ABSTRACT
Purpose: Primary open-angle glaucoma (POAG) is a leading cause of blindness, and its primary risk factor is elevated intraocular pressure (IOP) due to pathologic changes in the trabecular meshwork (TM). We previously showed that there is a cross-inhibition between TGFß and Wnt signaling pathways in the TM. In this study, we determined if activation of the Wnt signaling pathway using small-molecule Wnt activators can inhibit TGFß2-induced TM changes and ocular hypertension (OHT). Methods: Primary human TM (pHTM) cells and transduced SBE-GTM3 cells were treated with or without Wnt and/or TGFß signaling activators and used for luciferase assays; for the extraction of whole-cell lysate, conditioned medium, cytosolic proteins, and nuclear proteins for Western immunoblotting (WB); or for immunofluorescent staining. Human donor eyes were perfusion cultured to study the effect of Wnt activators on IOP. Results: We found that the small-molecule Wnt activators (GSK3ß inhibitors) (BIO, SB216763, and CHIR99021) activated canonical Wnt signaling in pHTM cells without toxicity at tested concentrations. This activation inhibited TGFß signaling as well as TGFß2-induced extracellular matrix deposition and formation of cross-linked actin networks in pHTM cells or SBE-GTM3 cells. We also observed nuclear translocation of both Smad4 and ß-catenin in pHTM cells, which suggested that the cross-inhibition between the TGFß and Wnt signaling pathways may occur in the nucleus. Using our ex vivo model, we found that CHIR99021 inhibited TGFß2-induced OHT in perfusion-cultured human eyes. Conclusions: Our results showed that small-molecule Wnt activators have the potential for treating TGFß signaling-induced OHT in patients with POAG.
Subject(s)
Glaucoma, Open-Angle , Glycogen Synthase Kinase 3 beta , Intraocular Pressure , Trabecular Meshwork , Humans , Trabecular Meshwork/metabolism , Trabecular Meshwork/drug effects , Intraocular Pressure/physiology , Intraocular Pressure/drug effects , Glaucoma, Open-Angle/metabolism , Glaucoma, Open-Angle/drug therapy , Cells, Cultured , Glycogen Synthase Kinase 3 beta/metabolism , Glycogen Synthase Kinase 3 beta/antagonists & inhibitors , Blotting, Western , Wnt Signaling Pathway/drug effects , Wnt Signaling Pathway/physiology , Ocular Hypertension/metabolism , Ocular Hypertension/drug therapy , Signal Transduction , Transforming Growth Factor beta/metabolism , Transforming Growth Factor beta2/pharmacologySubject(s)
Dose-Response Relationship, Drug , Eplerenone , Intraocular Pressure , Mineralocorticoid Receptor Antagonists , Spironolactone , Intraocular Pressure/drug effects , Intraocular Pressure/physiology , Humans , Eplerenone/pharmacology , Eplerenone/therapeutic use , Eplerenone/administration & dosage , Mineralocorticoid Receptor Antagonists/administration & dosage , Mineralocorticoid Receptor Antagonists/pharmacology , Spironolactone/administration & dosageABSTRACT
BACKGROUND: To investigate if there are improvements in trabeculectomy outcomes supporting filtration bleb formation caused by Rho-associated protein kinase (ROCK) inhibitors. METHODS: This prospective, multicentre, randomised, open-label clinical study examined open-angle glaucoma patients who underwent trabeculectomy or trabeculectomy combined with cataract surgery followed by 3-month postoperative ripasudil treatments. After randomly allocating patients to ripasudil-ROCK inhibitor (ripasudil) or without ripasudil (non-ripasudil) groups. Mean intraocular pressure (IOP) changes, success rate, and number of eyedrops were compared for both groups. RESULTS: A total of 17 and 15 subjects dropped out in the ripasudil group and non-ripasudil group, respectively. At baseline, the mean IOP was 16.8±5.0 mm Hg in the ripasudil group (38 patients) and 16.2±4.4 in the non-ripasudil group (52 patients). The IOP decreased to 11.4±3.2 mm Hg, 10.9±3.9 mm Hg and 10.6±3.5 mm Hg at 12, 24 and 36 months in the ripasudil group, while it decreased to 11.2±4.1 mm Hg, 10.5±3.1 mm Hg and 10.9±3.2 mm Hg at 12, 24 and 36 months in the non-ripasudil group, respectively. There was a significant decrease in the number of IOP-lowering medications after trabeculectomy in the ripasudil group versus the non-ripasudil group at 24 (p=0.010) and 36 months (p=0.016). There was no statistically significant difference between the groups for the 3-year cumulative probability of success. CONCLUSION: Although ripasudil application did not increase the primary trabeculectomy success rate, it did reduce IOP-lowering medications after trabeculectomy with mitomycin C.
