Relationship between Intraocular Pressure Fluctuation and Visual Field Progression Rates in the United Kingdom Glaucoma Treatment Study.

PURPOSE: To investigate whether intraocular pressure (IOP) fluctuation is associated independently with the rate of visual field (VF) progression in the United Kingdom Glaucoma Treatment Study. DESIGN: Randomized, double-masked, placebo-controlled multicenter trial. PARTICIPANTS: Participants with ≥5 VFs (213 placebo, 217 treatment). METHODS: Associations between IOP metrics and VF progression rates (mean deviation [MD] and five fastest locations) were assessed with linear mixed models. Fluctuation variables were mean Pascal ocular pulse amplitude (OPA), standard deviation (SD) of diurnal Goldmann IOP (diurnal fluctuation), and SD of Goldmann IOP at all visits (long-term fluctuation). Fluctuation values were normalized for mean IOP to make them independent from the mean IOP. Correlated nonfluctuation IOP metrics (baseline, peak, mean, supine, and peak phasing IOP) were combined with principal component analysis, and principal component 1 (PC1) was included as a covariate. Interactions between covariates and time from baseline modeled the effect of the variables on VF rates. Analyses were conducted separately in the two treatment arms. MAIN OUTCOME MEASURES: Associations between IOP fluctuation metrics and rates of MD and the five fastest test locations. RESULTS: In the placebo arm, only PC1 was associated significantly with the MD rate (estimate, -0.19 dB/year [standard error (SE), 0.04 dB/year]; P < 0.001), whereas normalized IOP fluctuation metrics were not. No variable was associated significantly with MD rates in the treatment arm. For the fastest five locations in the placebo group, PC1 (estimate, -0.58 dB/year [SE, 0.16 dB/year]; P < 0.001), central corneal thickness (estimate, 0.26 dB/year [SE, 0.10 dB/year] for 10 µm thicker; P = 0.01) and normalized OPA (estimate, -3.50 dB/year [SE, 1.04 dB/year]; P = 0.001) were associated with rates of progression; normalized diurnal and long-term IOP fluctuations were not. In the treatment group, only PC1 (estimate, -0.27 dB/year [SE, 0.12 dB/year]; P = 0.028) was associated with the rates of progression. CONCLUSIONS: No evidence supports that either diurnal or long-term IOP fluctuation, as measured in clinical practice, are independent factors for glaucoma progression; other aspects of IOP, including mean IOP and peak IOP, may be more informative. Ocular pulse amplitude may be an independent factor for faster glaucoma progression. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Comparative Study of Latanoprost Drug Delivery Systems for Glaucoma Treatment and Their Interaction with the Tear Film Lipid Layer Models.

This study investigates the interaction of two approved and one newly developed latanoprost formulation with in vitro and in silico models of the tear film and tear film lipid layer (TFLL). Latanoprost, a prostaglandin analogue used for intraocular elevated pressure treatment, is topically delivered by nanocarriers within aqueous solutions or emulsions. The study focuses on the impact of these carriers on drug interactions with the tear film and their effect on the TFLL. Three different types of latanoprost carriers, micellar, nanoemulsion, and polymer-based, were compared, and each revealed distinct interaction patterns with the TFLL. Surface pressure kinetics demonstrated a rapid increase for the benzalkonium chloride formulation and a slow rise for the preservative-free variants. Visualization of the acellular in vitro TFLL model revealed different patterns of incorporation for each formulation, indicating unique interaction mechanisms. Molecular dynamics simulations further revealed different mechanisms of drug release in the TFLL between micellar and nanoemulsion formulations. In-depth examination highlighted the role of triglyceride molecules in replenishing the nonpolar layer of the TFLL, which suggests potential improvements in ocular surface compatibility by adjusting the quality and concentration of the oily phase. These findings suggest the potential for optimizing latanoprost formulations by tuning the oily phase-to-surfactant ratio and selecting suitable surfactants.

MERCURY-3: a randomized comparison of netarsudil/latanoprost and bimatoprost/timolol in open-angle glaucoma and ocular hypertension.

