Comparing the effect of benzalkonium chloride-preserved, polyquad-preserved, and preservative-free prostaglandin analogue eye drops on cultured human conjunctival goblet cells.

PURPOSE: To investigate the effect of benzalkonium chloride (BAK)-preserved latanoprost and bimatoprost, polyquad (PQ)-preserved travoprost, and preservative-free (PF) latanoprost and tafluprost, all prostaglandin analogues (PGAs), on human conjunctival goblet cell (GC) survival. Furthermore, to investigate the effect of BAK-preserved and PF latanoprost on the cytokine secretion from GC. METHODS: Primary human conjunctival GCs were cultivated from donor tissue. Lactate dehydrogenase (LDH) and tetrazolium dye colorimetric (MTT) assays were used for the assessment of GC survival. A cytometric bead array was employed for measuring secretion of interleukin (IL)-6 and IL-8 from GC. RESULTS: BAK-preserved latanoprost and bimatoprost reduced cell survival by 28% (p = 0.0133) and 20% (p = 0.0208), respectively, in the LDH assay compared to a negative control. BAK-preserved latanoprost reduced cell proliferation by 54% (p = 0.003), BAK-preserved bimatoprost by 45% (p = 0.006), PQ-preserved travoprost by 16% (p = 0.0041), and PF latanoprost by 19% (p = 0.0001), in the MTT assay compared to a negative control. Only PF tafluprost did not affect the GCs in either assay. BAK-preserved latanoprost caused an increase in the secretion of pro-inflammatory IL-6 and IL-8 (p = 0.0001 and p = 0.0019, respectively) compared to a negative control, which PF latanoprost did not. CONCLUSION: BAK-preserved PGA eye drops were more cytotoxic to GCs than PQ-preserved and PF PGA eye drops. BAK-preserved latanoprost induced an inflammatory response in GC. Treatment with PF and PQ-preserved PGA eye drops could mean better tolerability and adherence in glaucoma patients compared to treatment with BAK-preserved PGA eye drops.

Generic benzalkonium chloride-preserved travoprost eye drops are not identical to the branded polyquarternium-1-preserved travoprost eye drop: Effect on cultured human conjunctival goblet cells and their physicochemical properties.

PURPOSE: To investigate the effect of polyquaternium-1 (PQ)-preserved and benzalkonium chloride (BAK)-preserved travoprost eye drops on viability of primary human conjunctival goblet cell (GC) cultures and on secretion of mucin and cytokines. Furthermore, to evaluate the physicochemical properties of the branded travoprost eye drop Travatan® and available generics. METHODS: The effect of travoprost eye drops was evaluated on GC cultures. Cell viability was assessed through lactate dehydrogenase (LDH) and tetrazolium dye (MTT) colorimetric assays. Mucin secretion was evaluated by immunohistochemical staining. Secretion of interleukin (IL)-6 and IL-8 was measured using BD Cytometric Bead Arrays. pH, viscosity, droplet mass, osmolality and surface tension were measured for all included eye drops. RESULTS: In the LDH assay, BAK travoprost caused significant GC loss after 2 hrs of incubation compared to the control. PQ travoprost caused no GC loss at any time point. Both PQ- and BAK travoprost caused secretion of mucin to the cytoplasma. No difference in IL-6 and IL-8 secretion was identified compared to controls. The pH values for the generics were lower (pH 6.0) than the pH value for Travatan (pH 6.7; p < 0.0001). The viscosity was lowest for Travatan, while the mean droplet mass was higher for Travatan (35 mg) than the generics (28-30 mg; p ≤ 0.0318). The osmolality and surface tension did not differ between the eye drops investigated. CONCLUSION: BAK travoprost caused GC loss, indicating that PQ preservation may be preferable in treatment of glaucoma. Furthermore, physicochemical properties of branded and generic travoprost eye drops can not be assumed to be identical.

In Vitro Corneal and Conjunctival Wound-Healing Assays as a Tool for Antiglaucoma Prostaglandin Formulation Characterization.