Subject(s)
Glaucoma, Open-Angle , Intraocular Pressure , Isoquinolines , Mitomycin , Sulfonamides , Trabeculectomy , Humans , Trabeculectomy/methods , Male , Intraocular Pressure/drug effects , Prospective Studies , Female , Glaucoma, Open-Angle/surgery , Glaucoma, Open-Angle/drug therapy , Isoquinolines/therapeutic use , Isoquinolines/administration & dosage , Aged , Sulfonamides/therapeutic use , Sulfonamides/administration & dosage , Mitomycin/therapeutic use , Mitomycin/administration & dosage , Middle Aged , rho-Associated Kinases/antagonists & inhibitors , Treatment Outcome , Alkylating Agents/administration & dosage , Alkylating Agents/therapeutic useABSTRACT
PURPOSE: To study the effect of brimonidine on vascular density and flow index of optic nerve head (ONH) and macula in primary open angle glaucoma (POAG) using optical coherence tomography angiography (OCTA). METHODS: Twenty-three brimonidine-naïve POAG patients were started on brimonidine. They underwent OCTA ONH and macula before commencing brimonidine and one month thereafter. Systemic arterial blood pressure (SABP) and intraocular pressure (IOP) were measured at each visit to calculate mean ocular perfusion pressure (MOPP). The OCT angiograms were analyzed using ImageJ software to calculate ONH and macular flow indices. RESULTS: Thirty-seven eyes (23 patients) with a mean age of 56.7 ± 12.49 years were included of whom 60.8% were males. Brimonidine was associated with an increase in the superficial flow index (SFI) (P-value = 0.02) and optic nerve head flow index (ONHFI) (P-value = 0.01). Also, superficial vascular density (SVD) for whole image, superior-hemi and fovea increased (P-value = 0.03, 0.02, 0.03 respectively). ONH inferior-hemi vascular density decreased (P-value = 0.01) despite an increase in inferior quadrant retinal nerve fiber layer thickness (RNFLT) (P-value = 0.03). There was no statistically significant correlation between flow indices and MOPP at baseline and follow-up. A moderate negative correlation was found between SVD and DVD at the fovea and MOPP at baseline and follow-up (P-value = 0.03, 0.05) (P-value = 0.02, 0.01) respectively. CONCLUSIONS: Brimonidine was associated with an increase in SFI, ONHFI and SVD indicating improved GCC and RNFL perfusion in POAG. Despite the increase in inferior quadrant RNFLT, the concomitant decrease in inferior-hemi ONHVD precluded a conclusion of hemodynamically-mediated improvement of RNFLT.
Subject(s)
Brimonidine Tartrate , Fluorescein Angiography , Glaucoma, Open-Angle , Intraocular Pressure , Macula Lutea , Optic Disk , Retinal Vessels , Tomography, Optical Coherence , Humans , Glaucoma, Open-Angle/physiopathology , Glaucoma, Open-Angle/drug therapy , Glaucoma, Open-Angle/diagnosis , Male , Optic Disk/blood supply , Brimonidine Tartrate/administration & dosage , Brimonidine Tartrate/pharmacology , Brimonidine Tartrate/therapeutic use , Middle Aged , Female , Tomography, Optical Coherence/methods , Macula Lutea/blood supply , Macula Lutea/diagnostic imaging , Intraocular Pressure/physiology , Intraocular Pressure/drug effects , Retinal Vessels/diagnostic imaging , Retinal Vessels/physiopathology , Retinal Vessels/drug effects , Fluorescein Angiography/methods , Regional Blood Flow/physiology , Regional Blood Flow/drug effects , Aged , Fundus Oculi , Prospective Studies , Visual Fields/physiology , Retinal Ganglion Cells/pathology , Retinal Ganglion Cells/drug effects , Antihypertensive Agents/therapeutic use , Nerve Fibers/pathology , Nerve Fibers/drug effects , Adult , Follow-Up StudiesABSTRACT
BACKGROUND: Glaucoma treatment often involves multi-drug regimens, which can lead to poor adherence and side effects. Fixed-dose combinations aim to improve adherence and reduce side effects compared to traditional therapies. This study aimed to compare the prevalence and clinical characteristics of ocular allergy in glaucoma patients using brinzolamide 1.0%/brimonidine 0.2% fixed combination (BBFC), with and without concurrent ß-blocker. METHODS: Of these, 176 patients used a ß-blocker concurrently, whereas 96 patients did not. Allergy prevalence, allergy type, and allergy occurrence time were compared between the concurrent and non-concurrent ß-blocker-usage groups. Ocular allergies were classified and evaluated using Kaplan-Meier survival analysis. RESULTS: Allergy prevalence was 10.23% and 15.63% (p = 0.193), whereas allergy occurrence time was 15.92 ± 13.80 months and 6.26 ± 6.20 months (p = 0.04) in the concurrent and non-concurrent ß-blocker-usage groups, respectively. Kaplan-Meier survival analysis indicated that half of the allergies in the concurrent ß-blocker-usage group occurred within 12.5 months, with the BBFC discontinuation rate gradually increasing up to 36 months. Contrarily, half of the allergies in the non-concurrent ß-blocker-usage group occurred within 3.3 months, with a rapid increase in BBFC discontinuation rate the first 6 months. Intergroup differences in allergy types were significant (p = 0.015). Among all patients with allergy, the average allergy occurrence time of blepharoconjunctivitis, papillary conjunctivitis, and follicular conjunctivitis was 12.52, 9.53, and 13.23 months, respectively. Follicular conjunctivitis tended to occur later than papillary conjunctivitis (p = 0.042). In the concurrent ß-blocker-usage group, follicular conjunctivitis was the most prevalent allergy type (61.1%), whereas papillary conjunctivitis was the most common (66.7%) in in the non-concurrent ß-blocker-usage group. CONCLUSIONS: Concurrent use of ß-blocker with BBFC decreases allergy prevalence, delays allergy onset, and predominantly results in follicular conjunctivitis, thereby facilitating longer treatment duration. Understanding these characteristics of allergy in BBFC users is useful to manage patients and improve treatment adherence. This study provides insights into the role of ß-blockers in modulating ocular allergy in BBFC-treated glaucoma patients, highlighting implications for clinical practice and patient education.
