This study compared the effect of preservative-containing (PC) and preservative-free (PF) prostaglandin analogue (PGA) formulations on the ocular surface, especially on the meibomian gland (MG) in patients with open-angle glaucoma (OAG). This is a retrospective study of treatment-naïve patients with OAG (n=80) and healthy controls (n=40). OAG patients were randomized into groups using either PC-PGA or PF-PGA for 12 months. All participants underwent ocular surface and MG examinations including their meibum score, meiboscore, and lid margin abnormality score (LAS). Eighty OAG patients were randomized into two groups (n=42 in PC, n=38 in PF). All PGA and control groups showed similar ocular surface and MG parameters at the baseline. Both PC- and PF-PGA groups showed increased meibum scores, meiboscores, and LASs at 12 months compared to the baseline (all p<0.05). At the 12-months visit, PC-PGA group showed severe OSDI, shorter TBUT, greater OSS, and worse MG parameters than those of the other two groups (all p<0.05). In addition, PF-PGA group showed worse meiboscores, meibum scores, and severe OSS scores than those of the control group (all p<0.05). Both PC and PF formulations can cause damage to the MG in patients using PGA. However, PC formulations induced more ocular discomfort, poorer ocular surface, and more severe MG loss compared to PF formulations. Therefore, it would be advisable to use PF formulations in patients with a preexisting or concomitant ocular surface disease or MGD.
Benzalkonium Compounds ; Glaucoma ; Glaucoma, Open-Angle ; Humans ; Meibomian Glands ; Preservatives, Pharmaceutical ; Prostaglandins, Synthetic ; Retrospective Studies

Glaucoma is a progressive degenerative disease of the optic nerve head, characterized by a specific pattern of axonal loss and visual field deterioration. This review aims at introducing the different novel pharmacologic agents for its treatment, as well as their mechanisms. Most glaucoma patients require lifelong care and individualized treatment. Intraocular pressure (IOP), which is regulated by aqueous humor production, outflow via the trabecular meshwork (parasympathomimetics only) and uveoscleral outflow pathways, is currently the only treatable target for glaucoma treatment. Conventional glaucoma medications are categorized as β blockers, α agonists, carbonic anhydrase inhibitors, parasympathomimetics, and prostaglandin analogues. The development of basic research-derived novel classes of pharmacologic agents features novel action mechanisms, which are different from those of conventional medications. New classes of recently approved or clinical trial-tested medications include Rho-kinase inhibitors, nitric oxide donors, adenosine agonists, and prostaglandin analogs targeting E-type prostanoid receptors, etc. Their integration and future development will facilitate the expansion and customization of therapeutic options.
Adenosine ; Aqueous Humor ; Axons ; Carbonic Anhydrase Inhibitors ; Glaucoma ; Humans ; Intraocular Pressure ; Nitric Oxide Donors ; Ocular Hypertension ; Optic Disk ; Parasympathomimetics ; Prostaglandins, Synthetic ; rho-Associated Kinases ; Trabecular Meshwork ; Visual Fields

PURPOSE: To evaluate the effects of short-term prostaglandin analogues treatment on the corneal biomechanics of patients with normal tension glaucoma. METHODS: This study included 52 eyes of 52 patients who were diagnosed with normal tension glaucoma. All patients were divided into two groups; one group (27 eyes) received tafluprost while the other group (25 eyes) received travoprost. Intraocular pressure, Biomechanical properties were measured by using goldmann applanation tonometer, ocular response analyzer before treatment and at 8-week after treatment. RESULTS: The mean decrease in intraocular pressure, Goldmann-correlated IOP (IOPg), corneal-compensated intraocular pressure by using Goldmann applanation tonometer, and Ocular response analyzer were statistically significant in total patients, tafluprost, and travoprost group after using prostaglandin analogues (p < 0.001, p < 0.001, p < 0.001, respectively). Corneal hysteresis showed no statistical differences after treatment in total, tafluprost and travoprost group but corneal resistance factor (CRF) showed statistically significant decrease after using prostaglandin analogues in total, tafluprost, and travoprost group (p < 0.001, p = 0.025, p < 0.001). Upon multivariate analysis, the higher initial IOPg and the lower initial CRF checked, the variation of CRF (CRF in baseline – CRF at 8 weeks) got higher (β = 0.134, p = 0.017). CONCLUSIONS: It is needed to carefully monitor and evaluate the effects of prostaglandin analogues on intraocular pressure associated with initial intraocular pressure and the changes of CRF after prostaglandin treatment in normal tension glaucoma patients. CRF is sensitive factor to short-term changes of intraocular pressure after prostaglandin analogues treatment, and it is required to consider the properties of CRF when we evaluate between progression of glaucoma and corneal biomechanical properties.
Glaucoma ; Humans ; Intraocular Pressure ; Low Tension Glaucoma* ; Multivariate Analysis ; Prostaglandins, Synthetic

