Anterior uveitis refers to inflammation affecting the anterior uvea, the rostral-most component of the vascular tunic of the eye. It is characterized by breakdown of the blood-aqueous barrier and other typical signs of inflammation. Anterior uveitis in dogs may result from a vast array of ocular and systemic disorders, including infection, neoplasia, trauma, and immune-mediated disease.1 In addition to causing pain, chronic or severe anterior uveitis may damage vision or the globe. Given its potentially dire consequences, anterior uveitis typically requires aggressive treatment with topically and systemically administered anti-inflammatory medications.
Corticosteroid medications form the mainstay of topical anti-inflammatory treatment for uveitis in both human and veterinary medicine.2,3 Aided by its good corneal penetration, 1% prednisolone acetate suspension is currently the most effective topical medication for moderate to severe anterior uveitis.1,4 Despite its efficacy, prednisolone acetate has some potentially important drawbacks, including those related to cost, compliance (frequent administration is required), administration (vigorous shaking of the suspension is required before instillation), and undesirable effects (eg, corneal lipid deposits).4–6 A need exists for topical corticosteroid medications that circumvent some of these drawbacks without compromising clinical efficacy.
Difluprednate is an extremely potent synthetic corticosteroid derived from prednisolone acetate. It differs from the parent compound in that fluorine moieties are substituted on carbons 6 and 9 of the prednisolone backbone and a butyrate is positioned on carbon 7.7,8 These substitutions act to improve corneal penetration and potency, respectively, compared with the effects of prednisolone acetate.8,9 Difluprednate was approved in 2008 by the US FDA for the treatment of postoperative ocular inflammation and pain in humans, and it was subsequently approved for the treatment of endogenous uveitis.9 Several clinical studies5,10–20 in humans have shown the efficacy of topically applied difluprednate for controlling various forms of uveitis and treatment of other intraocular diseases. Although studies6,14,20,21 have shown similar safety and efficacy between difluprednate and prednisolone acetate, several beneficial attributes have been ascribed to ophthalmic difluprednate, compared with prednisolone acetate, which notably include less frequent administration, an emulsion formulation that does not require shaking before instillation, dose uniformity, a preservative with potentially less irritation, and efficacy for treating posterior segment disease in humans.
Anterior chamber paracentesis (ie, aqueocentesis) refers to the removal of fluid from the anterior chamber of the eye for diagnostic or therapeutic purposes.22,23 The technique is performed by inserting a fine hypodermic needle into the anterior chamber through the perilimbal aspect of the cornea, with care taken to avoid contact with and trauma to intraocular tissues.24 Aqueocentesis induces intraocular inflammation in the treated eye, with larger needles causing a more pronounced anterior uveitis.23 The predictable intraocular inflammation caused by aqueocentesis has enabled this technique to be useful in research settings, particularly for the evaluation of medications used to treat uveitis.25,26
The blood-aqueous barrier is formed by the endothelium of the iris blood vessels, the nonpigmented layer of the ciliary epithelium, and the posterior pigmented epithelium of the iris.27 These structures typically prevent substances in the blood from entering the eye. When the barrier is disrupted, the blood vessels dilate and plasma proteins leak into the aqueous humor.28 Although a semiquantitative method for grading of the aqueous flare is most commonly used to assess the degree of blood-aqueous barrier breakdown in clinical settings, objective techniques have been described, including fluorophotometry, laser flare photometry, and measurement of aqueous humor protein concentrations. Anterior chamber fluorophotometry is used to noninvasively measure the fluorescein concentration in the anterior chamber after systemic administration of fluorescein. Greater amounts of fluorescein entering the anterior chamber indicate greater permeability of the blood-aqueous barrier; therefore, fluorophotometry can be used to quantify the degree of disruption of the blood-aqueous barrier.
