Dexamethasone intravitreal implant in combination with laser photocoagulation for the treatment of diffuse diabetic macular edema.

PURPOSE: To evaluate Ozurdex (dexamethasone intravitreal implant [DEX implant]; Allergan, Inc, Irvine, CA) 0.7 mg combined with laser photocoagulation compared with laser alone for treatment of diffuse diabetic macular edema (DME). DESIGN: Randomized, controlled, multicenter, double-masked, parallel-group, 12-month trial. PARTICIPANTS: Two hundred fifty-three patients with retinal thickening and impaired vision resulting from diffuse DME in at least 1 eye (the study eye) were enrolled. INTERVENTION: Patients were randomized to treatment in the study eye with DEX implant at baseline plus laser at month 1 (combination treatment; n = 126) or sham implant at baseline and laser at month 1 (laser alone; n = 127) and could receive up to 3 additional laser treatments and 1 additional DEX implant or sham treatment as needed. MAIN OUTCOME MEASURES: The primary efficacy variable was the percentage of patients who had a 10-letter or more improvement in best-corrected visual acuity (BCVA) from baseline at month 12. Other key efficacy variables included the change in BCVA from baseline and the area of vessel leakage evaluated with fluorescein angiography. Safety variables included adverse events and intraocular pressure (IOP). RESULTS: The percentage of patients who gained 10 letters or more in BCVA at month 12 did not differ between treatment groups, but the percentage of patients was significantly greater in the combination group at month 1 (P<0.001) and month 9 (P = 0.007). In patients with angiographically verified diffuse DME, the mean improvement in BCVA was significantly greater with DEX implant plus laser treatment than with laser treatment alone (up to 7.9 vs. 2.3 letters) at all time points through month 9 (P ≤ 0.013). Decreases in the area of diffuse vascular leakage measured angiographically were significantly larger with DEX implant plus laser treatment through month 12 (P ≤ 0.041). Increased IOP was more common with combination treatment. No surgeries for elevated IOP were required. CONCLUSIONS: There was no significant between-group difference at month 12. However, significantly greater improvement in BCVA, as demonstrated by changes from baseline at various time points up to 9 months and across time based on the area under the curve analysis, occurred in patients with diffuse DME treated with DEX implant plus laser than in patients treated with laser alone. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Twice-daily 0.2% brimonidine-0.5% timolol fixed-combination therapy vs monotherapy with timolol or brimonidine in patients with glaucoma or ocular hypertension: a 12-month randomized trial.

OBJECTIVE: To evaluate the intraocular pressure (IOP)-lowering efficacy and safety of a fixed combination of 0.2% brimonidine tartrate and 0.5% timolol maleate (fixed brimonidine-timolol) compared with the component medications. METHODS: In 2 identical, 12-month, randomized, double-masked multicenter trials, patients with ocular hypertension or glaucoma were treated with fixed brimonidine-timolol twice daily (n = 385), 0.2% brimonidine tartrate 3 times daily (n = 382), or 0.5% timolol maleate twice daily (n = 392). MAIN OUTCOMES MEASURES: Mean change from baseline IOP and incidence of adverse events. RESULTS: The mean decrease from baseline IOP during 12-month follow-up was 4.4 to 7.6 mm Hg with fixed brimonidine-timolol, 2.7 to 5.5 mm Hg with brimonidine, and 3.9 to 6.2 mm Hg with timolol. Mean IOP reductions were significantly greater with fixed brimonidine-timolol compared with timolol at all measurements (P< or =.002) and brimonidine at 8 am, 10 am, and 3 pm (P<.001) but not at 5 pm. The incidence of treatment-related adverse events in the fixed-combination group was lower than that in the brimonidine group (P = .006) but higher than that in the timolol group (P<.001). The rate of discontinuation for adverse events was 14.3% with the fixed combination, 30.6% with brimonidine, and 5.1% with timolol. CONCLUSIONS: Twice-daily fixed brimonidine-timolol therapy provides sustained IOP lowering superior to monotherapy with either thrice-daily brimonidine or twice-daily timolol and is better tolerated than brimonidine but less well tolerated than timolol. APPLICATION TO CLINICAL PRACTICE: Fixed brimonidine-timolol is an effective and convenient IOP-lowering therapy.

A randomized, investigator- masked clinical trial comparing the efficacy and safety of gatifloxacin 0.3% administered BID versus QID for the treatment BID versus QID for the treatment of acute bacterial conjunctivitis of acute bacterial conjunctivitis.

