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.

Efficacy and Safety of the Travoprost Intraocular Implant in Reducing Topical IOP-Lowering Medication Burden in Patients with Open-Angle Glaucoma or Ocular Hypertension.

PURPOSE: A randomized, double-masked, multicenter, phase 2 trial to evaluate the long-term safety and efficacy of travoprost intraocular implant, an extended-release drug delivery system designed to provide uninterrupted sustained intraocular pressure (IOP)-lowering therapy, thereby reducing patient treatment burden and improving adherence with IOP-lowering medication. METHODS: Patients with open-angle glaucoma or ocular hypertension were administered a fast-eluting implant (FE implant, n = 51) and received twice-daily (BID) placebo eye drops, a slow-eluting (SE implant, n = 54) and received BID placebo eye drops, or underwent a sham surgical procedure and received BID timolol 0.5% (n = 49). IOP was measured at baseline, day 1-2, day 10, week 4, week 6, month 3, and every 3 months thereafter through 36 months. Efficacy was evaluated by mean change from 8:00 AM unmedicated baseline IOP through month 36, and the percentage of patients receiving the same or fewer topical IOP-lowering medications as at screening (pre-study). Safety was evaluated by adverse events and ophthalmic parameters. RESULTS: Clinically and statistically relevant IOP-lowering treatment effects were observed through month 36 after a single administration of the travoprost implant compared with BID timolol with mean IOP reductions ranging from 7.6 to 8.8 mmHg for the FE implant group, from 7.3 to 8.0 mmHg for the SE implant group, and from 7.3 to 7.9 for the timolol group at the 8:00 AM timepoint (P < 0.0001 for all treatment groups at all visits). At months 12, 24, and 36, a greater percentage of FE and SE implant patients versus timolol patients were well controlled on the same or fewer topical IOP-lowering medications compared with screening with 63 and 69% for the FE and SE implants groups, respectively, versus 45% for the timolol group at month 36. The safety profile of the implant was favorable; there were no dislodgements, no explantations, no adverse events of conjunctival hyperemia or periorbital fat atrophy, no discontinuations due to study eye adverse events, nor any serious adverse events in the study eye. Comparable changes from baseline in corneal endothelial cell counts were observed in the three treatment groups over the 36 months. CONCLUSION: The travoprost intraocular implant demonstrated robust IOP-lowering and substantially reduced topical IOP-lowering medication burden for up to 36 months following a single administration, while maintaining a favorable safety profile. The travoprost intraocular implant promises to be a meaningful addition to the interventional glaucoma armamentarium by addressing the key shortcomings of topical IOP-lowering medications, including low adherence and topical side effects while controlling IOP for up to 36 months. TRIAL REGISTRY: ClinicalTrials.gov identifier NCT02754596 registered 28 April 2016.

The use of benzalkonium chloride in topical glaucoma treatment: An investigation of the efficacy and safety of benzalkonium chloride-preserved intraocular pressure-lowering eye drops and their effect on conjunctival goblet cells.