Subject(s)
Adrenergic beta-Antagonists , Brimonidine Tartrate , Drug Combinations , Glaucoma , Ophthalmic Solutions , Sulfonamides , Thiazines , Humans , Male , Female , Retrospective Studies , Brimonidine Tartrate/administration & dosage , Brimonidine Tartrate/therapeutic use , Brimonidine Tartrate/adverse effects , Aged , Adrenergic beta-Antagonists/therapeutic use , Adrenergic beta-Antagonists/administration & dosage , Thiazines/administration & dosage , Thiazines/therapeutic use , Thiazines/adverse effects , Middle Aged , Prevalence , Sulfonamides/administration & dosage , Sulfonamides/adverse effects , Glaucoma/epidemiology , Glaucoma/drug therapy , Drug Hypersensitivity/epidemiology , Carbonic Anhydrase Inhibitors/administration & dosage , Carbonic Anhydrase Inhibitors/therapeutic use , Antihypertensive Agents/therapeutic use , Antihypertensive Agents/administration & dosage , Drug Therapy, Combination , Intraocular Pressure/physiology , Intraocular Pressure/drug effects , Aged, 80 and overABSTRACT
PURPOSE: This study evaluates the long-term adjunctive use of netarsudil ophthalmic solution 0.02% in lowering IOP in patients with refractory glaucoma. METHODS: This retrospective chart review study was conducted at a tertiary care center. Patients who were prescribed add-on netarsudil therapy and on ≥ 3 topical glaucoma medications from 01/01/2018 to 08/31/2020 were reviewed. 47 patients (69 eyes) met the inclusion criteria. Baseline IOPs prior to the addition of netarsudil were compared to IOPs measured at 3-, 6-, and 12-month intervals. Any patients with inadequate follow-up or who had glaucoma surgery after netarsudil initiation were excluded. RESULTS: Median baseline IOP (± SD) was 21 ± 5.8 mmHg (median of 2 visits prior to initiation of netarsudil). At 3-month follow-up, 64 eyes had a median IOP of 16 ± 6.7 mmHg (p < 0.01). At 6-month follow-up, 56 eyes had a median IOP of 18 ± 4.6 mmHg (p < 0.01). At 12-month follow-up, 44 eyes had a median IOP of 15 ± 6.8 mmHg (p < 0.01). At the conclusion of the study, 64% of eyes reached 1 year follow-up due to several reasons. CONCLUSIONS: Patients with refractory glaucoma showed statistically and clinically significant IOP reductions on netarsudil. IOP reduction was stable long-term with the largest decrease in IOP seen at 12 months. Although some patients will still go on to require further laser or incisional surgery, for most patients netarsudil is an effective treatment for adjunctive use in refractory glaucoma.
Subject(s)
Benzoates , Intraocular Pressure , Ophthalmic Solutions , beta-Alanine , Humans , Retrospective Studies , Male , Female , Intraocular Pressure/physiology , Intraocular Pressure/drug effects , beta-Alanine/analogs & derivatives , beta-Alanine/administration & dosage , beta-Alanine/therapeutic use , Aged , Ophthalmic Solutions/administration & dosage , Middle Aged , Benzoates/administration & dosage , Benzoates/therapeutic use , Follow-Up Studies , Treatment Outcome , Glaucoma/drug therapy , Glaucoma/physiopathology , Antihypertensive Agents/administration & dosage , Antihypertensive Agents/therapeutic use , Tonometry, Ocular , Visual Acuity , Aged, 80 and overABSTRACT
PURPOSE: To investigate outcomes of suprachoroidal triamcinolone acetonide (XIPERE, Bausch + Lomb) for the treatment of refractory postoperative cystoid macular edema. METHODS: Medical records of patients receiving suprachoroidal triamcinolone acetonide for postoperative cystoid macular edema were reviewed. Primary outcomes were visual acuity and central foveal thickness. RESULTS: A total of 32 eyes from 32 patients with a median (interquartile range) follow-up duration of 6 (2-7) months and 1 (1-2) suprachoroidal triamcinolone acetonide injection were included; 19 (59.4%) had a history of vitrectomy. The median (interquartile range) central foveal thickness decreased from 492 (379-629) µm to 267 (187-388) µm at 1 month (P < 0.001), 362 (218-521) µm at 3 months (P = 0.005), and 339 (206-514) µm at the final visit (P < 0.001). The median logarithm of the minimal angle of resolution visual acuity improved from 0.65 (0.48-0.97, 20/89) at baseline to 0.54 (0.35-0.88, 20/69) (P = 0.058) at 1 month, 0.54 (0.33-0.84, 20/69) at 3 months (P = 0.121), and 0.60 (0.33-0.88, 20/80) at the final visit (P = 0.021). Vitrectomized eyes had similar findings. Six eyes (18.8%) developed elevated intraocular pressure (>24 mmHg) (range: 25-49 mmHg) with a median intraocular pressure elevation of 13.5 mmHg compared with baseline, and all had prior glaucoma or ocular hypertension. CONCLUSION: Suprachoroidal triamcinolone acetonide reduced macular edema and improved vision in refractory postoperative cystoid macular edema, including vitrectomized eyes. Intraocular pressure should be monitored, especially in those with a history of glaucoma or ocular hypertension.