PURPOSE: To compare the efficacy and safety of To compare the efficacy and safety of gatifloxacin ophthalmic solution 0.3% (Zymar) administered BID versus QID in patients with acute bacterial conjunctivitis. METHODS: In a randomized, investigator-masked clinical trial, patients diagnosed with bacterial conjunctivitis (based on signs and symptoms) received gatifloxacin either BID or QID for 5 days. Visits were scheduled at day 0, day 3, and day 5. Conjunctival cultures were taken at each visit. The clinical cure rate at day 5 was determined for the entire patient population (primary endpoint). Additionally, clinical cure at day 5 was evaluated for a population of patients defined a priori (per protocol) as being culture positive at baseline and with no substantial protocol deviations. Safety was determined through recording of adverse events. Minimal inhibitory concentrations (MIC) and susceptibility of isolates to gatifloxacin were determined using a broth dilution method. RESULTS: Patient characteristics in both the BID and QID groups (N = 104) were similar in terms NN of baseline demographics and disposition. The clinical cure rate on day 5 in the entire, intentto-treat (ITT) population was 86.5% (45/52) in the gatifloxacin BID group and 71.2% (37/52) in the gatifloxacin QID group (95% CI: [-0.03, 30.80]; p = 0.096). In both treatment groups, 5/52 patients (9.6%) reported adverse events. The most common adverse event was conjunctivitis. No serious adverse events were reported. In the a priori-defined per-protocol (PP) population, the clinical cure rate on day 5 was 95.5% (21/22) in the gatifloxacin BID group and 85.7% (18/21) in the gatifloxacin QID group (95% CI: [-7.57, 21.05]; p = 0.294). At baseline, 96.1% (98/102) of the isolates were susceptible to gatifloxacin. The overall MIC(90) (mean +/- standard error of the mean) was 0.5 +/- 1.3 microg/mL. CONCLUSION: In this study, gatifloxacin 0.3% administered BID was as effective and as safe as gatifloxacin 0.3% administered QID for 5 days for the treatment of bacterial conjunctivitis.

Comparison of a digital retinal imaging system and seven-field stereo color fundus photography to detect diabetic retinopathy in the primary care environment.

BACKGROUND AND OBJECTIVE: Because patients with diabetes mellitus may visit their primary care physician regularly but not their ophthalmologist, a retinal risk assessment in the primary care setting could improve the screening rate for diabetic retinopathy. An imaging system for use in the primary care setting to identify diabetic retinopathy requiring referral to an ophthalmologist was evaluated. PATIENTS AND METHODS: In a masked prospective study, images were obtained from 11 patients with diabetes mellitus using both the digital retinal imaging system and seven-field stereo color fundus photography. The ability to obtain gradable images and to identify diabetic retinal lesions was compared. RESULTS: Of all images, 85% of digital retinal imaging system images and 88% of seven-field images were gradable. Agreement based on "no retinopathy" versus "any retinopathy" was excellent (Kappa = 0.96). Agreement based on "microaneurysms or less retinopathy" versus "retinal hemorrhages or worse retinopathy" was very good (Kappa = 0.83). CONCLUSIONS: The agreement between the digital retinal imaging system and seven-field photography indicates that the digital retinal imaging system may be useful to screen for diabetic retinopathy.

Brimonidine and timolol fixed-combination therapy versus monotherapy: a 3-month randomized trial in patients with glaucoma or ocular hypertension.

PURPOSE: The aim of this study was to compare the safety and intraocular pressure (IOP)- lowering efficacy of a fixed combination of brimonidine 0.2% and timolol 0.5% (fixed brimonidine/ timolol) versus each drug used as monotherapy. METHODS: Patients with glaucoma or ocular hypertension were randomized to receive fixed brimonidine/timolol BID (n = 385), brimonidine 0.2% TID (n = 382), or timolol 0.5% BID (n = 392) in a multicenter, double-masked study. The primary outcome measure was decrease from baseline IOP. RESULTS: Over all follow-up measurements, the mean decrease from baseline IOP ranged from 4.9 to 7.6 mmHg with brimonidine/timolol, from 3.1 to 5.5 mmHg with brimonidine, and from 4.3 to 6.2 mmHg with timolol. Mean IOP reductions from baseline were significantly larger with fixed brimonidine/timolol than with timolol at all follow-up measurements (P < or = 0.026); the difference was greater than 1.5 mmHg at 10 AM (peak effect for each treatment). Mean IOP reductions from baseline were significantly larger with fixed brimonidine/ timolol than with brimonidine at 8 AM, 10 AM, and 3 PM (P < 0.001); the difference was greater than 1.5 mmHg. The rate of discontinuations owing to adverse events was 3.6% in the fixed timolol/brimonidine group. CONCLUSIONS: The fixed combination of brimonidine and timolol was well-tolerated and provided significantly better IOP control compared with either brimonidine or timolol used alone.

Efficacy of a preservative-free formulation of fixed-combination bimatoprost and timolol (Ganfort PF) in treatment-naïve patients vs previously treated patients.