PURPOSE: Chronic use of topical hypotensive agents induces several side effects caused by preservatives. The purpose of this study was to evaluate the effects of prostaglandin analogs with varying concentrations of benzalkonium chloride (BAC), preservative-free (PF), and alternative preservatives on mouse corneal tissue. METHODS: Thirty-five, 8- to 10-week-old female C57BL/6 mice (five mice for each group) were used for this study. To the control group, we applied normal saline, and to each drug-treated group we applied 0.02% BAC, bimatoprost 0.01% (with BAC 0.02%), latanoprost 0.005% (with BAC 0.02%), travoprost 0.004% (with 0.001% polyquad) or tafluprost 0.0015% with/without 0.001% BAC, once a day (9 p.m.) for 4 weeks. Corneal fluorescein staining was evaluated in all groups. After harvest, the corneal tissues were embedded in paraffin and then Hematoxylin-Eosin stain was performed for histopathological examination. Immunofluorescence staining was done against TNF-alpha, IL-6, HLA DR, pJNK, and pAkt. RESULTS: In corneal fluorescein staining, severe punctate epithelial keratitis was seen in the groups of 0.02% BAC, 0.02% BAC containing bimatoprost 0.01% and latanoprost 0.005%. The surface desquamation, irregular surface, loss of cell borders, anisocytosis and stromal shrinkage were observed in the groups of BAC-containing eye drops. Moreover, the groups treated with BAC-containing eye drops have high inflammatory markers, significantly decreased cell viability-related signal, pAkt, and higher apoptosis-inducing signal, pJNK, than the control group. On the other hand, travoprost 0.004% and PF tafluprost 0.0015% have less cellular morphologic changes, lower inflammation, and higher cellular viability than BAC-containing formulations. CONCLUSIONS: Corneal damage, increased inflammation and apoptosis and low cell viability were observed in BAC-containing groups. PF or alternatively preserved glaucoma medications seem to be a reasonable and viable alternative to those preserved with BAC.
Animals ; Cell Survival ; Conjunctiva/drug effects/*pathology ; Disease Models, Animal ; Epithelium, Corneal/drug effects/*pathology ; Female ; Glaucoma/*drug therapy/pathology ; Mice ; Mice, Inbred C57BL ; Microscopy, Fluorescence ; Ophthalmic Solutions ; Preservatives, Pharmaceutical ; Prostaglandins, Synthetic/*administration & dosage