Subject(s)
Glucocorticoids , Macular Edema , Tomography, Optical Coherence , Triamcinolone Acetonide , Visual Acuity , Humans , Macular Edema/drug therapy , Macular Edema/etiology , Macular Edema/physiopathology , Macular Edema/diagnosis , Triamcinolone Acetonide/administration & dosage , Triamcinolone Acetonide/therapeutic use , Female , Male , Glucocorticoids/administration & dosage , Glucocorticoids/therapeutic use , Retrospective Studies , Aged , Middle Aged , Postoperative Complications , Choroid , Follow-Up Studies , Intraocular Pressure/physiology , Intraocular Pressure/drug effects , Treatment Outcome , Vitrectomy/methodsABSTRACT
BACKGROUND: Glaucoma is one of the major irreversible blinding eye diseases in the world. Reducing intraocular pressure (IOP) is the primary treatment option, and taking eye drops daily is the common method. However, short drug duration and poor bioavailability of eye drops may lead to unsatisfied therapeutic effects and inadequate patient compliance. METHODS: A brimonidine-loaded silicone rubber insert (BRI@SR@PT) was prepared by loading brimonidine into a surface-modified silicone rubber ring, followed by polydopamine/thermoplastic polyurethane coatings. The physical properties, in vitro cytocompatibility and drug release of BRI@SR@PT were investigated. The BRI@SR@PT was administrated in the conjunctival sac of rabbit eyes, and its in vivo drug release, IOP-lowering efficacy and biosafety were assessed. RESULTS: The BRI@SR@PT presented great thermal stability and excellent elasticity. The BRI@SR@PT was able to release BRI sustainably for 28 days with little toxicity in vitro. Compared to BRI eye drops, the BRI@SR@PT effectively lowered IOP for 21 days based on the sustained BRI release with great biosafety when administrated in conjunctival sac of rabbit eyes in a noninvasive fashion. CONCLUSIONS: The conjunctival sac insert (BRI@SR@PT), as a promising drug-delivery platform, may provide a sustained IOP-lowering treatment for patients with ocular hypertension or glaucoma, without the need for invasive procedures.
Subject(s)
Brimonidine Tartrate , Delayed-Action Preparations , Drug Liberation , Glaucoma , Intraocular Pressure , Polyurethanes , Rabbits , Animals , Intraocular Pressure/drug effects , Glaucoma/drug therapy , Brimonidine Tartrate/administration & dosage , Brimonidine Tartrate/pharmacology , Brimonidine Tartrate/therapeutic use , Polyurethanes/chemistry , Polyurethanes/administration & dosage , Drug Delivery Systems , Polymers/chemistry , Silicone Elastomers/chemistry , Conjunctiva , Ophthalmic Solutions/administration & dosage , Indoles/administration & dosage , Indoles/pharmacokinetics , Male , Biological Availability , Humans , Antihypertensive Agents/administration & dosage , Antihypertensive Agents/pharmacology , Antihypertensive Agents/pharmacokinetics , Antihypertensive Agents/chemistryABSTRACT
Purpose: Glucocorticoid-induced glaucoma (GIG) is a prevalent complication associated with glucocorticoids (GCs), resulting in irreversible blindness. GIG is characterized by the abnormal deposition of extracellular matrix (ECM) in the trabecular meshwork (TM), elevation of intraocular pressure (IOP), and loss of retinal ganglion cells (RGCs). The objective of this study is to investigate the effects of nicotinamide riboside (NR) on TM in GIG. Methods: Primary human TM cells (pHTMs) and C57BL/6J mice responsive to GCs were utilized to establish in vitro and in vivo GIG models, respectively. The study assessed the expression of ECM-related proteins in TM and the functions of pHTMs to reflect the effects of NR. Mitochondrial morphology and function were also examined in the GIG cell model. GIG progression was monitored through IOP, RGCs, and mitochondrial morphology. Intracellular nicotinamide adenine dinucleotide (NAD+) levels of pHTMs were enzymatically assayed. Results: NR significantly prevented the expression of ECM-related proteins and alleviated dysfunction in pHTMs after dexamethasone treatment. Importantly, NR protected damaged ATP synthesis, preventing overexpression of mitochondrial reactive oxygen species (ROS), and also protect against decreased mitochondrial membrane potential induced by GCs in vitro. In the GIG mouse model, NR partially prevented the elevation of IOP and the loss of RGCs. Furthermore, NR effectively suppressed the excessive expression of ECM-associated proteins and mitigated mitochondrial damage in vivo. Conclusions: Based on the results, NR effectively enhances intracellular levels of NAD+, thereby mitigating abnormal ECM deposition and TM dysfunction in GIG by attenuating mitochondrial damage induced by GCs. Thus, NR has promising potential as a therapeutic candidate for GIG treatment.
