Journal of Ocular Pharmacology and Therapeutics最新文献

Purpose: Ocular trauma leads to loss of corneal clarity resulting in vision deficits. Autophagy plays a critical role in the extracellular matrix, tissue repair, and homeostasis but its precise mechanistic role in regulating corneal function remains unknown. The present study investigated the modulation of autophagy-related genes (LC3, Beclin1, Sqstm1/p62, and Lamp1) in healthy and injured canine corneal stromal fibroblasts (CSFs). Methods: Primary CSFs were generated from healthy donor canine corneas and grown in minimum essential medium. Following incubation, cultures were exposed to nitrogen mustard (NM) and subjected to an autophagy activator, rapamycin (R), or vehicle treatment. Phase-contrast microscopy, quantitative reverse transcription polymerase chain reaction (qRT-PCR), and immunofluorescence staining were used to study the role of autophagy genes in canine corneal wound healing in vitro. Results: Phase-contrast microscopy showed that NM exposure led to morphological changes with stress fibers in CSFs, which was noticeably decreased by rapamycin treatment. Treatment of CSFs with rapamycin alone showed fibroblast hypertrophy while vehicle-treated population of CSFs exhibited typical spindle morphology. The qRT-PCR showed increased expression of LC3, Beclin1, and Lamp1 mRNA when treated with NM, NM+R, and R in comparison to vehicle-treated CSFs. Sqstm1/p62 expression was upregulated in the NM and NM+R treatment groups but was reduced in the R-treated group. Immunofluorescence showed similar results of the protein levels. Conclusions: This study suggests that autophagy is an essential component in corneal healing post-injury. Further, results suggest that targeting autophagy may offer an attractive treatment option to reestablish corneal clarity following ocular insult.

Purpose: Cyclosporine A (CsA) is a primary treatment for dry eye disease (DED). Ophthalmic solutions containing CsA are available in concentrations of 0.05%, 0.09%, and 0.1%. While 0.1% CsA solutions have been used to treat DED, their safety and effectiveness remains somewhat uncertain. Therefore, we conducted a meta-analysis to evaluate their safety and efficacy. Methods: We searched PubMed, Cochrane Database, Embase, and Web of Science for randomized controlled trials (RCTs) that compared 0.1% CsA solutions with their vehicle. Statistical analysis was performed using Review Manager 5.4.1. Results: We included six RCTs (2,170 patients) with follow-up periods ranging from 4 weeks to 6 months. A total of 1,119 patients (51.56%) with DED were treated with 0.1% CsA. The mean age of patients was 57.9 ± 4.8 years, with 79.7% being female. The total corneal fluorescein staining (tCFS) at last follow-up [mean differences (MD) -0.49; 95% confidence interval (CI) (-0.73, -0.24); P < 0.0001], at 4 weeks [MD -0.64; 95% CI (-1.07, -0.22); P = 0.003], and central corneal fluorescein staining (cCFS) [MD -0.19; 95% CI (-0.35, -0.03); P = 0.02] scores were lower in patients treated with 0.1% CsA compared with vehicle. The Lissamine Green conjunctival staining (LGCS) [MD -0.51; 95% CI (-0.78, -0.24); P = 0.0002] and ocular surface disease index (OSDI) scores [MD -3.04; 95% CI (-5.84, -0.23); P = 0.03] were lower in the 0.1% CsA group compared with vehicle. Adverse events associated with 0.1% CsA solution in the treatment of DED varied across studies, but were generally mild to moderate. Notably, similar events were also significantly present in the vehicle group, supporting the safety profile of this treatment. Conclusion: Ophthalmic 0.1% CsA seems safe for treating DED, and significantly reduced tCFS, cCFS, LGCS, and OSDI scores compared with vehicle solutions.

