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1.
Nanotechnology ; 35(33)2024 Jun 03.
Article in English | MEDLINE | ID: mdl-38829163

ABSTRACT

Dry eye disease (DED) is a major global eye disease leading to severe eye discomfort and even vision impairment. The incidence of DED has been gradually increasing with the high frequency of use of electronic devices. It has been demonstrated that celastrol (Cel) has excellent therapeutic efficacy in ocular disorders. However, the poor water solubility and short half-life of Cel limit its further therapeutic applications. In this work, a reactive oxygen species (ROS) sensitive polymeric micelle was fabricated for Cel delivery. The micelles improve the solubility of Cel, and the resulting Cel loaded micelles exhibit an enhanced intervention effect for DED. Thein vitroresults demonstrated that Cel-nanomedicine had a marked ROS responsive release behavior. The results ofin vitroandin vivoexperiments demonstrated that Cel has excellent biological activities to alleviate inflammation in DED by inhibiting TLR4 signaling activation and reducing pro-inflammatory cytokine expression. Therefore, the Cel nanomedicine can effectively eliminate ocular inflammation, promote corneal epithelial repair, and restore the number of goblet cells and tear secretion, providing a new option for the treatment of DED.


Subject(s)
Dry Eye Syndromes , Micelles , Nanomedicine , Pentacyclic Triterpenes , Reactive Oxygen Species , Triterpenes , Dry Eye Syndromes/drug therapy , Pentacyclic Triterpenes/pharmacology , Animals , Reactive Oxygen Species/metabolism , Mice , Nanomedicine/methods , Triterpenes/pharmacology , Triterpenes/chemistry , Inflammation/drug therapy , Toll-Like Receptor 4/metabolism , Humans , Tears/metabolism , Tears/drug effects
2.
Invest Ophthalmol Vis Sci ; 65(6): 2, 2024 Jun 03.
Article in English | MEDLINE | ID: mdl-38829670

ABSTRACT

Purpose: The purpose of this study was to investigate the involvement of the TLR4/NF-κB/NLRP3 signaling pathway and its underlying mechanism in diabetic dry eye. Methods: Two models of diabetic dry eye were established in high glucose-induced human corneal epithelial (HCE-T) cells and streptozotocin (STZ)-induced C57BL/6 mice, and the TLR4 inhibitor fosfenopril (FOS) was utilized to suppress the TLR4/NF-κB/NLRP3 signaling pathway. The expression changes in TLR4, NF-κB, NLRP3, and IL-1ß, and other factors were detected by Western blot and RT‒qPCR, the wound healing rate was evaluated by cell scratch assay, and the symptoms of diabetic mice were evaluated by corneal sodium fluorescein staining and tear secretion assay. Results: In the diabetic dry eye model, the transcript levels of TLR4, NF-κB, NLRP3, and IL-1ß were raised, and further application of FOS, a TLR4 inhibitor, downregulated the levels of these pathway factors. In addition, FOS was found to be effective in increasing the wound healing rate of high glucose-induced HCE-T cells, increasing tear production, and decreasing corneal fluorescence staining scores in diabetic mice, as measured by cell scratch assay, corneal sodium fluorescein staining assay, and tear production. Conclusions: The current study found that the TLR4/NF-κB/NLRP3 signaling pathway regulates diabetic dry eye in an in vitro and in vivo model, and that FOS reduces the signs of dry eye in diabetic mice, providing a new treatment option for diabetic dry eye.


Subject(s)
Diabetes Mellitus, Experimental , Dry Eye Syndromes , Mice, Inbred C57BL , NF-kappa B , NLR Family, Pyrin Domain-Containing 3 Protein , Signal Transduction , Toll-Like Receptor 4 , Animals , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors , Toll-Like Receptor 4/metabolism , Toll-Like Receptor 4/antagonists & inhibitors , Mice , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/metabolism , NF-kappa B/metabolism , NF-kappa B/antagonists & inhibitors , Dry Eye Syndromes/drug therapy , Dry Eye Syndromes/metabolism , Epithelium, Corneal/drug effects , Epithelium, Corneal/metabolism , Humans , Male , Blotting, Western , Disease Models, Animal , Cells, Cultured , Tears/metabolism , Real-Time Polymerase Chain Reaction
3.
J Nanobiotechnology ; 22(1): 229, 2024 May 08.
Article in English | MEDLINE | ID: mdl-38720321

ABSTRACT

Efficiently removing excess reactive oxygen species (ROS) generated by various factors on the ocular surface is a promising strategy for preventing the development of dry eye disease (DED). The currently available eye drops for DED treatment are palliative, short-lived and frequently administered due to the short precorneal residence time. Here, we developed nanozyme-based eye drops for DED by exploiting borate-mediated dynamic covalent complexation between n-FeZIF-8 nanozymes (n-Z(Fe)) and poly(vinyl alcohol) (PVA) to overcome these problems. The resultant formulation (PBnZ), which has dual-ROS scavenging abilities and prolonged corneal retention can effectively reduce oxidative stress, thereby providing an excellent preventive effect to alleviate DED. In vitro and in vivo experiments revealed that PBnZ could eliminate excess ROS through both its multienzyme-like activity and the ROS-scavenging activity of borate bonds. The positively charged nanozyme-based eye drops displayed a longer precorneal residence time due to physical adhesion and the dynamic borate bonds between phenyboronic acid and PVA or o-diol with mucin. The in vivo results showed that eye drops could effectively alleviate DED. These dual-function PBnZ nanozyme-based eye drops can provide insights into the development of novel treatment strategies for DED and other ROS-mediated inflammatory diseases and a rationale for the application of nanomaterials in clinical settings.