PURPOSE: To evaluate, using subgroup analysis, the effect of treatment status on the intraocular pressure (IOP)-lowering efficacy of a preservative-free formulation of fixed-combination bimatoprost 0.03%/timolol 0.5% (FCBT PF). METHODS: A primary, multicenter, randomized, double-masked, 12-week study compared the efficacy and safety of FCBT PF with preserved FCBT (Ganfort(®)) in 561 patients diagnosed with glaucoma or ocular hypertension. For this analysis, eligible patients were treatment-naïve or had inadequate IOP lowering and underwent a washout of previous treatment. IOP (8 am, 10 am, and 4 pm) was measured at baseline and weeks 2, 6, and 12. Subgroup analysis of the FCBT PF arm assessed changes in average eye IOP from baseline in treatment-naïve vs previously treated patients. To evaluate the effect of treatment status at baseline (treatment-naïve vs previously treated) on IOP reduction in the FCBT PF treatment group, an analysis of covariance model was used with treatment status and investigator as fixed effects, and baseline average eye IOP, age, glaucoma diagnosis, and baseline average eye corneal thickness as covariates. P-values and the 95% confidence intervals were determined using the model. RESULTS: In the FCBT PF arm, IOP mean changes from baseline ranged from -8.7 mmHg to -9.8 mmHg in treatment-naïve patients (N=50), compared with -7.3 mmHg to -8.5 mmHg in previously treated patients (N=228). Baseline IOP, age, glaucoma diagnosis, and corneal thickness significantly affected IOP reduction in the FCBT PF group. Adjusting for these covariates, FCBT PF had a greater IOP-lowering effect (0.8-1.7 mmHg) in treatment-naïve patients than previously treated patients, which was statistically significant (P≤0.05) at seven of nine time points. CONCLUSION: In this subgroup analysis, FCBT PF reduced IOP more effectively in treatment-naïve than in previously treated patients possibly due, in part, to altered responsiveness or tachyphylaxis that has been associated with prior ocular hypotensive agent treatment.

Efficacy and tolerability of ophthalmic epinastine: a randomized, double-masked, parallel-group, active- and vehicle-controlled environmental trial in patients with seasonal allergic conjunctivitis.

BACKGROUND: Epinastine hydrochloride is an antihistamine with mast cell-stabilizing and anti-inflammatory activity. OBJECTIVE: The aim of this study was to assess the efficacy and tolerability of ophthalmic epinastine in patients with seasonal allergic conjunctivitis (SAC) exposed to environmental allergens. METHODS: This randomized (age-stratified), double-masked, parallel-group, active- and vehicle-controlled, environmental, Phase III clinical trial was conducted at 6 ophthalmology clinics in the United States. Patients aged >or=9 years diagnosed with SAC and who had a positive reaction in a conjunctival allergen challenge were enrolled. Patients were randomly assigned in a 2:2:1 ratio to receive 1 drop/eye BID of epinastine hydrochloride 0.05% ophthalmic solution, levocabastine hydrochloride 0.05% ophthalmic suspension, or vehicle of epinastine, respectively, for 8 weeks. The primary end point was ocular itching, and secondary end points included ocular hyperemia, chemosis, ocular mucous discharge (all assessed on a 5-point scale), eyelid swelling (assessed on a 4-point scale), and tearing (present or absent). Efficacy analyses used assessments from the two 1-week periods with the highest pollen counts. For tolerability assessment slit-lamp biomicroscopy and visual acuity examinations were conducted at each study visit (weeks 0, 2, 4, 6, and 8). RESULTS: Two-hundred ninety-eight patients (159 females, 139 males; mean [SD] age, 32.7 [14.6] years [range, 9-71 years]) entered the study; 118 received epinastine, 118 received levocabastine, and 62 received vehicle. Epinastine-treated patients reported significantly less ocular itching than those receiving vehicle (P=0.045); scores for hyperemia were similar between these 2 groups. Ocular itching and hyperemia scores were similar between the epinastine and levocabastine groups. No clinically or statistically significant between-group differences were seen in slit-lamp biomicroscopy findings, changes in visual acuity from baseline, or the incidence of treatment-related adverse effects. CONCLUSIONS: In this study of patients with SAC, ophthalmic epinastine instilled twice daily was more effective than vehicle for the control of ocular itching and was similar in efficacy to levocabastine for control of ocular itching and hyperemia. Epinastine was well tolerated.

Efficacy and tolerability of ophthalmic epinastine assessed using the conjunctival antigen challenge model in patients with a history of allergic conjunctivitis.

