Treatment of Secondary Full-Thickness Macular Holes with Topical Therapy.

PURPOSE: To report the outcomes of secondary full-thickness macular holes (FTMHs) treated with topical therapy. DESIGN: Retrospective case series. PARTICIPANTS: Patients with secondary FTHMs initially treated with topical therapy in a referral-based retina practice. METHODS: Patients evaluated between April 14, 2016, and February 22, 2019, for secondary FTMHs who underwent topical therapy were included. Patient demographics, ocular history, type of drops used, duration of therapy, and duration of follow-up as well as anatomic features on OCT, including hole diameter and presence of vitreomacular traction, epiretinal membrane (ERM), and cystoid macular edema (CME), were analyzed. MAIN OUTCOME MEASURES: Closure rate of FTMHs and change in visual acuity. RESULTS: A total of 123 FTMHs were seen during the study, of which 12 were secondary macular holes. Topical therapy was attempted in 9 eyes (8 patients). Six of these 9 FTMHs were associated with prior retinal detachment (RD). Previous pars plana vitrectomy (PPV) had been performed in 3 eyes (1 for RD, 2 for ERM). One eye had vitreomacular traction and a remote history of blunt trauma. Average initial hole diameter was 79.6 µm (range, 44-132 µm). Average follow-up was 53 weeks (range, 5-153 weeks). All FTMHs had some element of ERM and CME. All patients received difluprednate with the addition of a topical carbonic anhydrase inhibitor in 6 eyes and nonsteroidal anti-inflammatory drug (NSAID) drops in 2 eyes. Eight eyes (89%) achieved successful hole closure and resolution of CME with concurrent improvement in visual acuity after an average of 6 weeks of therapy (range, 2-19 weeks). Average vision among all 9 eyes improved from 0.69 to 0.37 logarithm of the minimum angle of resolution (Snellen equivalent from approximately 20/100 to approximately 20/50). No episodes of corneal melts or ulcers occurred. One patient showed mild keratopathy and elevation of intraocular pressure with topical NSAID and steroid therapy that resolved when the topical NSAID was stopped and difluprednate was tapered down to once weekly. CONCLUSIONS: Topical therapy achieved high closure rates in secondary FTMH and can be considered as an initial treatment option especially in those with small holes and CME.

Outcomes of difluprednate treatment for corneal graft rejection.

OBJECTIVE: To evaluate outcomes of difluprednate treatment in penetrating keratoplasty (PK) graft rejection DESIGN: Retrospective, interventional case series. PARTICIPANTS: Patients treated with difluprednate for acute endothelial rejection after PK. METHODS: Data were collected on resolution of rejection, treatment regimen used, best spectacle-corrected visual acuity (BSCVA), intraocular pressure (IOP), and side effects. MAIN OUTCOME MEASURE: rate of rejection resolution. SECONDARY OUTCOME MEASURES: BSCVA change and side-effect rates. RESULTS: Thirty-three eyes of 33 patients aged 56.7 ± 17.9 years were included. Twenty-four grafts (72.7%) were high-risk grafts. Complete treatment success was achieved in 19 of 33 grafts (57.6%) over 1.8 ± 1.4 months. Non-high-risk grafts had 100% treatment success rate (9 of 9 grafts). All treatment failures occurred in high-risk grafts, which had a significantly lower treatment success rate of 41.7% (10 of 24 grafts) compared with non-high-risk grafts (p = 0.004). Mean BSCVA in the treatment-success group improved from 1.07 ± 0.74 logMAR at the time of rejection to 0.44 ± 0.33 logMAR after treatment (p = 0.003). High-dose difluprednate (every 1-3 hours while awake) was used in 93.9% of eyes. IOP elevation and toxic epitheliopathy were each seen in 21.2% of patients. IOP elevation was managed successfully with topical medication and/or difluprednate discontinuation. Epitheliopathy resolved in all cases after completion of difluprednate treatment, except for one case complicated by an infected ulcer. CONCLUSIONS: High-dose difluprednate was effective in treating PK graft rejection, especially in non-high-risk grafts. Adjunct treatment may be required in high-risk grafts. Monitoring for IOP elevation and for toxic epitheliopathy is recommended.

Management of cataract in the setting of uveitis: a review of the current literature.