The purpose of the study reported here was to evaluate the efficacy of topical administration of 0.05% difluprednate ophthalmic emulsion and 1% prednisolone acetate ophthalmic suspension for limiting the severity and duration of anterior uveitis. Efficacy was evaluated by use of a well-characterized fluorophotometric method for assessing the breakdown of the blood-aqueous barrier in dogs.22,23 Although investigators of a recent investigation29 found topically administered difluprednate superior to betamethasone for minimizing aqueous humor protein and prostaglandin E2 concentrations 1 hour after paracentesis, we are unaware of any veterinary studies in which topically administered difluprednate has been compared with topically administered prednisolone acetate for the control of iatrogenic or acquired uveitis in companion animals.
Materials and Methods
Animals
Thirty-four healthy young (1 to 2 years old) sexually intact Beagles (19 males and 15 females) with a mean body weight of 12.8 kg were included in the study. The dogs were group housed in kennels and owned by Iowa State University. Ambient temperature was maintained at 18.3° to 23.9°C, and lights were automatically turned on at 6 am and off at 6 pm. A complete ophthalmic examination, including fluorescein staining, tonometry, slit-lamp evaluation, and fundoscopy, was performed on each dog prior to inclusion in the study. None of the dogs had any ophthalmic abnormalities. Dogs were monitored daily throughout the study by veterinary personnel. All procedures in the study were approved by the Institutional Animal Care and Use Committee at Iowa State University.
Topical corticosteroid medications
Dogs were allocated to a control group (ophthalmic saline [0.9% NaCl] solution administered to both eyes 4 times/d; n = 8) and 4 treatment groups. Dogs in the treatment groups received 1 drop of 1% prednisolone acetate ophthalmic suspensiona in both eyes 2 times/d (group P2; n = 6) or 4 times/d (group P4; 7) or 1 drop of 0.05% difluprednate ophthalmic emulsionb in both eyes 2 times/d (group D2; 6) or 4 times/d (group D4; 7). Dogs in groups P2 and D2 also received topically administered ophthalmic saline solution twice daily; thus, every dog received 1 drop in both eyes 4 times/d. Investigators were careful to vigorously shake the bottle containing prednisolone acetate before each administration. Eye drops were topically administered to all dogs for 5 consecutive days. Days 1 and 2 consisted of only topical administration of eye drops, with aqueocentesis and fluorophotometry performed on day 3. Owing to logistics of the study, the investigators were aware of the treatment administered to each dog.
Aqueocentesis
On day 3, controlled anterior chamber paracentesis was performed in 1 randomly selected eye (determined by coin flip). A catheter was placed in a peripheral vein, and dogs were sedated with butorphanol tartrate (0.3 mg/kg, IV) and dexmedetomidine hydrochloride (2.5 μg/kg, IV); additional dexmedetomidine was administered as needed to maintain sedation. Topical anesthetic (0.5% proparacaine) and diluted povidone-iodine ophthalmic solution were applied to the eye, and aqueocentesis was performed by use of a 30-gauge, 0.5-inch needle attached to a 0.3-mL U-100 insulin syringe. The globe undergoing aqueocentesis was stabilized with fine-toothed Bishop-Harmon forceps, the needle was inserted through the dorsolateral aspect of the limbal cornea, and 0.1 mL of aqueous humor was slowly removed with the insulin syringe over a period of 5 seconds. Care was taken to avoid contact of the needle tip with the iris, lens, and adjacent corneal endothelium. The needle bevel was transiently paused within the corneal stroma during needle removal to limit continued egress of aqueous humor through the needle tract.
Fluorophotometry
An automated fluorophotometer with an anterior chamber adapterc was used to perform fluorophotometry on the central ocular axis of both eyes of each study dog on day 3 (immediately before [baseline] and 20 minutes after aqueocentesis) as well as 24 and 48 hours after aqueocentesis. Dogs were sedated with butorphanol and dexmedetomidine for fluorophotometry. A solution of 10% sodium fluoresceind (20 mg/kg) was administered IV. Automated fluorophotometry was performed between 30 and 90 minutes after IV administration of sodium fluorescein, as has been previously advocated.22 Dogs were positioned in sternal recumbency with the head manually stabilized and the eyelids held open by digital manipulation. The eye then was aligned in front of the scanner. For consistency, the right eye was always scanned first, followed immediately by the left eye, with no more than 3 minutes elapsing between scanning of both eyes at each time point. Relative fluorescence was calculated for each session. This value was defined as fluorescence of the eye that had undergone aqueocentesis divided by fluorescence of the contralateral eye.