Subject(s)
Dry Eye Syndromes , Ophthalmic Solutions , Reactive Oxygen Species , Ophthalmic Solutions/chemistry , Ophthalmic Solutions/pharmacology , Dry Eye Syndromes/drug therapy , Animals , Reactive Oxygen Species/metabolism , Mice , Oxidative Stress/drug effects , Cornea/drug effects , Cornea/metabolism , Polyvinyl Alcohol/chemistry , Humans , Free Radical Scavengers/chemistry , Free Radical Scavengers/pharmacology , Borates/chemistry , Nanoparticles/chemistry , Male
4.
J Nanobiotechnology ; 22(1): 233, 2024 May 09.
Article in English | MEDLINE | ID: mdl-38725011

ABSTRACT

BACKGROUND: Dry Eye Disease (DED) is a prevalent multifactorial ocular disease characterized by a vicious cycle of inflammation, oxidative stress, and mitochondrial dysfunction on the ocular surface, all of which lead to DED deterioration and impair the patients' quality of life and social functioning. Currently, anti-inflammatory drugs have shown promising efficacy in treating DED; however, such drugs are associated with side effects. The bioavailability of ocular drugs is less than 5% owing to factors such as rapid tear turnover and the presence of the corneal barrier. This calls for investigations to overcome these challenges associated with ocular drug administration. RESULTS: A novel hierarchical action liposome nanosystem (PHP-DPS@INS) was developed in this study. In terms of delivery, PHP-DPS@INS nanoparticles (NPs) overcame the ocular surface transport barrier by adopting the strategy of "ocular surface electrostatic adhesion-lysosomal site-directed escape". In terms of therapy, PHP-DPS@INS achieved mitochondrial targeting and antioxidant effects through SS-31 peptide, and exerted an anti-inflammatory effect by loading insulin to reduce mitochondrial inflammatory metabolites. Ultimately, the synergistic action of "anti-inflammation-antioxidation-mitochondrial function restoration" breaks the vicious cycle associated with DED. The PHP-DPS@INS demonstrated remarkable cellular uptake, lysosomal escape, and mitochondrial targeting in vitro. Targeted metabolomics analysis revealed that PHP-DPS@INS effectively normalized the elevated level of mitochondrial proinflammatory metabolite fumarate in an in vitro hypertonic model of DED, thereby reducing the levels of key inflammatory factors (IL-1ß, IL-6, and TNF-α). Additionally, PHP-DPS@INS strongly inhibited reactive oxygen species (ROS) production and facilitated mitochondrial structural repair. In vivo, the PHP-DPS@INS treatment significantly enhanced the adhesion duration and corneal permeability of the ocular surface in DED mice, thereby improving insulin bioavailability. It also restored tear secretion, suppressed ocular surface damage, and reduced inflammation in DED mice. Moreover, it demonstrated favorable safety profiles both in vitro and in vivo. CONCLUSION: In summary, this study successfully developed a comprehensive DED management nanosystem that overcame the ocular surface transmission barrier and disrupted the vicious cycle that lead to dry eye pathogenesis. Additionally, it pioneered the regulation of mitochondrial metabolites as an anti-inflammatory treatment for ocular conditions, presenting a safe, efficient, and innovative therapeutic strategy for DED and other inflammatory diseases.


Subject(s)
Dry Eye Syndromes , Inflammation , Liposomes , Mitochondria , Oxidative Stress , Dry Eye Syndromes/drug therapy , Animals , Mitochondria/drug effects , Mitochondria/metabolism , Mice , Oxidative Stress/drug effects , Liposomes/chemistry , Inflammation/drug therapy , Humans , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Anti-Inflammatory Agents/chemistry , Nanoparticles/chemistry , Antioxidants/pharmacology , Antioxidants/therapeutic use , Cornea/metabolism , Cornea/drug effects , Drug Delivery Systems , Oligopeptides
5.
Int Ophthalmol ; 44(1): 211, 2024 May 02.
Article in English | MEDLINE | ID: mdl-38696090