PURPOSE OF REVIEW: This review aims to cover the preoperative planning, intraoperative considerations, and postoperative management that aids in successful outcomes of patients with cataract and uveitis. Disease-specific management and pediatric management will also be addressed. RECENT FINDINGS: Dexamethasone implants appear to be a safe and effective addition to standard steroid treatment in decreasing the incidence of postoperative cystoid macular edema (CME). Intravitreal steroids and topical difluprednate have shown utility in CME treatment. SUMMARY: Cataract surgery in eyes with uveitis is generally safe and effective if inflammation is well controlled; however, complication rates are still higher than in eyes without uveitis. Future investigations should delineate outcomes for eyes with different etiologies of uveitis, and further research is needed to adequately control inflammation and avoid postoperative complications.

Understanding drug distribution and release in ophthalmic emulsions through quantitative evaluation of formulation-associated variables.

Establishing bioequivalence (BE) of ophthalmic emulsions in the absence of in vivo data is challenging. In these emulsions, drug release is a complex process due to drug distribution among various phases which are difficult to characterize. The objective of this study is to investigate the process of drug distribution and mechanism of drug release in the context of formulation-associated variables. A previously reported kinetic method for determining drug partitioning was used to quantitatively evaluate the drug distribution within a simplified biphasic (emulsion) system employing cyclosporine and difluprednate as model drugs. The impacts of formulation variables, such as the amount of polysorbate 80, glycerin, and carbomer copolymer as well as the area of oil-water interface were investigated. Polysorbate 80 was found to have the greatest influence on the drug distribution. It enhanced both the rate and extent of the drug distribution from oil to aqueous phase. Glycerin was found to slightly reduce the rate and extent of drug distribution of cyclosporine into the aqueous phase, probably by suppressing the solubilization capability of the micelles. Carbomer slowed down the diffusion of drug into the oil phase and shifted the equilibrium drug distribution towards the aqueous phase. Furthermore, increase in the interfacial area significantly increased the rate of drug diffusion across the oil-aqueous interface but had negligible effect on the extent of drug distribution. It is noteworthy that the experimental setup utilized a planar interface rather than an interface with curvature, which may have slightly underestimated the influence of globule size on equilibrium drug distribution. The findings of this study give insight into the drug distribution and diffusion in complex ophthalmic emulsions and assist with formulation design as well as development of in vitro methods to support BE assessment of ophthalmic emulsions.

Difluprednate 0.05% versus Prednisolone Acetate 1% for Endogenous Anterior Uveitis: Pooled Efficacy Analysis of Two Phase 3 Studies.

Purpose: To analyse pooled data from 2 similar phase 3 noninferiority studies comparing difluprednate 0.05% versus prednisolone acetate 1% in patients with endogenous anterior uveitis. Methods: Patients received difluprednate alternating with vehicle or prednisolone acetate for 14 days (8 drops/day in both groups), followed by tapering from day 14 to 28. All patients were observed until day 42. Results: More patients on difluprednate than on prednisolone acetate were cleared of anterior chamber cells on day twenty one (71.3% vs 54.7%; p = 0.02); results were similar at the other time points. Treatment withdrawals were higher with prednisolone acetate than difluprednate (19.8% vs 7.4%; log-rank p = 0.02). Study discontinuation due to lack of efficacy was also higher with prednisolone acetate than difluprednate (14.0% vs 0%; p = 0.0002 [pre-specified exploratory analysis]). Conclusions: More difluprednate-treated eyes were quiet following 21 days of treatment, and difluprednate-treated patients were much less likely to be withdrawn from the study because of treatment failure.

Toxic anterior segment syndrome following phakic posterior chamber IOL: a rarity.

Implantable collamer lenses (ICL) have gained popularity for correction of myopia where kerato-refractive procedures are not indicated as in cases of high myopic refractive errors. Toxic anterior segment syndrome (TASS) is a very uncommonly reported postoperative complication following ICL implantation. A young patient developed severe corneal oedema and anterior segment inflammation on the first day after ICL implantation. Analysing retrospectively, possible idiosyncratic response to intracameral pilocarpine was considered as a cause for TASS. Prompt and intensive therapy with oral and topical potent steroids was visually rewarding. TASS, though a sterile inflammation can have catastrophic sequelae such as corneal decompensation and secondary glaucoma. Hence, timely identification and management is important.

In vitro effects of three equimolar concentrations of methylprednisolone acetate, triamcinolone acetonide, and isoflupredone acetate on equine articular tissue cocultures in an inflammatory environment.

