;10951164.

    • Search Google Scholar
    • Export Citation
  • 2. Olivero D, Riis R, Dutton A. Feline lens displacement. A retrospective analysis of 345 cases. Prog Vet Comp Ophthalmol 1991; 1: 239244.

    • Search Google Scholar
    • Export Citation
  • 3. Tchernitchin AN, Tchernitchin N. Gluococorticoid localization by radioautography in the rabbit eye following systemic administration of 3H-dexamethasone. Experientia 1981; 37: 11201121.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4. Hernandez M, Weng E, Weinstein B, et al. Corneal-conjunctival uptake of topical 3H-dexamethasone in the rabbit eye. Invest Ophthalmol Vis Sci 1981; 20: 120123.

    • Search Google Scholar
    • Export Citation
  • 5. Schleimer R. The mechanism of anti-inflammatory steroid action in allergic disease. Annu Rev Pharmacol 1985; 85: 381412.

  • 6. Flower RJ. Lipocortin and the mechanism of action of the glucocorticoids. Br J Ophthalmol 1988; 94: 9871015.

  • 7. Goppelt-Struebe M, Wolter D, Resch K. Glucocorticoids inhibit prostaglandin synthesis not only at the level of phospholipase A2 but also at the level of cyclo-oxygenase/PG isomerase. Br J Pharmacol 1989; 98: 12871295.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8. Karalis K, Mastorakos G, Sano H, et al. Somatostatin may participate in the antiinflammatory actions of glucocorticoids. Endocrinology 1995; 136: 41334138.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9. van den Broek AH, Stafford WL. Epidermal and hepatic glucocorticoid receptors in cats and dogs. Res Vet Sci 1992; 52: 312315.

  • 10. Graham-Mize C, Rosser E, Hauptman J. Absorption, bioavailability and activity of prednisone and prednisolone in cats. In: Hillier A, Foster A, Kwochka K, eds. Advances in veterinary dermatology. Vol 5. Ames, Iowa: Blackwell, 2005;152.

    • Search Google Scholar
    • Export Citation
  • 11. Vane J, Botting R. Overview: mechanisms of action of anti-inflammatory drugs. In: Vane J, Botting J, Botting R, eds. Improved non-steroid anti-inflammatory drugs: COX2 enzyme inhibitors. Dordrecht, The Netherlands: Kluwer Academic Publishers, 1995;127.

    • Search Google Scholar
    • Export Citation
  • 12. Vane J, Bakhle Y, Botting R. Cyclooxygenases 1 and 2. Annu Rev Pharmacol 1998; 38: 97120.

  • 13. Ward D, Ferguson D, Ward S, et al. Comparison of the blood-aqueous barrier stabilizing effects of steroidal and nonsteroidal anti-inflammatory agents in the dog. Prog Vet Comp Ophthalmol 1992; 2: 117124.

    • Search Google Scholar
    • Export Citation
  • 14. Dziezyc J, Millichamp N, Smith W. Effect of flurbiprofen and corticosteroids on the ocular irritative response in dogs. Vet Comp Ophthalmol 1995; 5: 4245.

    • Search Google Scholar
    • Export Citation
  • 15. Brightman A, Helper L, Hoffman W. Effect of aspirin on aqueous protein values in the dog. J Am Anim Hosp Assoc 1981; 178: 572573.

  • 16. Krohne S, Blair M, Bingaman D, et al. Carprofen inhibition of flare in the dog measured by laser flare photometry. Vet Ophthalmol 1998; 1: 8184.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17. Gilmour MA, Lehenbauer TW. Comparison of tepoxalin, carprofen, and meloxicam for reducing intraocular inflammation in dogs. Am J Vet Res 2009; 70: 902907.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18. Pinard CL, Gauvin D, Moreau M, et al. Measurements of canine aqueous humor inflammatory mediators and the effect of carprofen following anterior chamber paracentesis. Vet Ophthalmol 2011; 14: 296303.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19. Jampel H, Brown A, Robets A, et al. Effect of paracentesis upon the blood-aqueous barrier of cynomolgus monkeys. Invest Ophthalmol Vis Sci 1992; 33: 165171.

    • Search Google Scholar
    • Export Citation
  • 20. Ward DA, Ferguson DC, Kaswan RL, et al. Fluorophotometric evaluation of experimental blood-aqueous barrier disruption in dogs. Am J Vet Res 1991; 52: 14331437.

