Cone photoreceptor macular function and recovery after photostress in early non-exudative age-related macular degeneration.

PURPOSE: To identify parameters from cone function and recovery after photostress that detect functional deficits in early non-exudative age-related macular degeneration (AMD) and to determine the repeatability of these parameters. METHODS: Cone-mediated visual function recovery after photostress was examined in three groups of subjects: young normal subjects (ages 20-29; N=8), older normal subjects (ages 50-90; N=9), and early non-exudative AMD subjects (ages 50-90; N=12). Eight AMD and four normal subjects were retested 1 year after the initial evaluation. Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) and parameters of cone function (baseline cone sensitivity and cone recovery half-life following photobleach) were measured and compared between AMD and normal subjects. Short-term repeatability was assessed for each subject's initial evaluation. Long-term repeatability was assessed by comparing outcomes from the initial evaluation and 1-year follow-up. RESULTS: The mean baseline cone threshold was significantly worse in subjects with early AMD compared to older normal subjects (-1.80±0.04 vs -1.57±0.06 log cd/m2p=0.0027). Moreover, the baseline cone threshold parameter exhibited good short-term (intraclass correlation coefficient [ICC]=0.88) and long-term (ICC=0.85) repeatability in all subjects. The cone intercept parameter and ETDRS VA were not significantly different between AMD and older normal subject groups. Cone recovery half-life was significantly different between older normal and AMD subject groups (p=0.041). Neither ETDRS VA nor cone function parameters were significantly different for any group at the 1-year follow-up. CONCLUSION: The baseline cone threshold shows potential as a novel parameter to assess visual dysfunction in early AMD. This outcome consistently detected deficits in AMD subjects, and differentiated them from age-matched controls with high test-retest repeatability.

Clinical pharmacology of alcaftadine, a novel antihistamine for the prevention of allergic conjunctivitis.

PURPOSE: In this report, we characterize the in vitro pharmacokinetic properties of a new antihistamine, alcaftadine. In addition, we report results from phase 1 studies of several ophthalmic formulations of alcaftadine and examine the pharmacokinetic properties of one formulation in detail. METHODS: In vitro pharmacology employed a human liver microsome assay combined with index substrates or inhibitors for specific cytochromes. Metabolic fate of (14)C-alcaftadine was determined by high-performance liquid chromatography-based separation of parent compound from metabolites. Plasma protein binding was determined by equilibrium dialysis using (3)H-labeled alcaftadine and (3)H-labeled alcaftadine carboxylic acid metabolite. Relative tolerability (comfort) of 4 concentrations and 3 formulations of alcaftadine ophthalmic solution was assessed in 2 double-masked, randomized, placebo-controlled, contralateral studies in which formulations were compared to Tears Naturale II (placebo) in normal adult subjects. Data analysis focused on the mean differences in subject-reported drop comfort scores (within each dose level, at each time point) and compared the study-treatment eye with the placebo eye. Pharmacokinetics of alcaftadine 0.25% ophthalmic solution were determined in an open-label, single-center study after a single bilateral dose and after 7 days of once-a-day bilateral doses in healthy subjects 18-55 years old. RESULTS: Alcaftadine is not significantly metabolized by microsomal cytochromes, but it is rapidly converted to the carboxylic acid metabolite by one or more cytosolic enzymes. Neither the parent compound nor its carboxylic acid metabolite displayed significant plasma protein binding. Over a range of formulations and concentrations (0.05%-0.5%), alcaftadine was well tolerated and subjects reported little or no discomfort or taste perversion in any treatment group. Pharmacokinetic studies showed that both the parent compound and the carboxylic acid metabolite reach peak serum levels within minutes of administration and fall below detectable levels within 3 h of dosing. CONCLUSIONS: Based upon pharmacokinetic and phase 1 studies, the novel antihistamine alcaftadine is an appropriate drug for use as an ophthalmic formulation for prevention and treatment of ocular allergic conditions such as allergic conjunctivitis (alcaftadine ophthalmic solution 0.25% was recently approved for use by the FDA). Topical administration of alcaftadine 0.25% ophthalmic solution was well tolerated and had an acceptable safety profile.