ABSTRACT

PURPOSE: To evaluate the effects of sodium hyaluronate drops on dry eye parameters and corneal epithelial thickness following cataract surgery. METHODS: The study included 84 patients who underwent uncomplicated phacoemulsification. In Group A, 0.15% sodium hyaluronate drops were added to the postoperative antibiotic/anti-inflammatory treatment. In Group B, only antibiotic/anti-inflammatory treatment was applied. Preoperatively and at 1 week and 1 month postoperatively, all the patients were evaluated in respect of tear break-up time (TBUT), the Schirmer test under anesthesia, the corneal fluorescein staining (CFS) score, mean central corneal thickness (CCT) and mean central corneal epithelial thickness (CCET), and the two groups were compared. RESULTS: A statistically significant difference was determined between the two groups at postoperative 1 month in respect of TBUT, Schirmer test, CFS score, and CCET (p < 0.01). In Group A, a statistically significant increase was determined in the TBUT and Schirmer values at 1 month postoperatively (p < 0.01, p = 0.01, respectively) and in Group B, these values were decreased compared to preoperatively (p < 0.01). The CCET was determined to be significantly thinner in Group B 1 month postoperatively (p < 0.01). A significant increase in CCT was observed in both groups at postoperative 1 week (p < 0.01) and preoperative values were reached at 1 month postoperatively. CONCLUSION: In the patient group using sodium hyaluronate, significant differences were determined in all dry eye parameters and CCET. The use of hyaluronate sodium drops after cataract surgery was seen to improve dry eye parameters and contribute to a healthy ocular surface by ensuring continuity of the corneal epithelium.


Subject(s)
Dry Eye Syndromes , Epithelium, Corneal , Hyaluronic Acid , Ophthalmic Solutions , Phacoemulsification , Humans , Hyaluronic Acid/administration & dosage , Dry Eye Syndromes/drug therapy , Dry Eye Syndromes/diagnosis , Female , Male , Aged , Epithelium, Corneal/drug effects , Epithelium, Corneal/pathology , Middle Aged , Ophthalmic Solutions/administration & dosage , Phacoemulsification/methods , Viscosupplements/administration & dosage , Prospective Studies , Tears/metabolism , Postoperative Complications/prevention & control , Cataract Extraction/methods
6.
Int J Nanomedicine ; 19: 4045-4060, 2024.
Article in English | MEDLINE | ID: mdl-38736656

ABSTRACT

Purpose: Dry eye disease (DED) is a multifactorial ocular surface disease with a rising incidence. Therefore, it is urgent to construct a reliable and efficient drug delivery system for DED treatment. Methods: In this work, we loaded C-dots nanozyme into a thermosensitive in situ gel to create C-dots@Gel, presenting a promising composite ocular drug delivery system to manage DED. Results: This composite ocular drug delivery system (C-dots@Gel) demonstrated the ability to enhance adherence to the corneal surface and extend the ocular surface retention time, thereby enhancing bioavailability. Furthermore, no discernible ocular surface irritation or systemic toxicity was observed. In the DED mouse model induced by benzalkonium chloride (BAC), it was verified that C-dots@Gel effectively mitigated DED by stabilizing the tear film, prolonging tear secretion, repairing corneal surface damage, and augmenting the population of conjunctival goblet cells. Conclusion: Compared to conventional dosage forms (C-dots), the C-dots@Gel could prolong exhibited enhanced retention time on the ocular surface and increased bioavailability, resulting in a satisfactory therapeutic outcome for DED.


Subject(s)
Antioxidants , Carbon , Cornea , Dry Eye Syndromes , Hydrogels , Animals , Dry Eye Syndromes/drug therapy , Mice , Carbon/chemistry , Antioxidants/chemistry , Antioxidants/pharmacokinetics , Antioxidants/pharmacology , Antioxidants/administration & dosage , Hydrogels/chemistry , Hydrogels/administration & dosage , Hydrogels/pharmacokinetics , Cornea/drug effects , Drug Delivery Systems/methods , Disease Models, Animal , Biological Availability , Tears/drug effects , Tears/chemistry , Benzalkonium Compounds/chemistry , Benzalkonium Compounds/administration & dosage , Benzalkonium Compounds/pharmacokinetics , Female , Male , Temperature , Quantum Dots/chemistry
7.
Vestn Oftalmol ; 140(2): 102-111, 2024.
Article in Russian | MEDLINE | ID: mdl-38742506

ABSTRACT

Dry eye disease (DED) is pathogenetically based on inflammation of the ocular surface. A step-by-step approach to DED treatment involves early initiation of anti-inflammatory therapy, including instillation of cyclosporine A (CsA). However, recommendations for the use of topical CsA in clinical practice are limited. This article presents an expert consensus on practical recommendations for the management of patients with DED, including indications, time of initiation and duration of CsA therapy, comparison of CsA forms currently registered in the Russian Federation, as well as issues of patient education.


Subject(s)
Cyclosporine , Emulsions , Humans , Administration, Ophthalmic , Cyclosporine/administration & dosage , Dry Eye Syndromes/drug therapy , Dry Eye Syndromes/etiology , Immunosuppressive Agents/administration & dosage , Ophthalmic Solutions/administration & dosage , Treatment Outcome , Xerophthalmia/etiology , Xerophthalmia/drug therapy , Xerophthalmia/diagnosis
8.
Exp Biol Med (Maywood) ; 249: 10175, 2024.
Article in English | MEDLINE | ID: mdl-38756167