Statistical analysis
Gamma regression was conducted by use of a generalized mixed model procedure.e Gamma mixed-effects regression (with logarithmic link) was used for analysis because the data were skewed to the right, which resulted in a skewed distribution of errors in parametric testing. Transformation of the dependent variable would also have been an option, but it was preferable to compare the logarithms of means rather than to transform the data first and then compare means of the logarithms. In addition, there was no indication that transformation was beneficial. The regression coefficients were interpreted as logarithmic; an inverse logarithm was used to convert the coefficients to units of the dependent variable (ie, RF). Time and treatment groups were treated as fixed effects, whereas dog (ie, subject) was treated as a random effect. Predictor variables included time point, drug, and dose. Pearson residuals from the γ regression were normally distributed (as confirmed by examination of Q-Q plots), with some deviation from normality at higher predicted values, which confirmed the model selection. Residuals were also reasonably homoscedastic, as confirmed by a scatter plot of residuals across the range of predicted values.
In addition to testing the predictors within the mixed model, pairwise comparisons of estimated marginal means for each time and treatment combination were performed. Bonferroni adjustment (α = 0.05) was used for post hoc pairwise comparisons at time points within and between treatment groups. Values of P < 0.05 were considered significant.
Results
For the overall mixed model, time (P < 0.001), treatment group (P = 0.002), and the time-by-treatment group interaction (P < 0.001) significantly predicted RF values. Time and treatment group were important predictors of RF, whereas their interaction also provided additional prediction beyond the main effects, which suggested that the relationship between time and fluorescence depended on treatment group.
The fixed effects of time and treatment, when examined individually, had significant differences. For time, the measurement at 20 minutes after aqueocentesis was significantly (P = 0.001) increased, compared with the baseline measurement, which reflected the initial breakdown of the blood-aqueous barrier after the procedure. The effect of treatment on RF independent of time was significant (P = 0.038) only for group P4.
Analysis of the time-by-treatment group interaction revealed several differences at individual time points (Figure 1). At 20 minutes after aqueocentesis, there were no significant differences between the 4 treatment groups and the control group, although the small sample size and large variability in the inflammation response may have made it difficult to detect differences at this time point. At 24 hours, the RF was significantly lower for groups D2 (P = 0.025) and P4 (P < 0.001) than for the control group; however, the RF for groups P2 and D4 did not differ significantly from the RF for the control group (P = 0.105 and P = 0.224, respectively). At 48 hours, only group P4 had a significantly (P < 0.001) lower RF than did the control group.
Mean RF of eyes measured before (baseline) and after aqueocentesis for dogs receiving ophthalmic saline (0.9% NaCl) solution administered to both eyes 4 times/d (n = 8; plus signs), 1 drop of 1% prednisolone acetate ophthalmic suspension to both eyes 2 times/d (group P2; 6; diamonds) or 4 times/d (group P4; 7; triangles), or 1 drop of 0.05% difluprednate ophthalmic emulsion to both eyes 2 times/d (group D2; 6; circles) or 4 times/d (group D4; 7; squares). Dogs in groups P2 and D2 also received topically administered ophthalmic saline solution twice daily; thus, every dog received 1 drop in both eyes 4 times/d for 5 days. Aqueocentesis was performed in 1 randomly selected eye of each dog on day 3.
Citation: American Journal of Veterinary Research 81, 3; 10.2460/ajvr.81.3.260
To determine when the RF returned to baseline values, pairwise time point comparisons were investigated within each treatment group, with sequential Bonferroni adjustment (α = 0.05). For the control group, the RF did not return to baseline values during the study because the RF was significantly higher at 20 minutes (P = 0.006), 24 hours (P < 0.001), and 48 hours (P < 0.001) after aqueocentesis, compared with the RF at baseline. For groups D2, P2, and P4, no significant changes in mean RF were found, despite apparent changes over time. Group D4 had a significant (P = 0.029) increase in RF at 20 minutes after aqueocentesis, compared with the baseline value. The RF at 20 minutes after aqueocentesis was also significantly (P = 0.029) greater than the RF at 48 hours after aqueocentesis, although the baseline RF did not differ from the RF at 24 and 48 hours after aqueocentesis. No significant (P = 0.064) difference was identified for group D4 in the RF measured at 20 minutes and 24 hours.
