Journal of Ocular Pharmacology and Therapeutics最新文献

Purpose: To protect the corneal endothelium, various ophthalmical viscoelastic devices (OVDs) are used during cataract surgery. In this study, we compared two sodium hyaluronate-based OVD, the bacteria-derived FIDIAL PLUS OVD (test) with the animal-derived IAL^®-F OVD (reference) during the surgical procedure. Methods: Fifty patients with bilateral cataract participated in the study: 50 eyes randomly received FIDIAL PLUS and 50 eyes received IAL^®-F (ratio 1:1). Noninferior efficacy of FIDIAL PLUS compared with reference OVD (first objective) was evaluated using a paired t-test comparing the mean percent loss of corneal endothelial cells (CECs) with FIDIAL PLUS against the mean percent loss with IAL^®-F. Corneal endothelial protection during cataract surgery with FIDIAL PLUS without significant (≥30 mmHg) postoperative intraocular pressure (IOP) increase (main secondary objective) was assessed using a repeated measures logistic model comparing the incidence of significant postoperative IOP elevation between the two groups. Safety, tolerability, and efficacy were also evaluated by assessing secondary endpoints before and after surgery. Results: FIDIAL PLUS showed a statistically noninferior efficacy compared with IAL^®-F; there was no significant increase in IOP in either group or different trends of the secondary endpoints were observed between the OVD groups. The safety profile was similar in both OVD groups and no adverse device effects were reported. Conclusions: This study demonstrates the equivalent efficacy, tolerability, and safety of the bacteria-derived FIDIAL PLUS compared with the animal-derived IAL^®-F, confirming the clinical value of this product.

Purpose: Activation of the classical complement pathway is thought to contribute to the development and progression of glaucoma. The role of alternative complement or amplification pathways in glaucoma is not well understood. We evaluated complement factor B (FB) expression in postmortem human ocular tissues with or without glaucoma and the effect of FB inhibition and deletion in a mouse ocular hypertensive model of glaucoma induced by photopolymerized hyaluronic acid glycidyl methacrylate (HAGM). Methods: Human CFB mRNA in human eyes was assessed by RNAscope and TaqMan. HAGM model was performed on C57BL6/J mice. The effect of FB in HAGM model was evaluated with an oral FB inhibitor and Cfb^-/- mice. Complement mRNA and proteins in mouse eyes were assessed by TaqMan and western blot, respectively. Results: CFB mRNA in human glaucomatous macular neural retina and optic nerve head was upregulated. Cfb mRNA is also upregulated in the HAGM model. Oral FB inhibitor, ED-79-GX17, dosed daily at 200 mg/kg for 3 days after intraocular pressure (IOP) induction in wild-type mice showed complement inhibition in ocular tissues and significantly inhibited systemic complement levels. Daily dosing of ED-79-GX17 for 30 days or Cfb deletion was also unable to prevent retinal ganglion cell or axon loss 30 days after IOP induction in mice. Conclusion: The alternative complement component FB may not substantially contribute to RGC loss in the HAGM mouse glaucoma model despite upregulation of Cfb expression and activation of the alternative pathway. The relevance of these findings to human glaucoma remains to be determined.

Uveitis remains one of the leading causes of blindness worldwide, with different etiologies requiring separate approaches to treatment. For over a decade, oral, topical, and local injection of corticosteroids as well as systemic conventional disease-modifying antirheumatic drugs (DMARDs) have remained the most effective treatment for noninfectious uveitis (NIU). Systemic administration of antitumor necrosis factor-α and other biological DMARDs have been used for treating cases that responded inadequately to conventional treatments. Unfortunately, some refractory patients still suffer from frequent attacks despite the combination of multiple treatments. Recently, there has been promising evidence for Janus kinase (JAK) inhibitors as the next-generation therapy for NIU. The JAK/signal transducers and activators of the transcription (STAT) signaling pathway mediate the downstream events involved in immune fitness, tissue repair, inflammation, apoptosis, and adipogenesis by binding various ligands, such as cytokines, growth hormones, and growth factors. The mutation or loss of JAK/STAT components is implicated in autoimmune diseases, thus inhibition of such pathways has been an important area of research in therapeutic development.¹ In this review, we provide a comprehensive overview of the efficacy and safety of JAK inhibitors for the management of NIU, with evidence from current trials and case reports.

Purpose: The present study aimed to determine the dose-response relationship between targeted nanocarriers released from a novel, sustained release formulation and their ability to specifically deplete cells responsible for the development of posterior capsular opacification (PCO) in month-long, dynamic cell cultures. Methods: Injectable, thermosensitive poly(D,L-lactic-co-glycolic acid)-b-poly(ethylene glycol)-b-poly(D,L-lactic-co-glycolic acid) triblock copolymer hydrogels were loaded with either a low or a high dose of doxorubicin-loaded antibody-targeted nanocarriers (G8:3DNA:Dox). Human rhabdomyosarcoma cells, selected for their expression of PCO marker brain-specific angiogenesis inhibitor 1 (BAI1), were kept under dynamic media flow and received either a low or high dose of nanocarriers. Cells were fixed and stained at predetermined time points to evaluate targeted depletion of BAI1+ cells. Results: A lower dose of nanocarriers in hydrogel depleted BAI1+ cells at a slower rate than the higher dose, whereas both reached over 90% BAI1+ cellular nonviability at 28 days. Both treatment groups also significantly lowered the relative abundance of BAI1+ cells in the population compared with the control group. Conclusions: Controlled release of a lower dose of nanocarriers can still achieve therapeutically relevant effects in the prevention of PCO, while avoiding potential secondary effects associated with the administration of a higher dose.