ENGLISH SUMMARY: Glaucoma is a leading cause of the global prevalence of irreversible blindness. The pathogenesis of glaucoma is not entirely known, but the major risk factors include advancing age, genetic predisposition, and increased intraocular pressure (IOP). The only evidence-based treatment is a lowering of IOP through the use of eye drops, laser procedures, or surgical interventions. Although laser treatment is gaining recognition as a first-choice treatment option, the most common approach for managing glaucoma is IOP-lowering eye drops. A major challenge in the treatment is the occurrence of adverse events and poor adherence. In this context, the ocular surface is an area of great concern, as most glaucoma patients have dry eye disease (DED), which is largely caused by eye drops. Preservation with benzalkonium chloride (BAK) is a controversial topic due to its potential role as a significant cause of DED. A systematic review and meta-analyses investigate potential differences in efficacy and safety between BAK-preserved and BAK-free anti-glaucomatous eye drops (I). Many of the included studies report on ocular surface damage caused by the application of BAK-preserved eye drops. However, the meta-analyses addressing hyperemia, number of ocular adverse events, and tear break-up time did not identify any significant differences. The latter is likely due to varying measurement methods, different endpoints, and study durations. It is, therefore, possible that the large variations between the studies conceal differences in the safety profiles. The efficacy meta-analysis finds that there are no differences in the IOP-lowering effect between BAK-preserved and BAK-free eye drops, indicating that BAK is not necessary for the effectiveness of eye drops. To promote more homogeneous choices of endpoints and methods when evaluating BAK-preserved and BAK-free glaucoma treatments, a Delphi consensus statement was performed. In this study, glaucoma experts and ocular surface disease experts reached consensus on the key factors to consider when designing such studies (II). The hope is to have more studies with comparable endpoints that can systematically show the potentially adverse effects of BAK. The preclinical studies in the current Ph.D. research focus on conjunctival goblet cells (GCs). GCs are important for the ocular surface because they release the mucin MUC5AC, which is an essential component of the inner layer of the tear film. BAK preservation may damage the GCs and result in a low GC density, leading to an unstable tear film and DED. The most commonly used IOP-lowering drugs are prostaglandin analogs (PGAs). Thus, the conducted studies investigate the effect of PGAs preserved in different ways on GCs. BAK-preserved latanoprost is cytotoxic to primary cultured human conjunctival GCs and results in a scattered expression of MUC5AC, in contrast to negative controls, where MUC5AC is localized around the cell nucleus (III). Preservative-free (PF) latanoprost is not cytotoxic and does not affect the MUC5AC expression pattern. Furthermore, BAK-preserved travoprost is found to be cytotoxic in a time-dependent manner, while Polyquad®-preserved travoprost does not affect GC survival at any measured time point (IV). Both Polyquad and BAK induce scattered expression of MUC5AC. The cytotoxicity of BAK-preserved PGA eye drops is higher compared to the safer profile of PF and Polyquad-preserved PGA eye drops (V). Additionally, PF latanoprost does not increase the release of the inflammatory markers interleukin (IL)-6 and IL-8, unlike BAK-preserved latanoprost. A review highlights the active and inactive components of IOP-lowering eye drops (VI). Several preclinical and clinical studies have identified adverse effects of BAK. Although other components, such as the active drug and phosphates, can also cause adverse events, the review clearly states that BAK alone is a major source of decreased tolerability. The conclusion of this thesis is that BAK preservation is unnecessary and harmful to the ocular surface. The preclinical studies demonstrate that GCs die when exposed to BAK. Furthermore, they find that BAK induces a pro-inflammatory response. The review included in the thesis concludes that BAK should be phased out of eye drops for chronic use. Overall, the inclusion of BAK poses a risk of developing DED and poor adherence, which can ultimately lead to disease progression and blindness.

Effect of retrobulbar prostaglandin analog injection on orbital fat in rats.

PURPOSE: Periorbital fat atrophy is a known side effect of topical prostaglandin analogs (PA). This side effect may have implications in the treatment of diseases like thyroid orbitopathy. In this in vivo study we aimed to evaluate the effects of retrobulbar injection of three different PAs on orbital fat. METHODS: Eighteen adult male Wistar-albino rats were divided into three groups of six animals. 0.1 ml of 0.03% bimatoprost, 0.005% latanoprost, or 0.005% travoprost was injected into the right orbits and saline was injected into the left orbits, as controls. Both orbits were exenterated after 3 weeks. Histological cross-sections were analyzed using ImageJ image analysis software. Intraconal adipocyte density was calculated. RESULTS: There was no significant difference in the adipocyte density between the PA injected orbits and the control side in each of the three groups. When calculations from all three groups were analyzed together, again the difference in the adipocyte density between the PA injected orbits and the control side was not significant. CONCLUSION: No significant fat atrophy was noted in this rat model three weeks after retrobulbar injection of PAs. To evaluate retrobulbar injection of PA as a potential therapy for orbital diseases with fat proliferation, in vivo studies in different animal models, higher concentrations of PA, or longer follow-up duration are required.

Primary Open-Angle Glaucoma Progression in Glaucoma Patients with Unchanged Topical Treatment over 3 Years - Retrospective Observational Cohort Analysis.