Post hoc testing was conducted with additional pairwise testing to determine differences from baseline values as well as differences among groups at the various time points. No significant differences were identified among groups at baseline, and despite differences in mean RF at 20 minutes after aqueocentesis, there were also no significant differences among the 4 treatment groups at this time point. High variability in the RF at 20 minutes after aqueocentesis resulted in extremely broad estimates for the mean confidence intervals, but variability was lower by 24 hours after aqueocentesis. Although the RF for group D4 did not differ significantly (P = 0.070) from that of the control group at 24 hours, the RF at 24 hours was significantly lower for groups D2 (P = 0.001), P2 (P = 0.004), and P4 (P = 0.012), compared with the RF for the control group. There were no significant differences among the 4 treatment groups at this time point. At the final 48-hour measurement, the RF was significantly lower for groups D2 (P = 0.005), D4 (P = 0.037), P2 (P = 0.004), and P4 (P = 0.037), compared with the RF for the control group; however, there were no significant differences among the 4 treatment groups (Table 1).
Values of central tendency and variability for the RF of eyes of dogs in 5 treatment groups* before (baseline) and at various points after aqueocentesis in 1 randomly selected eye.
| Time | Group | Mean | Median | SD | Interquartile range |
|---|---|---|---|---|---|
| Baseline | Control | 0.880 | 0.965 | 0.199 | 0.530 |
| D2 | 1.072 | 1.040 | 0.121 | 0.310 | |
| D4 | 1.066 | 1.050 | 0.194 | 0.490 | |
| P2 | 0.972 | 1.010 | 0.096 | 0.260 | |
| P4 | 1.029 | 1.030 | 0.121 | 0.360 | |
| 20 min | Control | 4.628 | 4.100 | 2.684 | 8.590 |
| D2 | 2.748 | 2.735 | 1.006 | 2.920 | |
| D4 | 4.233 | 2.780 | 3.502 | 8.570 | |
| P2 | 2.948 | 2.455 | 1.664 | 4.060 | |
| P4 | 2.401 | 1.790 | 1.933 | 5.660 | |
| 24 h | Control | 2.665 | 1.945 | 1.331 | 3.520 |
| D2 | 1.010 | 1.285 | 0.476 | 1.050 | |
| D4 | 1.534 | 1.460 | 0.225 | 0.640 | |
| P2 | 1.165 | 1.220 | 0.366 | 0.940 | |
| P4 | 1.303 | 1.310 | 0.153 | 0.380 | |
| 48 h | Control | 2.100 | 2.055 | 1.227 | 3.810 |
| D2 | 1.025 | 1.035 | 0.116 | 0.360 | |
| D4 | 1.197 | 1.220 | 0.133 | 0.370 | |
| P2 | 1.013 | 1.000 | 0.158 | 0.430 | |
| P4 | 1.204 | 1.210 | 0.160 | 0.410 |
Dogs received ophthalmic saline 0.9% NaCl solution] administered to both eyes 4 times/d (control group; n = 8), 1 drop of 1% prednisolone acetate ophthalmic suspension to both eyes 2 times/d (group P2; 6) or 4 times/d (group P4; 7), or 1 drop of 0.05% difluprednate ophthalmic emulsion to both eyes 2 times/d (group D2; 6) or 4 times/d (group D4; 7). Dogs in groups P2 and D2 also received topically administered ophthalmic saline solution twice daily; thus, every dog received 1 drop in both eyes 4 times/d for 5 days.
Interquartile range = 75th–25th percentile.
Discussion
All 4 treatments (0.05% difluprednate or 1% prednisolone acetate administered 2 or 4 times/d) were effective for reducing RF of the eyes of dogs relative to that in the control group, regardless of the drug or frequency of administration. Interpretation of the mixed model was limited because of the small sample numbers and high variability, particularly for interaction effects wherein there were extremely small sample numbers for time-by-treatment group combinations. Because treatment groups D2 and P4 had better performance (ie, a significantly lower RF than for the control group) than did groups D4 and P2, as determined on the basis of interaction effects, additional studies are needed to determine whether these drug and frequency of administration combinations did have better performance or whether the treatments will be more consistently effective in a larger study.