BACKGROUND: Epinastine hydrochloride is a nonsedating antihistamine with a high affinity for histamine H(1) receptors, together with mast cell-stabilizing and anti-inflammatory activities. OBJECTIVE: The aim of this study was to assess the efficacy and tolerability of topically administered ophthalmic epinastine using the conjunctival antigen challenge (CAC) model in patients with a history of allergic conjunctivitis. METHODS: This prospective, single-center, randomized, double-masked, vehicle-controlled, Phase III clinical trial was conducted at the Ophthalmic Research Associates study center (North Andover, Massachusetts) from November 2000 to January 2001. Eligible participants were asymptomatic but had a history of allergic conjunctivitis and had positive CAC reactions at the initial screening (week 0) and at a confirmation visit (week 1). Patients were randomly assigned by eye to receive epinastine hydrochloride 0.05% ophthalmic solution in 1 eye and vehicle in the contralateral eye. Each eye received 1 drop of study medication 15 minutes before antigen application (onset challenge; week 3) or 8 hours before antigen application (duration challenge; week 5). Primary end points were ocular itching and conjunctival hyperemia. Itching was recorded 3, 5, and 10 minutes after antigen challenge. Hyperemia was recorded 5, 10, and 20 minutes after antigen challenge, as were secondary end points, which included eyelid swelling, episcleral and ciliary hyperemia, chemosis, tearing, and ocular mucous discharge. Tolerability was assessed by patient interview and slit-lamp biomicroscopy. RESULTS: Sixty-seven patients (37 females, 30 males; mean [SD] age, 38.4 [14.2] years [range, 12-67 years]) were included in the study. Mean severity scores for the following signs and symptoms were significantly lower with epinastine compared with vehicle at all time points after onset and duration challenges: ocular itching (P<0.001); eyelid swelling (P<0.001); conjunctival ( P<0.001), episcleral ( P<0.001), and ciliary hyperemia (P<0.001); and chemosis (Por=8 hours). The tolerability of epinastine was similar to that of vehicle.

Validity and reliability of the Cataract TyPE Spec: an instrument for measuring outcomes of cataract extraction.

PURPOSE: To design and validate a survey instrument that measures vision-related functional status, which is appropriate for self-administration in a clinical practice and mail survey setting. DESIGN: Observational, validation study in sequential patients. METHODS: A prototype visual function instrument (the Cataract TyPE Spec) was developed based on focus group input and then validated in an outcomes study conducted among 1,823 patients who underwent cataract extraction performed by 22 surgeons at six centers in the United States. Reliability was determined by calculating Cronbach alpha for different types of administration (self-administration at the site of care and mailed survey) and across race and gender. Criterion validity was determined by correlating scores on the TyPE Spec with baseline measures and changes in visual acuity, overall rating of vision, and general quality of life. RESULTS: The instrument was internally valid (Chronbach alpha = 0.94), both on self-administration in the patient care setting and upon mailed survey administration and across patient race and gender. The TyPE Spec score was highly correlated with overall rating of vision (r =.54, P <.0001) and moderately correlated with Snellen acuity (r =.32, P <.0001), rating of vision in the better eye (r =.42, P <.0001), and quality of life, as measured by the physical component summary score of the SF-36 (r =.27, P <.001). Change in TyPE Spec similarly correlated with change in rating of vision overall, change in best-corrected Snellen acuity, and change in rating of vision in the operated eye. CONCLUSIONS: The cataract TyPE Spec instrument was found to be equally valid and internally consistent when administered in the patient care setting and by mail survey.

Safety and efficacy of ketorolac tromethamine 0.4% ophthalmic solution in post-photorefractive keratectomy patients.

PURPOSE: To evaluate the safety and analgesic efficacy of ketorolac tromethamine 0.4% ophthalmic solution in postoperative photorefractive keratectomy (PRK) patients. SETTING: Fifteen clinical sites in the eastern and southern United States. METHODS: This pooled analysis of 2 multicenter, randomized, double-masked, vehicle-controlled, parallel-group studies comprised 313 patients having unilateral PRK. After surgery, patients were treated with 1 drop of ketorolac tromethamine 0.4% ophthalmic solution (Acular(R) LS) (n = 156) or vehicle (n = 157) 4 times daily for up to 4 days. Pain intensity, pain relief, use of escape medication, and severity of ocular symptoms were assessed. Adverse events, epithelial healing, and visual acuity were recorded. RESULTS: There was significantly less pain intensity experienced by patients in the ketorolac group (P<.001). During the first 12 hours post PRK, 50% fewer patients in the ketorolac group than in the vehicle group had severe to intolerable pain (41.6% [64/154] and 84.5% [131/155], respectively). The median time to no pain was 30 hours in the ketorolac group and 54 hours in the vehicle group (P<.001, survival analysis). Ketorolac patients reported significantly greater pain relief than vehicle patients throughout the study (P<.001). Ketorolac patients used significantly less escape medication than vehicle patients for 48 hours post PRK (P< or =.008). Treatment-related adverse events occurred in 2.6% (4/156) of ketorolac patients and 6.4% (10/157) of vehicle patients. CONCLUSION: Ketorolac 0.4% ophthalmic solution is safe and effective in reducing ocular pain when used 4 times daily for up to 4 days post PRK.