Subject(s)
Disease Models, Animal , Extracellular Matrix , Glaucoma , Glucocorticoids , Intraocular Pressure , Mice, Inbred C57BL , Mitochondria , Niacinamide , Pyridinium Compounds , Trabecular Meshwork , Animals , Niacinamide/analogs & derivatives , Niacinamide/pharmacology , Pyridinium Compounds/pharmacology , Glucocorticoids/toxicity , Mitochondria/metabolism , Mitochondria/drug effects , Mice , Glaucoma/metabolism , Glaucoma/drug therapy , Extracellular Matrix/metabolism , Extracellular Matrix/drug effects , Intraocular Pressure/drug effects , Humans , Trabecular Meshwork/metabolism , Trabecular Meshwork/drug effects , Trabecular Meshwork/pathology , Cells, Cultured , Retinal Ganglion Cells/drug effects , Retinal Ganglion Cells/metabolism , Retinal Ganglion Cells/pathology , Reactive Oxygen Species/metabolism , Dexamethasone/pharmacology , MaleABSTRACT
Although biomechanical changes of the trabecular meshwork (TM) are important to the pathogenesis of glucocorticoids-induced ocular hypertension (GC-OHT), there is a knowledge gap in the underlying molecular mechanisms of the development of it. In this study, we performed intravitreal triamcinolone injection (IVTA) in one eye of 3 rhesus macaques. Following IVTA, we assessed TM stiffness using atomic force microscopy and investigated changes in proteomic and miRNA expression profiles. One of 3 macaques developed GC-OHT with a difference in intraocular pressure of 4.2 mmHg and a stiffer TM with a mean increase in elastic moduli of 0.60 kPa versus the non-injected control eye. In the IVTA-treated eyes, proteins associated with extracellular matrix remodeling, cytoskeletal rearrangement, and mitochondrial oxidoreductation were significantly upregulated. The significantly upregulated miR-29b and downregulated miR-335-5p post-IVTA supported the role of oxidative stress and mitophagy in the GC-mediated biomechanical changes in TM, respectively. The significant upregulation of miR-15/16 cluster post-IVTA may indicate a resultant TM cell apoptosis contributing to the increase in outflow resistance. Despite the small sample size, these results expand our knowledge of GC-mediated responses in the TM and furthermore, may help explain steroid responsiveness in clinical settings.
Subject(s)
Glucocorticoids , Intraocular Pressure , Intravitreal Injections , Macaca mulatta , MicroRNAs , Proteomics , Trabecular Meshwork , Animals , MicroRNAs/genetics , MicroRNAs/metabolism , Trabecular Meshwork/drug effects , Trabecular Meshwork/metabolism , Glucocorticoids/pharmacology , Glucocorticoids/administration & dosage , Proteomics/methods , Intraocular Pressure/drug effects , Intraocular Pressure/physiology , Ocular Hypertension/metabolism , Triamcinolone Acetonide/pharmacology , Biomechanical Phenomena , Disease Models, Animal , Microscopy, Atomic Force , Triamcinolone/pharmacology , Triamcinolone/administration & dosageABSTRACT
The aim of this study was to explore the neuroprotective effects of the P2X7 receptor antagonist A740003 on retinal ganglion cells (RGCs) in chronic intraocular hypertension (COH) experimental glaucoma mouse model. Bioinformatics was used to analyze the glaucoma-related genes. Western blot, real-time fluorescence quantitative PCR, and immunofluorescence staining techniques were employed to explore the mechanisms underlying the neuroprotective effects of A740003 on RGCs in COH retinas. Bioinformatic analysis revealed that oxidative stress, neuroinflammation, and cell apoptosis were highly related to the pathogenesis of glaucoma. In COH retinas, intraocular pressure elevation significantly increased the levels of translocator protein, a marker of microglial activation, which could be reversed by intravitreal preinjection of A740003. A740003 also suppressed the increased mRNA levels of proinflammatory cytokines interleukin (IL) 1ß and tumor necrosis factor α in COH retinas. In addition, although the mRNA levels of anti-inflammatory cytokine IL-4 and IL-10 were kept unchanged in COH retinas, administration of A740003 could increase their levels. The mRNA and protein levels of Bax and cleaved caspase-3 were increased in COH retinas, which could be partially reversed by A740003, while the levels of Bcl-2 kept unchanged in COH retinas with or without the injections of A740003. Furthermore, A740003 partially attenuated the reduction in the numbers of Brn-3a-positive RGCs in COH mice. A740003 could provide neuroprotective roles on RGCs by inhibiting the microglia activation, attenuating the retinal inflammatory response, reducing the apoptosis of RGCs, and enhancing the survival of RGCs in COH experimental glaucoma.