BACKGROUND: Benzalkonium chloride (BAK)-containing antiglaucoma therapies alter the ocular surface over the long term. We used an in vitro scraping model to compare the effects of preserved and unpreserved topical commercial prostaglandins (PGs) in a wound-healing model. METHODS: Standardized mechanical scraping was performed in confluent immortalized human corneal/conjunctival epithelial cell layers. Cytotoxicity, cell migration and proliferation, as well as the percentage of closure, were analyzed 2 h and 1/2/3/6 days after a 30-min exposure to 1/10 dilutions in phosphate buffered saline (PBS) used also as control, BAK solutions at concentrations ranging from 0.0001% to 0.1%, latanoprost-0.02%BAK, travoprost-0.015%BAK, bimatoprost-0.005%BAK, BAK-free Tafluprost, latanoprost in cationic emulsion, and travoprost (Polyquad® and SofZia®). RESULTS: PG eyedrop preparations with BAK preservative delayed corneal healing, which is primarily related to the presence of BAK, in a dose-dependent manner, especially at day 1, as evidenced through actin disorganization and decreased Ki-67-positive cell numbers. The PGs (BAK-free tafluprost, latanoprost in cationic emulsion,travoprost (Polyquad® and SofZia®)) maintained a normal healing process with results similar to those of control. Conjunctiva-derived cell layers healed more slowly than corneal cell layers and were more sensitive in in vitro cytotoxicity tests. CONCLUSIONS: This novel in vitro scraping model mimics the damaged ocular surface epithelia observed in glaucoma patients affected by ocular surface disease, such as toxic-induced dry eye (TIDE) and offers a tool to assess the potential cytotoxic effects of PG formulations with or without BAK.

Effect of travoprost, latanoprost and bimatoprost PGF2α treatments on the biomechanical properties of in-vivo rabbit cornea.

Prostaglandin F2α analogues (PGF2α), one of the most commonly prescribed classes of hypotensive agents, could decrease collagen fibril density and remodel the extracellular matrix in cornea. We hypothesized that PGF2α's would induce corneal softening, reduce the accuracy of intraocular pressure (IOP) measurement and lead to uncertainty in the effectiveness of the therapy. We determined the stress-strain behavior of rabbit cornea after PGF2α usage and evaluated the effect of biomechanical changes associated with PGF2α treatment on IOP measurements by Goldmann Applanation Tonometry (GAT). The tangent modulus decreased after PGF2α treatment, while the stromal interfibrillar spacing increased. PGF2α was shown to also affect the lateral eye with lower effect, which did not undergo direct eyedrop treatment. Significant decreases in the numerical predictions of GAT-IOP were predicted in all treated groups relative to control groups. Different PGF2α's (travoprost, latanoprost and bimatoprost) were associated with different extents of reduction in tissue stiffness and changes in corneal microstructure. PGF2α-induced changes in corneal mechanical properties could reduce the accuracy of IOP measurement and may cause an overestimation of the effect of PGF2α in lowering IOP, possibly leading to uncertainties in glaucoma management.

NCX 1741, a Novel Nitric Oxide-Donating Phosphodiesterase-5 Inhibitor, Exerts Rapid and Long-Lasting Intraocular Pressure-Lowering in Cynomolgus Monkeys.