OBJECTIVE To compare the effects of 3 equimolar concentrations of methylprednisolone acetate (MPA), triamcinolone acetonide (TA), and isoflupredone acetate (IPA) on equine articular tissue cocultures in an inflammatory environment. SAMPLE Synovial and osteochondral explants from the femoropatellar joints of 6 equine cadavers (age, 2 to 11 years) without evidence of musculoskeletal disease. PROCEDURES From each cadaver, synovial and osteochondral explants were harvested from 1 femoropatellar joint to create cocultures. Cocultures were incubated for 96 hours with (positive control) or without (negative control) interleukin (IL)-1ß (10 ng/mL) or with IL-1ß and MPA, TA, or IPA at a concentration of 10-4, 10-7, or 10-10M. Culture medium samples were collected from each coculture after 48 and 96 hours of incubation. Concentrations of prostaglandin E2, matrix metalloproteinase-13, lactate dehydrogenase, and glycosaminoglycan were determined and compared among treatments at each time. RESULTS In general, low concentrations (10-7 and 10-10M) of MPA, TA, and IPA mitigated the inflammatory and catabolic (as determined by prostaglandin E2 and matrix metalloproteinase-13 quantification, respectively) effects of IL-1ß in cocultures to a greater extent than the high (10-4M) concentration. Mean culture medium lactate dehydrogenase concentration for the 10-4M IPA treatment was significantly greater than that for the positive control at both times, which was suggestive of cytotoxicosis. Mean culture medium glycosaminoglycan concentration did not differ significantly. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that the in vitro effects of IPA and MPA were similar to those of TA at clinically relevant concentrations (10-7 and 10-10M).

Effect of 0.05% Difluprednate Ophthalmic Emulsion on Proinflammatory Cytokine Levels After Retinal Laser Photocoagulation in Rabbits.

PURPOSE: We aimed to evaluate the effect of the topical application of a strong corticosteroid, difluprednate, on the levels of inflammatory and angiogenic cytokine in the vitreous and aqueous humor after laser photocoagulation. METHODS: Pigmented rabbits were treated with retinal laser photocoagulation and divided into 4 groups, namely control (no additional treatment), topical application of difluprednate 0.05%, betamethasone sodium phosphate 0.1%, and sub-Tenon injection of triamcinolone acetonide (STTA). Samples of vitreous and aqueous humor were collected on posttreatment days 0, 1, 7, and 14. The levels of intraocular vascular endothelial growth factor (VEGF), interleukin-6 (IL-6), intercellular adhesion molecule-1 (ICAM-1), and monocyte chemotactic protein-1 (MCP-1) were measured using an immunoassay. Intraocular pressure (IOP) was monitored in each group. RESULTS: VEGF, IL-6, ICAM-1, and MCP-1 were significantly elevated on day 1 and were reduced in both the vitreous and aqueous humor following topical application of difluprednate and STTA. Topical betamethasone reduced their levels in the aqueous humor but not in the vitreous. A significant increase of IOP induced by difluprednate returned to control levels after withdrawal of administration. CONCLUSION: Although the elevation of IOP was an expected, manageable side effect, topical application of difluprednate was more effective than STTA and betamethasone for reducing inflammatory cytokine levels after laser treatment.

Difluprednate for the Treatment of Uveitic Cystoid Macular Edema.

PURPOSE: To describe clinical outcomes associated with the use of topical difluprednate in treating uveitic cystoid macular edema. DESIGN: Retrospective, interventional case series. METHODS: Setting: Medical record review in a tertiary care uveitis center. PATIENT POPULATION: Fifty-eight patients (72 eyes) with uveitic cystoid macular edema (CME) treated with difluprednate 0.05% ophthalmic solution between June 2012 and May 2016. MAIN OUTCOME MEASURES: Macular central subfield thickness (CST) determined by optical coherence tomography, improvement of CME (≥20% reduction in CST or resolution), and resolution of CME (CST ≤ 320 µm with no cysts) at 30 days after starting treatment. Outcomes were assessed up to 90 days. RESULTS: CST on average decreased by 17% (95% CI: -33%, -7%) for eyes using only difluprednate (n = 43) and by 6% (95% CI: -17%, -2%) for eyes in patients using concomitant systemic immunosuppressive therapy (n = 29) at 30 days, a 12% difference between groups (95% CI: 2%, 21%, P = .02). Of eyes on difluprednate alone, 76% had improvement and 48% had resolution of CME. In patients using systemic therapy, 37% of eyes had improvement and 17% had resolution. Eight eyes (11%) had an intraocular pressure (IOP) > 24 mm Hg within the first 30 days. By 90 days, CME had improved in 69% of all eyes and resolved in 43% of eyes, with only 9 patients starting or increasing systemic immunosuppressive medications and 2 patients receiving periocular corticosteroid injections. CONCLUSIONS: Difluprednate was associated with an improvement in uveitic CME and could be a reasonable first-line therapy. IOP should be closely monitored.