PURPOSE: To investigate the effects of topical prostaglandin analogue drugs on the differentiation of adipocytes. METHODS: Differentiation of 3T3-L1 preadipocytes was induced with isobutylmethylxanthine, dexamethasone, and insulin. 3T3-L1 cells were exposed to 0.008, 0.08, 0.2 microM of latanoprost and travoprost. Reverse transcription polymerase chain reaction for mRNA expression of lipoprotein lipase and peroxisome proliferator-activated receptor gamma 2 (PPARgamma2), and glycerol-3-phosphate dehydrogenase (G3PDH) assays were performed to examine the effects on early and late differentiation, respectively. Also, glycerol assays were done to evaluate the effect of prostaglandin analogues on lipolysis after differentiation. RESULTS: Both prostaglandin analogues inhibited differentiation of preadipocytes. Topical prostaglandin analogues significantly decreased G3PDH activity, a marker of late differentiation. However, topical prostaglandin analogues did not change mRNA expressions of lipoprotein lipase and PPARgamma2, markers of early differentiation. The activities of the early markers of differentiation were not changed significantly before and after growth arrest. Compared to latanoprost, travoprost decreased G3PDH activity more significantly (p < 0.05). Both prostaglandin analogues did not affect the lipolysis of differentiated adipocytes (p > 0.05). CONCLUSIONS: Prostaglandin analogues display an inhibitory effect on the differentiation of adipocytes when the cells start to differentiate especially in the late stage of differentiation. Thus, commercial topical prostaglandin analogues may decrease the fat contents of eyelids.
3T3-L1 Cells ; Adipocytes/drug effects/*pathology ; Animals ; Antihypertensive Agents/administration & dosage ; Cell Differentiation/drug effects ; Disease Models, Animal ; Glaucoma/*drug therapy/pathology ; Lipolysis/*drug effects ; Mice ; Neuroprotective Agents/administration & dosage ; Ophthalmic Solutions/administration & dosage ; Prostaglandins F, Synthetic/*administration & dosage ; Prostaglandins, Synthetic/*administration & dosage

PURPOSE: To compare the efficacy and safety of latanoprost, bimatoprost, travoprost and timolol in reducing intraocular pressure (IOP) in patients with primary open angle glaucoma. METHODS: This was a prospective study conducted at a tertiary-care centre. One hundred and forty patients with newly diagnosed primary open angle glaucoma were randomly assigned to treatment with latanoprost (0.005%), bimatoprost (0.03%), travoprost (0.004%) or timolol gel (0.5%); 35 patients were assigned to each group. All patients were followed for 2, 6, and 12 weeks. The main outcome measure studied was the change in IOP at week 12 from the baseline values. Safety measures included recording of adverse events. RESULTS: The mean IOP reduction from baseline at week 12 was significantly more with bimatoprost (8.8 mmHg, 35.9%) than with latanoprost (7.3 mmHg, 29.9%), travoprost (7.6 mmHg, 30.8%) or timolol (6.7 mmHg, 26.6%) (ANOVA and Student's t-tests, p < 0.001). Among the prostaglandins studied, bimatoprost produced a maximum reduction in IOP (-2.71; 95% confidence interval [CI], -2.25 to -3.18) followed by travoprost (-1.27; 95% CI, -0.81 to -1.27) and latanoprost (-1.25; 95% CI, -0.79 to -1.71); these values were significant when compared to timolol at week 12 (Bonferroni test, p < 0.001). Latanoprost and travoprost were comparable in their ability to reduce IOP at each patient visit. Ocular adverse-events were found in almost equal proportion in patients treated with bimatoprost (41.3%) and travoprost (41.9%), with a higher incidence of conjunctival hyperemia (24.1%) seen in the bimatoprost group. Timolol produced a significant drop in heart rate (p < 0.001) at week 12 when compared to the baseline measurements. CONCLUSIONS: Bimatoprost showed greater efficacy when compared to the other prostaglandins, and timolol was the most efficacious at lowering the IOP. Conjunctional hyperemia was mainly seen with bimatoprost. However, the drug was tolerated well and found to be safe.
Adolescent ; Adult ; Aged ; Aged, 80 and over ; Antihypertensive Agents/adverse effects/*therapeutic use ; Bimatoprost/adverse effects/therapeutic use ; Blood Pressure/drug effects ; Female ; Glaucoma, Open-Angle/*drug therapy/physiopathology ; Heart Rate/drug effects ; Humans ; Intraocular Pressure/drug effects ; Male ; Middle Aged ; Prostaglandins F, Synthetic/adverse effects/therapeutic use ; Timolol/adverse effects/therapeutic use ; Tonometry, Ocular ; Travoprost/adverse effects/therapeutic use ; Treatment Outcome ; Visual Acuity/drug effects ; Visual Field Tests ; Visual Fields/drug effects