Purpose: We studied the IOP-lowering effects of NCX 1741, a novel nitric oxide (NO)-donating derivative of the phosphodiesterase type-5 inhibitor, avanafil, in Cynomolgus monkey with laser-induced ocular hypertension (OHT-monkeys). NCX 1193 (NO-donating moiety), NCX 1744 (NCX 1741 without ester nitrate moiety), and travoprost (PGF2α analogue) were used for comparison. Ocular exposure after NCX 1741 dosing also was addressed. Methods: Vehicle (phosphate buffer pH 6.0, Kolliphor® 5%, DMSO 0.3%, benzalkonium chloride 0.02%), NCX 1741, NCX 1193, NCX 1744, or travoprost were instilled (30 µL; single dose) masked and conscious IOPs were measured by pneumatonometry. LC-MS/MS-based methods were employed to monitor ocular exposure of NCX 1741 and main metabolites after ocular dosing in New Zealand White rabbits. Results: NCX 1741 (2.2%, 0.8 µmol/eye) lowered IOP with an Emax (ΔΔIOP, IOP change vs. pre-dose and vehicle) between 5 and 8 h post-dosing (ΔΔIOP5h, -5.3 ± 2.0 mmHg and ΔΔIOP8h, -6.0 ± 2.1 mmHg). Conversely, equimolar (0.47%, 0.8 µmol/eye) NCX 1193 IOP-lowering effects were maximal 3 h post-dosing (ΔΔIOP3h, -4.7 ± 1.6 mmHg) and declined thereafter (ΔΔIOP5h, -1.6 ± 1.1 mmHg). In a follow-up study, NCX 1741 (1.5%, 0.5 µmol/eye) was more effective than NCX 1744 despite a similar duration. Further, NCX 1741 was as effective as travoprost (0.1%, 0.06 µmol/eye) at 5 and 8 h post-dosing (travoprost, ΔΔIOP5h, -3.4 ± 2.2 mmHg and ΔΔIOP8h, -4.9 ± 1.3 mmHg) but had shorter duration (NCX 1741, ΔΔIOP24h, -1.5 ± 1.1 mmHg; travoprost, ΔΔIOP24h, -7.1 ± 2.8 mmHg). NCX 1741 resulted in significant aqueous humor exposure, as determined by the levels of the main metabolite, avanafil. Conclusions: NCX 1741 rapidly and effectively lowers IOP in OHT-monkeys for several hours post-dosing. How these effects translate in humans is still to be defined.

Biomechanical Effects of Two Forms of PGF2α on Ex-vivo Rabbit Cornea.

PURPOSE: To investigate the biomechanical effects of two synthetic prostaglandin F2α analogues (PGF2α), namely Travoprost and Tafluprost, on the ex-vivo rabbit cornea. MATERIALS AND METHODS: Ninety-six eyes of 48 Japanese white rabbits were divided into 3 equal groups randomly; the Travoprost treated group (Tra), the Tafluprost treated group (Taf) and the control group (Co). Eyes in Tra and Taf groups were preserved in storage medium for 10 days with 1:10 Travoprost and Tafluprost diluents, respectively; while the Co eyes were preserved in a similar but PGF2α-free medium. Twenty-four corneas of each group were tested under inflation conditions with up to 30 mmHg posterior pressure. The pressure-deformation data obtained experimentally were used in an inverse analysis process to derive the stress-strain behavior of the tissue, using which the tangent modulus, a direct measure of the tissue's material stiffness, was calculated. The remaining eight specimens of each group were analyzed using electron microscopy for fibril diameter and interfibrillar spacing. RESULTS: Although the central corneal thickness increased significantly in the three groups after storage (p < .01), it was similar in all groups both before (p = .598) and after storage (p = .181). After treatment with Travoprost and Tafluprost, the corneas exhibited lower tangent modulus (by 29.2% and 29.8%, respectively, at 6 kPa stress) and larger stromal interfibril spacing (by 21.9% and 23.6%) compared with the control group. There was no significant change in fibril diameter with either Travoprost or Tafluprost treatment (p = .769). CONCLUSIONS: The results demonstrated significant reductions in tangent modulus and increases in interfibrillar spacing, which were of similar magnitudes, with the application of two different forms of PGF2α.

Self-assembled DNA nanoparticles loaded with travoprost for glaucoma-treatment.

Lipid DNA nanoparticles (NPs) exhibit an intrinsic affinity to the ocular surface and can be loaded by hybridization with fluorophore-DNA conjugates or with the anti-glaucoma drug travoprost by hybridizing an aptamer that binds the medication. In the travoprost-loaded NPs (Trav-NPs), the drug is bound by specific, non-covalent interactions, not requiring any chemical modification of the active pharmaceutical ingredient. Fluorescently labeled Trav-NPs show a long-lasting adherence to the eye, up to sixty minutes after eye drop instillation. Biosafety of the Trav-NPs was proved and in vivo. Ex vivo and in vivo quantification of travoprost via LC-MS revealed that Trav-NPs deliver at least twice the amount of the drug at every time-point investigated compared to the pristine drug. The data successfully show the applicability of a DNA-based drug delivery system in the field of ophthalmology for the treatment of a major retinal eye disease, i.e. glaucoma.