PURPOSE   : To compare the efficacy and safety of the fixed-dose combination (FDC) of netarsudil 0.02%/latanoprost 0.005% ophthalmic solution (NET/LAT; Roclanda®) with bimatoprost 0.03%/timolol maleate 0.5% (BIM/TIM; Ganfort®) ophthalmic solution in the treatment of open-angle glaucoma (OAG) and ocular hypertension (OHT). METHODS: MERCURY-3 was a 6-month prospective, double-masked, randomized, multicenter, active-controlled, parallel-group, non-inferiority study. Patients (≥ 18 years) with a diagnosis of OAG or OHT in both eyes that was insufficiently controlled with topical medication (IOP ≥ 17 mmHg in ≥ 1 eye and < 28 mmHg in both eyes) were included. Following washout, patients were randomized to once-daily NET/LAT or BIM/TIM for up to 6 months; efficacy was assessed at Week 2, Week 4, and Month 3; safety was evaluated for 6 months. Comparison of NET/LAT relative to BIM/TIM for mean IOP at 08:00, 10:00, and 16:00 h was assessed at Week 2, Week 6, and Month 3. Non-inferiority of NET/LAT to BIM/TIM was defined as a difference of ≤ 1.5 mmHg at all nine time points through Month 3 and ≤ 1.0 mmHg at five or more of nine time points through Month 3. RESULTS: Overall, 430 patients were randomized (NET/LAT, n = 218; BIM/TIM, n = 212), and all received at least one dose of study medication. Efficacy analyses were performed at Month 3 on 388 patients (NET/LAT, n = 184; BIM/TIM, n = 204). NET/LAT demonstrated non-inferiority to BIM/TIM, with a between-treatment difference in IOP of ≤ 1.5 mmHg achieved at all time points and ≤ 1.0 mmHg at the majority of time points (six of nine) through Month 3. Mean diurnal IOP during the study ranged from 15.4 to 15.6 mmHg and 15.2 to 15.6 mmHg in the NET/LAT and BIM/TIM groups respectively, with no between-group statistically significant difference. No significant differences were observed in key secondary endpoints. No serious, treatment-related adverse events (AEs) were observed, and AEs were typically mild/moderate in severity. The most common treatment-related AEs were conjunctival hyperemia (NET/LAT, 30.7%; BIM/TIM, 9.0%) and cornea verticillata (NET/LAT, 11.0%; BIM/TIM, 0%). CONCLUSIONS: Once-daily NET/LAT was non-inferior to BIM/TIM in IOP reduction in OAG and OHT, with AEs consistent with previous findings. NET/LAT offers a compelling alternative FDC treatment option for OAG and OHT.

Narrowband ultraviolet B phototherapy combined with intralesional injection of either latanoprost or platelet-rich plasma for stable nonsegmental vitiligo.

BACKGROUND: Narrowband ultraviolet B (NB-UVB) phototherapy is the cornerstone of vitiligo treatment. Its combination with other treatments usually yields a better response. Latanoprost, a prostaglandin F2α analog, and autologous platelet-rich plasma (PRP) have been reported to be effective for vitiligo. AIM: To evaluate the efficacy of NB-UVB combined with intralesional latanoprost or PRP for stable nonsegmental vitiligo (NSV). METHODS: Sixty patients with stable NSV were recruited and randomly allocated to two equal groups. NB-UVB phototherapy was administered twice a week for all patients. Additionally, group A received intralesional latanoprost injections once weekly, while group B received intralesional autologous PRP injections every 2 weeks. RESULTS: At 24 weeks, excellent repigmentation response was observed in 26.7% and 13.3% of patients in the latanoprost/NB-UVB and PRP/NB-UVB groups, respectively, with no significant difference in degrees of repigmentation between the two groups. However, the Vitiligo Extent Score for a Target Area (VESTA) score was significantly higher in the latanoprost/NB-UVB group (p = .032). Moreover, lesions located on nonacral skin responded significantly better than those on acral skin. Only erythema was significantly higher in the PRP/NB-UVB group, while the recurrence of depigmentation was significantly higher in the latanoprost/NB-UVB group. CONCLUSIONS: Both latanoprost and PRP have the potential to be effective add-on therapies to NB-UVB phototherapy for stable NSV, with latanoprost resulting in a greater repigmentation response and PRP producing a more stable response.

A triple combination of latanoprost, fractional CO2 laser, and platelet-rich plasma in localized vitiligo: A clinical and histopathologic study.

