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: Topical tacrolimus is currently used in ocular surface pathologies as a corticosteroid-sparing immunosuppressive agent. It could also help prevent endothelial corneal graft rejection and inflammatory diseases; however, its hydrophobic nature and high molecular weight theoretically limit its intraocular penetration. The aim of this study is to investigate the corneal and intraocular penetration of a 0.1% tacrolimus ophthalmic suspension. Methods: Sixteen rabbits were randomly spread into four groups defined by the delay between the last tacrolimus instillation and corneal sampling (2, 6, 11, and 24 h). Three rabbits per group received bilateral instillations of tacrolimus twice daily for 5 days, the 4th subject in each group serving as negative controls. The 5th day, conjunctiva, corneal epithelium, anterior stroma, posterior stroma, corneal endothelium, iris, choroid/retina, aqueous humor, and plasma samples were collected. Tacrolimus concentrations were determined using high-performance liquid chromatography coupled with tandem mass spectrometry. Results: Maximum mean concentration was reached after 2 h in the epithelium, anterior and posterior stroma, and endothelium: 12794 (±2656), 436 (±178), 341 (±179), and 4125 (±1673) ng/g, respectively. The descending rank order of exposure over 24 h was: corneal epithelium; corneal endothelium; conjunctiva; anterior stroma; posterior stroma; iris; and chorioretina with 158.0; 39.99; 4.620; 4.134; 3.350; 0.384; 0.270 ng.h/mg, respectively. Conclusions: Tacrolimus concentrations measured in the corneal tissues are significantly higher than that described as lower limit of efficacy in solid organ transplantation. Topical 0.1% tacrolimus could therefore become an alternative to corticosteroids for endothelial graft rejection prevention and endothelial inflammatory pathologies management.

Purpose: To evaluate myopia progression in children treated with 0.01% atropine eye drops compared with controls. Methods: Two longitudinal cohorts of myopic children (atropine and control) were observed in different time periods. All children had an increase in myopia of greater than -0.50 diopters (D) or axial length (AL) growth of >0.20 mm in the previous year. Patients were examined at baseline and every 6 months for 18 months. The primary outcomes were the annual progression rate of spherical equivalent refractive error (SER) and AL. Response to treatment was categorized as insufficient, moderate, or good. Progression according to age was also evaluated. Statistical significance was defined as P < 0.05. Results: The study included 243 myopic children [127 (44.7%) female; mean age, 10.19 ± 2.29 years]. The atropine group comprised 158 (65%) children. At 18 months, the mean (95% confidence interval) change in SER was -0.85 D (-1.00, -0.69) in the control group and -0.73 D (-0.85, -0.61) in atropine (p = 0.295). The mean increase in AL was 0.41 mm (0.32, 0.50) in the control group and 0.33 mm (0.28, 0.39) in the atropine (p = 0.160). Children aged <9 years had the lowest percentage of success [3/21 (27.8%)] in the atropine group and the highest percentage of failure (63.2%) (p = 0.03). Conclusion: Atropine drops at 0.01% did not slow myopia progression. Increasing the concentration or combining with optical treatments may be necessary, particularly for children aged <9 years, who showed the greatest progression but also had the highest potential for myopia control.

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.

Purpose: To evaluate the durability of thermomechanical device treatment effect in patients with meibomian gland dysfunction (MGD) at 6 months post-treatment. Methods: This was an extension of an initial 3-month, prospective, controlled, randomized, masked, multicenter pivotal study, in which subjects with MGD were randomized to thermomechanical device treatment (3 sessions, 2 weeks apart) or a single control treatment. The extension study was a single-arm, observational study in the same 5 sites of the pivotal study. A subset of subjects from the thermomechanical device group with an increase in tear break-up time (TBUT) of 2.5 s or greater in at least 1 eye at 1- or 3-month follow-up and able to attend the 6-month follow-up were included. Effectiveness endpoints included changes in TBUT, Meibomian gland score (MGS), and Ocular Surface Disease Index (OSDI) from baseline to 6 months. Device-related adverse events (AEs) were also assessed. Results: At 6 months post-treatment, 21 subjects (42 eyes) demonstrated significant improvements from baseline in mean TBUT (5.2 ± 3.8 s; P < 0.001), mean MGS (18.2 ± 10.9; P < 0.0001), and mean OSDI (-24.3 ± 26.5; P = 0.0004). Improvements in corneal staining scores were also observed. No ocular AEs were reported. Conclusions: The findings of the extension study demonstrate that the clinical benefit of the thermomechanical device, evaluated by TBUT, MGS, and OSDI, can be maintained out to 6 months and that the device is safe and effective in improving the signs and symptoms of evaporative dry eye disease in MGD.