Effects of a prostaglandin F2alpha derivative glaucoma drug on EGF expression and E-cadherin expression in a corneal epithelial cell line.

Purpose: We examined the effects of travoprost on cell proliferation-related signals and E-cadherin expression in vitro and in situ in order to obtain evidence to support the hypothesis that topical travoprost impairs the integrity of the corneal epithelium.Methods: A human corneal epithelial cell culture was treated with travoprost (0.4 mg/ml) and/or PD168393 (an EGF receptor inhibitor, 10 µM). The culture was then processed for cell proliferation, an mRNA expression analysis of epidermal growth factor (EGF) and E-cadherin, and protein expression analysis of E-cadherin by immunocytochemistry and Western blotting. The eyes of C57/BL6 mice were incubated in serum-free medium plus travoprost (0.4 mg/ml) and/or PD168393 (10 µM). After being cultured for 24 h, the expression patterns of phospho-EGFR, phospho-ERK, E-cadherin, and Ki67 were immunohistochemically examined in paraffin sections.Results: The addition of travoprost up-regulated EGF mRNA expression and cell proliferation in the corneal epithelial cell culture, and this was cancelled by the addition of PD168393. This FP agonist also decreased E-cadherin expression levels in the cell-cell contact zone, and this was cancelled by the addition of PD168393. In the organ culture, the addition of travoprost to the medium up-regulated the expression of phospho-EGFR and phospho-ERK as well as cell proliferation, and down-regulated the expression of E-cadherin in the corneal epithelium, particularly in basal cells, whereas PD168393 reversed these effects.Conclusions: Travoprost activates epithelial cell proliferation by up-regulating an EGF-related signal in association with the suppression of E-cadherin localization in the cell-cell contact zone. Modulation of the EGF signal may be a strategy to minimize the negative impact of this mitogen on reformation of corneal barrier function during epithelial renewal.

Decreasing intraocular pressure significantly improves retinal vessel density, cytoarchitecture and visual function in rodent oxygen induced retinopathy.

We attempted to explore a noninvasive, easily applicable and economically affordable therapy for retinopathy of prematurity (ROP). Rat pups were raised in 80% oxygen from postnatal day 7 to P12, and returned to room air. Travoprost eye drops were administered twice a day for 7 days, to reduce intraocular pressure (IOP) by about 20%. Immunohistochemical staining was performed to visualize vessel endothelial cells, to analyze retinal neurons and cytoarchitecture. Behavioral experiments were carried out to test visual acuity and contrast sensitivity. At the end of the 7-day treatment, the number of vessels extending to the vitreous body was significantly reduced and retinal vessel density increased. This improvement was maintained to the end of the 12th week. In the central retina of the model group, the horizontal cells were completely wiped out, the outer plexiform layer was undetectable, and the rod bipolar cell dendrites sprouted into the outer nuclear layer. The treatment partially reverted these architectural changes. Most importantly, behavioral experiments revealed significantly improved visual acuity and contrast sensitivity in the treated group. Therefore, reducing IOP could potentially serve as a safe and economical measure to treat ROP.

Effects of Anti-Glaucoma Prostaglandin Ophthalmic Solutions on Cultured Human Corneal Epithelial Cells.

Purpose: We compare the cytotoxicity of anti-glaucoma prostaglandin ophthalmic solutions on human corneal epithelial cells and elucidate mechanisms of toxicity. Methods: Cell viability was examined using MTS assay, and morphological changes of the cells were observed. Induction of necrosis/apoptosis was measured by colorimetric caspase assay. The production of Reactive oxygen species (ROS) and release of cytokines were analyzed using 2', 7'-dichlorodihydrofluorescein diacetate and bead-based indirect immunofluorescent assay, respectively. Results: Xalatan, Lumigan 0.01%, and Lumigan 0.03% decreased cell viability and induced morphological changes. Xalatan and Lumigan 0.01% induced necrosis. Xalatan, Lumigan 0.01%, Lumigan 0.03%, and Taflotan stimulated ROS production. Travatan and Lumigan 0.03% increased concentrations of Interleukin (IL)-6 and IL-8 in culture media. Conclusions: Xalatan and Lumigan 0.01% ophthalmic solutions demonstrated potent cytotoxicity compared with Lumigan 0.03%, Travatan, Taflotan, and Taflotan UD. Taflotan UD, compared to Taflotan 0.0015%, induced less oxidative stress and apoptotic signalling. The cytotoxicity might be partly associated with benzalkonium chloride.