Nonclinical Development of ENV905 (Difluprednate) Ophthalmic Implant for the Treatment of Inflammation and Pain Associated with Ocular Surgery.

PURPOSE: Topical corticosteroids are widely used in the treatment of inflammation and pain after ocular surgery, but they possess several shortcomings, including frequent dosing and low patient adherence. We evaluated the efficacy and pharmacokinetics of ENV905 (difluprednate or DFBA) Ophthalmic Implant, a single-dose drug delivery system, compared with 0.05% Durezol. METHODS: PRINT® technology was used to fabricate ENV905 implants for either intracameral (IC) or subconjunctival (SCJ) delivery of extended-release DFBA. A postoperative inflammation model and ocular pharmacokinetics studies of ENV905 or Durezol were conducted in albino rabbits for a maximum of 12 weeks. RESULTS: Suppression of ocular inflammation was marked for both IC and SJC ENV905 compared with placebo, and it was superior or equivalent to that observed with QID Durezol. Concentrations of desacetyl difluprednate (DFB, active metabolite) peaked on day 1 and tapered over time for ENV905, with IC ENV905 delivering DFB to the target tissue at the time of greatest inflammation, whereas SJC produced a longer duration of exposure. Durezol eyes demonstrated consistent exposure over time with maximal exposure in the cornea. Although the pharmacokinetic profile differed for the two routes, efficacy was similar. CONCLUSION: ENV905 was well tolerated and demonstrated a robust reduction in ocular inflammation with targeted drug delivery. The results from these studies show that ENV905 provides a sustained therapeutic effect after a single dose. By resolving low patient compliance and eliminating the peaks and troughs in drug concentration, sustained drug delivery via ENV905 may further improve the overall control of postoperative inflammation and pain.

Safety of Fixed drug Combination in Post -Operative Cataract Patients, at Tertiary Care Centre - In South India.

INTRODUCTION: Cataract is any opacification in lens or its capsule, which accounts for about 50% of treatable blindness worldwide. The prevalence of cataract in India is about 62.6%. The incidence of post operative endophthalmitis ranges from 0.05% - 0.14% and so the use of post-operative antibiotics and steroids is necessary to control infection and prevent inflammation. Fixed drug combinations not only cut the cost but also the dosage and improve the compliance of patients in the immediate post operative period. In this regard, the present study was conducted with the aim of studying the efficacy of using fixed drug combination (Difluprednate and Moxifloxacin) in reducing ocular inflammation and pain in post-operative patients undergoing cataract surgery. METHODOLOGY: Study design: Prospective interventional study, in which 749 eyes underwent SICS with IOL. All of them were treated with Difluprednate and Moxifloxacin, combination eye drops postoperatively 4 times a day, and reviewed on day 1, 5 and once in two weeks up to 6 weeks. RESULTS: Out of 749 eyes, 730 were normal, 10 eyes had minimal raise in IOP in the range of 21 mmHg-31mmHg (considering 21mmHg as baseline) which decreased without any intervention within 3 weeks and only 9 eyes had raise in IOP of more than 31mmHg, which did not decrease in spite of discontinuing the drops and needed anti-glaucoma treatment. CONCLUSION: Our study clearly shows that fixed drug combination of antibiotic and steroid does not cause raised IOP in about 97% of cases of SICS in the post-operative period and also improves the compliance of the patients.

RESOLUTION OF NONINFECTIOUS UVEITIC CYSTOID MACULAR EDEMA WITH TOPICAL DIFLUPREDNATE.