Concentrations of besifloxacin, gatifloxacin, and moxifloxacin in human conjunctiva after topical ocular administration.

PURPOSE: To evaluate the pharmacokinetic properties of besifloxacin, gatifloxacin, and moxifloxacin in the conjunctival tissue of healthy volunteers after topical application. METHODS: One-hundred eight (108) subjects were randomly assigned to receive one drop of besifloxacin (0.6% suspension), gatifloxacin (0.3% solution), or moxifloxacin (0.5% solution) ophthalmic formulations in one eye prior to conjunctival biopsy. Conjunctival samples were taken from subjects at either 15 minutes, 30 minutes, 2 hours, 6 hours, 12 hours, or 24 hours after dosing. RESULTS: All three fluoroquinolones reached a peak mean concentration 15 minutes after dosing. The mean concentrations of besifloxacin, gatifloxacin, and moxifloxacin at 15 minutes were 2.30 +/- 1.42 mug/g, 4.03 +/- 3.84 mug/g, and 10.7 +/- 5.89 mug/g, respectively. Concentrations decreased with each subsequent time point. At 24 hours after dosing, concentrations of besifloxacin were measurable in 4 of 6 subjects, compared with 3 of 6 subjects for gatifloxacin and 2 of 6 subjects for moxifloxacin. Besifloxacin had the greatest mean residence time (4.7 hours) in the conjunctival tissue. With regard to methicillin-resistant strains of Staphylococcus aureus and Staphylococcus epidermidis, besifloxacin had the greatest area-under-the-curve (AUC) to MIC(90) ratio. Nine percent (9%) of study subjects (N = 7) experienced a transient reduction in visual acuity. CONCLUSION: All three fluoroquinolones were well tolerated and reached levels in the conjunctiva above the MIC(90)s of methicillin-sensitive S. aureus and S. epidermidis for at least 2 hours.

Clinical cure of bacterial conjunctivitis with azithromycin 1%: vehicle-controlled, double-masked clinical trial.

PURPOSE: To analyze the effect of azithromycin 1% ophthalmic solution in DuraSite (InSite Vision, Inc, Alameda, California, USA) on bacterial conjunctivitis. DESIGN: Prospective, randomized, vehicle-controlled, parallel-group, double-masked multicenter clinical study. METHODS: Eligible male or female participants with a clinical diagnosis of acute bacterial conjunctivitis were randomized to either 1% azithromycin in DuraSite or vehicle for five days. Infected eyes were dosed twice daily on days 1 and 2 and once daily on days 3 through 5. Conjunctival cultures were obtained at baseline, visit 2 (day 3 or 4), and visit 3 (day 6 or 7). The primary end point was clinical resolution of signs and symptoms (rating of zero on ocular discharge, bulbar and palpebral injection) at visit 3. Efficacy measures were clinical resolution and bacterial eradication as evaluated in the per-protocol population. Safety was assessed by adverse events, slit-lamp findings, and ophthalmoscopy. RESULTS: Two hundred and seventy-nine participants (n = 130, 1% azithromycin in DuraSite; n = 149, vehicle), age one to 96 years, were evaluated for efficacy. Clinical resolution with azithromycin ophthalmic solution was statistically significant compared with that of vehicle (P = .030) at visit 3. Bacterial eradication rates with azithromycin ophthalmic solution reached 88.5% at visit 3 (P < .001) and included some pathogens resistant to azithromycin in vitro. Overall, adverse event rates were similar in both treatment groups. CONCLUSIONS: Azithromycin 1% ophthalmic solution in DuraSite showed statistically significant differences in clinical resolution and bacterial eradication rates when compared with vehicle. Because it was well tolerated in this population, it may be a viable treatment option for children and adults with bacterial conjunctivitis.

Phase 3 safety comparisons for 1.0% azithromycin in polymeric mucoadhesive eye drops versus 0.3% tobramycin eye drops for bacterial conjunctivitis.