Additional pairwise testing that relaxed some of the strict requirements inherent to the γ regression yielded results suggestive of largely equivalent efficacy among the treatment groups. Under these testing parameters, all treatment groups, except group D4, had less anterior uveitis 24 hours after aqueocentesis, compared with findings for the control group, and all treatment groups had less anterior uveitis 48 hours after aqueocentesis than did the control group. Furthermore, there were no differences among the 4 treatment groups at any time point. These results suggested similar efficacy between ophthalmic 0.05% difluprednate and 1% prednisolone acetate administered topically at the 2 dosing frequencies for controlling breakdown of the blood-aqueous barrier in dogs caused by aqueocentesis.
The mean RF did not differ significantly over time for most of the treatment groups, with all groups having an increased mean RF 20 minutes after aqueocentesis with a subsequent return to baseline values. Group D4 was the only treatment group in which mean RF changed significantly over time, which was likely secondary to a significantly higher mean RF than for the other treatment groups at 20 minutes after aqueocentesis, but then returned to baseline values by 24 hours after aqueocentesis. The reason the mean RF did not differ over time for the other treatment groups may have been attributable to the small sample size and adjustment for multiple comparisons. Because P values for the analysis of the postprocedure time points and baseline values were close to 0.05 (after adjustment), additional research is needed to determine whether these differences would be significant with a larger sample size.
Results of the present study suggested similar drug efficacy, so prednisolone acetate may be the more cost-effective option for treating anterior uveitis at this time, given the current financial disparity between these medications (0.05% difluprednate is approximately 4.5 times as expensive as 1% prednisolone acetate). Because the anticipated cost of difluprednate will decrease in the future when the patent expires, the financial aspects may become negligible, and similar efficacy of difluprednate may be most desirable given the aforementioned benefits (emulsion, dose uniformity, less irritating preservative, and potential posterior segment penetration).6,14,20,21 Although investigators in a recent study29 found that difluprednate was superior to betamethasone sodium phosphate ophthalmic solution when used immediately after aqueocentesis, their invasive model for measuring breakdown of the blood-aqueous barrier on the basis of protein and prostaglandin E2 concentrations in the aqueous humor allowed for only 1 follow-up time point at 60 minutes after aqueocentesis. Thus, there was no serial assessment of difluprednate treatment frequency, and no clinical recommendation could be made.
A study5 of anterior uveitis in human patients revealed noninferiority of 0.05% difluprednate administered less frequently than 1% prednisolone acetate. The small sample size and wide variation in RF in the present study largely precluded such useful comparisons, although both treatments D2 and P4 did control breakdown of the anterior chamber blood-aqueous barrier better than did the control treatment at 24 hours after aqueocentesis according to the statistical model with strict requirements. A larger sample size might reveal significant differences in mean RF between each treatment group and the control group at the various time points after aqueocentesis.
The high degree of variance in anterior chamber fluorescence values as measured by automated fluorophotometry yielded high SDs and made it difficult to discern subtle differences in anterior uveitis control. This latter drawback may be inherent to fluorophotometry, owing to the high sensitivity of the technique and natural variation in permeability of the blood-aqueous barrier among dogs.22 An additional limitation of the study reported here was the inability to mask investigators to the treatments administered to each dog for logistical reasons. Despite these considerations, the present study effectively demonstrated the apparent clinical equivalence of topically administered difluprednate and prednisolone acetate for controlling breakdown of the blood-aqueous barrier.