Purpose: To test the effects of dedicator of cytokinesis protein 1 (DOCK1) with its binding partner engulfment and cell motility protein 1 (ELMO1)-Rac1 axis on the vitreous-induced biological functions of retinal pigment epithelial (RPE) cells. Methods: Rac1 activity in RPE cells after vitreous stimulation was detected via a pull-down assay. The related protein expression levels were examined via western blot analysis. DOCK1 and ELMO1 knockdown cells were generated via CRISPR-Cas9 technology. Cytoskeletal reorganization was detected by immunofluorescent localization of F-actin. Cell proliferation, migration, invasion, and contraction ability were measured via the CCK8 assay, wound healing assay, transwell invasion assay, and collagen contraction assay. Results: Rac1 activity was significantly elevated in ARPE-19 cells stimulated with vitreous fluid for 30 min to 3 h. Depletion of either DOCK1 or ELMO1 with CRISPR/Cas9 attenuated vitreous-stimulated Rac1 activity, thus reversing the vitreous-induced cytoskeletal rearrangements. The functional cell biology results revealed that deficiencies of DOCK1 and ELMO1 significantly impeded the migration, invasion, and contraction abilities of vitreous-stimulated human RPE cells. Conclusion: This study demonstrated that the DOCK1/ELMO1-Rac1 axis plays an essential role in the pathogenesis of proliferative vitreoretinopathy (PVR), thus suggesting that interruption of this axis has potential for PVR therapy.

Background/Aims: To investigate the effectiveness of re-esterified triglyceride form of omega 3 (rTG-omega 3) on patients with meibomian gland dysfunction (MGD) after cataract surgery. Methods: This multicenter, randomized, investigator-blinded, clinical study was conducted between June 2021 and March 2023 and enrolled 107 patients with MGD who had undergone cataract surgery within 3 months at seven sites across South Korea. Patients were randomly assigned to rTG-omega 3 group or a control group. We compared (1) tear film break-up time (TBUT) (s), (2) corneal fluorescein staining score [National Eye Institute/Industry (NEI) scale], (3) conjunctival fluorescein staining score (NEI scale), (4) strip meniscometry (SM) tube score (mm), (5) MGD stage, (6) MG quality, (7) MG expressibility, (8) Standard Patient Evaluation of Eye Dryness (SPEED) score, and (9) Ocular Surface Disease Index (OSDI) scores at baseline and 6 and 12 weeks. Results: TBUT, corneal fluorescein staining score, and SM tube score were significantly improved in the rTG-omega 3 group compared with control group (P = 0.005, P = 0.003, and P = 0.0049, respectively). Subjective questionnaire responses were also improved significantly (SPEED score, P = 0.022; OSDI score, P = 0.0011). MGD parameters were not significantly different. However, during subanalysis, significant improvements in MG quality and expressibility were observed in the MGD stage 4 group with rTG-omega 3 supplementation (P = 0.0177 and P = 0.0205, respectively). Discussion: rTG-omega 3 supplementation facilitated improvements in both objective and subjective parameters. In particular, MG quality and expressibility were significantly improved in the severe MGD group.

Background: Glaucoma is a chronic, progressive disease of visual loss and blindness that is often managed pharmacologically. The objective of this study was to evaluate glaucoma drug prescribing trends by ophthalmologists in the United States from 2018 to 2022. Methods: Data on ophthalmologist prescribers were abstracted from Medicare Part D Prescriber Public Use Files to identify the total number of claims for each drug. Drugs were classified by type (generic or brand-name) and by drug class (carbonic anhydrase inhibitors, alpha-2 agonists, beta-blockers, prostaglandin analogs, rho kinase inhibitors, parasympathomimetic drugs, and mixed-mechanism drugs). The types of drugs prescribed were compared longitudinally. Results: Forty glaucoma drugs were prescribed under Medicare Part D from July 1st, 2018, to June 30th, 2022. A dip in total claims and claims by drug class was observed from 2018-2019 to 2019-2020. This was followed by increases to the greater number of claims in 2021-2022. Prostaglandin analogues were the most frequently prescribed class, and the most commonly prescribed drugs were latanoprost, timolol, and the dorzolamide/timolol combination. The majority of claims consisted of generics, and this value increased longitudinally as well. The most rapidly growing class prescribed by physicians was rho kinase inhibitors. Conclusion: Longitudinal differences in Medicare Part D glaucoma drug claims may reflect changing practice patterns and preferences among providers. An increasing number of claims annually, with the exception of the COVID-19 pandemic onset, reflects the growing prevalence of glaucoma. The utilization of new glaucoma agents, such as rho kinase inhibitors, is rapidly increasing as a new therapeutic option.