ABSTRACT

Diabetes mellitus is a prevalent disease that is often accompanied by ocular surface abnormalities including delayed epithelial wound healing and decreased corneal sensitivity. The impact of diabetes on the lacrimal functional unit (LFU) and the structures responsible for maintaining tear homeostasis, is not completely known. It has been shown that the Opioid Growth Factor Receptor (OGFr), and its ligand, Opioid Growth Factor (OGF), is dysregulated in the ocular surface of diabetic rats leading to overproduction of the inhibitory growth peptide OGF. The opioid antagonist naltrexone hydrochloride (NTX) blocks the OGF-OGFr pathway, and complete blockade following systemic or topical treatment with NTX restores the rate of re-epithelialization of corneal epithelial wounds, normalizes corneal sensitivity, and reverses dry eye in diabetic animal models. These effects occur rapidly and within days of initiating treatment. The present study was designed to understand mechanisms related to the fast reversal (<5 days) of dry eye by NTX in type 1 diabetes (T1D) by investigating dysregulation of the LFU. The approach involved examination of the morphology of the LFU before and after NTX treatment. Male and female adult Sprague-Dawley rats were rendered hyperglycemic with streptozotocin, and after 6 weeks rats were considered to be a T1D model. Rats received topical NTX twice daily to one eye for 10 days. During the period of treatment, tear production and corneal sensitivity were recorded. On day 11, animals were euthanized and orbital tissues including conjunctiva, eyelids, and lacrimal glands, were removed and processed for histologic examination including immunohistochemistry. Male and female T1D rats had significantly decreased tear production and corneal insensitivity, significantly decreased number and size of lacrimal gland acini, decreased expression of aquaporin-5 (AQP5) protein and decreased goblet cell size. Thus, 10 days of NTX treatment restored tear production and corneal sensitivity to normal values, increased AQP5 expression, and restored the surface area of goblet cells to normal. NTX had no effect on the number of lacrimal gland acini or the number of conjunctival goblet cells. In summary, blockade of the OGF-OGFr pathway with NTX reversed corneal and lacrimal gland complications and restored some components of tear homeostasis confirming the efficacy of topical NTX as a treatment for ocular defects in diabetes.


Subject(s)
Aquaporin 5 , Diabetes Mellitus, Experimental , Lacrimal Apparatus , Naltrexone , Rats, Sprague-Dawley , Tears , Animals , Lacrimal Apparatus/metabolism , Lacrimal Apparatus/drug effects , Lacrimal Apparatus/pathology , Tears/metabolism , Tears/drug effects , Naltrexone/pharmacology , Male , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/pathology , Rats , Aquaporin 5/metabolism , Administration, Topical , Dry Eye Syndromes/drug therapy , Dry Eye Syndromes/pathology , Dry Eye Syndromes/metabolism
9.
AAPS PharmSciTech ; 25(5): 119, 2024 May 30.
Article in English | MEDLINE | ID: mdl-38816667

ABSTRACT

Loteprednol etabonate (LE) is a topical corticosteroid for the symptomatic management of ocular conditions, encompassing both allergic and infectious etiologies. Owing to the dynamic and static barriers of the eye, LE exhibits significantly low bioavailability, necessitating an increase in the frequency of drug administration. The objective of this study is to overcome the limitations by developing niosomal systems loaded with LE. Design of Experiments (DoE) approach was used for the development of optimal niosome formulation. The optimal formulation was characterized using DLS, FT-IR, and DSC analysis. In vitro and ex vivo release studies were performed to demonstrate drug release patterns. After that HET-CAM evaluation was conducted to determine safety profile. Then, in vivo studies were carried out to determine therapeutic activity of niosomes. Zeta potential (ZP), particle size, polydispersity index (PI), and encapsulation efficacy (EE) were -33.8 mV, 89.22 nm, 0.192, and 89.6%, respectively. Medicated niosomes had a broad distribution within rabbit eye tissues and was absorbed by the aqueous humor of the bovine eye for up to 6 h after treatment. Cumulative permeated drug in the bovine eye and rabbit eye were recorded 52.45% and 54.8%, respectively. No irritation or hemorrhagic situation was observed according to the results of HET-CAM study. Thus, novel LE-loaded niosomal formulations could be considered as a promising treatment option for the dry-eye-disease (DED) due to enhanced bioavailability and decreased side effects.


Subject(s)
Delayed-Action Preparations , Dry Eye Syndromes , Liposomes , Loteprednol Etabonate , Animals , Rabbits , Delayed-Action Preparations/administration & dosage , Delayed-Action Preparations/pharmacokinetics , Loteprednol Etabonate/administration & dosage , Loteprednol Etabonate/pharmacokinetics , Dry Eye Syndromes/drug therapy , Cattle , Drug Liberation , Particle Size , Disease Models, Animal , Administration, Ophthalmic , Biological Availability , Drug Delivery Systems/methods , Eye/metabolism , Eye/drug effects , Aqueous Humor/metabolism , Chemistry, Pharmaceutical/methods , Ophthalmic Solutions/administration & dosage , Ophthalmic Solutions/pharmacokinetics
10.
Int J Pharm ; 658: 124222, 2024 Jun 10.
Article in English | MEDLINE | ID: mdl-38735632