BACKGROUND: Several treatment modalities are available for the treatment of vitiligo due to the lack of a uniformly effective therapy. Topical latanoprost 0.005% is an effective topical treatment. Fractional CO2 laser alone or combined with platelet-rich plasma (PRP) has been proposed as effective adjunctive therapies. OBJECTIVES: We aimed to compare the efficacy of topical latanoprost 0.005% (Ioprost®, Orchidia, Egypt) combined with either add-on fractional CO2 laser or fractional CO2 -PRP versus topical latanoprost monotherapy in the treatment of localized stable vitiligo. PATIENTS/METHODS: The study included 60 patients randomly assigned into three equal groups. Group A patients received topical latanoprost drops only. Group B patients received topical latanoprost drops and fractional CO2 laser sessions at 2-week interval for 3 months. Group C patients received topical latanoprost drops and fractional CO2 laser sessions combined with PRP at a 2-week interval for 3 months. The mean improvement score by the physician was calculated 4 months after the start of the study. Punch skin biopsies were obtained before treatment and 4 months from the beginning of the study and stained with H&E and HMB-45 antibody for evaluation of pigmentation. RESULTS: Significant clinical improvement of vitiligo lesions with significant increase of re-pigmentation were reported in the three treated groups. Latanoprost in combination with fractional CO2 and PRP was associated with more significant therapeutic outcomes than either combined latanoprost and fractional CO2 or latanoprost alone. CONCLUSION: Fractional CO2 laser-PRP enhances the therapeutic efficacy of latanoprost 0.005% in the treatment of localized stable vitiligo.

A phase III, multicentre, randomised, investigator-masked, cross-over, comparative, non-inferiority trial evaluating the efficacy and tolerability of generic preservative-free Latanoprost (Polpharma S.A.) compared to Xalatan® (Pfizer) in patients with ocular hypertension or primary open-angle glaucoma.

BACKGROUND: Primary open-angle glaucoma (POAG), often associated with increased intraocular pressure (IOP), can lead to permanent damage of the optic nerve, concomitant visual field loss, and blindness. Latanoprost, a prostaglandin F2α analogue, reduces IOP and is used to treat glaucoma. In this clinical trial, we evaluated the efficacy of Latanoprost Polpharma, a generic preservative-free latanoprost 0.05 mg/ml eye drops solution, in lowering IOP when compared to the originator Xalatan® (latanoprost 0.005% ophthalmic solution, Pfizer). METHODS: This was a Phase III, multicentre, randomized, investigator-masked, cross-over, comparative, non-inferiority trial carried out in 5 sites in Hungary and Russia. The primary endpoint was to evaluate the non-inferiority of the test product when compared to the reference product with respect to the differences in the mean diurnal IOP on Day 1 (baseline) and Day 29. The secondary endpoints included efficacy, ocular tolerance, safety, and usability. We recruited adult patients (18-75 years) with open-angle glaucoma or ocular hypertension. RESULTS: Forty-nine patients were randomised and received at least one dose of the test or reference product. A virtually identical reduction of the mean diurnal IOP of 7.04 ± 2.14 mmHg or 7.17 ± 2.11 mmHg was found after treatment with test or reference product, respectively (N = 44). In the intention to treat analysis, the reduction was 7.29 ± 2.53 mmHg (95% CI: 6.55-8.04) or 7.43 ± 2.78 mm Hg (95%CI: 6.61-8.24) after treatment with test or reference product, respectively (N = 47). There were no serious adverse events. CONCLUSIONS: Latanoprost Polpharma was shown to be non-inferior to Xalatan®. Both investigational products were equally well tolerated and safe. The data show a trend in favour of the test product with regards to the severity of hyperaemia and to the velocity of remission of ocular discomfort. Latanoprost Polpharma, being preservative-free, also avoids the cytotoxicity of benzalkonium chloride, the side effects of which may affect patient compliance and lower the quality of life. TRIAL REGISTRATION: The study had the ethical and regulatory approval from the National Institute of Pharmacy and Nutrition (OGYEI, OGYEI/41,779- 11/2018) and the Ethics Committee for Clinical Pharmacology (KFEB) of Hungary and from the Ministry of Healthcare of the Russian Federation (MOH of Russia) prior to the beginning of the study (642/25.12.2018) (clinical trial identification number: 848,300,144/0103/1 - POP03; IND number/EudraCT number: 2018-001727-39).

Evaluation of the effects of latanoprost and benzalkonium chloride on the cell viability and nonpolar lipid profile produced by human meibomian gland epithelial cells in culture.