Age-related macular degeneration (AMD) poses a significant threat to visual health among the elderly, necessitating urgent preventive measures as the global population ages. Extensive research has implicated oxidative stress (OS)-induced retinal damage as a primary contributor to AMD pathogenesis, prompting investigations into potential therapeutic interventions. Among the various nutrients studied for their potential in AMD risk reduction, antioxidants have shown promise, with initial findings from the Age-Related Eye Disease Study suggesting a correlation between antioxidant supplementation and decreased AMD progression. This article explores the scientific foundation supporting the therapeutic efficacy of tocotrienol-rich fraction (TRF) as a viable candidate for slowing AMD progression, based on interventional studies. AMD is characterized by OS, inflammation, dysregulated lipid metabolism, and angiogenesis, all of which TRF purportedly addresses through its potent anti-inflammatory, lipid-lowering, antiangiogenic, and antioxidant properties. The review underscores TRF's promising attributes, aiming to deepen understanding of AMD pathogenesis and advocate for TRF-based pharmacological interventions to enhance therapeutic outcomes. Given the pressing need for effective AMD treatments, TRF represents a promising avenue for intervention, offering hope for improved vision outcomes and enhanced quality of life for individuals affected by this debilitating condition.

Purpose: Keratoconus is a progressive corneal ectasia characterized by irregular astigmatism, leading to corneal scarring and decreased vision. Corneal cross-linking (CXL) is the standard treatment to halt disease progression, but its effectiveness in transepithelial (epithelium-on, epi-on) approaches is limited by the low permeability of the corneal epithelium to riboflavin (Rb). This study aimed to enhance transepithelial Rb penetration in ex vivo bovine corneas using Rb-modified tannic acid-coated superparamagnetic iron oxide nanoparticles (Rb-TA-SPIONs) under an external magnetic field. Methods: SPIONs were synthesized via co-precipitation, modified with TA and Rb, and characterized by physicochemical techniques. The average size of the Rb-TA-SPIONs was 46 ± 5.3 nm, with a saturation magnetization of 55.9 emu/g. Ex vivo experiments involved the application of 0.1% Rb to bovine corneas, and penetration was evaluated under epi-on conditions with iontophoresis (1-5 mA, 5 min). In addition, a 0.1% Rb-containing nanocarrier solution was tested under magnetic fields of 1-300 Gauss. Results: Results showed increased Rb penetration with rising electric current density and Rb-TA-SPION penetration with stronger magnetic fields, compared with epi-on control groups. Specifically, Rb penetration increased from 0.036% (P ≤ 0.01) at 1 mA to 0.059% (P ≤ 0.001) at 5 mA in the iontophoresis group and from 0.035% (P ≤ 0.001) at 1 G to 0.054% (P ≤ 0.001) at 300 G in the magnetic group. Conclusion: These findings indicate that magnetic nanoparticle-assisted Rb delivery, guided by an external magnetic field, could improve potential CXL efficacy by enhancing Rb penetration and corneal permeability.

Posterior segment ocular diseases, such as diabetic retinopathy, age-related macular degeneration, and retinal vein occlusion, are leading causes of vision impairment and blindness worldwide. Effective management of these conditions remains a formidable challenge due to the unique anatomical and physiological barriers of the eye, including the blood-retinal barrier and rapid drug clearance mechanisms. To address these hurdles, nanostructured drug delivery systems are proposed to overcome ocular barriers, target the retina, and enhance permeation while ensuring controlled release. Traditional therapeutic approaches, such as intravitreal injections, pose significant drawbacks, including patient discomfort, poor compliance, and potential complications. Therefore, understanding the physiology and clearance mechanism of eye could aid in the design of novel formulations that could be noninvasive and deliver drugs to reach the target site is pivotal for effective treatment strategies. This review focuses on recent advances in formulation strategies for posterior segment ocular drug delivery, highlighting their potential to overcome these limitations. Furthermore, the potential of nanocarrier systems such as in-situ gel, niosomes, hydrogels, dendrimers, liposomes, nanoparticles, and nanoemulsions for drug delivery more effectively and selectively is explored, and supplemented with illustrative examples, figures, and tables. This review aims to provide insights into the current state of posterior segment drug delivery, emphasizing the need for interdisciplinary approaches to develop patient-centric, minimally invasive, and effective therapeutic solutions.