Experimental Evaluation of Travoprost-Induced Changes in Biomechanical Behavior of Ex-Vivo Rabbit Corneas.

Purpose: To assess the effects of prostaglandin F2α analogues travoprost on the biomechanical behavior of ex-vivo rabbit cornea. Materials and Methods: 18 Japanese white rabbits were included in the study. The left eye (treated group, Tr) of each rabbit was preserved for 10 days in storage medium Eusol-C solution with 1:10 travoprost diluent, while the contralateral eye (control group, Co) was preserved in a similar but travoprost-free medium. Strips of corneal tissue were dissected and tested under cyclic load conditions with up to 0.1 N uniaxial tension force. The resulting load-elongation data were used to derive the stress-strain behavior and the tangent modulus (Et) of the tissue. Differences in Et between the treated (Et-Tr) and control group (Et-Co) were assessed statistically to determine the biomechanical effects of travoprost on the cornea. Results: Central corneal thickness (CCT) in the two groups was similar before (P = 0.073) and remained similar after storage (P = 0.303) although it became significantly thicker in both groups after preservation (P < 0.01). Compared with the control group, the travoprost treated corneas exhibited lower Et values but the differences reduced and became insignificant with rises in stress to which the tissue was subjected (1 - Et-Tr/Et-Co = -11.7 ± 41.8%, P < 0.05 at 10 kPa stress; -9.2 ± 36.1%, P > 0.05 at 20 kPa; -7.3 ± 35.4%, P > 0.05 at 30 kPa). Conclusions: Significant reductions in corneal stiffness, that are associated with the use of travoprost, were observed experimentally under low applied stresses. This stiffness-reduction effect should be considered in clinical management, especially in primary open angle glaucoma treatment.

The Effects of Latanoprost With Benzalkonium Chloride Versus Travoprost With SofZia on the Ocular Surface.

PURPOSE: To assess ocular surface changes in participants using latanoprost with benzalkonium chloride (Xalatan) and travoprost with SofZia (Travatan Z). METHODS: In this prospective, open-label, nonrandomized cohort study, participants were classified into two groups: group 1 (n=28) naive to glaucoma therapy, group 2 (n=27) on previous Xalatan monotherapy in both eyes. Both groups started (or continued) Xalatan in the right eye and Travatan Z in the left eye. Baseline, 1-, and 2-month measurements of tear breakup time (TBUT), corneal staining score, conjunctival staining score, conjunctival hyperemia score, tear production, and intraocular pressure were obtained. The Ocular Surface Disease Index questionnaire measured participants' comfort and dryness symptoms. Medication preference was recorded. RESULTS: Data were collected from 55 participants. Tear breakup time at baseline and 1-month follow-up in group 1 was significantly longer than that of group 2 (P=0.005). At 2 months, there was no significant difference in TBUT between the two groups (P=0.779). Tear production in group 1 at all three time points was significantly higher than group 2 (P<0.05). Conjunctival staining score at 2 months in group 1 was significantly higher than group 2 (P=0.031). There was no significant difference in other parameters between the groups at any other time point. No significant difference in any parameter was found between Xalatan and Travatan Z (intragroup comparison). CONCLUSIONS: Significant differences in ocular surface characteristics were detected between groups, but no significant difference was detected between participants treated with Xalatan and Travatan Z.

Effect of Travoprost and Nonsteroidal Anti-Inflammatory Drug on Diurnal Intraocular Pressure in Normal Subjects with Low-Teen Baseline Intraocular Pressure.