BACKGROUND: Lowering intraocular pressure (IOP) is a mainstay of glaucoma therapy. It is, however, still an open question whether a comparable level of long-term IOP lowering achieved by different medications results in comparable protection for the retinal ganglion cells. The purpose of this study was to retrospectively analyze glaucoma damage progression in two cohorts of primary open-angle glaucoma patients with different and unchanged therapy over a period of 3 years, and the main objective of this study was to determine possible differences in terms of structural [retinal nerve fiber layer thickness (RNFL)] and functional [visual field (VF)] outcome. PATIENTS AND METHODS: The retrospective observational cohort analysis compared two differently treated groups of glaucoma patients with their original, at study entry, topical therapy unchanged over 3 years. The main endpoint was the time course of RNFL thickness and VF mean defect (MD). RESULTS: Twenty-one eyes were included in each group. The first group (21 eyes) was on a fixed combination of timolol and dorzolamide twice a day and the second group on one drop of prostaglandin analog, either latanoprost alone (15 eyes) or travoprost alone (6 eyes), in an unchanged regimen over a period of 3 years. IOP in mmHg at baseline and at 36 months was 11.9 ± 2.4 and 13.0 ± 2.1 in the first, and 12.9 ± 3.0 and 14.1 ± 3.2 in the second group, respectively. RNFL thickness values in micrometers were at baseline and at 36 months 77.8 ± 12.3 and 76.6 ± 15.2 in the first, and 77.5 ± 15.2 and 72.8 ± 14.5 in the second group, respectively. VF MD in dB were 1.7 ± 2.5 and 1.2 ± 2.9 in the first, and 0.9 ± 2.3 and 0.7 ± 2.6 in the second group, respectively. CONCLUSION: Both groups had comparable baseline, as well as mean overall IOP. However, the course of IOP levels over time was different in the two groups, showing earlier and more pronounced long-term drift in the prostaglandin analog-treated group. RNFL thickness was comparable at baseline, however, RNFL thinning over time was more pronounced in the prostaglandin analog-treated group. There were no statistical differences between the groups in terms of VF MD at baseline and over time.

Prostaglandin analogs in ophthalmology.

Glaucoma is a major cause of irreversible blindness worldwide. Reducing intraocular pressure (IOP) is currently the only approach to prevent further optic nerve head damage. Pharmacotherapy is the mainstay of treatment for glaucoma patients. In recent years, a significant milestone in glaucoma treatment has been a transition to prostaglandin analogs (PGAs) as the first line of drugs. The rapid shift from traditional ß-blockers to PGAs is primarily due to their excellent efficacy, convenient once-a-day usage, better diurnal control of IOP, and systemic safety profiles. This review article aims to provide information regarding the various PGAs in practice and also the newer promising drugs.

Effects of topical prostaglandin therapy on corneal layers thickness in primary open-angle glaucoma patients using anterior segment optical coherence tomography.

PURPOSE: To evaluate the effects of latanoprost, bimatoprost, and travoprost eye drops and their preservatives on each corneal layer thickness in patients with primary open-angle glaucoma (POAG). METHODS: We retrospectively analyzed 79 eyes of 79 patients with POAG who were receiving prostaglandin therapy. Patients were divided into three subgroups according to monotherapy with latanoprost, bimatoprost, and travoprost during a mean of 43.14 ± 19.12 months follow-up period. In addition, the central corneal epithelial thickness (CET), central corneal stromal thickness (CST), and total central corneal thickness (CCT) were measured by anterior segment optical coherence tomography (AS-OCT) at baseline and every six months after treatment initiation at each visit between 9 and 12 o'clock in the morning. Furthermore, intraocular pressure (IOP) was measured with Goldmann applanation tonometry (GAT) after AS-OCT measurements at each visit. RESULTS: All three groups were not significantly different in age, gender, follow-up period, and mean intraocular pressure values (p > 0.05 for all). The reduction of CCT in the latanoprost, bimatoprost, and travoprost groups was 6.53 ± 3.17, 18.59 ± 8.42, and 10.1 ± 1.13 µm, respectively. The decrease in CST values was 4.65 ± 1.54, 15.84 ± 7.47, 9.69 ± 1.45 µm, and CET values were 1.88 ± 1.66, 2.75 ± 0.73, 0.41 ± 0.54 µm in all groups, respectively. A statistically significant thinning was observed in all corneal layers (p < 0.05) except the CST values in the latanoprost group and CET values in the travoprost group. However, no significant difference was found in the average reduction of CET, CST, and CCT values among the three groups (p > 0.05). CONCLUSION: Topical treatment with latanoprost, bimatoprost, and travoprost affects each layer of the cornea separately according to the active and protective substances contained in these eye drops. On the other hand, the thinning effect on the corneal layers was similar in these three drugs because there was no significant difference between the three groups in the total amount of thinning of the corneal layers during the follow-up period.