Purpose: The purpose of this study was to explore the effects of a PGF2α analog, latanoprost, and its preservative, benzalkonium chloride (BAK), on the cell viability and lipidomic expression of immortalized human meibomian gland epithelial cells (HMGECs). Methods: Differentiated HMGECs were exposed to latanoprost (0.05 to 50 µg/ml), BAK (0.2 to 200 µg/ml), or combined latanoprost-BAK (0.05-0.2 to 50-200 µg/ml). EP- and FP-type receptors, the cognate receptors of PGE2 and PGF2α, were inhibited, thereby sparing and isolating the function of each receptor to one condition. Cell viability was assessed by ATP quantitation, and lipid extracts were analyzed by ESI-MSMSALL with a Triple TOF 5600 Mass Spectrometer (SCIEX, Framingham, MA) using SCIEX LipidView 1.3. Results: Latanoprost and BAK were found to be lethal to HMGECs at the highest concentrations (p < 0.001 for both). The cytotoxicity of latanoprost was mediated through FP- and EP-independent mechanisms. Both latanoprost and BAK significantly modulated the lipidomic expression of several cholesteryl esters (8% and 30%, respectively) and triacylglycerols (10% and 12%, respectively). The combined latanoprost-BAK agent appeared to be no more toxic and to only negligibly alter the lipid profile relative to its individual components. Conclusions: The use of latanoprost and BAK in glaucoma may alter the viability of the meibomian glands and their lipid expression in vivo. Sublethal concentrations of BAK appear to modulate meibum lipid expression, particularly in relation to sterol biosynthesis. Non-preserved latanoprost had less cytotoxicity at lower doses and fewer lipidomic effects compared to BAK, further strengthening the argument in favor of BAK-free pharmaceutical preparations.

Timolol maleate, a ß blocker eye drop, improved edema in a retinal vein occlusion model.

Purpose: To investigate the therapeutic effects of eye drops, namely, timolol maleate, a ß-adrenergic receptor antagonist, and latanoprost, a prostaglandin F2α analog, on retinal edema in a murine retinal vein occlusion (RVO) model. Methods: An RVO model was established using laser-induced RVO in mice, which were administered timolol maleate and latanoprost eye drops several times after venous occlusion. Subsequently, the thickness of the inner nuclear layer (INL) and the expression levels of such genes as Vegf and Atf4, which are stress markers of the endoplasmic reticulum, were examined. Primary human cultured retinal microvascular endothelial cells (HRMECs) were treated with timolol under hypoxic conditions, after which the gene expression pattern was investigated. Importantly, an integrated stress response inhibitor (ISRIB) was used in the RVO model, he known ISRIB, which suppresses the expression of ATF4 in retinal edema. Results: Increased INL thickness was suppressed by timolol eye drops, as were the expressions of Vegf and Atf4, in the RVO model. However, latanoprost eye drops did not induce any change in INL thickness. In HRMECs, hypoxic stress and serum deprivation increased the Vegf and Atf4 expressions; in response, treatment with timolol suppressed the Vegf expression. Furthermore, the ISRIB decreased the Vegf expression pattern and edema formation, which are associated with RVO. Conclusions: These results indicate that timolol eye drops may be a potential option for RVO treatment.

FP and EP2 prostanoid receptor agonist drugs and aqueous humor outflow devices for treating ocular hypertension and glaucoma.

Prostaglandin (PG) receptors represent important druggable targets due to the many diverse actions of PGs in the body. From an ocular perspective, the discovery, development, and health agency approvals of prostaglandin F (FP) receptor agonists (FPAs) have revolutionized the medical treatment of ocular hypertension (OHT) and glaucoma. FPAs, such as latanoprost, travoprost, bimatoprost, and tafluprost, powerfully lower and control intraocular pressure (IOP), and became first-line therapeutics to treat this leading cause of blindness in the late 1990s to early 2000s. More recently, a latanoprost-nitric oxide (NO) donor conjugate, latanoprostene bunod, and a novel FP/EP3 receptor dual agonist, sepetaprost (ONO-9054 or DE-126), have also demonstrated robust IOP-reducing activity. Moreover, a selective non-PG prostanoid EP2 receptor agonist, omidenepag isopropyl (OMDI), was discovered, characterized, and has been approved in the United States, Japan and several other Asian countries for treating OHT/glaucoma. FPAs primarily enhance uveoscleral (UVSC) outflow of aqueous humor (AQH) to reduce IOP, but cause darkening of the iris and periorbital skin, uneven thickening and elongation of eyelashes, and deepening of the upper eyelid sulcus during chronic treatment. In contrast, OMDI lowers and controls IOP by activation of both the UVSC and trabecular meshwork outflow pathways, and it has a lower propensity to induce the aforementioned FPA-induced ocular side effects. Another means to address OHT is to physically promote the drainage of the AQH from the anterior chamber of the eye of patients with OHT/glaucoma. This has successfully been achieved by the recent approval and introduction of miniature devices into the anterior chamber by minimally invasive glaucoma surgeries. This review covers the three major aspects mentioned above to highlight the etiology of OHT/glaucoma, and the pharmacotherapeutics and devices that can be used to combat this blinding ocular disease.