PURPOSE: To compare the safety and tolerability of 1.0% azithromycin in a polymeric mucoadhesive delivery system with 0.3% tobramycin ophthalmic solution for the treatment of bacterial conjunctivitis. METHODS: This study was a prospective, randomized, active-controlled, double-masked, phase 3 trial conducted from August 6, 2004, to October 6, 2005, at 47 sites. Subjects with a clinical diagnosis of bacterial conjunctivitis were randomly assigned to receive either 1% azithromycin in DuraSite (AzaSite; InSite Vision, Alameda, CA) (n = 365) or 0.3% tobramycin (n = 378). Both groups received masked medication four times daily for 5 days, but participants received an active dose of 1% azithromycin in DuraSite only twice a day on days 1 and 2 and daily on days 3 to 5. Conjunctival cultures were taken, and ocular signs and symptoms were evaluated at baseline and at two follow-up visits. RESULTS: A total of 743 patients were randomized, and 710 (96%) completed the trial. Both study medications were well tolerated. The most frequently observed ocular adverse events in the azithromycin group were eye irritation (1.9%), conjunctival hyperemia (1.1%), and worsening bacterial conjunctivitis (1.1%). These rates compared favorably with those obtained with tobramycin. Rates of microbial eradication (an efficacy parameter) and bacterial infection recurrence (a safety parameter) were the same in both groups. CONCLUSIONS: This is the first report of the safety and tolerability of a commercially manufactured preparation of azithromycin for ophthalmic use. Azithromycin 1% in DuraSite is safe and can be administered in a regimen of less frequent doses than can tobramycin, while producing an equivalent clinical outcome. The formulation is well tolerated in patients over the age of 1 year for the eradication of bacteria commonly associated with conjunctivitis. (ClinicalTrials.gov number, NCT00105469.).

A randomized trial assessing the clinical efficacy and microbial eradication of 1% azithromycin ophthalmic solution vs tobramycin in adult and pediatric subjects with bacterial conjunctivitis.

OBJECTIVE: The study was designed to evaluate the efficacy of an ophthalmic formulation of 1% azithromycin in DuraSite((R)) (AzaSite, InSite Vision, Alameda CA, USA) and demonstrate equivalence with 0.3% tobramycin ophthalmic solution, USP, for the treatment of bacterial conjunctivitis as defined by the resolution of clinical signs and the eradication of pathogens. DESIGN: Prospective, randomized, active-controlled, double-masked, phase 3 trial conducted at 47 US sites between 6 August 2004 and 6 October 2005. PARTICIPANTS: Subjects aged 1 year or older with diagnosis of acute bacterial conjunctivitis. METHODS: Bacteriologically confirmed participants received either 1% azithromycin in Dura-Site (n = 159) or tobramycin (n = 157). Masked study medications were dosed 4 times a day for 5 days. Participants in the 1% azithromycin in DuraSite group were dosed twice a day with active drug on days 1 and 2 and once daily on days 3 through 5. The other doses were vehicle. Clinical signs and bacterial cultures were evaluated at visit 3 (day 6 + 1). RESULTS: Clinical resolution was observed in 79.9% of participants in the 1% azithromycin in DuraSite group, as compared with 78.3% of those in the tobramycin group (95% CI: -7.4-10.5). Bacterial eradication was 88.1% in the 1% azithromycin in DuraSite group vs 94.3% in the tobramycin group (95% CI: -12.4-0.0). Analyses of resistance confirmed that 1% azithromycin in DuraSite eradicated Staphylococci and Streptococci strains that are commonly resistant to azithromycin, erythromycin, and fluoroquinolones. CONCLUSIONS: The efficacy of 1% azithromycin in DuraSite and tobramycin are equivalent; however, this formulation of azithromycin also permits effective dosing intervals of twice a day on days 1 and 2 followed by once daily on the last 3 days of therapy, for a total of 65% fewer doses. In vitro, the killing spectrum of 1% azithromycin in DuraSite appears to be enhanced relative to 1% azithromycin without DuraSite.