The cytotoxic effects of preserved and preservative-free prostaglandin analogs on human corneal and conjunctival epithelium in vitro and the distribution of benzalkonium chloride homologs in ocular surface tissues in vivo.

PURPOSE: To investigate the cytotoxicity of benzalkonium chloride (BAC)-containing ophthalmic solutions of prostaglandin analogs (latanoprost, travoprost, bimatoprost, and preservative-free (PF) tafluprost), BAC mixture (BACmix) and BAC homologs with different alkyl chain lengths using human corneal epithelial (HCE) and conjunctival epithelial (IOBA-NHC) cell cultures. The distribution of BAC homologs in rabbit ocular surface tissues in vivo was examined. METHODS: The cells were exposed for one hour to prostaglandin analogs, BACmix and three homologs. Cytotoxicity was assessed with the WST-1 and lactate dehydrogenase (LDH) assays for cellular viability and cell membrane integrity. BAC 0.02% solution was instilled on the rabbit eye daily for 14 days and the concentrations of BAC homologs in external ocular tissues were determined. RESULTS: The order of decreasing cytotoxicity in the WST-1 test was latanoprost ≥ travoprost > bimatoprost ≥ PF tafluprost. IOBA-NHC cells were more sensitive than HCE cells. In HCE, only latanoprost diluted to 10% increased LDH leakage. In IOBA-NHC, LDH leakage was statistically significant with 3-10% travoprost and 10% latanoprost. The order of decreasing cytotoxicity of preservatives was C14 > C12 > BACmix > C16 in HCE and C12 > C14 > BACmix > C16 in IOBA-NHC. Following treatment with BAC 0.02% solution, the amounts of BAC-C12, -C14 and -C16 in rabbit cornea and conjunctiva, respectively were: 0.37 ± 0.08 and 2.64 ± 0.27 ng/mg; 0.42 ± 0.07 and 4.77 ± 0.43 ng/mg; 0.04 ± 0.01 and 0.54 ± 0.05 ng/mg. CONCLUSIONS: The cytotoxic effects of latanoprost, travoprost, and bimatoprost were dependent on the BAC concentration in their formulations. BACmix was cytotoxic at the concentrations above those corresponding to 0.001% BAC in ophthalmic medications. PF tafluprost was the least toxic of the drugs tested. Within studied BAC homologs, those with longer alkyl chain and higher lipophility penetrated effectively into rabbit external ocular tissues.

Corneal penetration into rabbit aqueous humor is comparable between preserved and preservative-free tafluprost.

BACKGROUND: Some studies have shown that benzalkonium chloride (BAK), a preservative used in antiglaucoma medications, can increase corneal permeability by acting as a penetration enhancer. Tafluprost is a new prostaglandin F(2)(alpha) analog in clinical use for the treatment of ocular hypertension and glaucoma. METHODS: This study evaluated the corneal penetration of preservative-free tafluprost 0.0015% eye drops and tafluprost 0.0015% eye drops preserved with 0.01% BAK into the aqueous humor of rabbits. RESULTS: After the administration of a single topical dose (30 microl), the maximum concentrations at 45 min of tafluprost acid in aqueous humor were 4.50 ng/ml for preservative-free tafluprost and 3.99 ng/ml for preserved tafluprost. The area under the concentration-time curves from 45 min to 3 h was 5.14 ng h/ml for the preservative-free formulation and 4.54 ng h/ml for the preserved formulation. CONCLUSIONS: These data indicate that BAK does not affect the corneal penetration of tafluprost into the rabbit aqueous humor.

Increased anterior chamber penetration of topical levofloxacin 0.5% after pulsed dosing in cataract patients.

PURPOSE: This study aimed to investigate the rise in aqueous humour (AH) levels of levofloxacin after a specific perioperative pulsed topical drop regimen. METHODS: Thirty patients undergoing phacoemulsification surgery were administered two preoperative drops of levofloxacin 0.5%, 30 mins apart, and three pulsed drops postoperatively, 5 mins apart. Aqueous humour levels of levofloxacin were measured at the start of surgery and from 5 mins to 90 mins after the last postoperative drop. Samples from individual patients were collected at the time of surgery and at one additional sampling interval by aqueous tap, and analysed using a high-performance liquid chromatography assay. RESULTS: Aqueous humour levels of levofloxacin continued to rise gradually, reaching a mean peak level (C(max)) of 4.4 microg/ml (+/- 2.5) at 60 mins after the last postoperative drop was administered. This level exceeded the minimum inhibitory concentration of common ocular pathogens at least fourfold. At 90 mins after the last drop, mean AH levels remained > 3 microg/ml. CONCLUSIONS: This is the first study to measure AH levels of levofloxacin after postoperative pulsed dosing in humans. Higher AH levels were found than in previously reported studies in which only preoperative drops were given and levels were measured at the time of surgery. Levels of levofloxacin continued to rise for 60 mins after administration of the last postoperative drop, demonstrating that delivery and maintenance of effective antibiotic levels may be achievable with alternative dosing schedules.

Penetration of topically applied levofloxacin 0.5% and ofloxacin 0.3% into the vitreous of the non-inflamed human eye.

BACKGROUND: The aim of the study was to evaluate the vitreous penetration of two commercially available ophthalmic fluoroquinolones: ofloxacin and levofloxacin. METHODS: This prospective, double-blind, randomized clinical trial comprised 16 patients scheduled for vitrectomy surgery of one eye for macular hole or macular pucker. The patients were randomly assigned to receive topical ofloxacin 0.3% (n=9) or levofloxacin 0.5% (n=7) the day before, one drop at noon, 4 p.m., 8 p.m. and midnight. The next morning, patients were given their assigned masked antibiotic every 5 min for four doses starting 1 h before surgery. The vitreous humour samples, at least 0.3 ml each, were collected 1 h after the administration of the last dose, at the beginning of the pars plana vitrectomy with infusion disconnected. Samples were assayed for ofloxacin and levofloxacin concentrations by a method using high-performance liquid chromatography (HPLC) coupled with single mass spectrometry with electrospray ionization RESULTS: Equal topical administration of levofloxacin yielded 2.5 times higher vitreal concentration than ofloxacin. The mean vitreous concentrations of ofloxacin and levofloxacin were 5.30+/-3.04 (SD) ng/ml and 13.09+/-5.24 ng/ml, respectively (P=0.002). CONCLUSIONS: Equal dosing with topical administration of levofloxacin 0.5% and ofloxacin 0.3% allows better penetration into the vitreous for levofloxacin, but the levels of mean concentrations of each drug did not exceed the MIC(90) or MIC(50) for most ocular pathogenic bacteria in terms of conventional endophthalmitis therapy.