Purpose: Although it is now understood that most antiglaucoma surgeries fail because of scarring of the filtering tract, the underlying mechanism remains to be elucidated. The present study investigated the mechanism by which the interleukin (IL)-22/IL-22 receptor alpha 1 (IL-22RA1) signaling pathway regulates scar formation in glaucoma patients. Method: A total of 31 glaucoma patients who underwent trabeculectomy surgery with uncontrollable intraocular pressure because of scarring and 19 strabismus patients as the control patient group were included in the present study. ELISA was performed to measure the content of IL-22 in peripheral blood. Serum from patients was used to incubate human Tenon's capsule fibroblasts (HTFs) cells and IL-22 antibody rescued the effect of IL-22 on the biological functions. qPCR and Western blot were performed to determine IL-22RA1 mRNA and protein expression levels. Flow cytometry was performed to assess the cell cycle distribution and the Cell Counting Kit-8 assay was used to analyze cell proliferation. Results: The ELISA assay revealed that the serum IL-22 level of glaucoma patients was significantly higher than the healthy group (29.80 ± 5.1 ng/µL vs. 5.21 ± 0.9 ng/µL). After incubation with patient serum, the proliferation and activation of human Tenon fibroblasts (HTFs) were promoted. IL-22 mediated the biological function of HTFs via directly binding IL-22RA1. Moreover, transfection of the siR-IL-22RA1 or IL-22RA1 gene resulted in significant antifibrosis or profibrosis in HTFs. When a signal transducer and activator of transcription (STAT) 3 inhibitor (BAY) was introduced to the IL-22RA1 overexpression group, IL-22-induced proliferation was reduced in HTFs. Additionally, glaucoma patients had increased levels of IL-22 expression following surgery. Conclusions: The IL-22/IL-22RA1/STAT3 signaling pathway promoted fibroblast cell proliferation and alpha-smooth muscle actin, potentially regulating fibrosis in glaucoma filtration tracts. Our results provide hitherto undocumented insights into the pathophysiology of postoperative scarring.

Objective: This study aims to investigate the effect of NADPH oxidase 4 (NOX4)-mediated inflammation on concanavalin A (ConA)-induced dry eye syndrome (DES) in mice. Methods: Thirty-six mice were randomly divided into Control, Model, no-load Control, and NOX4 interference group. Adenovirus was injected (10 μL) into the lacrimal glands of both eyes of mice in no-load Control group and NOX4 interference group. Four days after adenovirus injection, the Control group was injected with phosphate-buffered saline, and the other groups were injected with ConA (200 μg) in the lacrimal glands of mice to establish DES models. The tear secretion rate was estimated by phenol red thread test. Lissamine green eye staining was used to evaluate conjunctival damage. The corneal surface was observed by hematoxylin-eosin (HE) staining and scanning electron microscopy (SEM). The morphology and quantity of conjunctival epithelial cells and goblet cells were observed by Periodic acid-Schiff staining. The expression of NOX4, NOD-like receptor thermal protein domain-associated protein 3 (NLRP3), interleukin-1β (IL-1β), and mucin 5 subtype AC (MUC5AC) was detected by immunohistochemistry. Results: Compared with the Control group, the Model group showed a significant decrease in tear secretion and an upregulation in microscopic image score. The HE staining and SEM showed corneal and conjunctiva damage in the Model group. The protein expression of NOX4, NLRP3, and IL-1β was upregulated, but MUC5AC was downregulated in the Model group. After interfering with NOX4, all these indicators were reversed. Conclusion: The pathological process of concanavalin A-induced DES appears to be related to NOX4.

Purpose: Antibody-drug conjugates (ADCs) are a relatively recent advance in the delivery of chemotherapeutics that improve targeting of cytotoxic agents. However, despite their antitumor activity, severe ocular adverse effects, including vision loss, have been reported for several ADCs. The nonspecific uptake of ADCs into human corneal epithelial cells (HCECs) and their precursors via macropinocytosis has been proposed to be the primary mechanism of ocular toxicity. In this study, we evaluated the ability of a novel polymer, poly(l-lysine)-graft-poly(ethylene glycol) (PLL-g-PEG), to decrease the ADC rituximab-mc monomethylauristatin F (MMAF) (RIX) uptake into human corneal epithelial (HCE-T) cells. Methods: HCE-T cells were exposed to increasing concentrations of RIX to determine inhibition of cell proliferation. HCE-T cells were treated with PLL-g-PEG, the macropinocytosis inhibitor 5-(N-ethyl-N-isopropyl) amiloride (EIPA), or vehicle. After 30 min of incubation, RIX was added. ADC was detected by fluorescent anti-human immunoglobulin G and fluorescently conjugated dextran as viewed by microscopy. Results: RIX caused dose-dependent inhibition of HCE-T cell proliferation. EIPA significantly reduced RIX uptake and decreased macropinocytosis as assessed by direct quantification of RIX using a fluorescently conjugated anti-human antibody as well as quantification of macropinocytosis using fluorescently conjugated dextran. PLL-g-PEG resulted in a dose-dependent inhibition of RIX uptake with half-maximal inhibitory concentrations of 0.022%-0.023% PLL-g-PEG. Conclusion: The data show PLL-g-PEG to be a potent inhibitor of RIX uptake by corneal epithelial cells and support its use as a novel therapeutic approach for the prevention of ocular adverse events associated with ADC therapy.