Latanoprost-Loaded Nanotransfersomes Designed for Scalp Administration Enhance Keratinocytes Proliferation.

Latanoprost (LAT) has been shown to have a hypertrichotic effect, which makes it a promising candidate for alopecia treatments. For the first time, LAT has been encapsulated in nanotransfersomes in order to increase its efficacy. Ex vivo skin biodistribution was studied by confocal laser microscopy both in human scalp and pig skin. Results showed that nanotransfersomes increase the penetration of two different fluorochromes, with similar patterns in both species, compared with fluorochrome solutions containing no nanotransfersomes. Nanotransfersomes were stable under accelerated conditions (40 °C/75% RH) and long-term conditions (25 °C/60% RH) for up to 1 year, with no differences in vesicle size and polydispersity when LAT was loaded. Nanotransfersomes increased the LAT cell proliferation effect in HaCaT cell via MAPK signaling pathway. Collectively, our results demonstrate LAT-nanotransfersomes formulation could be a promising therapy for hair growth disorders.

Screening, characterization, and determination of suspected additives bimatoprost and latanoprost in cosmetics using NMR and LC-MS methods.

Recently, many new types of cosmetic illegal additives have been screened in the market. Most of the new additives were new drugs or analogues with very similar structures to other prohibited additives, which were difficult to be identified by liquid chromatography-mass spectrometry (LC-MS) only. Therefore, a new strategy is proposed, which is chromatographic separation combined with nuclear magnetic resonance spectroscopy (NMR) structural identification. The suspected samples were screened by ultra-high-performance liquid chromatography tandem high-resolution mass spectrometry (UPLC-Q-TOF-MS), followed by purification and extraction through silica-gel column chromatography and preparative high-performance liquid chromatography (HPLC). Finally, the extracts were identified unambiguously by NMR as bimatoprost and latanoprost, which were identified to be new cosmetic illegal additives in eyelash serums in China. Meanwhile, bimatoprost and latanoprost were quantified by high-performance liquid chromatography tandem triple quadrupole mass spectrum (HPLC-QQQ-MS/MS). The quantitative method demonstrated good linearity in the range of approximately 0.25-50 ng/mL (R2 > 0.9992), with limit of detection (LOD) and limit of quantification (LOQ) values of 0.01 and 0.03 mg/kg, respectively. The accuracy, precision, and reproducibility were confirmed to be acceptable.

The effectiveness and tolerability of fixed-dose combination netarsudil 0.02%/latanoprost 0.005% at a tertiary glaucoma center.

PURPOSE: To assess real-world effectiveness and tolerability of fixed-dose combination netarsudil 0.02%/latanoprost 0.005% (FCNL) in management of glaucoma patients in a tertiary eye care center. METHODS: This retrospective cohort study included glaucoma patients initiated on FCNL from January 2018 to July 2021 with at least 1-month follow-up. Demographic and clinical data were collected at baseline and at follow-up visits through 12 months. Patient-solicited side effects were recorded at each visit. Maximum glaucoma pharmacotherapy was defined as surgery/laser being the next treatment option following an intensive pharmacotherapy regimen, or when pharmacotherapy could not be increased due to allergy/intolerance or all pharmacologic mechanisms already being in use. RESULTS: Seventy-nine eyes of 47 patients were included. Mean age was 67.7 ± 14.7 years. Baseline IOP was 18.7 ± 4.9 mmHg; mean change in IOP (∆IOP) each study visit compared to baseline ranged from - 1.6 ± 3.5 to - 4.4 ± 4.1 mmHg (all p < 0.05). The eyes on maximum glaucoma pharmacotherapy (73.4%) had similar ∆IOP compared to those on non-maximal therapy at each visit (p > 0.2 for all). Forty-three (54.4%) eyes were switched from a prostaglandin analog alone, producing a 1-month IOP reduction of - 4.7 ± 3.9 mmHg at 1 month which remained significant at each visit for the 12-month study period (all p < 0.05). Across all study visits, conjunctival hyperemia was documented in 26 (32.9%) eyes. Subjective blurry vision was reported in 22 (27.8%) eyes without significant worsening of visual acuity at any visit (all p > 0.05). Six (7.6%) and 7 (8.9%) eyes required further medical or surgical/laser intervention, respectively. Kaplan-Meier analysis revealed no significant difference in the need for subsequent medical or surgical intervention between those on maximum and non-maximal pharmacotherapy (p > 0.4). CONCLUSION: FCNL was well-tolerated and demonstrated a significant and sustained reduction in IOP, even as last-line therapy before incisional or laser surgery in those on maximum glaucoma pharmacotherapy. FCNL is a viable treatment option for glaucomatous eyes before consideration of surgical intervention.