PURPOSE: To evaluate the effects of a bimatoprost/timolol fixed combination (BTFC) and a latanoprost/timolol fixed combination (LTFC) on diurnal intraocular pressure (IOP) and anterior ocular parameters in healthy subjects. METHODS: We enrolled 58 healthy subjects in this prospective clinical study. Thirty subjects were treated with BTFC and 28 subjects were treated with LTFC. IOP was measured every 2 hours except from 01:00 and 05:00. Axial length, corneal curvature, and anterior chamber depth were obtained using the IOL master at baseline and 24 hours later. Adverse events were assessed by patient interview and by slit lamp examination. RESULTS: The largest difference in IOP between treated and untreated eyes 8 hours after instillation was 1.67 mmHg in the BTFC group (p < 0.001). The largest difference in IOP between treated and untreated eyes 10 hours after instillation was 1.93 mmHg in the LTFC group (p < 0.001). For anterior ocular parameters such as axial length, corneal curvature, anterior chamber depth at baseline and 24 hours after instillation, there were no significant differences between the baseline and 24-hour values in either the BTFC or LTFC group. The most frequently occurring adverse event was conjunctival hyperemia, which was found in 33.3% (n = 10) of the BTFC group and 25.0% (n = 7) of the LTFC group (p = 0.486). CONCLUSIONS: BTFC and LTFC provided a significant reduction in IOP from baseline without changing any anterior ocular parameters. Our results provide a reference for monocular trials to assess the effect of eye drops in a clinical condition.
Adult ; Aged ; Aged, 80 and over ; Amides/*administration & dosage ; Antihypertensive Agents/administration & dosage ; Circadian Rhythm/*physiology ; Cloprostenol/administration & dosage/*analogs & derivatives ; Dose-Response Relationship, Drug ; Drug Therapy, Combination ; Female ; Follow-Up Studies ; Glaucoma, Open-Angle/drug therapy/*physiopathology ; Healthy Volunteers ; Humans ; Intraocular Pressure/drug effects/*physiology ; Male ; Middle Aged ; Ophthalmic Solutions ; Prospective Studies ; Prostaglandins F, Synthetic/*administration & dosage ; Timolol/*administration & dosage ; Tonometry, Ocular ; Treatment Outcome

PURPOSE: To evaluate the effects of a bimatoprost/timolol fixed combination (BTFC) and a latanoprost/timolol fixed combination (LTFC) on diurnal intraocular pressure (IOP) and anterior ocular parameters in healthy subjects. METHODS: We enrolled 58 healthy subjects in this prospective clinical study. Thirty subjects were treated with BTFC and 28 subjects were treated with LTFC. IOP was measured every 2 hours except from 01:00 and 05:00. Axial length, corneal curvature, and anterior chamber depth were obtained using the IOL master at baseline and 24 hours later. Adverse events were assessed by patient interview and by slit lamp examination. RESULTS: The largest difference in IOP between treated and untreated eyes 8 hours after instillation was 1.67 mmHg in the BTFC group (p < 0.001). The largest difference in IOP between treated and untreated eyes 10 hours after instillation was 1.93 mmHg in the LTFC group (p < 0.001). For anterior ocular parameters such as axial length, corneal curvature, anterior chamber depth at baseline and 24 hours after instillation, there were no significant differences between the baseline and 24-hour values in either the BTFC or LTFC group. The most frequently occurring adverse event was conjunctival hyperemia, which was found in 33.3% (n = 10) of the BTFC group and 25.0% (n = 7) of the LTFC group (p = 0.486). CONCLUSIONS: BTFC and LTFC provided a significant reduction in IOP from baseline without changing any anterior ocular parameters. Our results provide a reference for monocular trials to assess the effect of eye drops in a clinical condition.
Adult ; Aged ; Aged, 80 and over ; Amides/*administration & dosage ; Antihypertensive Agents/administration & dosage ; Circadian Rhythm/*physiology ; Cloprostenol/administration & dosage/*analogs & derivatives ; Dose-Response Relationship, Drug ; Drug Therapy, Combination ; Female ; Follow-Up Studies ; Glaucoma, Open-Angle/drug therapy/*physiopathology ; Healthy Volunteers ; Humans ; Intraocular Pressure/drug effects/*physiology ; Male ; Middle Aged ; Ophthalmic Solutions ; Prospective Studies ; Prostaglandins F, Synthetic/*administration & dosage ; Timolol/*administration & dosage ; Tonometry, Ocular ; Treatment Outcome