PURPOSE: To evaluate the short-term safety and efficacy of topical difluprednate (0.05%) for the treatment of noninfectious uveitic cystoid macular edema. METHODS: Twenty-seven patients (35 eyes) undergoing treatment with difluprednate 4 times daily for 3 weeks for noninfectious uveitic cystoid macular edema were reviewed for visual acuity, intraocular pressure, optical coherence tomography, and fluorescein angiography results. A mixed model analysis was fit with each measure as the outcome, visit as the primary predictor, and patient and eye as random effects. RESULTS: Mean central foveal thickness decreased by 117 µm (P < 0.001) at 30 ± 15 days, 124 µm (P < 0.001) at 60 ± 15 days, and 152 µm (P < 0.001) at 180 ± 30 days. Complete resolution of intraretinal fluid was observed in 15 of 34 (44%) eyes at 30 ± 15 days, 11 of 21 (52%) eyes at 60 ± 15 days, and 9 of 12 (75%) eyes at 180 ± 30 days. Improvement in fluorescein leakage was noted in 7 of 8 eyes (88%). Visual acuity improved by a mean of 5 letters (P = 0.001) at 30 ± 15 days, 5.5 letters (P = 0.007) at 60 ± 15 days, and 7 letters (P = 0.032) at 180 ± 30 days. Mean increase in intraocular pressure was 1.48 mmHg at 30 ± 15 days (P = 0.080), 1.92 mmHg at 60 ± 15 days (P = 0.110), and 6.18 mmHg (P = 0.001) at 180 ± 30 days. CONCLUSION: Topical difluprednate is a well-tolerated and effective treatment for noninfectious uveitic cystoid macular edema with decreased central foveal thickness, mild improvement in visual acuity, and elevation of intraocular pressure observed in a few patients.

Topical difluprednate for treatment of serous retinal detachment and panuveitis associated with Vogt-Koyanagi-Harada disease.

Patients with bilateral serous retinal detachments and panuveitis related to Vogt-Koyanagi-Harada disease are commonly managed with oral corticosteroids, immunosuppressive agents, and/or intravitreal injections. We present the case of a 56-year-old Hispanic man with Harada disease whose bilateral serous retinal detachments and panuveitis were treated with topical corticosteroid difluprednate alone. Functional and anatomical recoveries were assessed by fluorescein angiograms and optical coherence tomography studies over a period of 9 months. The patient's serous retinal detachments resolved, and his vision and panuveitis improved dramatically over a period of 2 weeks, after which he was placed on a drop taper and maintenance therapy for the remainder of the 9 months.

Inducible scAAV2.GRE.MMP1 lowers IOP long-term in a large animal model for steroid-induced glaucoma gene therapy.

Current treatment of glaucoma relies on administration of daily drops or eye surgery. A gene therapy approach to treat steroid-induced glaucoma would bring a resolution to millions of people worldwide who depend on glucocorticoid therapy for a myriad of inflammatory disorders. Previously, we had characterized a short-term Adh.GRE.MMP1 gene vector for the production of steroid-induced MMP1 in the trabecular meshwork and tested reduction of elevated intraocular pressure (IOP) in a sheep model. Here we conducted a trial transferring the same transgene cassette to a clinically safe vector (scAAV2), and extended the therapeutic outcome to longer periods of times. No evidence of ocular and/or systemic toxicity was observed. Viral genome distributions showed potential reinducible vector DNAs in the trabecular meshwork (0.4 v.g. per cell) and negligible copies in six major internal organs (0.00002-0.005 v.g. per cell). Histological sections confirmed successful transduction of scAAV2.GFP to the trabecular meshwork. Optimization of the sheep steroid-induced hypertensive model revealed that topical ophthalmic drug difluprednate 0.05% (durezol) induced the highest IOP elevation in the shortest time. This is the first efficacy/toxicity study of a feasible gene therapy treatment of steroid-induced hypertension using clinically accepted self-complementary adeno-associated vectors (scAAV) vectors in a large animal model.

Efficacy and safety of topical difluprednate in persistent diabetic macular edema.

To evaluate the efficacy and safety of treatment of diabetic macular edema (persistent type) with difluprednate ophthalmic emulsion 0.05 % (off label use). 20 patients with persistent diabetic macular edema were enrolled. In all subjects, more than 4 months had passed since prior treatment. All patients were treated with difluprednate ophthalmic emulsion 0.05 % three times daily for 3 months. At the end of 3 months the visual acuity had increased by two lines to a mean value of 0.61 ± 0.18 on logMAR from a baseline value of 0.885 ± 0.20 and the central retinal thickness had decreased from 423 ± 72.04 microns to 345 ± 68.7 microns. Hence, there was a total of 18.4 % decrease in retinal thickness on difluprednate. Major side effects included raised intraocular pressure in 20 %. Difluprednate is a potent and strong steroid which causes a rapid decrease in persistent diabetic macular edema. However, the potential side effect of raised intraocular pressure limits its use as an adjuvant therapy in non-steroid responders.