Additional research is warranted to evaluate the comparative efficacy of these 2 topical medications for controlling other forms of uveitis in dogs (eg, idiopathic uveitis or postoperative uveitis) and to assess their relative complications (eg, corneal stromal deposits). Similar evaluation is necessary in other species because anterior uveitis is commonly described in both horses and cats, with topical prednisolone acetate frequently prescribed for treatment. Given the recognized risks for complications with topical prednisolone acetate administration in these species (eg, possible corticosteroid-induced ocular hypertension in cats, herpetic recrudescence in cats, and fungal keratitis in horses), clinical value exists in evaluating difluprednate as a therapeutic alternative, although it is reasonable to anticipate similar corticosteroid-associated complications. However, caretakers can find it challenging to administer topical medications to cats and horses, and such administration can be stressful to the patients. The lower dosing frequency for difluprednate, as possibly suggested in the present study on the basis of results for the time-by-treatment group interaction and determined for human patients with uveitis, might improve client or patient compliance and clinical outcome.14 Evaluating the risk of corneal deposits in veterinary species after long-term treatment with difluprednate would also be clinically useful. Finally, the efficacy of topical difluprednate for ameliorating posterior segment inflammation is deserving of further study given promising results from recent studies17,20 in humans.
Results of the present study supported the clinical equivalence of 0.05% difluprednate emulsion and 1% prednisolone acetate suspension in healthy young dogs with experimentally induced anterior uveitis. All treatments were effective for reducing aqueocentesis-induced anterior uveitis in these dogs, regardless of the drug or dosing frequency. Given the findings, 0.05% difluprednate might be a clinically useful alternative to 1% prednisolone acetate for the treatment of anterior uveitis in dogs. Additional research is warranted and may reveal additional clinical indications for the use of 0.05% difluprednate in veterinary medicine.
Acknowledgments
Supported in part by a Veterinary Clinical Sciences Research Incentive Grant through the College of Veterinary Medicine at Iowa State University.
The authors declare that there were no conflicts of interest.
Presented in abstract form at the 47th Annual Conference of the American College of Veterinary Ophthalmologists, Monterey, Calif, October 2016.
The authors thank Brian Harward for assistance with the statistical analysis.
ABBREVIATIONS
| RF | Relative fluorescence |
Footnotes
Sandoz, Princeton, NJ.
Durezol, Alcon, Fort Worth, Tex.
Fluorotron Master, OcuMetrics, Mountain View, Calif.
AK-Fluor, Akorn Inc, Lake Forest, Ill.
SPSS Inc, Chicago, Ill.
References
1. Stiles J, Townsend W. Diseases and surgery of the canine anterior uvea. In: Gelatt KN, ed. Veterinary ophthalmology. 5th ed. Ames, Iowa: Blackwell Publishing, 2013;1146–1198.
2. Prete M, Dammaco R, Fatone MC, et al. Autoimmune uveitis: clinical, pathogenetic, and therapeutic features. Clin Exp Med 2016;16:125–136.
3. Townsend WM. Canine and feline uveitis. Vet Clin North Am Small Anim Pract 2008;38:323–346.
4. Rankin A. Clinical pharmacology and therapeutics: anti-inflammatory and immunosuppressant drugs. In: Gelatt KN, ed. Veterinary ophthalmology. 5th ed. Ames, Iowa: Blackwell Publishing, 2013;407–422.
5. Foster CS, Davanzo R, Flynn TE, et al. Durezol (difluprednate ophthalmic emulsion 0.05%) compared with pred forte 1% ophthalmic suspension in the treatment of endogenous anterior uveitis. J Ocul Pharmacol Ther 2010;26:475–483.
6. Stringer W, Bryant R. Dose uniformity of topical corticosteroid preparations: difluprednate ophthalmic emulsion 0.05% versus branded and generic prednisolone acetate ophthalmic suspension 1%. Clin Ophthalmol 2010;4:1119–1124.
7. Takeda K, Arase S, Takahashi S. Side effects of topical corticosteroids and their prevention. Drugs 1988;36:15–23.
8. Bikowski J, Pillai R, Shroot B. The position not the presence of the halogen in corticosteroids influences potency and side effects. J Drugs Dermatol 2006;5:125–130.
9. Mulki L, Foster CS. Difluprednate for inflammatory eye disorders. Drugs Today (Barc) 2011;47:327–333.
10. Korenfeld MS, Silverstein SM, Cooke DL, et al. Difluprednate ophthalmic emulsion 0.05% for postoperative inflammation and pain. J Cataract Refract Surg 2009;35:26–34.