PURPOSE: The main purpose was to determine whether a nonsteroidal anti-inflammatory drug (NSAID) ophthalmic solution would affect the intraocular pressure (IOP)-lowering effect of a benzalkonium chloride (BAK)-free prostaglandin analog, travoprost. The secondary purpose was to confirm the IOP-lowering effect of BAK-free travoprost on the diurnal IOP. METHODS: This was a prospective, randomized, double-blind, placebo-controlled 1-month trial. After baseline diurnal IOP was confirmed, travoprost was administered once daily to both eyes. Bromfenac sodium hydrate was then randomly assigned to one eye, while flavin adenine dinucleotide sodium was applied to the other eye as a control. Both solutions were administered twice daily. IOP was measured three times daily (8:00, 14:00, and 20:00). The IOP of both groups was compared using Student's t-test. The effect of NSAID on IOP was investigated by repeated measures analysis of variance (ANOVA). RESULTS: Twenty-eight normal Japanese subjects (mean age, 36.6 years) completed the study. After the start of travoprost, remarkable IOP lowering was gained and it settled to 10-11 mmHg. The diurnal IOPs of the NSAID group showed similar tendencies to that of the control group (P = 0.69-1.0). In a 1-month period, the range of IOP reductions compared with the baseline IOP of both groups showed no significant difference (P = 0.76-0.92). NSAID did not have an influence on IOP (F-value = 0.0036, P = 0.95). CONCLUSIONS: Although BAK-free travoprost showed a powerful IOP-lowering effect in diurnal and 1-month readings, even in eyes with an IOP of <13 mmHg, the NSAID ophthalmic solution did not affect its IOP-lowering effect.

Effects of prostaglandin analogs on blood flow velocity and resistance in the ophthalmic artery of rabbits.

PURPOSE: The aim of this study was to investigate the effects of prostaglandin analogs on blood flow in the ophthalmic artery of clinically healthy rabbits. METHODS: Fifty-five clinically healthy New Zealand white rabbits were divided into six groups, and the left eyes were treated for four weeks with the preservative benzalkonium chloride (BAK) only or a topical formulation of different prostaglandin analogs (bimatoprost BAK, tafluprost BAK-free, travoprost BAK, travoprost POLYQUAD, and latanoprost BAK). Color Doppler imaging was performed before and after the treatments. The mean values of the peak systolic velocity (PSV) and end diastolic velocity and the resistive index (RI) were calculated. Statistical analysis was performed to compare the differences pre- and post-treatment for each drug and post-treatment among the drugs. RESULTS: The prostaglandin analogs did not affect PSV. Bimatoprost BAK, travoprost POLYQUAD, and latanoprost BAK did not change RI. Tafluprost BAK-free and travoprost BAK therapy resulted in similar reductions in RI. No significant differences pre- and post-treatment were found when BAK was administered alone. CONCLUSION: The prostaglandin analogs tafluprost BAK-free and travoprost BAK improved blood flow in the ophthalmic artery in healthy New Zealand white rabbits, which suggests that these drugs enhance the prevention of the progression the progression of glaucoma.

Effects of prostaglandin analogs on blood flow velocity and resistance in the ophthalmic artery of rabbits / Efeitos dos análogos da prostaglandina na velocidade do fluxo sanguíneo e resistência na artéria oftálmica de coelhos

ABSTRACT Purpose: The aim of this study was to investigate the effects of prostaglandin analogs on blood flow in the ophthalmic artery of clinically healthy rabbits. Methods: Fifty-five clinically healthy New Zealand white rabbits were divided into six groups, and the left eyes were treated for four weeks with the preservative benzalkonium chloride (BAK) only or a topical formulation of different prostaglandin analogs (bimatoprost BAK, tafluprost BAK-free, travoprost BAK, travoprost POLYQUAD, and latanoprost BAK). Color Doppler imaging was performed before and after the treatments. The mean values of the peak systolic velocity (PSV) and end diastolic velocity and the resistive index (RI) were calculated. Statistical analysis was performed to compare the differences pre- and post-treatment for each drug and post-treatment among the drugs. Results: The prostaglandin analogs did not affect PSV. Bimatoprost BAK, travoprost POLYQUAD, and latanoprost BAK did not change RI. Tafluprost BAK-free and travoprost BAK therapy resulted in similar reductions in RI. No significant differences pre- and post-treatment were found when BAK was administered alone. Conclusion: The prostaglandin analogs tafluprost BAK-free and travoprost BAK improved blood flow in the ophthalmic artery in healthy New Zealand white rabbits, which suggests that these drugs enhance the prevention of the progression the progression of glaucoma.

