Journal of Ocular Pharmacology and Therapeutics最新文献

Purpose: Benzalkonium chloride (BAK) is a commonly used preservative to maintain sterility for multiuse eye drops such as latanoprost. One option to minimize the deleterious effects of BAK in eye drops may be to reduce the volume administered. The aim of this study was to assess the response of cells from the ocular surface to latanoprost+BAK administered by the Optejet technology, which dispenses a microdose (∼8 µL) ophthalmical spray. Methods: Cultured human conjunctival epithelial cells were exposed to the following treatments: (1) no treatment, (2) drop form of latanoprost without BAK (∼35 µL), (3) drop form of latanoprost with 0.01% BAK (∼35 µL), (4) ophthalmical spray form of latanoprost with 0.01% BAK delivered by the Optejet technology (∼8 µL). After 5 h, cells were assessed for changes in cytotoxicity, morphology, and inflammatory marker expression. Results: Latanoprost+BAK delivered by a drop induced cytotoxicity, cytoplasmic shrinkage, and loss of cell-cell contact, and expression of chemokine (C-C motif) ligand 2 and interleukin-6. In contrast, latanoprost+BAK delivered by the Optejet technology was both well tolerated and similar to no treatment controls and BAK-free latanoprost treatment. Conclusions: A microdose of latanoprost+BAK ophthalmical spray administered with the Optejet technology prevented the cytotoxicity associated with larger volumes found in eye drops. Precision dosing by the Optejet technology has the potential to decrease ocular surface disorder typically associated with eye drops containing preservatives.

Purpose: Leber congenital amaurosis (LCA) is a sight-threatening inherited retinal disorder (IRD) caused by numerous genetic mutations. Multi-characteristic opsin (MCO)-based optogenetic therapy allows the recruitment of residual cells of the retina in LCA for alternative vision transduction while being mutation-agnostic. Using rd12 mice, we investigated the in vivo efficacy of an adeno-associated virus2 (AAV2)-transduced ambient light-activatable MCO (MCO-010) containing a metabotropic glutamate receptor-6 bipolar cell-specific promoter/enhancer. Methods: Mice requiring > 40 s to reach and board a dimly lit hidden platform in a water-maze were selected and randomly divided into 2 cohorts. These mice were intravitreally (IVT) injected with either 1.7E9 gene copies/eye of MCO-010 or control AAV2 and re-tested in the water-maze. Spectral-domain optical coherence tomography (SD-OCT), hematoxylin and eosin staining of retinas, and electroretinographic (ERG) studies were also conducted. Results: Safety of MCO-010 in rd12 mice was confirmed by the lack of significant detrimental changes in the mouse behavior, b-wave amplitudes and in retinal thickness. rd12 control mice performed relatively poorly in the water-maze test requiring ≥ 30-60 s to find and board the platform. MCO-010-treated rd12 mice reached the platform much faster than the AAV2-treated rd12 mice, with some mice only requiring < 5 s to achieve this goal (P < 0.01-0.0024). Conclusions: IVT MCO-010 treatment was well tolerated by rd12 mice, and it prevented the decrease in retinal thickness, and preserved ERG parameters. It also significantly improved the vision in rd12 mice relative to control AAV2-injected mice. MCO-010 therefore represents a novel and efficacious optogenetic therapeutic to treat LCA and other IRDs irrespective of the genetic defect(s).

