Cyclosporine A (0.05%) Ophthalmic Gel in the Treatment of Dry Eye Disease: A Multicenter, Randomized, Double-Masked, Phase III, COSMO Trial.

Purpose: To confirm the efficacy and safety of a novel ophthalmic cyclosporine A gel (CyclAGel, 0.05% CsA) in treating patients with moderate-to-severe dry eye disease (DED). Patients and Methods: The COSMO trial was a randomized, multicenter, double-masked, vehicle-controlled, phase III trial. Patients with moderate-to-severe DED were enrolled in 37 hospitals in China between November 2020 and April 2021. Eligible patients were randomized 1:1 to receive CyclAGel 0.05% or vehicle eye drops once nightly (QD). The primary endpoint was the proportion of subjects with at least a 1-point improvement in ICSS at day 84. Treatment-emergent adverse events (TEAEs) were recorded. Results: The full analysis set (FAS) included 315 and 312 participants in the CyclAGel and vehicle groups, respectively. The primary efficacy endpoint was achieved. The proportion of subjects with at least a 1-point improvement in ICSS from baseline to day 84 was significantly higher in the CyclAGel group than in the vehicle group (73.7% [232/315] vs 53.2% [166/312], P<0.0001). Significant improvements relative to the vehicle were also observed in the ICSS and Oxford scale scoring of corneal and conjunctival fluorescein staining at day 14, 42, and 84. The Schirmer tear test results were significantly higher in the CyclAGel group than in the vehicle group on days 14 and 84 (all P<0.05). The CyclAGel 0.05% was well tolerated, and the TEAEs were mostly mild. The most frequent treatment-related TEAE was eye pain (6.9% vs 1.6% in the CyclAGel and vehicle groups, respectively). No serious treatment-related TEAEs were reported. Conclusion: Clinically and statistically significant improvements in ICSS, tear production, and symptoms were observed in participants administered CyclAGel 0.05% QD for moderate-to-severe DED. CyclAGel 0.05% QD is a new effective, safe, and well-tolerated therapeutic option that might bring additional benefits of convenience and compliance as a once-A-day treatment for DED.

Potential Therapeutic Role of Pituitary Adenylate Cyclase-Activating Polypeptide for Dry Eye Disease.

Dry eye disease (DED) is caused by a reduction in the volume or quality of tears. The prevalence of DED is estimated to be 100 million in the developed world. As aging is a risk factor for DED, the prevalence of DED is expected to grow at a rapid pace in aging populations, thus creating an increased need for new therapies. This review summarizes DED medications currently in clinical use. Most current medications for DED focus on stimulating tear secretion, mucin secretion, or suppressing inflammation, rather than simply replenishing the ocular surface with moisture to improve symptoms. We recently reported that the neuropeptide PACAP (pituitary adenylate cyclase-activating polypeptide) induces tear secretion and suppresses corneal injury caused by a reduction in tears. Moreover, it has been reported that a PACAP in water and a 0.9% saline solution at +4 °C showed high stability and achieved 80-90% effectiveness after 2 weeks of treatment. These results reveal PACAP as a candidate DED medication. Further research on the clinical applications of PACAP in DED is necessary.

Once-Daily Topical Phosphosulindac Is Efficacious in the Treatment of Dry Eye Disease: Studies in Rabbit Models of Its Main Clinical Subtypes.

Purpose: Dry eye disease (DED) is classified as aqueous deficient, evaporative, or mixed. We investigated the therapeutic effect of the novel anti-inflammatory drug phosphosulindac (PS) in rabbit models of DED encompassing its pathogenesis, and its transition to chronicity. Methods: We treated three rabbit models of DED with PS (hydrogel formulation) or vehicle topically applied 1 × /day. We induced aqueous-deficient DED (acute and chronic) by injecting Concanavalin A into lacrimal glands; evaporative DED by injecting into the upper eyelid inactivated Mycobacterium tuberculosis in complete Freund's adjuvant; and mixed DED through desiccative stress, induced by holding open the eye for 3 h. We determined corneal sensitivity, tear break-up time (TBUT), Schirmer's tear test (STT), tear osmolality, and fluorescein staining of the ocular surface. Results: PS reversed all abnormal DED parameters. In acute DED, PS dose dependently normalized corneal sensitivity and tear osmolality; and improved TBUT, STT, and fluorescein staining. PS normalized corneal sensitivity and improved all other parameters in chronic aqueous-deficient DED. In evaporative DED, PS normalized corneal sensitivity and improved TBUT and fluorescein staining (osmolality and STT were not significantly changed in this model). In the desiccative stress model, PS improved TBUT and fluorescein staining but had no effect on STT or tear osmolality. Conclusions: PS rapidly reversed almost all DED parameters in its three subtypes. The normalization of the suppressed corneal sensitivity suggests the possibility of marked symptomatic relief by PS. The hydrogel formulation allows once-daily dosing. PS merits further development as a potential treatment for DED.