Analysing the change in contrast sensitivity post-travoprost treatment in primary open-angle glaucoma patients using Spaeth Richman contrast sensitivity test.

OBJECTIVE: To determine the ability of the Internet-based Spaeth/Richman Contrast Sensitivity (SPARCS) in assessing the change in contrast sensitivity (both central and peripheral) post-treatment with travoprost 0.004%. DESIGN: This is a prospective observational study. METHODS AND PARTICIPANTS: Data of 62 eyes (33 patients) undergoing treatment for naïve POAG patients were analysed. Patients were followed up for a period of six months after starting topical travoprost (Travatan 0.004%, Alcon), and the change in central and peripheral CS was studied. RESULTS: Mean total SPARCS score at baseline was 69 ± 10.99, improved to 74.62 ± 9.50 after 6 months of therapy (p: 0.001) in all the glaucoma severity groups. Mean SPARCS score at baseline in mild glaucoma group was 72.05 ± 9.87, in the moderate glaucoma group, it was 62.23 ± 9.2, and in the severe glaucoma group, it was 59.36 ± 11.65. After 6 months of treatment with travoprost, the CS improved to 76.05 ± 8.36 in mild group, 76.69 ± 8.82 in moderate group and 67.18 ± 11.15 in severe group (p value: 0.014). The percentage change in the CS from baseline showed significant improvement in the superotemporal quadrant at 1 month (p value: 0.032), superonasal quadrant (p value: 0.049), inferotemporal quadrant at 3 months (p value: 0.003) and 6 months (p value: 0.039). Inferonasal quadrant was affected most by glaucoma. A statistically significant correlation was seen between total SPARCS score with MD and PSD. Correlation was also seen between the percentage change in CS and average RNFL thickness at 3 and 6 months. CONCLUSION: Both central and peripheral CS improve following IOP reduction with travoprost. Change in the CS has a significant correlation with RNFL thickness and the perimetric indices.

Identification of CB1 Ligands among Drugs, Phytochemicals and Natural-Like Compounds: Virtual Screening and In Vitro Verification.

Cannabinoid receptor type 1 (CB1) is an important modulator of many key physiological functions and thus a compelling molecular target. However, safe CB1 targeting is a non-trivial task. In recent years, there has been a surge of data indicating that drugs successfully used in the clinic for years (e.g. paracetamol) show CB1 activity. Moreover, there is a lot of promise in finding CB1 ligands in plants other than Cannabis sativa. In this study, we searched for possible CB1 activity among already existing drugs, their metabolites, phytochemicals, and natural-like molecules. We conducted two iterations of virtual screening, verifying the results with in vitro binding and functional assays. The in silico procedure consisted of a wide range of structure- and ligand-based methods, including docking, molecular dynamics, and quantitative structure-activity relationship (QSAR). As a result, we identified travoprost and ginkgetin as CB1 ligands, which provides a starting point for future research on the impact of their metabolites or preparations on the endocannabinoid system. Moreover, we found five natural-like compounds with submicromolar or low micromolar affinity to CB1, including one mixed partial agonist/antagonist viable for hit-to-lead phase. Finally, the computational procedure established in this work will be of use for future screening campaigns for novel CB1 ligands.

Screening and quantification of undeclared PGF2α analogs in eyelash-enhancing cosmetic serums using LC-MS/MS.

In recent years, cosmetics deemed equivalent to pharmaceutical products containing prostaglandin F2α (PGF2α) analogs have been distributed overseas in the form of eyelash serums that can be purchased via the internet. The purpose of this study was to investigate the presence or absence of PGF2α analogs in eyelash serums procured in Japan via the internet to elucidate the actual composition. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) measurement system was developed for the determination of 14 PGF2α analogs in cosmetic serums. In total, 64 eyelash serum samples were purchased from 34 websites. After pretreatment, eyelash serum samples were screened for PGF2α analogs using the LC-MS/MS system. Products containing PGF2α analogs were subjected to quantification of these compounds. Of the 64 products, four were found to contain bimatoprost, among which, three did not indicate their contents on their package labels. In contrast, no samples were found to contain latanoprost, travoprost, or tafluprost, which are prescribed for glaucoma treatment. Additionally, eight products contained other PGF2α analogs, which have not been used as pharmaceuticals. The ease of access to cosmetic serums containing PGF2α analogs via online purchases presents a risk of serious side effects, particularly when consumers are not informed of their contents on the packages. This issue requires serious consideration to avoid the incorporation of pharmaceutical substances into cosmetic products.