11. Donnenfeld ED. Difluprednate for the prevention of ocular inflammation postsurgery: an update. Clin Ophthalmol 2011;5:811–816.
12. Donnenfeld ED, Holland EJ, Solomon KD, et al. A multicenter randomized controlled fellow eye trial of pulse-dosed difluprednate 0.05% versus prednisolone acetate 1% in cataract surgery. Am J Ophthalmol 2011;152:609–617.e1.
13. Chalam K, Khetpal V, Patel CJ. Spectral domain optical coherence tomography documented rapid resolution of pseudophakic cystoid macular edema with topical difluprednate. Clin Ophthalmol 2012;6:155–158.
14. Sheppard JD, Toyos MM, Kempen JH, et al. Difluprednate 0.05% versus prednisolone acetate 1% for endogenous anterior uveitis: a phase III, multicenter, randomized study. Invest Ophthalmol Vis Sci 2014;55:2993–3002.
15. Asahi MG, Bobarnac Dogaru GL, Onishi SM, et al. Strong topical steroid, NSAID, and carbonic anhydrase inhibitor cocktail for treatment of cystoid macular edema. Int Med Case Rep J 2015;8:305–312.
16. Onishi SM, Asahi MG, Chou C, et al. Topical difluprednate for the treatment of Harada's disease. Clin Ophthalmol 2015;9:157–167.
17. Lu S, Taban M. Topical difluprednate for treatment of serous retinal detachment and panuveitis associated with Vogt-Koyanagi-Harada disease. Digit J Ophthalmol 2016;22:54–57.
18. Kusne Y, Kang P, Fintelmann RE. A retrospective analysis of intraocular pressure changes after cataract surgery with the use of prednisolone acetate 1% versus difluprednate 0.05%. Clin Ophthalmol 2016;10:2329–2336.
19. Wilson ME, O'Halloran H, VanderVeen D, et al. Difluprednate versus prednisolone acetate for inflammation following cataract surgery in pediatric patients: a randomized safety and efficacy study. Eye (Lond) 2016;30:1187–1194.
20. Feiler DL, Srivastava SK, Pichi F, et al. Resolution of noninfectious uveitic cystoid macular edema with topical difluprednate. Retina 2017;37:844–850.
21. Tripathi BJ, Tripathi RC, Kolli SP. Cytotoxicity of ophthalmic preservatives on human corneal epithelium. Lens Eye Toxic Res 1992;9:361–375.
22. Ward DA, Ferguson DC, Kaswan RL, et al. Fluorometric evaluation of experimental blood-aqueous barrier disruption in dogs. Am J Vet Res 1991;52:1433–1437.
23. Allbaugh RA, Roush JK, Rankin AJ, et al. Fluorophotometric and tonometric evaluation of ocular effects following aqueocentesis performed with needles of various sizes in dogs. Am J Vet Res 2011;72:556–561.
24. May DR, Noll FG. An improved approach to aqueous paracentesis. Ophthalmic Surg 1988;19:821–822.
25. Rankin AJ, Khrone SG, Stiles J. Evaluation of four drugs for inhibition of paracentesis-induced blood-aqueous humor barrier breakdown in cats. Am J Vet Res 2011;72:826–832.
26. Rankin AJ, Sebbag L, Bello NM, et al. Effects of oral administration of anti-inflammatory medications on inhibition of paracentesis-induced blood-aqueous barrier breakdown in clinically normal cats. Am J Vet Res 2013;74:262–267.
27. Freddo TF. Shifting the paradigm of the blood-aqueous barrier. Exp Eye Res 2001;73:581–592.
28. Butler JM, Unger WG, Grierson I. Recent experimental studies on the blood-aqueous barrier: the anatomical basis of the response to injury. Eye (Lond) 1988;2:S213–S220.
29. Sato K, Iwasake K, Nagai N, et al. Comparison of early post-treatment effects of two steroidal anti-inflammatory ophthalmic drugs on the ocular inflammatory response induced by paracentesis in healthy canine eyes. Vet Ophthalmol 2019;22:607–613.