The Differential Reactive Oxygen Species Production of Tear Neutrophils in Response to Various Stimuli In Vitro.

A large number of polymorphonuclear neutrophils (PMNs) invade the ocular surface during prolonged eye closure (sleep); these leukocytes are commonly referred as tear PMNs. PMNs contribute to homeostasis and possess an arsenal of inflammatory mediators to protect against pathogens and foreign materials. This study examined the ability of tear PMNs to generate reactive oxygen species (ROS), an essential killing mechanism for PMNs which can lead to oxidative stress and imbalance. Cells were collected after sleep from healthy participants using a gentle eye wash. ROS production in stimulated (phorbol-12-myristate-13-acetate (PMA), lipopolysaccharides (LPS) or N-Formylmethionyl-leucyl-phenylalanine (fMLP)) and unstimulated tear PMNs was measured using luminol-enhanced chemiluminescence for 60 min. A high level of constitutive/spontaneous ROS production was observed in tear PMNs in the absence of any stimulus. While tear PMNs were able to produce ROS in response to PMA, they failed to appropriately respond to LPS and fMLP, although fMLP-stimulated tear PMNs generated ROS extracellularly in the first three minutes. Higher ROS generation was observed in isolated tear PMNs which may be due to priming from the magnetic bead cell separation system. The differential responses of tear PMNs in ROS generation provide further evidence of their potential inflammatory roles in ocular complications involving oxidative stress.

Effect of Platelet-Rich Plasma on Corneal Epithelial Healing after Phototherapeutic Keratectomy: An Intraindividual Contralateral Randomized Study.

PURPOSE: To assess the effect of platelet-rich plasma (PRP) on the healing response of the corneal epithelium in eyes undergoing phototherapeutic keratectomy (PTK). METHODS: We prospectively examined 20 eyes of 10 patients undergoing bilateral PTK for granular corneal dystrophy or band keratopathy. Patients were randomly assigned to start topical administration of PRP ophthalmic suspension (PRP group) or artificial tears (control group) 4 times daily for 2 weeks. Immediately, 1, and 2 days, and 1 week after PTK, we quantitatively measured the staining area of the corneal epithelium, using slit-lamp photography. We also determined the subjective symptoms and the satisfaction, using the visual analogue system (VAS). RESULTS: The staining area in the PRP group was significantly smaller than that in the control group on days 1 and 2 (Wilcoxon signed-rank test, p = 0.022 and p = 0.017, respectively), but not on day 7 (p = 0.317). The recovery rate of the corneal epithelium in the PRP group was significantly higher than that in the control group on days 1 and 2 (p = 0.022 and p = 0.017, respectively), but not on day 7 (p = 0.317). We found no significant differences in pain (p = 0.139), foreign body sensation (p = 0.108), epiphora (p = 1.000), or satisfaction (p = 0.295), between the two groups. Postoperative complications did not occur in any of the eyes in the study. CONCLUSIONS: The PRP treatment was effective for enhancing corneal epithelial recovery in the early postoperative period, without significant adverse events, in post-PTK-treated eyes, suggesting that it may hold promise as one of the treatment options for treating such postsurgical patients.

Efficacy of Artificial Tears Based on an Extract of Artemia salina Containing Dinucleotides in a Rabbit Dry Eye Model.

(1) Background: Artemia salina is a brine shrimp containing high concentrations of dinucleotides, molecules with properties for dry eye treatment. For this reason, the purpose of the study was to evaluate the effect of the artificial tears based on an extract of Artemia salina in a rabbit dry eye model. (2) Methods: A prospective and randomized study was carried out. Twenty rabbits were divided into 4 groups (n = 5, each group): healthy rabbits, dry eye rabbits, dry eye rabbits treated with hypromellose (HPMC), and dry eye rabbits treated with Artemia salina. Dry eye was induced by the topical instillation of 0.2% benzalkonium chloride. The measurements were performed before and after the treatment for 5 consecutive days. (3) Results: The topical instillation of artificial tears containing Artemia salina showed beneficial effects on tear secretion, tear break-up time, corneal staining, the density of Goblet cells, heigh of mucin cloud secreted by these cells, and mRNA levels of IL-1ß and MMP9 in conjunctival cells. Compared with the HPMC, there was a statistically significant improvement (p < 0.05) with the Artemia salina in all the variables under study, except for the conjunctival hyperemia, density of Goblet cells, and mRNA levels of IL-6. (4) Conclusions: The potential of artificial tears based on Artemia salina as a secretagogue agent for dry eye treatment was confirmed, opening the door for future clinical trials and studies to extrapolate the findings for dry eye patients.