    • Search Google Scholar
    • Export Citation
  • 21. Stjernschantz J, Uusitalo R, Palkama A. The aqueous proteins of the rat in normal eye and after aqueous withdrawal. Exp Eye Res 1973; 16: 215221.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22. Unger W, Cole D, Hammond B. Disruption of the blood aqueous barrier following paracentesis in the rabbit. Exp Eye Res 1975; 20: 255270.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23. Rankin AJ, Krohne SG, Glickman NW, et al. Laser flaremetric evaluation of experimentally induced blood-aqueous barrier disruption in cats. Am J Vet Res 2002; 63: 750756.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24. Okisaka S. Effects of paracentesis on the blood-aqueous barrier: a light and electron microscopic study on cynomolgus monkey. Invest Ophthalmol Vis Sci 1976; 15: 824834.

    • Search Google Scholar
    • Export Citation
  • 25. Bartels S, Pederson J, Gaasterland D, et al. Sites of breakdown of the blood-aqueous barrier after paracentesis of the rhesus monkey eye. Invest Ophthalmol Vis Sci 1979; 18: 10501060.

    • Search Google Scholar
    • Export Citation
  • 26. Cole DF, Unger WG. Prostaglandins as mediators for the responses of the eye to trauma. Exp Eye Res 1973; 17: 357368.

  • 27. Neufeld A, Jampol L, Sears M. Aspirin prevents the disruption of the blood-aqueous barrier in the rabbit eye. Nature 1972; 238: 158159.

  • 28. Graff G, Brady MT, Gamache DA, et al. Transient loss of prostaglandin synthetic capacity in rabbit iris-ciliary body following anterior chamber paracentesis. Ocul Immunol Inflamm 1998; 6: 227238.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29. Eakins K. Prostaglandin and non-prostaglandin mediated breakdown of the blood-aqueous barrier. Exp Eye Res 1977; 25: 483493.

  • 30. Millichamp N, Dziezyc J. Mediators of ocular inflammation. Prog Vet Comp Ophthalmol 1991; 1: 4158.

  • 31. Dziezyc J, Millichamp NJ, Keller CB, et al. Effects of prostaglandin F and leukotriene D4 on pupil size, intraocular pressure, and blood-aqueous barrier in dogs. Am J Vet Res 1992; 53: 13021304.

    • Search Google Scholar
    • Export Citation
  • 32. Hayasaka Y, Hayasaka S, Zhang X, et al. Effects of topical corticosteroids and nonsteroidal anti-inflammatory drugs on prostaglandin E2-induced aqueous flare elevation in pigmented rabbits. Ophthalmic Res 2003; 35: 341344.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 33. Regnier A, Whitley RD, Bernard P, et al. Effect of flunixin meglumine on the breakdown of the blood-aqueous barrier following paracentesis in the canine eye. J Ocul Pharmacol 1986; 2: 165170.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 34. Ward DA. Comparative efficacy of topically applied flurbiprofen, diclofenac, tolmetin, and suprofen for the treatment of experimentally induced blood-aqueous barrier disruption in dogs. Am J Vet Res 1996; 57: 875878.

    • Search Google Scholar
    • Export Citation
  • 35. Colburn W, Sibley C, Buller R. Comparative serum prednisone and prednisolone concentrations following prednisone and prednisolone administration to Beagle dogs. J Pharm Sci 1976; 65: 9971001.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 36. Tse F, Welling P. Prednisolone bioavailability in the dog. J Pharm Sci 1977; 66: 17511754.

  • 37. Begg EJ, Atkinson HC, Gianarakis N. The pharmacokinetics of corticosteroid agents. Med J Aust 1987; 146: 3741.

  • 38. Ferry J, Horvath A, Berkersky I, et al. Relative and absolute bioavailability of prednisone and prednisolone after separate oral and intravenous doses. J Clin Pharmacol 1989; 28: 8187.

    • Search Google Scholar
    • Export Citation

Contributor Notes

Dr. Sebbag's present address is Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616.

Dr. Crumley's present address is Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104.

Dr. Allbaugh's present address is Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA 50011.

Supported by a Kansas State University Small Research Grant.

Presented in abstract form at the 43rd Annual American College of Veterinary Ophthalmology Meeting, Portland, Ore, October 2012.

Address correspondence to Dr. Rankin (arankin@vet.k-state.edu).