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.

A Non-Inferiority Study of Combination of Latanoprost and Timolol Formulation to Their Separate Use in Drug-Naive Primary Open Angle Glaucoma and Ocular Hypertension Nigerian Patients. {RCT 93803536 (Nigeria Clinical Trial Registry)}.

BACKGROUND: Control of intraocular pressure continues to be the mainstay of the management of primary open-angle glaucoma. It is also one of the key factors to consider in the diagnosis and risk of conversion of ocular hypertension to glaucoma (POAG). Medical management of IOP control is central to the treatment of POAG especially in resource-poor countries. AIM: This study aimed to demonstrate the non-inferiority of a fixed combination of front-line drugs in the medical management of glaucoma (latanoprost and timolol) compared to concomitant use of the same drugs. METHODOLOGY: It was a double-blind, randomized clinical trial (RCT) in which 116 sequentially consenting participants 40 years and above were recruited and randomized to receive either a fixed combination (group A) or a concomitant combination of latanoprost and timolol (group B). The study was carried out across two tertiary centers in southwest Nigeria. RESULTS: One hundred and fifteen (115) patients were analysed, 58 in group A and 57 in group B. The mean age of participants was 57.9 (± 11.5) years. There were 51 (44.3%) females. Primary open-angle glaucoma (POAG) was the diagnosis in 88 (76.5%) of the participants. No statistically significant difference between the two groups at recruitment. Mean IOP reduction from baseline to day 28 was -17.30 ± 7.8 (95% CI: -15.37 to -19.15), and -14.59 ± 6.1 (95% CI: -12.98 to -16.19) for groups A and B. Group A thus had a 54.97% IOP reduction from baseline values while group B had 51.81% (p = 0.770). The mean intergroup difference (MeD) in IOP reduction (µA - µB) between the two groups on day 28 was 2.05 ± 5.74 (95% CI: 0.6 - 1.61) p=0.04. CONCLUSION: The study was able to demonstrate a noninferiority relationship between the fixed combination dosage form of latanoprost and timolol as compared to the concomitant dosage forms.