Purpose: To evaluate the efficacy of subconjunctival tranexamic acid (TXA) in reducing intraoperative bleeding, shortening surgery duration, and improving postoperative outcomes in pterygium surgery. Methods: In this double-blind, randomized controlled trial, 50 eyes of 50 patients undergoing pterygium surgery were randomly assigned to receive either subconjunctival injection of 0.25 mL of 5% TXA (TXA group, n = 25) or an equivalent volume of saline (control group, n = 25). Baseline characteristics, including age, gender, working environment, allergies, preoperative logMAR best-corrected visual acuity, and systemic anticoagulant or antiplatelet therapy, were similar between the groups. The primary outcome measures were intraoperative bleeding, surgery duration, and the number of eye spears used. Secondary outcome measures included postoperative visual acuity and pterygium recurrence rates at 3 years post-surgery. Results: No significant differences were observed between the TXA group and the control group in terms of surgery duration (445.3 ± 94.8 s vs. 423.5 ± 80.6 s, P = 0.40), the number of eye spears used (3.5 ± 2.4 vs. 3.5 ± 2.6, P = 0.97), or the weight of absorbed blood (1.94 ± 1.40 grams vs. 1.90 ± 1.25 grams, P = 0.91). Additionally, there were no significant differences in postoperative visual acuity (0.14 ± 0.13 logMAR vs. 0.20 ± 0.19 logMAR, P = 0.39) or pterygium recurrence rates at 3 years post-surgery (8.0% vs. 4.4%, P = 0.60). Subconjunctival TXA injection was safe, with no reported adverse events or complications associated with its use. Conclusion: Subconjunctival injection of TXA did not significantly reduce intraoperative bleeding, shorten surgery duration, or improve postoperative outcomes in pterygium surgery. The intervention was safe and well-tolerated, but further research is warranted to explore alternative interventions or modifications to the surgical technique that may improve outcomes in pterygium surgery.

Montelukast, a Food and Drug Administration-approved drug for asthma and allergic rhinitis modulates leukotriene (LT) receptors and serves as a critical anti-inflammatory agent. Recent research suggests that the LT signaling pathway targeted by montelukast has broader implications for diseases such as fibrosis, cardiovascular diseases, cancer, cerebrovascular disease, and immune defense. This expanded understanding highlights montelukast's potential for repurposing in conditions involving aberrant stress mechanisms, including ocular diseases marked by inflammation, oxidative stress, ER stress, and apoptosis, among several others. This review delves into montelukast's therapeutic mechanisms across various diseases, draws parallels to ocular conditions, and examines clinical trials and associated adverse effects to underscore the unmet need for cysteinyl LT receptor antagonism by montelukast as an effective therapy for visual deficits.

Purpose: The goal of this study was to develop a lot release assay for iPSC residuals following directed differentiation of iPSCs to retinal pigment epithelial (RPE) cells. Methods: RNA Sequencing (RNA Seq) of iPSCs and RPE derived from them was used to identify pluripotency markers downregulated in RPE cells. Quantitative real time PCR (qPCR) was then applied to assess iPSC residuals in iPSC-derived RPE. The limit of detection (LOD) of the assay was determined by performing spike-in assays with known quantities of iPSCs serially diluted into an RPE suspension. Results: ZSCAN10 and LIN28A were among 8 pluripotency markers identified by RNA Seq as downregulated in RPE. Based on copy number and expression of pseudogenes and lncRNAs ZSCAN10 and LIN28A were chosen for use in qPCR assays for residual iPSCs. Reverse transcription PCR indicated generally uniform expression of ZSCAN10 and LIN28A in 21 clones derived from 8 iPSC donors with no expression of either in RPE cells derived from 5 donor lines. Based on qPCR, ZSCAN10, and LIN28A expression in iPSCs was generally uniform. The LOD for ZSCAN10 and LIN28A in qPCR assays was determined using spike in assays of RPE derived from 2 iPSC lines. Analysis of ΔΔC_t found the limit of detection to be <0.01% of cells, equivalent to <1 iPSC/10,000 RPE cells in both iPSC lines. Conclusions: qPCR for ZSCAN10 and LIN28A detects <1 in 10,000 residual iPSCs in a population of iPSC-derived RPE providing an adequate LOD of iPSC residuals for lot release testing.