Purpose: Nanoparticle-based drug delivery systems offer a promising approach for overcoming the challenges of ocular drug delivery. Our study evaluated the biodistribution and potential targeting of reconstituted high-density lipoprotein nanoparticles (rHDL NPs) loaded with near-infrared dye IR780 to retinal ganglion cells (RGCs) and optic nerve head astrocytes (ONHAs) as a model for neuroprotective drug delivery in glaucoma. Methods: A stable rHDL-payload complex was formulated using IR780, phosphatidylcholine, and apolipoprotein A-I (Apo A-I) by using a novel preparation method. Fluorescent rHDL (rHDL-IR780) was assessed for cellular uptake in primary human ONHAs in vitro, whereas scavenger receptor class B1 (SR-B1) expression was confirmed by Western blot. Receptor-mediated uptake was examined by SR-B1 receptor blocking. Ex vivo biodistribution was evaluated by intravitreal injection of rHDL into postmortem human donor eyes. Results: Spectroscopic analysis confirmed IR780 encapsulation in rHDL NPs. Blocking SR-B1 receptors significantly reduced IR780 uptake by ONHAs, supporting an SR-B1-mediated delivery mechanism, in addition to confirming SR-B1 expression in human retinal lysates. In ex vivo experiments, 4 h postinjection, IR780 localized in the retinal nerve fiber and ganglion cell layers. By 24 h, IR780 penetrated deeper retinal layers, achieving RGC uptake. Conclusions: Our findings demonstrate that rHDL NPs facilitate targeted delivery to retinal tissues through an Apo A-I/SR-B1 pathway, overcoming ocular barriers to reach RGCs. This study supports the potential of rHDL NPs as a platform for neuroprotective drug delivery to treat glaucoma, enhancing both pharmacokinetics and targeted cellular uptake.

Purpose: To identify reasons for variable intraocular pressure (IOP) responses to latanoprost and timolol in healthy volunteers and to generate the control group as part of Eye Dynamics and Engineering Network. Methods: In this multicenter, randomized, crossover study (NCT01677507), both eyes of 106 healthy subjects (212 eyes) were treated with latanoprost or timolol for 7 days, with a 6-week washout between treatments. Ocular biometrics, tonometry, and aqueous humor dynamics (AHD) were assessed at baseline and day 8 of each treatment. Subjects were divided into responders and nonresponders using cutoffs of >15% or >10% IOP reduction. Treatment effects and correlations were analyzed with paired t-tests. Results: More subjects responded to latanoprost (54%) than timolol (27%) at >15% cutoff (p < 0.01). Responders had higher mean baseline IOP than nonresponders for both drugs at both cutoffs (p < 0.01). Among timolol nonresponders (n = 56), 39% responded to latanoprost in both eyes, 20% in one eye, and 41% in neither. Among latanoprost nonresponders (n = 31), 13% responded to timolol in both eyes, 13% in one eye, and 74% in neither. Latanoprost increased uveoscleral outflow, while timolol reduced aqueous flow and outflow facility. Low baseline uveoscleral outflow was associated with latanoprost response. Conclusions: Higher baseline IOP predicted better responses to both drugs. Higher baseline uveoscleral outflow predicted nonresponse to latanoprost. No AHD differences were linked to the timolol response. Timolol nonresponders were often responsive to latanoprost, but not vice versa.

Corticosteroid use as an anti-inflammatory agent in infective conjunctivitis has been met with concerns about prolonged infection. This systematic review aims to evaluate the safety and efficacy of corticosteroids as a treatment for infective conjunctivitis. A comprehensive search was conducted on PubMed, Cochrane, Scopus, ScienceDirect, Embase, and ProQuest for clinical trials of topical corticosteroids with or without combination with other medications in bacterial or viral conjunctivitis up to November 2023. The studies were screened, and data on safety and efficacy were extracted. The quality of studies was assessed using the Jadad Scale. Meta-analysis was performed using the random-effects model, with heterogeneity assessed with the I² statistic. We found ten clinical trials that met the inclusion criteria. Overall meta-analysis revealed significant clinical resolution in dexamethasone-containing therapy compared to non-corticosteroid treatment (OR 1.51; 95% CI 1.19-1.92), with several studies reporting significantly reduced clinical symptoms severity. Two of the six studies assessing viral and bacterial eradication reported significantly improved viral clearance rates. Meta-analysis indicated no difference in ocular adverse effects compared to nonsteroid therapy (OR 1.33; 95% CI 0.82-2.16). In conclusion, corticosteroid use in infective conjunctivitis is relatively safe and may help improve clinical resolution and reduce symptom severity, especially when combined with antibiotics and antiseptics.

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.