ABSTRACT

Dry eye disease (DED) is a chronic multifactorial disorder of the ocular surface caused by tear film dysfunction and constitutes one of the most common ocular conditions worldwide. However, its treatment remains unsatisfactory. While artificial tears are commonly used to moisturize the ocular surface, they do not address the underlying causes of DED. Apigenin (APG) is a natural product with anti-inflammatory properties, but its low solubility and bioavailability limit its efficacy. Therefore, a novel formulation of APG loaded into biodegradable and biocompatible nanoparticles (APG-NLC) was developed to overcome the restricted APG stability, improve its therapeutic efficacy, and prolong its retention time on the ocular surface by extending its release. APG-NLC optimization, characterization, biopharmaceutical properties and therapeutic efficacy were evaluated. The optimized APG-NLC exhibited an average particle size below 200 nm, a positive surface charge, and an encapsulation efficiency over 99 %. APG-NLC exhibited sustained release of APG, and stability studies demonstrated that the formulation retained its integrity for over 25 months. In vitro and in vivo ocular tolerance studies indicated that APG-NLC did not cause any irritation, rendering them suitable for ocular topical administration. Furthermore, APG-NLC showed non-toxicity in an epithelial corneal cell line and exhibited fast cell internalization. Therapeutic benefits were demonstrated using an in vivo model of DED, where APG-NLC effectively reversed DED by reducing ocular surface cellular damage and increasing tear volume. Anti-inflammatory assays in vivo also showcased its potential to treat and prevent ocular inflammation, particularly relevant in DED patients. Hence, APG-NLC represent a promising system for the treatment and prevention of DED and its associated inflammation.


Subject(s)
Apigenin , Drug Carriers , Dry Eye Syndromes , Lipids , Nanoparticles , Animals , Apigenin/administration & dosage , Apigenin/chemistry , Apigenin/pharmacology , Apigenin/pharmacokinetics , Drug Carriers/chemistry , Dry Eye Syndromes/drug therapy , Humans , Rabbits , Lipids/chemistry , Lipids/administration & dosage , Cell Line , Nanoparticles/chemistry , Administration, Ophthalmic , Drug Liberation , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/pharmacokinetics , Particle Size , Nanostructures/administration & dosage , Nanostructures/chemistry , Male
11.
ACS Appl Mater Interfaces ; 16(21): 27040-27054, 2024 May 29.
Article in English | MEDLINE | ID: mdl-38743443

ABSTRACT

Strong precorneal clearance mechanisms including reflex blink, constant tear drainage, and rapid mucus turnover constitute great challenges for eye drops for effective drug delivery to the ocular epithelium. In this study, cyclosporine A (CsA) for the treatment of dry eye disease (DED) was selected as the model drug. Two strategies, PEGylation for mucus penetration and cationization for potent cellular uptake, were combined to construct a novel CsA nanosuspension (NS@lipid-PEG/CKC) by coating nanoscale drug particles with a mixture of lipids, DSPE-PEG2000, and a cationic surfactant, cetalkonium chloride (CKC). NS@lipid-PEG/CKC with the mean size ∼173 nm and positive zeta potential ∼+40 mV showed promoted mucus penetration, good cytocompatibility, more cellular uptake, and prolonged precorneal retention without obvious ocular irritation. More importantly, NS@lipid-PEG/CKC recovered tear production and goblet cell density more efficiently than the commercial cationic nanoemulsion on a dry eye disease rat model. All results indicated that a combination of PEGylation and cationization might provide a promising strategy to coordinate mucus penetration and cellular uptake for enhanced drug delivery to the ocular epithelium for nanomedicine-based eye drops.


Subject(s)
Cyclosporine , Dry Eye Syndromes , Phospholipids , Polyethylene Glycols , Animals , Cyclosporine/chemistry , Cyclosporine/pharmacology , Cyclosporine/pharmacokinetics , Cyclosporine/administration & dosage , Polyethylene Glycols/chemistry , Rats , Dry Eye Syndromes/drug therapy , Dry Eye Syndromes/pathology , Phospholipids/chemistry , Rats, Sprague-Dawley , Nanoparticles/chemistry , Drug Delivery Systems , Cations/chemistry , Ophthalmic Solutions/chemistry , Ophthalmic Solutions/pharmacology , Humans , Male , Cornea/metabolism , Cornea/drug effects
12.
Adv Ther ; 41(6): 2477-2485, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38709396

ABSTRACT

INTRODUCTION: This study aimed to investigate the tolerability of high-viscosity diquafosol tetrasodium (DQS) ophthalmic solution (DIQUAS LX; DQSLX) and examine its usability and effect on clinical findings in patients with dry eye disease (DED). METHODS: This interventional retrospective study included 66 eyes of 66 patients with DED who switched from conventional DQS to DQSLX ophthalmic solution. Tear function assessments (tear film breakup time [BUT], keratoconjunctival vital staining [VS] score), evaluations of DED symptom relief, and a four-item usability questionnaire ("comfort upon instillation," "irritation upon instillation," "eye mucus discharge," "convenience of instillation frequency") assessed using a visual analog scale from 0 (worst) to 10 (best) were administered 4 weeks after switching to DQSLX. Factors associated with drug tolerability were assessed using multiple regression analysis. RESULTS: The symptoms improved by 64.2% after switching to DQSLX. The BUT value, VS score, and the questionnaire items "comfort upon instillation" and "convenience of instillation frequency" were significantly improved after switching to DQSLX. DQSLX tolerability was reported as acceptable in 56 (84.8%) and unacceptable in 10 (15.2%) patients. Overall, DQSLX tolerability was significantly associated with "comfort upon instillation" and "convenience of instillation frequency" and tended to be associated with a VS score ≥ 1. DQSLX tolerability depended on symptom and VS score improvements and absence of excessive "eye mucus discharge" in patients with a VS score ≥ 1 (39 patients), but on "comfort upon instillation" and absence of excessive "eye mucus discharge" in patients with a VS score = 0 (27 patients). CONCLUSION: The high-viscosity DQSLX ophthalmic solution was generally considered acceptable in the study population. However, drug tolerability seemingly differed between patients with DED with and without epithelial damage. The former were affected by improvements in symptoms and clinical findings, whereas the latter were affected by comfort upon instillation. TRIAL REGISTRATION: University Hospital Medical Information Network identifier, UMIN000051390.