Purpose: To evaluate the effects of rebamipide ophthalmic suspension on optical quality and efficacy of patients with dry eye under different conditions. Methods: A comprehensive search across five databases (PubMed, Cochrane Library, Web of Science, China National Knowledge Infrastructure, and Wan Fang) was conducted for studies published through May 13, 2024, focusing on rebamipide for dry eye treatment. Results: A total of 11 studies including 334 patients with dry eye were included. Tear breakup time (TBUT) values of patients with dry eye increased significantly after 2 weeks (standardized mean difference [SMD] =1.07, 95% confidence interval [CI] = [0.05, 2.09]), 4 weeks (SMD = 1.26, 95% CI = [0.77, 1.75]), and 12 weeks (SMD = 1.04, 95% CI = [0.37, 1.71]) of rebamipide treatment. Subgroup analysis revealed that patients with dry eye wearing soft contact lens (SCL) exhibited higher TBUT values after 4 weeks of rebamipide treatment compared with those who received rebamipide alone. In addition, rebamipide significantly improved fluorescein staining score of patients with dry eye after 4 weeks of treatment (SMD = -0.34, 95% CI = [-0.63, -0.06]). However, 4 weeks of rebamipide treatment showed no significant effect on Schirmer I test values (SMD = -0.04, 95%, CI = [-0.43, 0.35]) and higher-order aberrations (SMD = -0.73, 95% CI = [-1.77, 0.30]). Conclusions: These results indicate a significant improvement in the efficacy of rebamipide treatment for patients with dry eye, particularly for those wearing SCL. The effect of rebamipide on visual quality was found to correlate with the underlying dry eye status.

Dry eye disease (DED) is a rapidly growing ocular surface disease with a significant socioeconomic impact that affects the patients' visual function and, thus, their quality of life. It is distinguished by a loss of tear film homeostasis, leading to tear film instability, hyperosmolarity, ocular surface inflammation, and neurosensory abnormalities, with all of these playing etiological roles in the propagation of the vicious DED circle. While current treatments primarily focus on reducing tear film instability and hyperosmolarity, increasingly more attention is being placed on tackling the underlying inflammation that propagates and potentiates these factors. As such, preclinical models are crucial to further elucidate the DED pathophysiology and develop novel therapeutic strategies. This review outlines the role of inflammation in DED, highlighting related signs and diagnostic tools before focusing on relevant preclinical animal models and potential therapeutic strategies to tackle DED-associated inflammation.

Purpose: To examine the potential protective effects of adipose-derived mesenchymal stem cell-derived extracellular vesicles (ASC-EVs) on ARPE-19 cells exposed to hydrogen peroxide (H₂O₂) stress and to evaluate their ability to delay retinal degeneration in Royal College of Surgeons (RCS) rats. Methods: ARPE-19 cells were pre-treated with ASC-EVs for 24 h, followed by exposure to 200 μM H₂O₂ for an additional 24 h. RCS rats received an intravitreal injection of phosphate-buffered saline in one eye and ASC-EVs in the other eye. Results: ASC-EV pretreatment significantly protected against H₂O₂ in the Cell Counting Kit-8 assay and was also effective in the lactate dehydrogenase-release assay. It notably reduced early apoptosis (Annexin V-fluorescein isothiocyanate/propidium iodide assay) and late apoptosis (Terminal Deoxynucleotidyl Transferase dUTP Nick End Labeling assay), while significantly decreasing intracellular reactive oxygen species, glutathione levels, and superoxide dismutase activity. NFE2L2, HMOX1, and NQO1 mRNA levels, along with Nrf2, HO-1, and NQO1 protein levels, were significantly elevated with ASC-EV pretreatment. Compared with ARPE-19-derived EVs, 11 miRNAs were upregulated and 34 were downregulated in ASC-EVs. In RCS rats, intravitreal injections of ASC-EVs led to significant preservation of the outer nuclear layer and photoreceptor segments, along with increased nuclear Nrf2 expression and elevated HO-1 and NQO1 levels in the inner retina. Eyes that received intravitreal injections of ASC-EVs demonstrated significantly preserved electroretinography a- and b-wave amplitudes at 1 week post-injection, though this effect faded by 2 weeks. Conclusions: ASC-EVs mitigated apoptosis and oxidative stress in ARPE-19 cells subjected to H₂O₂ exposure and temporarily slowed retinal degeneration in RCS rats via Nrf2 pathway activation by miRNAs.