CONTEXTE: Le contrôle de la pression intraoculaire reste le pilier de la prise en charge du glaucome à angle ouvert primaire. C'est également l'un des principaux facteurs à considérer dans le diagnostic et le risque de conversion de l'hypertension oculaire en glaucome (POAG). La gestion médicale du contrôle de la pression intraoculaire est essentielle dans le traitement du POAG, surtout dans les pays à ressources limitées. OBJECTIF: Cette étude visait à démontrer la non-infériorité d'une combinaison fixe de médicaments de première ligne dans la gestion médicale du glaucome (latanoprost et timolol) par rapport à l'utilisation concomitante des mêmes médicaments. MÉTHODOLOGIE: Il s'agissait d'un essai clinique randomisé en double aveugle dans lequel 116 participants consécutifs âgés de 40 ans et plus ont été recrutés et répartis de manière aléatoire pour recevoir soit une combinaison fixe (groupe A) soit une combinaison concomitante de latanoprost et de timolol (groupe B). L'étude a été menée dans deux centres tertiaires du sud-ouest du Nigeria. RÉSULTATS: Cent quinze (115) patients ont été analysés, 58 dans le groupe A et 57 dans le groupe B. L'âge moyen des participants était de 57,9 (± 11,5) ans. Il y avait 51 (44,3%) femmes. Le glaucome à angle ouvert primaire (POAG) a été diagnostiqué chez 88 (76,5%) des participants. Aucune différence statistiquement significative entre les deux groupes au moment du recrutement. La réduction moyenne de la pression intraoculaire entre le début et le jour 28 était de -17,30 ± 7,8 (IC à 95% : -15,37 à ­19,15) et de -14,59 ± 6,1 (IC à 95% : -12,98 à -16,19) pour les groupes A et B. Le groupe A a ainsi présenté une réduction de 54,97 % de la PIO par rapport aux valeurs initiales tandis que le groupe B a enregistré 51,81 % (p = 0,770). La différence moyenne intergroupes (DMI) dans la réduction de la PIO (µA ­ µB) entre les deux groupes au jour 28 était de 2,05 ± 5,74 (IC à 95% : 0,6 ­ 1,61) p = 0,04. CONCLUSION: L'étude a pu démontrer une relation de noninfériorité entre la forme posologique fixe de latanoprost et de timolol par rapport aux formes posologiques concomitantes. MOTS-CLÉS: Glaucoma, Hypertension oculaire, Contrôle de la PIO, Nigérians, Latanoprost, Timolol, Hypotenseurs oculaires, Combinaison fixe, Patients naïfs aux médicaments.

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.

[ROCK (RHO-KINASE INHIBITORS) FOR THE TREATMENT OF OPEN-ANGLE GLAUCOMA AND OCULAR HYPERTENSION].

INTRODUCTION: Netarsudil ophthalmic solution 0.02% is a new treatment for open-angle glaucoma and ocular hypertension, which was approved for treatment in the United States and in the European Commission. The drug is a rho- kinase inhibitor (ROCK) that lowers intraocular pressure by enhancing the outflow at the trabecular meshwork and decreasing both aqueous humor production and episcleral venous pressure. This literature review aims to present this new treatment, characterize its specific mechanism of action, and discuss its effect and adverse events profile. The efficacy and safety of the drug were studied in the ROCKET and MERCURY clinical trials, in which Netarsudil was compared to other common drugs, including Timolol (Beta-blocker), Latanoprost (Prostaglandin analog), and a combination drop containing Netarsudil and Latanoprost. These trials showed a reduction of 16%-21% in the intraocular pressure (IOP) when using Netarsudil. Moreover, it was found that when using a combination of Netarsudil and Latanoprost, 64.5% of these patients achieved ≥30% reduction in mean diurnal IOP versus 28.8% of patients treated only with Netarsudil and 37.2% of patients treated only with Latanoprost (P<0.0001). The most common adverse event reported was conjunctival hyperemia, which was more frequent in patients using Netarsudil. However, this did not significantly affect the drug tolerance.

[Comparison of the effectiveness and safety of glaucoma drugs in the therapy of primary open-angle glaucoma]. / Sravnenie effektivnosti i bezopasnosti primeneniya protivoglaukomnykh preparatov v terapii pervichnoi otkrytougol'noi glaukomy.

The rise in the number of glaucoma drugs complicates the choice that the ophthalmologists have to do. PURPOSE: The study compares the effectiveness, safety and usability of the Russian latanoprost drug Trilaktan and the drug Xalatan in monotherapy for patients with primary open-angle glaucoma (POAG) and ocular hypertension (OH). MATERIAL AND METHODS: This is a multicenter observational study of the effectiveness and safety of eye drops Trilaktan (Groteks, Russia) and Xalatan (Pfizer MFG. Belgium N.V., Belgium) in monotherapy for patients with POAG of early and moderate stages or OH. The maximum duration of the regimen for the studied drugs was 87 days. The study included 76 patients: 56 (74%) women and 20 (26%) men aged 50-84 years (mean age 66.3±1.3 years). The groups were homogeneous in demographic, anthropometric and vital indicators. Effectiveness was assessed by the trends in intraocular pressure (IOP) changes, safety - by analyzing the adverse events, usability and ease of use - by the questionnaires the study patients filled. RESULTS: Both drugs investigated in this study decrease IOP by a mean of 6-8 mm Hg depending on tonometry method, with difference not exceeding 0.55 mm Hg. The proportion of patients with IOP decreased by 30% and more from the baseline level was 89.5% in both groups. The differences between the indicators of drug usability (by McMonnies conjunctival hyperemia scale, tear break-up time (TBUT), punctate keratopathy, OSDI questionnaire results) were insignificant, and the observed changes did not decrease the tolerability of the studied drugs. The patients using Trilaktan also commended the usability of the included eye drops dispenser. CONCLUSIONS: The results of this study allow a conclusion that the effectiveness and safety of Trilaktan (Groteks, Russia) eye drops are equal to those of Xalatan (Pfizer MFG. Belgium N.V., Belgium) eye drops in patients with POAG of early and moderate stages or OH. Trilaktan is easy to use thanks to the included eye drops dispenser.