Effect of prostaglandin analogues on central corneal thickness in patients with glaucoma: A systematic review and meta-analysis with trial sequential analysis.

The objective of this meta-analysis was to evaluate the effect of prostaglandin analogues (PGA) on central corneal thickness (CCT) in patients with glaucoma. Key electronic databases were searched for randomized controlled trials (RCTs) involving the CCT effects of prostaglandin use for glaucoma. Primary outcome measures were the mean difference in the CCT measurement from baseline to the last available assessment. Intraocular pressure and other corneal changes were recorded as secondary. Efficacy estimates were measured by their weighted mean difference (WMD) with 95% confidence intervals (CI's) by using the random-effects model for primary and secondary outcomes Trial sequential analysis was used to determine if the current evidence was sufficient and conclusive. Eight RCTs met our inclusion criteria. A total of 879 patients were included. The overall effect showed that PGA's had a significant CCT lowering effect (WMD = -7.04, 95%CI: -10.07 to -4.00, P < 0.00001). We pooled results of 5 RCT's on Travoprost (WMD = -10.44, 95%CI: -16.80 to -4.08, P = 0.001), seven trials on Latanoprost (WMD = -4.73, 95% CI: -9.70 to 0.25, P = 0.06), and three trials on Bimatoprost (WMD = -11.88, 95%CI: -21.03 to -2.73, P = 0.01). The WMD across groups in >6 months of PGA use was -11.37 (95%CI: -17.17 to -5.58, P = 0.0001), and in <6 months of PGAs group was -8.35 (95% CI: -12.01 to -4.69, P < 0.00001), suggesting a longitudinal effect of PGAs on CCT. In conclusion, Bimatoprost and Travoprost caused a statistically significant reduction in the thickness of central cornea. Though only a few studies were included, the narrow confidence intervals and adequate sample size suggest that these findings are valid.

Switching to Preservative-Free Tafluprost/Timolol Fixed-Dose Combination in the Treatment of Open-Angle Glaucoma or Ocular Hypertension: Subanalysis of Data from the VISIONARY Study According to Baseline Monotherapy Treatment.

INTRODUCTION: The VISIONARY study demonstrated statistically significant intraocular pressure (IOP) reductions with the preservative-free fixed-dose combination of tafluprost 0.0015% and timolol 0.5% (PF tafluprost/timolol FC) in open-angle glaucoma (OAG) or ocular hypertension (OHT) patients, sub-optimally controlled with topical prostaglandin analogue (PGA) or beta-blocker monotherapy. Current subanalyses have examined these data according to the baseline monotherapy. METHODS: A European, prospective, observational study included adults (aged ≥ 18 years) with OAG or OHT, who were switched to the PF tafluprost/timolol FC from PGA or beta-blocker monotherapy. Treatment outcomes were reported according to prior monotherapy subgroup: beta-blocker, preserved latanoprost, PF-latanoprost, bimatoprost, tafluprost, and travoprost. Endpoints included the mean change from baseline regarding IOP, conjunctival hyperemia, and corneal fluorescein staining (CFS) at Week 4 and Week 12, and at Month 6. RESULTS: The subanalysis included 577 patients. All prior monotherapy subgroups demonstrated statistically significant IOP reductions from baseline at Week 4, that were maintained through Month 6 (p < 0.001). Mean (SD) IOP change at Month 6 was 6.6 (4.16), 6.3 (4.39), 5.6 (3.67), 4.9 (2.97), 4.6 (4.39), and 4.7  (3.64) mmHg for prior beta-blocker, preserved latanoprost, PF-latanoprost, tafluprost, bimatoprost, and travoprost subgroups, respectively. The largest IOP change was observed in the preserved latanoprost subgroup for each of the ≥ 20%, ≥ 25%, ≥ 30%, and ≥ 35% IOP reduction categories at Month 6, demonstrating respective reductions of 8.06, 9.20, 10.64, and 11.55 mmHg. CFS was significantly reduced at Month 6 in the prior bimatoprost subgroup (p = 0.0013). Conjunctival hyperemia severity was significantly reduced at each study visit for prior preserved latanoprost users (p < 0.001). CONCLUSION: PF tafluprost/timolol FC therapy provided statistically and clinically significant IOP reductions from Week 4 over the total 6-month period, in patients with OAG/OHT, regardless of the type of prior PGA or beta-blocker monotherapy used. Conjunctival hyperemia severity and CFS decreased significantly in prior bimatoprost and preserved latanoprost users, respectively. CLINICAL STUDY NUMBER: European Union electronic Register of Post-Authorization Studies (EU PAS) register number: EUPAS22204.