RESUMO Objetivo: O objetivo deste estudo foi investigar os efeitos dos análogos da prostaglandina (PGAs) no fluxo sanguíneo da artéria oftálmica em coelhos. Métodos: Cinquenta e cinco coelhos da raça Nova Zelândia clinicamente saudáveis foram divididos em seis grupos para tratamento com formulação tópica de diferentes APGs (bimatoprosta BAK, tafluprosta BAK-free, travoprosta BAK, travoprosta POLYQUAD e latanoprosta BAK) e formulações contendo apenas o conservante cloreto de benzalcônio (BAK). Foi realizada ultrassonografia com Doppler antes e após os tratamentos. Os valores do pico da velocidade sistólica (PSV) e da velocidade diastólica final foram obtidos e o índice de resistência (RI) foi então calculado. A análise estatística foi realizada para comparar as diferenças entre cada droga no pré e pós-tratamento, além das diferenças no pós-tratamento entre as drogas. Resultados: Estes colírios PGAs não afetaram o PSV. A bimatoprosta com o conservante BAK, travoprosta com o conservante POLYQUAD e latanoprosta com o conservante BAK não alteraram o RI. Já o tratamento com tafluprosta sem conservante (BAK-free) e travoprosta com o conservante BAK promoveram redução similar dos valores do RI. Não houve diferença significativa na comparação entre valores pré e pós-tratamento quando BAK foi administrado isoladamente. Conclusão: Os PGAs tafluprosta BAK-free e travoprosta BAK melhoraram o fluxo sanguíneo na artéria oftálmica em coelhos da raça Nova Zelândia sugerindo que estes medicamentos possam contribuir na prevenção da progressão do glaucoma.

Comparison of the ocular surface changes following the use of two different prostaglandin F2α analogues containing benzalkonium chloride or polyquad in rabbit eyes.

OBJECTIVE: The aim of this study is to compare the effect of prostaglandin analogues preserved with either 0.015% or 0.001% benzalkoium chloride (BAK); or 0.001% polyquad (PQ) on the ocular surface of rabbit eyes. METHODS: Forty white rabbits were randomized to receive four-times daily instillation of either 0.0015% tafluprost (TF) preserved with 0.001% BAK (TF-BAK); 0.004% travoprost (TR) with 0.015% BAK (TR-BAK) or 0.001% PQ (TR-PQ); or preservative-free artificial tears in one eye for a 4-week period. Tear samples collected from the 40 rabbits were analyzed by enzyme-linked immunosorbent assays (ELISA) to identify the presence of inflammatory cytokines: interleukin (IL)-1ß and IL-6 on day 14. Subsequently, harvested cornea and bulbar conjunctiva were evaluated using light and transmission electron microscopy (TEM). RESULTS: IL-6 was significantly increased in TF-BAK and TR-BAK groups compared to controls and TR-PQ group (p = 0.005); however, IL-1ß level was not significantly different among four groups (p = 0.360). Rabbits treated with TR-BAK showed decreased goblet cell density of bulbar conjunctiva and increased pyknotic change and vacuolization of corneal epithelial cells on light microscopy; similar change occurred but was less severe in TF-BAK group. The TR-PQ group showed similar results as the controls. The destruction of the microvillar architecture of bulbar conjunctiva and cornea was most prominent in the TR-BAK group. CONCLUSIONS: Preservatives included in the anti-glaucoma eye-drops showed different ocular surface changes according to the concentration and type in the rabbits. Prostaglandin analogues preserved with higher level of BAK may cause more harmful effects on the ocular surface than PQ-preserved medications.