Subject(s)
Dry Eye Syndromes , Ophthalmic Solutions , Polyphosphates , Uracil Nucleotides , Humans , Dry Eye Syndromes/drug therapy , Male , Female , Uracil Nucleotides/therapeutic use , Uracil Nucleotides/administration & dosage , Ophthalmic Solutions/therapeutic use , Middle Aged , Retrospective Studies , Aged , Polyphosphates/therapeutic use , Polyphosphates/administration & dosage , Tears/drug effects , Adult , Delayed-Action Preparations , Treatment Outcome , Surveys and Questionnaires
13.
BMJ Open Ophthalmol ; 9(1)2024 May 03.
Article in English | MEDLINE | ID: mdl-38702178

ABSTRACT

BACKGROUND: Dry eye disease is the most commonplace multifractional ocular complication, which has already affected millions of people in the world. It is identified by the excessive buildup of reactive oxygen species, leading to substantial corneal epithelial cell demise and ocular surface inflammation attributed to TLR4. In this study, we aimed to identify potential compounds to treat of dry eye syndrome by exploring in silico methods. METHODS: In this research, molecular docking and dynamics simulation tests were used to examine the effects of selected compounds on TLR4 receptor. Compounds were extracted from different databases and were prepared and docked against TLR4 receptor via Autodock Vina. Celastrol, lumacaftor and nilotinib were selected for further molecular dynamics studies for a deeper understanding of molecular systems consisting of protein and ligands by using the Desmond module of the Schrodinger Suite. RESULTS: The docking results revealed that the compounds are having binding affinity in the range of -5.1 to -8.78 based on the binding affinity and three-dimensional interactions celastrol, lumacaftor and nilotinib were further studied for their activity by molecular dynamics. Among the three compounds, celastrol was the most stable based on molecular dynamics trajectory analysis from 100 ns in the catalytic pockets of 2Z63.pdb.pdb. Root mean square deviation of celastrol/2Z63 was in the range of 1.8-4.8 Å. CONCLUSION: In particular, Glu376 of TLR4 receptor is crucial for the identification and binding of lipopolysaccharides (LPS), which are part of Gram-negative bacteria's outer membrane. In our investigation, celastrol binds to Glu376, suggesting that celastrol may prevent the dry eye syndrome by inhibiting LPS's binding to TLR4.


Subject(s)
Dry Eye Syndromes , Molecular Docking Simulation , Molecular Dynamics Simulation , Pentacyclic Triterpenes , Pyrimidines , Toll-Like Receptor 4 , Dry Eye Syndromes/drug therapy , Toll-Like Receptor 4/antagonists & inhibitors , Toll-Like Receptor 4/metabolism , Toll-Like Receptor 4/chemistry , Humans , Pentacyclic Triterpenes/pharmacology , Pentacyclic Triterpenes/chemistry , Pentacyclic Triterpenes/therapeutic use , Pyrimidines/pharmacology , Pyrimidines/chemistry , Pyrimidines/therapeutic use , Triterpenes/pharmacology , Triterpenes/chemistry , Computer Simulation , Ligands , Aminopyridines/pharmacology , Aminopyridines/chemistry , Aminopyridines/therapeutic use
14.
J Refract Surg ; 40(4): e229-e238, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38593259

ABSTRACT

PURPOSE: To evaluate the effects of topical 0.05% cyclosporine A on Ocular Surface Disease Index (OSDI) score and ocular surface parameters after small incision lenticule extraction (SMILE) for myopia. METHODS: In this study, 151 patients who underwent SMILE were randomized into the control group (71 eyes) and the 0.05% cyclosporine A group (80 eyes). Both groups received standard treatment during the 1 month after SMILE. Over the next 3 months, The control group continued standard therapy (0.3% sodium hyaluronate) and the 0.05% cyclosporine A group received additional 0.05% cyclosporine A. OSDI total and subscale scores, non-invasive tear break-up time (NIBUT), tear lipid layer thickness (LLT), and tear meniscus height (TMH) were assessed preoperatively and postoperatively. RESULTS: Compared to baseline, the OSDI scores significantly increased in both groups (P < .001). The 0.05% cyclosporine A group exhibited lower OSDI total scores after administering 0.05% cyclosporine A versus the control group (P = .026). At 1 month of follow-up, NIBUT, LLT, and TMH values significantly decreased in both groups compared to baseline (P < .05). The 0.05% cyclosporine A group exhibited higher NIBUT, LLT, and TMH versus the control group, returning to preoperative values after 2 months. Overall, the OSDI total score and NIBUT values during follow-up were not significantly different between the two groups; however, the LLT and TMH values were significantly different between the two groups (P < .001 and .041, respectively) by repeated measures analysis of variance. CONCLUSIONS: Topical 0.05% cyclosporine A was effective in relieving subjective dry eye symptoms and maintaining ocular surface stability in the early postoperative period of SMILE. [J Refract Surg. 2024;40(4):e229-e238.].