Subject(s)
Glaucoma , Mice, Inbred C57BL , Neuroprotective Agents , Purinergic P2X Receptor Antagonists , Retinal Ganglion Cells , Animals , Retinal Ganglion Cells/drug effects , Retinal Ganglion Cells/metabolism , Retinal Ganglion Cells/pathology , Glaucoma/drug therapy , Glaucoma/metabolism , Neuroprotective Agents/pharmacology , Mice , Purinergic P2X Receptor Antagonists/pharmacology , Disease Models, Animal , Male , Benzopyrans/pharmacology , Neuroprotection/drug effects , Apoptosis/drug effects , Receptors, Purinergic P2X7/metabolism , Receptors, Purinergic P2X7/drug effects , Ocular Hypertension/drug therapy , Ocular Hypertension/metabolism , Intraocular Pressure/drug effects , CarbazolesABSTRACT
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).
Subject(s)
Antihypertensive Agents , Cross-Over Studies , Glaucoma, Open-Angle , Intraocular Pressure , Latanoprost , Ocular Hypertension , Ophthalmic Solutions , Humans , Latanoprost/therapeutic use , Glaucoma, Open-Angle/drug therapy , Glaucoma, Open-Angle/physiopathology , Male , Female , Middle Aged , Intraocular Pressure/drug effects , Ocular Hypertension/drug therapy , Antihypertensive Agents/therapeutic use , Antihypertensive Agents/adverse effects , Aged , Adult , Drugs, Generic/therapeutic use , Drugs, Generic/adverse effects , Treatment Outcome , Preservatives, Pharmaceutical/therapeutic use , Single-Blind Method , Tonometry, Ocular , Double-Blind MethodSubject(s)
Dose-Response Relationship, Drug , Eplerenone , Intraocular Pressure , Mineralocorticoid Receptor Antagonists , Intraocular Pressure/drug effects , Intraocular Pressure/physiology , Humans , Eplerenone/pharmacology , Eplerenone/therapeutic use , Eplerenone/administration & dosage , Mineralocorticoid Receptor Antagonists/administration & dosage , Mineralocorticoid Receptor Antagonists/therapeutic use , Mineralocorticoid Receptor Antagonists/pharmacology , Spironolactone/administration & dosageABSTRACT
Glaucoma is a chronic neurodegenerative disease that poses a significant threat of irreversible blindness worldwide. Current treatments for glaucoma focus on reducing intraocular pressure (IOP), which is the only modifiable risk factor. Traditional anti-glaucomatous agents, including carbonic anhydrase inhibitors, beta-blockers, alpha-2 agonists, and prostaglandin analogs, work by either improving uveoscleral outflow or reducing aqueous humor production. Rho kinase (ROCK) inhibitors represent a novel class of anti-glaucomatous drugs that have emerged from bench to bedside in the past decade, offering multifunctional characteristics. Unlike conventional medications, ROCK inhibitors directly target the trabecular meshwork outflow pathway. This review aims to discuss the mechanism of ROCK inhibitors in reducing IOP, providing neuroprotection, and preventing fibrosis. We also highlight recent studies and clinical trials evaluating the efficacy and safety of ROCK inhibitors, compare them with other clinical anti-glaucomatous medications, and outline future prospects for ROCK inhibitors in glaucoma treatment.
Subject(s)
Glaucoma , Intraocular Pressure , Protein Kinase Inhibitors , rho-Associated Kinases , Humans , Glaucoma/drug therapy , rho-Associated Kinases/antagonists & inhibitors , rho-Associated Kinases/metabolism , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/pharmacology , Intraocular Pressure/drug effects , AnimalsABSTRACT
Primary open-angle glaucoma (POAG) is a progressive optic neuropathy with a complex, multifactorial aetiology. Raised intraocular pressure (IOP) is the most important clinically modifiable risk factor for POAG. All current pharmacological agents target aqueous humour dynamics to lower IOP. Newer therapeutic agents are required as some patients with POAG show a limited therapeutic response or develop ocular and systemic side effects to topical medication. Elevated IOP in POAG results from cellular and molecular changes in the trabecular meshwork driven by increased levels of transforming growth factor ß (TGFß) in the anterior segment of the eye. Understanding how TGFß affects both the structural and functional changes in the outflow pathway and IOP is required to develop new glaucoma therapies that target the molecular pathology in the trabecular meshwork. In this study, we evaluated the effects of TGF-ß1 and -ß2 treatment on miRNA expression in cultured human primary trabecular meshwork cells. Our findings are presented in terms of specific miRNAs (miRNA-centric), but given miRNAs work in networks to control cellular pathways and processes, a pathway-centric view of miRNA action is also reported. Evaluating TGFß-responsive miRNA expression in trabecular meshwork cells will further our understanding of the important pathways and changes involved in the pathogenesis of glaucoma and could lead to the development of miRNAs as new therapeutic modalities in glaucoma.