PURPOSE: Long-term use of topical medication is needed for glaucoma treatment. One of the most commonly prescribed classes of hypotensive agents are prostaglandin analogs (PGs) used as both first-line monotherapy; as well as in combination therapy with other hypotensive agents. Several side effects of eye drops can be caused by preservatives. The purpose of this study was to evaluate the effects of PGs with varying concentrations of benzalkonium chloride (BAC), alternative preservatives, or no preservatives on human conjunctival fibroblast cells. METHODS: Primary human conjunctival fibroblast cells were used in these experiments. Cells were exposed to the following drugs: BAC at different concentrations, bimatoprost 0.01% (with BAC 0.02%), latanoprost 0.005% (with BAC 0.02%), tafluprost 0.0015% with/without 0.001% BAC and travoprost 0.004% (with 0.001% Polyquad) for 15 and 30 minutes. Cell cytotoxicity was evaluated by phase-contrast microscopy to monitor morphological changes of cells, Counting Kit-8 (CCK-8) assay to cell viability, and fluorescent activated cell sorting (FACS) analysis to measure apoptosis. RESULTS: BAC caused cell shrinkage and detachment from the plate in a dose-dependent manner. Morphological changes were observed in cells treated with bimatoprost 0.01% and latanoprost 0.005%. However, mild cell shrinkage was noted in cells treated with tafluprost 0.0015%, while a non-toxic effect was noted with travoprost 0.004% and preservative-free tafluprost 0.0015%. CCK-8 assay and FACS analysis showed all groups had a significantly decreased cell viability and higher apoptosis rate compared with the control group. However, travoprost 0.004% and preservative-free tafluprost 0.0015% showed lower cytotoxicity and apoptosis rate than other drugs. CONCLUSIONS: This in vitro study revealed that BAC-induced cytotoxicity is dose-dependent, although it is important to emphasize that the clinical significance of toxicity differences observed among the different PGs formulations has not yet been firmly established. Alternatively preserved or preservative-free glaucoma medications seem to be a reasonable and viable alternative to those preserved with BAC.
Apoptosis ; Cell Line ; Cell Survival/drug effects ; Conjunctiva/drug effects/*pathology ; Fibroblasts/drug effects/pathology ; Glaucoma/drug therapy/pathology ; Humans ; Preservatives, Pharmaceutical/*pharmacology ; Prostaglandins, Synthetic/*pharmacology

PURPOSE: To evaluate the efficacy of a monocular drug trial in eyes with normal-tension glaucoma (NTG). METHODS: This prospective study enrolled 74 patients with NTG. The monocular drug trial was started using latanoprost 0.005% for one week. If the intraocular pressure (IOP) reduction was greater than 15%, the same medication was administered to both eyes for one month. The unadjusted change and adjusted change (the change in the treated eye minus the change in the contralateral eye) in IOP were evaluated, and the predictors of IOP response were analyzed by multivariate linear regression. RESULTS: Among the initial 74 patients, 31 (41.9%) were included; others were excluded because they did not meet the requisite conditions. The most significant predictors of IOP response in the initial eye and subsequent eye were the baseline IOPs in both eyes (beta = 0.907, 0.771, respectively). The adjusted change in IOP of the initial eye had greater association (beta = 0.589) with the IOP after monocular trial in the initial eye than that of unadjusted IOP change (beta = 0.279). The adjusted change in IOP also had greater predictability (beta = 0.348) for IOP after monocular trial in the subsequent eye than that of the unadjusted IOP change (beta = 0.090). CONCLUSIONS: Although the monocular trial in NTG patients had limited efficacy due to its stringent conditions, it was useful for evaluating the IOP response in the initial eye and for predicting the IOP response in the subsequent eye.
Adult ; Aged ; Aged, 80 and over ; Antihypertensive Agents/*therapeutic use ; Female ; Humans ; Intraocular Pressure/drug effects ; Linear Models ; Low Tension Glaucoma/*drug therapy ; Male ; Middle Aged ; Prospective Studies ; Prostaglandins F, Synthetic/*therapeutic use ; Statistics, Nonparametric ; Treatment Outcome