Subject(s)
Dry Eye Syndromes , Keratomileusis, Laser In Situ , Myopia , Humans , Cyclosporine/therapeutic use , Myopia/surgery , Dry Eye Syndromes/diagnosis , Dry Eye Syndromes/drug therapy , Dry Eye Syndromes/etiology , Tears
16.
Int Ophthalmol ; 44(1): 193, 2024 Apr 24.
Article in English | MEDLINE | ID: mdl-38653918

ABSTRACT

PURPOSE: This study evaluated the tear film stability in patients with symptoms of dry eye after installation of dual polymer hydroxypropyl guar/sodium hyaluronate (DPHG/SH) vs single polymer SH. METHODS: Patients with recently diagnosed mild to moderate dry eye disease (OSDI score 23-32 points) were included. For each patient, the right eye was randomized to receive DPHG/SH or 0.15% SH. Just after the administration of the drop to the right eye, the fellow eye received the other eye drop. The first non-invasive Keratograph first break-up time (NIKBUT), average NIKBUT and tear meniscus height (TMH) were measured before administration of the eye drops, at 1-min, 15 min, 30 min, 60 min, 90 min, and 120 min after instillation. RESULTS: A total of 29 patients aged 22.8 ± 2.2 years participated in the study (21 women). No differences between the eye receiving DPHG/SH and single polymer SH were observed for the first NIKBUT (p = 0.45) and average NIKBUT (p = 0.24) variables at any time point. Both DPHG/SH and single polymer SH increased the TMH (p of time effect < 0.001), but with no difference between groups (p = 0.95). CONCLUSION: Both DPHG/SH and single polymer SH solutions provide lubrication of the eye surface, however, with no difference in NIKBUT and TMH evaluations for up to two hours following administration.


Subject(s)
Dry Eye Syndromes , Hyaluronic Acid , Ophthalmic Solutions , Tears , Humans , Dry Eye Syndromes/drug therapy , Dry Eye Syndromes/diagnosis , Female , Hyaluronic Acid/administration & dosage , Male , Ophthalmic Solutions/administration & dosage , Young Adult , Adult , Polysaccharides/administration & dosage , Polymers , Viscosupplements/administration & dosage , Prospective Studies
17.
ACS Nano ; 18(17): 11084-11102, 2024 Apr 30.
Article in English | MEDLINE | ID: mdl-38632691

ABSTRACT

Dry eye disease (DED) affects a substantial worldwide population with increasing frequency. Current single-targeting DED management is severely hindered by the existence of an oxidative stress-inflammation vicious cycle and complicated intercellular crosstalk within the ocular microenvironment. Here, a nanozyme-based eye drop, namely nanoceria loading cyclosporin A (Cs@P/CeO2), is developed, which possesses long-term antioxidative and anti-inflammatory capacities due to its regenerative antioxidative activity and sustained release of cyclosporin A (CsA). In vitro studies showed that the dual-functional Cs@P/CeO2 not only inhibits cellular reactive oxygen species production, sequentially maintaining mitochondrial integrity, but also downregulates inflammatory processes and repolarizes macrophages. Moreover, using flow cytometric and single-cell sequencing data, the in vivo therapeutic effect of Cs@P/CeO2 was systemically demonstrated, which rebalances the immune-epithelial communication in the corneal microenvironment with less inflammatory macrophage polarization, restrained oxidative stress, and enhanced epithelium regeneration. Collectively, our data proved that the antioxidative and anti-inflammatory Cs@P/CeO2 may provide therapeutic insights into DED management.


Subject(s)
Cerium , Cyclosporine , Dry Eye Syndromes , Cerium/chemistry , Cerium/pharmacology , Cyclosporine/pharmacology , Cyclosporine/administration & dosage , Dry Eye Syndromes/drug therapy , Dry Eye Syndromes/pathology , Animals , Mice , Humans , Reactive Oxygen Species/metabolism , Oxidative Stress/drug effects , Nanoparticles/chemistry , Macrophages/drug effects , Macrophages/metabolism , Macrophages/immunology , Mice, Inbred C57BL , Antioxidants/pharmacology , Antioxidants/chemistry , Antioxidants/administration & dosage , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/administration & dosage , Drug Delivery Systems
18.
AAPS PharmSciTech ; 25(5): 92, 2024 Apr 29.
Article in English | MEDLINE | ID: mdl-38684590