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.

Duración del efecto hipotensor de los análogos de prostaglandinas medido con la prueba de sobrecarga hídrica en pacientes con glaucoma / Duration of the hypotensive effect of prostaglandin analogues measured with the water drinking test in glaucoma patients

Objetivo Medir con la prueba de sobrecarga hídrica (PSH) la magnitud y duración del efecto hipotensor de dos análogos de prostaglandinas en pacientes con glaucoma. Métodos Los pacientes recibieron latanoprost o travoprost cada 24 horas y luego cada 48 horas. Se practicaron PSH sin tratamiento a las 7 am y con tratamiento 12, 36 y 44 horas después de la última dosis; se calcularon el pico de presión intraocular (PIO), la fluctuación y la diferencia entre el pico y las medidas aisladas de PIO en horas de consulta. Resultados Se incluyeron 41 ojos de 21 pacientes con glaucoma primario de ángulo abierto, 22 ojos recibieron latanoprost y 19, travoprost. La PIO aislada promedio sin tratamiento fue 17,20 desviación estándar (D.S.) 3,73 y 16,95 D.S. 2,61mmHg y el pico de presión 22,45 D.S. 2,91 y 21,58 D.S. 3,79mmHg, para los grupos de latanoprost y travoprost, respectivamente. Con tratamiento, la presión pico se redujo en 22,64% y 20,29% a las 12 horas, 18,44% y 14,64% a las 36 horas y 16,17% y 14,46% a las 44 horas, respectivamente. La fluctuación sin tratamiento fue 4,36 y 5,11mmHg, y con tratamiento a las 12 horas se redujo a 2,77 y 2,89mmHg, aumentando nuevamente a 36 y 44 horas. Conclusiones Se evidenció un efecto hipotensor hasta 44 horas después de la última dosis de latanoprost y travoprost, similar para los dos medicamentos y decreciente en el tiempo. La fluctuación de la PIO sólo se redujo a las 12 horas (AU)

Objective To measure the magnitude and duration of the hypotensive effect of two prostaglandin analogues in glaucoma patients using the water drinking test (WDT). Methods Patients received latanoprost or travoprost every 24hours and then every 48hours. Untreated WDT were performed at 7 am and with treatment 12, 36 and 44hours after the last dose; intraocular pressure (IOP) peak, fluctuation and the difference between peak and isolated IOP measurements at consultation times were calculated. Results Forty-one eyes of 21 patients with primary open-angle glaucoma were included; 22 eyes received latanoprost, and 19 received travoprost. Mean untreated isolated IOP was 17.20 standard deviation (S.D.) 3.73 and 16.95 S.D. 2.61mmHg and peak pressure 22.45 S.D. 2.91 and 21.58 S.D. 3.79mmHg, for the latanoprost and travoprost groups, respectively. With treatment, peak pressure was reduced by 22.64% and 20.29% at 12hours, 18.44% and 14.64% at 36hours and 16.17% and 14.46% at 44hours, respectively. The fluctuation without treatment was 4.36 and 5.11mmHg, and with treatment at 12hours was reduced to 2.77 and 2.89mmHg, increasing again at 36 and 44hours. Conclusions A hypotensive effect was evident up to 44hours after the last dose of latanoprost and travoprost, similar for the two drugs and decreasing over time. IOP fluctuation was only reduced at 12hours (AU)

Serous macular detachments associated with topical travoprost.

Here is presented a unique case of bilateral serous macular detachments as a side effect of topical travoprost (0.004%) therapy. Only three other cases in the literature have definitively associated this side effect with other topical prostaglandins. The aetiological and pathophysiological pathways remain to be clearly elucidated but are potentially related to increased choroidal vascular permeability. In this case, the subretinal fluid resolved rapidly and completely after cessation of travoprost drops, showing it to be a reversible pathology similar to prostaglandin-associated cystoid macular oedema. This uncommon association is therefore important to consider in the differential diagnosis of serous macular detachment. Increasing ophthalmic awareness could help to prevent unnecessary investigations in undifferentiated patients without other guiding historical or examination features. This may save time and expense for the patient and health systems.