Subject(s)
MicroRNAs , Trabecular Meshwork , Trabecular Meshwork/metabolism , Trabecular Meshwork/drug effects , Trabecular Meshwork/pathology , Humans , MicroRNAs/genetics , MicroRNAs/metabolism , Glaucoma, Open-Angle/genetics , Glaucoma, Open-Angle/metabolism , Glaucoma, Open-Angle/pathology , Transforming Growth Factor beta2/metabolism , Transforming Growth Factor beta2/genetics , Transforming Growth Factor beta/metabolism , Transforming Growth Factor beta1/metabolism , Cells, Cultured , Gene Expression Regulation/drug effects , Intraocular Pressure/drug effectsABSTRACT
Glaucoma is characterized by pathological elevation of intraocular pressure (IOP) due to dysfunctional trabecular meshwork (TM), which is the primary cause of irreversible vision loss. There are currently no effective treatment strategies for glaucoma. Mitochondrial function plays a crucial role in regulating IOP within the TM. In this study, primary TM cells treated with dexamethasone were used to simulate glaucomatous changes, showing abnormal cellular cytoskeleton, increased expression of extracellular matrix, and disrupted mitochondrial fusion and fission dynamics. Furthermore, glaucomatous TM cell line GTM3 exhibited impaired mitochondrial membrane potential and phagocytic function, accompanied by decreased oxidative respiratory levels as compared to normal TM cells iHTM. Mechanistically, lower NAD + levels in GTM3, possibly associated with increased expression of key enzymes CD38 and PARP1 related to NAD + consumption, were observed. Supplementation of NAD + restored mitochondrial function and cellular viability in GTM3 cells. Therefore, we propose that the aberrant mitochondrial function in glaucomatous TM cells may be attributed to increased NAD + consumption dependent on CD38 and PARP1, and NAD + supplementation could effectively ameliorate mitochondrial function and improve TM function, providing a novel alternative approach for glaucoma treatment.
Subject(s)
Glaucoma , Mitochondria , NAD , Trabecular Meshwork , Trabecular Meshwork/metabolism , Trabecular Meshwork/drug effects , Trabecular Meshwork/pathology , Mitochondria/metabolism , Mitochondria/drug effects , Mitochondria/pathology , Glaucoma/metabolism , Glaucoma/pathology , Glaucoma/drug therapy , NAD/metabolism , Humans , Membrane Potential, Mitochondrial/drug effects , Intraocular Pressure/drug effects , Cell Survival/drug effects , ADP-ribosyl Cyclase 1/metabolism , ADP-ribosyl Cyclase 1/genetics , Cell Line , Poly (ADP-Ribose) Polymerase-1/metabolism , Poly (ADP-Ribose) Polymerase-1/genetics , Dexamethasone/pharmacology , Cells, CulturedABSTRACT
In the context of glaucoma, intraocular pressure (IOP) and age are recognized as the primary factors contributing to its onset and progression. However, significant reductions in IOP fail to completely halt its advancement. An emerging body of literature highlights the role of neuroinflammation in glaucoma. This study aimed to explore Bromfenac's anti-inflammatory properties in mitigating neuroinflammation associated with glaucoma using an ischemia-reperfusion (IR) glaucoma model. Bromfenac's impact on microglia and astrocytes under pressure was assessed via Western blotting and an enzyme-linked immunosorbent assay. Immunohistochemical staining was used to evaluate glial activation and changes in inflammatory marker expression in the IR model. Bromfenac led to the downregulation of inflammatory markers, which were elevated in the conditions of elevated pressure, and necroptosis markers were downregulated in astrocytes. In the IR model, elevated levels of GFAP and Iba-1 indicated glial activation. Following Bromfenac administration, levels of iNOS, COX-2, and PGE2-R were reduced, suggesting a decrease in neuroinflammation. Furthermore, Bromfenac administration in the IR model resulted in the improved survival of retinal ganglion cells (RGCs) and preservation of retinal function, as demonstrated by immunohistochemical staining and electroretinography. In summary, Bromfenac proved effective in diminishing neuroinflammation and resulted in enhanced RGC survival.
Subject(s)
Astrocytes , Benzophenones , Bromobenzenes , Disease Models, Animal , Glaucoma , Reperfusion Injury , Bromobenzenes/pharmacology , Bromobenzenes/therapeutic use , Animals , Benzophenones/pharmacology , Benzophenones/therapeutic use , Reperfusion Injury/drug therapy , Reperfusion Injury/pathology , Reperfusion Injury/complications , Glaucoma/drug therapy , Glaucoma/pathology , Glaucoma/complications , Astrocytes/drug effects , Astrocytes/metabolism , Astrocytes/pathology , Neuroinflammatory Diseases/drug therapy , Neuroinflammatory Diseases/pathology , Retinal Ganglion Cells/drug effects , Retinal Ganglion Cells/pathology , Retinal Ganglion Cells/metabolism , Microglia/drug effects , Microglia/metabolism , Microglia/pathology , Male , Intraocular Pressure/drug effects , RatsABSTRACT
To evaluate the protective effect of gallic acid on the optic nerve by studying the inhibitory effect of gallic acid on oxidative stress in retinal ganglion cells. 100 male SD rats were randomly divided into four groups: normal control group, simple high IOP group, 0.5% gallic acid experimental group, and 1% gallic acid experimental group. HE staining, immunofluorescence, DHE staining, Western blot, and q-PCR were used to observe the antioxidant effect of gallic acid on the retina of acute ocular hypertension rats. HE staining of the retina of SD rats confirmed that the nucleus of RGCs was clear, the thickness of the RNFL was regular in the normal control group, and the nucleus of RGCs was ruptured and lysed in the simple high intraocular pressure (IOP) group and the gallic acid group, and the thickness of the RNFL was significantly thickened, but the thickness of the RNFL in the gallic acid group was significantly reduced compared with that in the simple high IOP group (p < 0.05). DHE staining showed that ROS content in the simple high IOP group was significantly increased compared with the normal control group, and ROS content was significantly decreased after the application of gallic acid (p < 0.05). Immunofluorescence staining with Brn-3a antibody confirmed that the number of RGCs was significantly reduced in the simple high IOP group compared with the normal control group, whereas after application of gallic acid, the number of RGCs was significantly more in the gallic acid group than in the simple high IOP group (p < 0.05). Western Blot and q-PCR confirmed that hypoxia-inducing factor 1α (HIF-1α) protein content and transcription level were significantly increased in the retinal tissue of the simple high IOP group, and gallic acid could inhibit HIF-1α protein content (p < 0.05) and reduce transcription factor level (p < 0.05). Gallic acid exerts a protective effect on RGC by inhibiting oxidative stress in rats with acute IOP elevation.