Central serous chorioretinopathy in African Americans.

PURPOSE: Central Serous Chorioretinopathy (CSCR) is presumed to be less prevalent in the African American population. The purpose of this study was to compare the characteristics of CSCR in African Americans and Caucasians. METHODS: A retrospective analysis was performed. Visual acuity (VA) evaluations that were recorded included best-corrected VA at diagnosis, worst VA recorded at follow-up, and best-corrected VA at the last clinic visit. Recurrences of CSCR, frequency of laser photocoagulation, and fluorescein angiographic patterns also were evaluated. RESULTS: Of the 74 patients with CSCR, 15 (20.3%) were African American and 59 (79.7%) were Caucasian. This ethnic distribution was similar to the ethnic distribution in the entire Henry Ford Health System population. The mean VA at presentation was significantly lower in African-Americans (20/55 vs. 20/30, P=0.004) and trended towards being lower during follow-up (20/58 vs. 20/32, P=0.04) and at final examination (20/28 vs. 20/22, P=0.04). Mean length of follow-up was 21 months for both groups. CONCLUSION: The rates and spectrum of symptomatic CSCR seen at Henry Ford Health System are comparable in African Americans and Caucasians.

Bimatoprost 0.03%/timolol 0.5% preservative-free ophthalmic solution versus bimatoprost 0.03%/timolol 0.5% ophthalmic solution (Ganfort) for glaucoma or ocular hypertension: a 12-week randomised controlled trial.

AIM: To compare the efficacy and safety of single-dose bimatoprost 0.03%/timolol 0.5% preservative-free (PF) ophthalmic solution with bimatoprost 0.03%/timolol 0.5% ophthalmic solution in patients with open-angle glaucoma or ocular hypertension. METHODS: In this multicentre, randomised, parallel-group study, patients were randomised to bimatoprost/timolol PF or bimatoprost/timolol once daily in the morning for 12 weeks. Primary efficacy endpoints, reflecting differing regional regulatory requirements, included change from baseline in worse eye intraocular pressure (IOP) in the per-protocol population at week 12, and the average eye IOP at weeks 2, 6 and 12 in the intent-to-treat population. RESULTS: 561 patients were randomised (278 to bimatoprost/timolol PF; 283 to bimatoprost/timolol); 96.3% completed the study. Both treatment groups showed statistically and clinically significant mean decreases from baseline in worse eye IOP and in average eye IOP at all follow-up time points (p<0.001). Bimatoprost/timolol PF met all pre-established criteria for non-inferiority and equivalence to bimatoprost/timolol. Ocular adverse events were similar between treatment groups, with conjunctival hyperaemia being the most frequent. Most were mild or moderate in severity. CONCLUSIONS: Bimatoprost/timolol PF demonstrated non-inferiority and equivalence in IOP lowering compared with bimatoprost/timolol, with no significant differences in safety and tolerability. TRIAL REGISTRATION NUMBER: NCT01177098.

Bimatoprost 0.03% preservative-free ophthalmic solution versus bimatoprost 0.03% ophthalmic solution (Lumigan) for glaucoma or ocular hypertension: a 12-week, randomised, double-masked trial.

BACKGROUND/AIM: To evaluate efficacy and safety of bimatoprost 0.03% preservative-free (PF) ophthalmic solution versus bimatoprost 0.03% (Lumigan) ophthalmic solution for glaucoma or ocular hypertension. METHODS: In this double-masked, parallel-group study, patients were randomised to bimatoprost PF or bimatoprost for 12 weeks. The primary analysis for non-inferiority was change from baseline in worse eye intraocular pressure (IOP) in the per-protocol population at week 12. For equivalence, it was average eye IOP in the intent-to-treat population at each time point at weeks 2, 6 and 12. RESULTS: 597 patients were randomised (bimatoprost PF, n=302 and bimatoprost, n=295). The 95% CI upper limit for worse eye IOP change from baseline was <1.5 mm Hg at each week 12 time point, meeting prespecified non-inferiority criteria. The 95% CI upper limit for the treatment difference for average IOP was 0.69 mm Hg and the lower limit was -0.50 mm Hg at all follow-up time points (hours 0, 2 and 8 at weeks 2, 6 and 12), meeting equivalence criteria. Both treatments showed decreases in mean average eye IOP at all follow-up time points (p<0.001), were safe and well tolerated. CONCLUSIONS: Bimatoprost PF is non-inferior and equivalent to bimatoprost in its ability to reduce IOP-lowering with a safety profile similar to bimatoprost.

Fixed-combination brimonidine-timolol versus latanoprost in glaucoma and ocular hypertension: a 12-week, randomized, comparison study.