Purpose: Pharmacokinetic evaluation of ocular penetration and systemic accumulation of preservative-free bimatoprost 0.01% ophthalmic gel (PFB 0.01% gel). Methods: In a preclinical study, pigmented rabbits received a single ocular administration of PFB 0.01% gel (N = 15) or preserved bimatoprost 0.01% or 0.03% ophthalmic solution [PB 0.01% (N = 15) or PB 0.03% (N = 15)]. The aqueous humor, iris, and ciliary body were analyzed for bimatoprost+bimatoprost free acid. In a Phase 1, randomized, open-label clinical study, healthy participants received PFB 0.01% gel (N = 20) or PB 0.01% (N = 20) daily in each eye (Days 1-15). Bimatoprost levels in human plasma were analyzed on Days 1 and 15. All serological analyses used validated methods. Adverse events were collected throughout and ocular assessments were performed on Days 1 and 15. Results: In the preclinical study, Cmax (bimatoprost+bimatoprost free acid) for PFB 0.01% gel, PB 0.01%, and PB 0.03% was 50.2, 26.3, and 59.9 ng/mL; AUC_0.5-8 h was 134.0 ng·h/mL, 67.0 ng·h/mL, and 148.0 ng·h/mL. In the clinical study, systemic exposure to bimatoprost (AUC_0-last) on Days 1 and 15 was lower for PFB 0.01% gel (0.5248 and 0.5645 ng·min/mL) than PB 0.01% (0.8461 and 0.7551 ng·min/mL), with no systemic accumulation of bimatoprost in either group. There were no clinically important differences between groups in ocular or systemic tolerability in the clinical study and no serious adverse events. Conclusions: PFB 0.01% gel showed improved ocular penetration compared with PB 0.01%. Systemic absorption was comparable, with a favorable clinical safety profile, supporting PFB 0.01% gel as a potential treatment for glaucoma and ocular hypertension.

Purpose: Meibomian gland dysfunction (MGD) may cause chronic ocular surface pain (COSP) with a neuropathic component that can significantly impact quality of life and be poorly responsive to conventional treatments of MGD. Intense pulsed light (IPL) is an emerging treatment already acknowledged as improving refractory MGD, potentially modulating inflammatory mediators on the ocular surface. This study aimed to assess the impact of IPL on COSP associated with unresponsive MGD. Methods: A monocentric prospective study has been conducted from 2021 to 2023 on patients presenting with moderate MGD and COSP non-responsive to conventional treatments of MGD. Neuropathic pain components were suspected when severe discomfort (OSDI score above 33/100) was observed despite moderate objective signs. Three sessions of IPL were performed at a two-week interval. The primary outcome was change in OSDI at day 60. Secondary outcomes included OSDI modification at D120, DEQ-5, and Pentascore results at D60/D120, together with changes in clinical [Schirmer I, Fluorescein Break-up time (BUT), fluorescein staining, and MGD classification] and paraclinical tests [noninvasive BUT, tear meniscus height (TMH), and meibography]. Results: A significant improvement of COSP (p < 0.05 for changes in OSDI and Pentascore results) was observed 2 and 4 months after the last IPL session, together with an improvement in tear film stability, corneal epitheliopathy, meibomian gland obstruction, and TMH. Conclusion: The results of this study suggest the beneficial effect of IPL on neuropathic component of COSP associated with MGD. The underlying mechanisms involved in that improvement, presumably related to downgrading of inflammatory effectors, remain however to be explored.