Effect of topical latanoprost on choroidal thickness and vessel area in Guinea pigs.

The aim of this study was to investigate the effect of latanoprost, an ocular hypotensive agent and prostaglandin analog, on choroidal thickness and structure in young adult guinea pigs. Young (three-month-old) guinea pigs (n = 10) underwent daily monocular treatment with topical 0.005% latanoprost for 2 weeks, followed by a washout period of 2 weeks. Tonometry (iCare) and retinoscopy were undertaken to monitor intraocular pressure (IOP) and refractive error (recorded as spherical equivalent refractive error; SER), respectively. Axial length (AL) and choroidal thickness (ChT) were measured using high frequency A-scan ultrasonography, with additional ChT data, as well as choroidal vessel (ChV) areas obtained from posterior segment imaging using Spectral Domain-Optical Coherence Tomography (SD-OCT). Image J was used to analyze SD-OCT images. As expected, latanoprost significantly reduced IOP in treated eyes. Mean interocular IOP difference (±SE) changed from -0.40 ± 0.31 mmHg at baseline to -2.23 ± 0.43 mmHg after 2 weeks of treatment (p = 0.05). However, SER and AL were unaffected; interocular difference changed from 0.41 ± 0.58 to 0.38 ± 0.43 D and from -0.002 ± 0.02 mm to -0.007 ± 0.01 mm (p > 0.05), respectively. Latanoprost had minimal effect on ChT. Interocular ChT differences were 0.01 ± 0.06 µm at baseline and 0.04 ± 0.06 µm after 2 weeks of treatment (SD-OCT; p > 0.05). However, treated eyes had significant increased ChV areas; interocular differences changed from -0.76 ± 69.2 to 100.78 ± 66.9 µm2 after treatment (p = 0.04). While this study was limited to otherwise untreated young adult guinea pigs, the possibility that choroidal vessel enlargement contributes to the previously reported inhibitory effect of topical latanoprost on myopia progression in young guinea pigs warrants investigation.

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.

Effects of PPAR-γ and RXR-α on mouse meibomian gland epithelial cells during inflammation induced by latanoprost.

The purpose of this study is to investigate the effects of latanoprost on the secretion of cytokines and chemokines from meibomian gland epithelial cells, and to evaluate the modulation of peroxisome proliferator-activated receptor γ (PPAR-γ) and retinoid X receptor α (RXR-α) during latanoprost-induced inflammation. Mouse meibomian gland epithelial cells were cultured in proliferation and differentiation medium, respectively. Cells were exposed to latanoprost, rosiglitazone (PPAR-γ agonist), or LG100268 (RXR-α agonist), respectively. The expression of IL-6, IL-1ß, TNF-α, MMP-9, MCP-1, and CCL-5 were detected by real-time PCR and ELISA. The effect of latanoprost, rosiglitazone, LG100268, and inflammatory cytokines on the differentiation of meibocyte were evaluated by related gene expression and lipid staining. The expression of Keratin-1, 6, 17 protein was detected by western immunoblotting. The results showed that the above cytokines could be induced by latanoprost in meibomian gland epithelial cells. LG100268 and rosiglitazone could inhibit the production of IL-6 and TNF-α induced by latanoprost, respectively. Latanoprost suppressed the expression of differentiation-related mRNA through a positive feedback loop by enhancement of COX-2 expression via FP receptor-activated ERK signaling. The expression of Keratin-17 was upregulated by rosiglitazone and suppressed by LG100268. The application of IL-6 and TNF-α showed negative effects on lipid accumulation in meibomian gland epithelial cells. These results demonstrated that latanoprost could induce inflammation and suppress differentiation of mouse meibomian gland epithelial cells. The activation of PPAR-γ and RXR-α showed an anti-inflammatory effect, showing a potential role to antagonize the effect of latanoprost eyedrops on meibomian gland epithelial cells.