OBJECTIVE: To evaluate the intraocular pressure (IOP)-lowering efficacy and safety of fixed-combination brimonidine 0.2%-timolol 0.5% compared with latanoprost 0.005% in patients with glaucoma or ocular hypertension. RESEARCH DESIGN AND METHODS: This was a prospective, randomized, multicenter, investigator-masked clinical trial. After washout of any previous IOP-lowering medications, patients with IOP of 24 mmHg or higher were randomized to twice-daily fixed-combination brimonidine 0.2%-timolol 0.5% (n = 73) or once-daily latanoprost 0.005% (n = 75, dosed in the evening, with vehicle control in the morning to maintain masking) for 12 weeks. IOP was measured at 8 a.m. (before dosing), 10 a.m., and 3 p.m. at baseline, week 6, and week 12. CLINICAL TRIAL REGISTRATION: The trial is registered with the identifier 00811564 at http://www.clinicaltrials.gov . MAIN OUTCOME MEASURES: The primary efficacy endpoint was diurnal IOP (averaged over 8 a.m., 10 a.m., and 3 p.m.) at week 12. Safety measures included biomicroscopy. RESULTS: There was no statistically significant difference between the treatment groups in mean diurnal IOP at baseline (p = 0.118). At week 12, the mean (SD) diurnal IOP was 17.8 (2.9) mmHg with brimonidine-timolol and 17.9 (3.9) mmHg with latanoprost (p = 0.794). The percentage of patients achieving at least a 20% decrease from baseline diurnal IOP at week 12 was 87.7% in the brimonidine-timolol group and 77.3% in the latanoprost group (p = 0.131). Measured biomicroscopic changes from baseline to week 12 were infrequent in both groups. CONCLUSIONS: Fixed-combination brimonidine-timolol was as effective as latanoprost in reducing IOP in patients with glaucoma or ocular hypertension. Both treatments demonstrated favorable ocular tolerability. The duration of the study was 12 weeks, and additional studies will be needed to compare the efficacy and safety of fixed-combination brimonidine-timolol and latanoprost during long-term treatment.

Control of intraocular pressure and fluctuation with fixed-combination brimonidine-timolol versus brimonidine or timolol monotherapy.

PURPOSE: To evaluate control of intraocular pressure (IOP) and IOP fluctuation in patients with ocular hypertension or glaucoma treated with fixed-combination brimonidine-timolol compared with brimonidine or timolol monotherapy. DESIGN: Post hoc analysis of data from 2 identical, 12-month, randomized, double-masked, multicenter trials. METHODS: Patients were treated bilaterally with fixed brimonidine-timolol twice a day (n = 385), brimonidine tartrate 0.2% 3 times a day (n = 382), or timolol 0.5% twice a day (n = 392). Diurnal IOP was measured at follow-up visits at weeks 2 and 6 and months 3, 6, 9, and 12. IOP fluctuation was defined as the standard deviation of IOP measurements. RESULTS: The percentage of patients with mean diurnal IOP <18 mm Hg and short-term (daily) IOP fluctuation ≤2 mm Hg was statistically significantly higher in the brimonidine-timolol group than in the brimonidine or timolol group at each follow-up visit (at month 12, brimonidine-timolol 43.0%; brimonidine 18.9%, timolol 33.5%, P ≤ .017). At each hour (8 AM, 10 AM, 3 PM, and 5 PM), the percentage of patients with mean IOP <18 mm Hg and long-term (intervisit) IOP fluctuation ≤2 mm Hg was statistically significantly higher with brimonidine-timolol than with brimonidine or timolol alone (at 8 AM, brimonidine-timolol 41.0%, brimonidine 11.3%, timolol 23.7%, P < .001). CONCLUSIONS: Patients treated with fixed-combination brimonidine-timolol were more likely than patients treated with either brimonidine or timolol alone to achieve a combination of low mean IOP and low short-term (daily) or long-term (intervisit) IOP fluctuation.

Ex vivo corneal epithelial wound healing following exposure to ophthalmic nonsteroidal anti-inflammatory drugs.