ABSTRACT

PURPOSE: Dry eye syndrome (DES), arising from various etiologic factors, leads to tear film instability and ocular surface damage. Given its anti-inflammatory effects, cyclosporine A (CsA) has been widely used as a short-term treatment option for DES. However, poor bioavailability and solubility of CsA in aqueous phase make the development of a cyclosporine A-based eye drop for ocular topical application a huge challenge. METHODS: In this study, a novel strategy for preparing cyclosporine A-loaded silk fibroin nanoemulsion gel (CsA NBGs) was proposed to address these barriers. Additionally, the rheological properties, ocular irritation potential, tear elimination kinetics, and pharmacodynamics based on a rabbit dry eye model were investigated for the prepared CsA NBGs. Furthermore, the transcorneal mechanism across the ocular barrier was also investigated. RESULTS: The pharmacodynamics and pharmacokinetics of CsA NBGs exhibited superior performance compared to cyclosporine eye drops, leading to a significant enhancement in the bioavailability of CsA NBGs. Furthermore, our investigation into the transcorneal mechanism of CsA NBGs revealed their ability to be absorbed by corneal epithelial cells via the paracellular pathway. CONCLUSION: The CsA NBG formulation exhibits promising potential for intraocular drug delivery, enabling safe, effective, and controlled administration of hydrophobic drugs into the eye. Moreover, it enhances drug retention within the ocular tissues and improves systemic bioavailability, thereby demonstrating significant clinical translational prospects.


Subject(s)
Biological Availability , Cyclosporine , Dry Eye Syndromes , Fibroins , Gels , Ophthalmic Solutions , Rabbits , Animals , Fibroins/chemistry , Cyclosporine/administration & dosage , Cyclosporine/pharmacokinetics , Cyclosporine/chemistry , Dry Eye Syndromes/drug therapy , Ophthalmic Solutions/administration & dosage , Drug Delivery Systems/methods , Administration, Ophthalmic , Solubility , Male , Emulsions/chemistry , Cornea/metabolism , Cornea/drug effects , Disease Models, Animal
19.
Int J Mol Sci ; 25(6)2024 Mar 20.
Article in English | MEDLINE | ID: mdl-38542500

ABSTRACT

The present study investigated the effect of orally administered Limosilactobacillus fermentum HY7302 (HY7302) on the relationship between ocular tissue and the microbiome in a corneal injury dry eye mouse model. Specifically, 0.1% benzalkonium chloride (BAC) was applied to the ocular surface for 14 days to induce corneal injury in male Balb/c mice. During the BAC treatment period, HY7302 (1 × 108 CFU/kg/day or 1 × 109 CFU/kg/day) or an omega-3 positive control (400 mg/kg/day) were administered orally (n = eight/group). To examine the signaling pathways affected by the HY7302 treatment, the in vitro effects of HY7302 on the tight junctions and the inflammatory response were investigated in the mouse colon epithelial cell line, CMT-93. BAC exposure decreased tear production, induced ocular inflammation and corneal epithelial detachment, and altered the gut microbiota. However, oral administration of HY7302 restored tear secretion and decreased corneal epithelial detachment in BAC-treated corneal injury mice. Further, HY7302 alleviated corneal inflammation via modulation of matrix metalloproteinase-9 (MMP-9) expression and affeted alterations in gut microbiota composition. These findings suggest that the gut-eye axis interaction between gut microbiota and corneal tissue affects disease severity in corneal injury, and that the alteration of the microbiota by HY7302 could improve eye health by regulating the inflammatory response.


Subject(s)
Corneal Injuries , Dry Eye Syndromes , Gastrointestinal Microbiome , Limosilactobacillus fermentum , Male , Mice , Animals , Inflammation/drug therapy , Benzalkonium Compounds , Dry Eye Syndromes/drug therapy , Dry Eye Syndromes/metabolism
20.
Biomolecules ; 14(3)2024 Mar 20.
Article in English | MEDLINE | ID: mdl-38540794

ABSTRACT

Polyunsaturated fatty acids (PUFAs) generate pro- and anti-inflammatory eicosanoids via three different metabolic pathways. This study profiled tear PUFAs and their metabolites and examined the relationships with dry eye (DE) and meibomian gland dysfunction (MGD) symptoms and signs. A total of 40 individuals with normal eyelids and corneal anatomies were prospectively recruited. The symptoms and signs of DE and MGD were assessed, and tear samples (from the right eye) were analyzed by mass spectrometry. Mann-Whitney U tests assessed differences between medians; Spearman tests assessed correlations between continuous variables; and linear regression models assessed the impact of potential confounders. The median age was 63 years; 95% were male; 30% were White; and 85% were non-Hispanic. The symptoms of DE/MGD were not correlated with tear PUFAs and eicosanoids. DE signs (i.e., tear break-up time (TBUT) and Schirmer's) negatively correlated with anti-inflammatory eicosanoids (11,12-dihydroxyeicosatrienoic acid (11,12 DHET) and 14,15-dihydroxyicosatrienoic acid (14,15, DHET)). Corneal staining positively correlated with the anti-inflammatory PUFA, docosahexaenoic acid (DHA). MGD signs significantly associated with the pro-inflammatory eicosanoid 15-hydroxyeicosatetranoic acid (15-HETE) and DHA. Several relationships remained significant when potential confounders were considered. DE/MGD signs relate more to tear PUFAs and eicosanoids than symptoms. Understanding the impact of PUFA-related metabolic pathways in DE/MGD may provide targets for new therapeutic interventions.


Subject(s)
Dry Eye Syndromes , Humans , Male , Middle Aged , Female , Dry Eye Syndromes/drug therapy , Eicosanoids/metabolism , Tears/metabolism , Cornea/metabolism , Docosahexaenoic Acids , Anti-Inflammatory Agents/therapeutic use
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