Pharmacokinetic comparisons of bromfenac in DuraSite and Xibrom.

PURPOSE: The purpose of this study was to compare the ocular pharmacokinetics of experimental solutions of bromfenac in DuraSite(®) to Xibrom™ (bromfenac ophthalmic solution) 0.09%. METHODS: The bromfenac content was measured in the aqueous humor of 84 Dutch Belted rabbits after a single dose of either 0.045% or 0.09% bromfenac in DuraSite in the left eye and the commercial preparation in the right eye. The drug content in the aqueous humor was measured at 0.5, 1, 2, 4, 8, 12, and 24 h after instillation. In a separate multi-dose study, rabbits received one drop of the 0.09% experimental or commercial preparation, 3 times daily for 14 days. For both experiments the drug content in ocular tissues was analyzed using liquid chromatography atmospheric pressure ionization tandem mass spectrometry. RESULTS: In single-dose experiments, the concentration of bromfenac in the aqueous humor was higher with the experimental preparations than with the commercial solution. The area under the concentration-time curve of 0.045% and 0.09% bromfenac in DuraSite was ∼2 and 4-fold higher than that of commercial bromfenac ophthalmic solution, 0.09%. After multi-dose experiments, ocular tissue concentrations of bromfenac were ∼3 times higher for the experimental than for the commercial formulation. CONCLUSIONS: The study demonstrates that the DuraSite topical drug delivery system can deliver bromfenac to various ocular tissues and attain considerably higher concentrations than the commercially available eye drop formulation. The higher aqueous concentration sustained with these experimental formulations could broaden the utility of bromfenac and/or reduce the currently approved dosing frequency of this drug.

Ototoxicity of topical azithromycin solutions in the guinea pig.

OBJECTIVE: To investigate possible ototoxic effects of topical azithromycin (AZ) in the guinea pig. DESIGN: A prospective, controlled animal study. SETTING: The University of Texas Southwestern Medical Center at Dallas. PARTICIPANTS: Twenty-three pigmented guinea pigs were given single, unilateral middle ear applications of a solution containing 3% (n = 3), 2% (n = 5), 1% (n = 5), or 0.5% (n = 5) AZ or saline (n = 5). The contralateral ear served as the untreated control. MAIN OUTCOME MEASURES: The animals were observed for behavioral changes for 2 weeks and then humanely killed. The ears were processed for anatomical evaluation. Morphologic changes were analyzed by quantitation of middle ear changes and cochlear inner and outer hair cell loss. Statistical analysis was performed to examine effects by dose. RESULTS: Analysis revealed extensive middle and inner ear changes associated with all formulations of AZ. Moderate correlation was found between the extent of middle ear changes and AZ concentration (r(2) = 0.59), whereas a strong correlation was seen between inner ear damage and AZ concentration (r(2) = 0.94). Both inner and outer hair cells were affected, with inner hair cell damage consistently greater than outer hair cell damage. CONCLUSIONS: The results of this study demonstrate that ototopical AZ can cause middle ear changes and significant hair cell loss in the guinea pig. This finding, together with previous clinical reports, indicates that topical AZ should be used with caution in the clinical setting.

Anti-inflammatory activity of azithromycin as measured by its NF-kappaB, inhibitory activity.

Growing data suggest that the antibiotic azithromycin mediates anti-inflammatory activity through the inhibition of the transcription factor NF-kappaB. The purpose of this study was to compare azithromycin's anti-inflammatory potency with that of hydrocortisone and dexamethasone as measured in an activated NF-kappaB assay. Dose-response curves and the corresponding inhibitory potencies (IC(50)) of azithromycin, hydrocortisone, and dexamethasone were evaluated in a fluorescence assay using A549 cells. All three compounds inhibited TNFalpha stimulated NF-kappaB activity in a dose-dependent manner. IC(50) values of azithromycin, hydrocortisone and dexamethasone were 56 microM, 2.6 nM, and 0.18 nM, respectively. Hydrocortisone was approximately 4 orders of magnitude more potent than azithromycin, while dexamethasone was approximately 14 times as potent as hydrocortisone. In relative terms the anti-inflammatory potency of azithromycin was about 4 orders of magnitude weaker than that of hydrocortisone.

Ocular pharmacokinetics of AzaSite Xtra-2% azithromycin formulated in a DuraSite delivery system.

PURPOSE: The pharmacokinetics of a 2% ocular solution of azithromycin in DuraSite was evaluated in rabbits to determine whether the PK/PD parameters support a once-a-day for three-day therapeutic regimen against bacterial conjunctivitis. MATERIALS AND METHODS: Mean levels of azithromycin were determined in tears, bulbar conjunctiva, cornea, and plasma following a single drop of 2% azithromycin. The levels were determined by HPLC-MS. RESULTS: Concentrations of azithromycin peaked at 30 minutes. At the end of 24 hours, ocular tissue concentrations exceeded the MIC breakpoint for the most common causative pathogens of bacterial conjunctivitis by at least 7-fold. CONCLUSION: The PK/PD profile of 2% azithromycin suggests efficacy against common causative bacteria with just one dose per day for three days.

Development of a topical polymeric mucoadhesive ocular delivery system for azithromycin.

PURPOSE: Azithromycin is an azalide class of antibiotic with pharmacodynamics that have made it a valuable agent in the treatment of soft tissue infections. In ophthalmology, oral administration of azithromycin has been proven effective for the treatment of trachoma. However, topical formulations of azithromycin to treat ocular surface infections have been challenging to develop because of the drug's hydrophobicity and instability in aqueous solutions at pH levels that are comfortable in the eye. The design of a polycarbophil polymer-based delivery system for a topical formulation of azithromycin was evaluated for its ability to provide drug stability, comfort, and increased retention of the formulation in the eye. METHODS: Formulations of 0.5% and 1.0% azithromycin were created in polycarbophil, a lightly cross-linked polyacrylic acid polymer that was adjusted to a viscosity, pH, and osmolality that are suitable for dispensing in the eye. RESULTS: The polycarbophil-based ophthalmic delivery system, DuraSite (InSite Vision, Alameda, CA), helps solubilize azithromycin and retard its degradation in aqueous solution. The formulation was stable at room temperature as well as 5 degrees C. Upon administration of a single drop of 1% azithromycin in DuraSite ophthalmic solution in rabbits' eyes, tear concentrations of azithromycin ranged from 87 to 288 microg/g and high concentrations were sustained for over a 24-h period. CONCLUSIONS: Azithromycin can be developed as an eyedrop in an aqueous ocular delivery system for the treatment of ocular surface infections. The ocular delivery system, DuraSite solubilizes azithromycin at a high concentration in an aqueous solution and protects it from degradation during manufacture and storage. The development of azithromycin in this delivery system enhances the antibiotic's usefulness in ophthalmology for the topical treatment of ocular surface bacterial infections and lid margin diseases.

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.