PURPOSE: Ketorolac 0.45% is a new formulation of topical ketorolac in which preservative (benzalkonium chloride, BAK) was removed and carboxymethylcellulose (CMC) was added to improve tolerability and reduce dosing frequency. This study compared the effects of ketorolac 0.45% on corneal wound healing to prior ketorolac formulations (0.4% and 0.5%), bromfenac 0.09%, and nepafenac 0.1%. METHODS: Two parallel-group comparisons were performed in series. A 5-mm central epithelial wound was made in fresh porcine corneas. After 24 hours in minimum essential medium (MEM), corneas were incubated for 10 minutes with study drugs, Triton X-100 1% (positive control), or MEM (negative control), followed by 24 hours in MEM. The remaining wound area was stained, photographed, and quantified (pixels). Study 1 compared ketorolac 0.45% to ketorolac 0.4% and ketorolac 0.5%. Study 2 compared ketorolac 0.45% to bromfenac 0.09% and nepafenac 0.1%. RESULTS: The mean (±SD) original wound area was 200,506 ± 4,363 pixels, which was reduced to 59,509 ± 4850 at 48 hours after exposure to Triton X-100 1%. In study 1, the mean remaining wound areas at 48 hours in pixels were 2969 ± 1633 with MEM, 586 ± 299 with ketorolac 0.45% (significantly reduced, P < 0.05 vs all other treatments), 10,228 ± 7541 with ketorolac 0.4%, and 50,674 ± 33,409 with ketorolac 0.5% (significantly enlarged, P < 0.05 vs MEM). In study 2, the mean remaining wound areas at 48 hours were 565 ± 1263 with MEM, 322 ± 229 with ketorolac 0.45% (significantly reduced, P < 0.01 vs bromfenac 0.09% and nepafenac 0.1%), 29,093 ± 14,295 with bromfenac 0.09% (significantly enlarged, P <0.01 vs MEM) and 47,322 ± 13,736 with nepafenac 0.1% (significantly enlarged, P < 0.01 vs MEM and vs bromfenac 0.09%). CONCLUSION: Corneas treated with ketorolac 0.45% healed as rapidly as those treated with MEM, likely secondary to addition of CMC and removal of BAK. In the ex vivo corneal organ culture model, ketorolac 0.45% had statistically less impact on corneal re-epithelialization than prior ketorolac formulations (0.4% and 0.5%), bromfenac 0.09%, and nepafenac 0.01%.

Ocular penetration and anti-inflammatory activity of ketorolac 0.45% and bromfenac 0.09% against lipopolysaccharide-induced inflammation.

PURPOSE: Anti-inflammatory activity of topical nonsteroidal anti-inflammatory drugs is mediated by suppression of cyclooxygenase (COX) isoenzymes. This study compared ocular penetration and inflammation suppression of topical ketorolac 0.45% and bromfenac 0.09% ophthalmic solutions in a rabbit model. METHODS: At hour 0, 36 rabbits received ketorolac 0.45%, bromfenac 0.09%, or an artificial tear 3 times once every 20 min. Half of the rabbits in each group then received intravenous injections of lipopolysaccharide (LPS) and fluorescein isothiocyanate (FITC)-dextran at hour 1, and the other half at hour 10. Aqueous and iris-ciliary body (ICB) samples were collected in the former group at hour 2 (peak) and in the latter group at hour 11 (trough) An additional group of 6 animals received only FITC-dextran, and samples were collected 1 h later. Peak and trough nonsteroidal anti-inflammatory drug concentrations were compared with previously determined half-maximal inhibitory concentrations (IC(50)) for COX isoenzymes. RESULTS: Peak and trough aqueous and ICB concentrations of ketorolac were at least 7-fold or greater than those of bromfenac. At peak levels, both ketorolac 0.45% and bromfenac 0.09% significantly inhibited LPS-induced aqueous prostaglandin E(2) and FITC-dextran elevation (P < 0.01). At trough, both study drugs significantly inhibited LPS-induced aqueous prostaglandin E(2) elevation (P < 0.05), but only ketorolac 0.45% significantly reduced LPS-induced aqueous FITC-dextran elevation (P < 0.01). Aqueous and ICB ketorolac concentrations exceeded its IC(50) for COX-1 and COX-2 at peak and trough. Aqueous and ICB bromfenac levels exceeded its IC(50) for COX-2 at peak and trough, but not for COX-1 at trough aqueous levels and peak and trough ICB levels. CONCLUSIONS: Both ketorolac 0.45% and bromfenac 0.09% effectively suppressed inflammation at peak. At trough, only ketorolac 0.45% effectively suppressed inflammation as measured by FITC-dextran leakage. The difference in inflammation suppression may be due to differences in tissue concentrations and/or greater COX-1 suppression by ketorolac 0.45%.

Dexamethasone intravitreal implant for noninfectious intermediate or posterior uveitis.