Subject(s)
Antioxidants , Disease Models, Animal , Gallic Acid , Glaucoma , Oxidative Stress , Rats, Sprague-Dawley , Retinal Ganglion Cells , Gallic Acid/pharmacology , Animals , Retinal Ganglion Cells/drug effects , Retinal Ganglion Cells/metabolism , Retinal Ganglion Cells/pathology , Antioxidants/pharmacology , Male , Rats , Glaucoma/metabolism , Glaucoma/drug therapy , Glaucoma/pathology , Oxidative Stress/drug effects , Reactive Oxygen Species/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Intraocular Pressure/drug effects , Ocular Hypertension/drug therapy , Ocular Hypertension/metabolism , Ocular Hypertension/pathologyABSTRACT
PURPOSE: To evaluate the clinical effects between dexamethasone and triamcinolone acetonide (TA) after phacoemulsification and intraocular lens implantation among cataract patients. METHODS: Pubmed, Embase, and the Cochrane Library were searched for studies published up to August 2020. The primary outcome was intraocular pressure. The secondary outcomes were the logarithm of the minimum angle of resolution (logMAR), anterior chamber cell, and anterior chamber flare. The pooled effect sizes were expressed as weighted mean differences (WMDs) or standardized mean differences (SMDs) of 95% confidence intervals (95% CIs). Cochrane Collaboration risk of bias tool and Newcastle-Ottawa scale criteria were used for the quality assessment of included studies. RESULTS: Seven relevant studies met the inclusion criteria. For the primary outcome, there was no significant difference between TA injection and dexamethasone in comparing intraocular pressure (IOP) (SMDâ =â 0.22, 95% confidence interval [CI] [-0.29, 0.73], Pâ =â .408; I²â =â 86.9%) in the first day after treatment and last day of assessment. For the secondary outcomes, the logMAR (WMDâ =â 0.01, 95% CI [-0.06, 0.08]) and the anterior chamber flare (SMDâ =â 0.08, 95% CI [-0.01, 0.18], Pâ =â .087; I²â =â 0%) showed no differences. However, the amount of anterior chamber cells (SMDâ =â -0.21, 95% CI [-0.42, -0.01], Pâ =â .044; I²â =â 0%) in the TA injection on the first day postoperative was higher than for dexamethasone. After treatment, there was no difference between the 2 groups. CONCLUSIONS: This study supports that there were no differences in IOP, logMAR, and anterior chamber flare between TA injection and dexamethasone among cataract patients. TA injection treatment on the first day showed higher amounts of anterior chamber cells than with dexamethasone.
Subject(s)
Dexamethasone , Glucocorticoids , Triamcinolone Acetonide , Humans , Cataract Extraction/methods , Dexamethasone/administration & dosage , Dexamethasone/therapeutic use , Glucocorticoids/administration & dosage , Glucocorticoids/therapeutic use , Intraocular Pressure/drug effects , Lens Implantation, Intraocular , Phacoemulsification/methods , Treatment Outcome , Triamcinolone Acetonide/administration & dosage , Triamcinolone Acetonide/therapeutic useABSTRACT
The main objective of this placebo-controlled, triple-blind, balanced crossover study was to assess the acute effects of phenylcapsaicin (PC) intake (2.5 mg) on intraocular pressure (IOP), ocular perfusion pressure (OPP), and heart rate (HR) during a 30-min cycling task performed at 15% of the individual maximal power. Twenty-two healthy young adults performed the cycling task 45 min after ingesting PC or placebo. IOP was measured with a rebound tonometer before exercise, during cycling (every 6 min), and after 5 and 10 min of recovery. OPP was assessed before and after exercise. HR was monitored throughout the cycling task. We found an acute increase of IOP levels related to PC consumption while cycling (mean difference = 1.91 ± 2.24 mmHg; p = .007, ηp2=.30), whereas no differences were observed for OPP levels between the PC and placebo conditions (mean difference = 1.33 ± 8.70 mmHg; p = .608). Mean HR values were higher after PC in comparison with placebo intake (mean difference = 3.11 ± 15.87 bpm, p = .019, ηp2=.24), whereas maximum HR did not differ between both experimental conditions (p = .199). These findings suggest that PC intake before exercise should be avoided when reducing IOP levels is desired (e.g., glaucoma patients or those at risk). Future studies should determine the effects of different ergogenic aids on IOP and OPP levels with other exercise configurations and in the long term.