A novel ophthalmic latanoprost 0.005% nanoemulsion: a cytotoxicity study.

BACKGROUND: Benzalkonium chloride (BAK), the most commonly used preservative in anti-glaucoma eye drops, inflicts damage to the ocular surface. A novel anti-glaucoma formulation that avoids the use of BAK has been developed. The aim of this study was to evaluate the cytotoxicity of this formulation and to compare it with an ophthalmic solution containing BAK. METHODS: Two different latanoprost eye drops were used: one ophthalmic solution (LSc) containing BAK 0.02% and one ophthalmic nanoemulsion (LNe) with a soft preservative (potassium sorbate 0.18%). Human epithelial conjunctival cells were incubated for 15, 30, and 60 min with either LSc or LNe. The cytotoxicity was determined by MTT assay. Cell death was measured by flow cytometry using annexin V-FITC and propidium iodide. RESULTS: The values of cell viability and proliferation obtained from cells exposed to LNe were between 80 and 90% relative to the control group, whereas values obtained from cells exposed to LSc were around 30% at all study times (p < 0.05 at 15 and 30 min; p < 0.01 at 60 min). The percentage of viable cells decreased significantly when cells were incubated with LSc compared with cells incubated with LNe at all the study times, while the percentage of cells in late apoptosis/necrosis increased significantly in cells exposed to LSc compared to LNe. CONCLUSIONS: The new latanoprost nanoemulsion is significantly less cytotoxic on human conjunctival cells than LSc. These results suggest that the new formulation might be gentler on the eye surface than currently available BAK-preserved latanoprost solutions.

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.

Spanlastics nanovesicular ocular insert as a novel ocular delivery of travoprost: optimization using Box-Behnken design and in vivo evaluation.

Currently, travoprost is a synthetic prostaglandin F2α analogue used in the treatment of glaucoma, it is delivered by eye drop solution. Due to its very low bioavailability and patient non-compliance, the objective of the current study was to enhance its bioavailability, and prolong its release Spanlastic nano-vesicles gels were designed and optimized using Box-Behnken design. The optimized spanlastic nano-vesicles gel exhibited the lowest particle size (PS), polydispersity index (PDI) and the highest zeta potential (ZP), encapsulation efficiency (EE) and mucoadhesive strength was fabricated into spanlastic nano-vesicles ocular insert by solvent casting. In vivo studies showed enhanced bioavailability of travoprost spanlastic nano-vesicles gel and ocular insert compared to the marketed eye drops (travoswix®), as proven by their higher Cmax and AUC0-∞, in addition to being nonirritant to ocular surfaces. However, spanlastic nano-vesicles ocular insert showed more prolonged effect than spanlastic nano-vesicles gel. According to our study, it can be suggested that travoprost spanlastic nano-vesicles ocular insert is a novel ocular delivery system for glaucoma treatment.

Ophthalmic drugs: in vitro paraoxonase 1 inhibition and molecular docking studies.

Glaucoma is a neuropathy disorder and is generally treated by drugs. Allergic conjunctivitis is a common ophthalmologic disease. Paraoxonase 1 (PON1) is an organophosphate hydrolyzer and antiatherogenic enzyme. PON1 is known for preventing atherosclerosis through lipid-modifying features, as well as which has decisive actions of antiapoptosis, anti-inflammatory, antithrombosis, and antiadhesion antioxidant activity properties. Thus, reducing the enzyme levels in hyperthyroidism, chronic renal failure, glaucoma, diabetes mellitus, and cardiovascular diseases is a significant risk. This study was tested some ophthalmic drugs used to treat the diseases, such as glaucoma and allergic conjunctivitis, mentioned above, travoprost, latanoprost, ketotifen, emedastine, and olopatadine, for their inhibition activities against PON1. These drugs displayed the potent inhibition effect with IC50 values ranging between 14.95 ± 0.15 and 299.60 ± 4.07 µM and KI constants ranging from 9.71 ± 2.63 to 261.50 ± 59.98 µM. Besides, the molecular docking analyses of the competitive inhibitors, travoprost, emedastine, and olopatadine, were performed to understand the binding interactions on the enzyme's binding site. According to both in vitro and in silico analysis results, travoprost had the most potent effect on PON1 enzyme activity.