OBJECTIVE: To evaluate the safety and efficacy of 2 doses of dexamethasone intravitreal implant (DEX implant) for treatment of noninfectious intermediate or posterior uveitis. METHODS: In this 26-week trial, eyes with noninfectious intermediate or posterior uveitis were randomized to a single treatment with a 0.7-mg DEX implant (n = 77), 0.35-mg DEX implant (n = 76), or sham procedure (n = 76). MAIN OUTCOME MEASURE: The main outcome measure was the proportion of eyes with a vitreous haze score of 0 at week 8. RESULTS: The proportion of eyes with a vitreous haze score of 0 at week 8 was 47% with the 0.7-mg DEX implant, 36% with the 0.35-mg DEX implant, and 12% with the sham (P < .001); this benefit persisted through week 26. A gain of 15 or more letters from baseline best-corrected visual acuity was seen in significantly more eyes in the DEX implant groups than the sham group at all study visits. The percentage of eyes with intraocular pressure of 25 mm Hg or more peaked at 7.1% for the 0.7-mg DEX implant, 8.7% for the 0.35-mg DEX implant, and 4.2% for the sham (P > .05 at any visit). The incidence of cataract reported in the phakic eyes was 9 of 62 (15%) with the 0.7-mg DEX implant, 6 of 51 (12%) with the 0.35-mg DEX implant, and 4 of 55 (7%) with the sham (P > .05). CONCLUSIONS: In patients with noninfectious intermediate or posterior uveitis, a single DEX implant significantly improved intraocular inflammation and visual acuity persisting for 6 months. Application to Clinical Practice Dexamethasone intravitreal implant may be used safely and effectively for treatment of intermediate and posterior uveitis. Trial Registration clinicaltrials.gov Identifier: NCT00333814.

Twice-daily, preservative-free ketorolac 0.45% for treatment of inflammation and pain after cataract surgery.

PURPOSE: To evaluate the efficacy and safety of twice-daily, preservative-free ketorolac 0.45% (Acuvail; Allergan, Inc, Irvine, California, USA) administration for treatment of inflammation and pain after cataract surgery. DESIGN: Prospective, randomized trial. METHODS: Two multicenter, double-masked studies randomized 511 cataract surgery patients (2:1) to receive twice-daily ketorolac 0.45% or vehicle in the operative eye for 16 days, beginning 1 day before surgery. The primary efficacy end point was the percentage of patients with a summed ocular inflammation score of 0 for anterior chamber cell and flare on postoperative day 14. The main secondary efficacy end point was the percentage of patients with no pain on postoperative day 1. RESULTS: On day 14, 52.5% of ketorolac patients and 26.5% of vehicle patients had an summed ocular inflammation score of 0 (P < .001). On day 1, 72.4% of ketorolac patients and 39.7% of vehicle patients had a pain score of 0 (P < .001). Median time to pain resolution was 1 day in the ketorolac group and 2 days in the vehicle group (P < .001). The percentage of ketorolac and vehicle patients who had a +3-line or more improvement in best-corrected visual acuity from baseline was 60.5% versus 44.0% on day 14 (P = .002). Overall, adverse events were more prevalent in the vehicle group than in the ketorolac group (48.5% vs 35.2%; P = .004). Burning or stinging (per a composite Medical Dictionary for Regulatory Activities) was reported by 1.5% of ketorolac patients and 0.6% of vehicle patients. CONCLUSIONS: Twice-daily ketorolac 0.45% was well tolerated and effectively treated inflammation and pain following cataract surgery.

Ocular pharmacokinetics of 0.45% ketorolac tromethamine.

PURPOSE: A new carboxymethylcellulose (CMC)-containing ophthalmic formulation of 0.45% ketorolac, pH 6.8 (Acuvail(®)) was recently developed for treatment of inflammation and pain after cataract surgery. This study compared pharmacokinetics of the new formulation with that of a prior formulation, 0.4% ketorolac, pH 7.4 (Acular LS(®)). METHODS: Ketorolac formulations were administered bilaterally (35 µL) to female New Zealand White rabbits. Samples from aqueous humor and iris-ciliary body were collected at multiple time points, and ketorolac was quantified using liquid chromatography-tandem mass spectrometry. RESULTS: In aqueous humor, the peak concentration (C(max)) and area under the concentration-time curve (AUC(0-τ)) of ketorolac were, respectively, 389 ng/mL and 939 ng·h/mL following administration of the CMC-containing 0.45% ketorolac, pH 6.8, and 211 ng/mL and 465 ng·hr/mL following administration of the 0.4% ketorolac, pH 7.4. In iris-ciliary body, C(max) and AUC(0-τ) of ketorolac were, respectively 450 ng/g and 2040 ng·h/g after administration of the CMC-containing 0.45% ketorolac, pH 6.8, and 216 ng/g and 699 ng·h/g after administration of the 0.4% ketorolac, pH 7.4. PK simulations predicted an AUC(0-τ) of 2910 ng·h/g for twice daily, CMC-containing 0.45% ketorolac, pH 6.8, compared to 725 ng·h/g for 4 times daily, 0.4% ketorolac, pH 7.4. CONCLUSIONS: The CMC-containing formulation of 0.45% ketorolac, pH 6.8, increased ketorolac bioavailability by 2-fold in aqueous humor and by 3-fold in iris-ciliary body in comparison to the 0.4% ketorolac, pH 7.4, allowing a reduced dosing schedule from 4 times daily to twice daily.