Ocular Surface Disease in Glaucoma Patients Randomized to Benzalkonium Chloride-Containing Latanoprost and Preservative-Free Bimatoprost.

Purpose: To investigate the influence of benzalkonium chloride (BAK) on ocular surface disease (OSD) in glaucoma patients receiving ocular-hypotensive agent. Methods: Patients were randomized to receive BAK-containing latanoprost (Xalatan) or preservative-free bimatoprost (Lumigan PF). Intraocular pressure (IOP), basal Schirmer's test, noninvasive keratograph tear-breakup time (TBUT), conjunctival redness score (R score), OSD index (OSDI), and corneal Oxford staining were recorded and compared between the 2 groups at 1-month and 4-month visits. The influence of BAK was analyzed by a generalized estimating equation model. Results: We enrolled 74 and 76 eyes treated with latanoprost and bimatoprost, respectively. The IOP decreased in both groups, although greater reduction was observed for latanoprost (13.95 vs. 15.42 mmHg, P = 0.0264). There was a significantly negative association between tear flow and latanoprost use (ß = -0.763, P = 0.0243). The first and average TBUT did not show intergroup differences, but the area with unstable tear film increased with latanoprost use and showed marginal significance at 4-month visit (9.33% vs. 5.94% P = 0.055). In both groups, OSDI decreased, whereas Oxford stain increased over time, and R scores showed improvement after transient increase in the first month. The bimatoprost group had significantly worse conjunctival hyperemia, whereas a negative association with conjunctival hyperemia was revealed for latanoprost use (R score-bulbar nasal: ß = -0.045, P = 0.0423). Conclusions: BAK-containing latanoprost was associated with decreased tear secretion and may be associated with tear-film instability, whereas bimatoprost was associated with worse conjunctival hyperemia. Ocular surface side effects should be considered when prescribing BAK-containing medication to glaucoma patients.

Effects of eye drops containing a mixture of 3% diquafosol sodium and tocopherol acetate (vitamin E) on the ocular surface of murine dry eye.

PURPOSE: To investigate the efficacy of topical application of 3% diquafosol sodium (DQS) and tocopherol (TCP) acetate mixtures in a mouse model of experimental dry eye (EDE). METHODS: After exposure to desiccating stress for 5 days, eye drops consisting of 3% DQS alone, 0.01% TCP alone, or 3% DQS and 0.005% or 0.01% TCP mixture were applied for the treatment of EDE. Tear volume, tear film break-up time (TBUT), corneal fluorescein staining scores (CFSS), and tear film lipid layer grades (TFLLG) were measured at 0, 5 and 10 days after treatment. The 2',7'-dichlorodihydrofluorescein diacetate assay (DCFDA) for reactive oxygen species (ROS) production, enzyme-linked immunosorbent assay (ELISA) for malondialdehyde (MDA), and flow cytometry for CD4 + interferon (IFN)-γ+ T cells were evaluated on the ocular surface at 10 days after treatment. In addition, levels of tumour necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, and chemokine CC motif ligand 4 (CCL4) in the conjunctiva were measured using a multiplex immunobead assay, and conjunctival goblet cells were counted by periodic acid-Schiff staining at 10 days after treatment. RESULTS: Both the TCP mixture groups indicated a significant improvement in TBUT, ROS production, and MDA concentrations compared to those in the DQS alone group. Furthermore, the 0.01% TCP mixture group also showed higher tear film lipid layer grades and conjunctival goblet cell density and lower corneal fluorescein staining scores, number of CD4 + IFN-γ+ T cells, and levels of TNF-α, IL-1ß, and CCL4 than the DQS alone group (P < 0.05). CONCLUSIONS: Application of eye drops containing the mixture of DQS and TCP could stabilize the tear film lipid layer, improve TBUT and corneal epithelial damages, decrease ROS production, inflammatory molecules, and T cells, and increase conjunctival goblet cell density on the ocular surface. Topical DQS and TCP mixtures may have a greater therapeutic effect on clinical signs, oxidative damage, and inflammation of dry eye than DQS eye drops.

Acetylcholine and Royal Jelly Fatty Acid Combinations as Potential Dry Eye Treatment Components in Mice.

Dry eye is a multifactorial disease characterized by ocular discomfort and visual impairment. Our previous studies have shown that royal jelly (RJ) has restored the capacity for tear secretion by modulating muscarinic calcium signaling. RJ contains acetylcholine, which is a major cholinergic neurotransmitter, and a unique set of fatty acids with C 8 to 12 chains, which are expected to be associated with health benefits. The purpose of the present study was to investigate the active components involved in tear secretion capacity, focusing on acetylcholine and fatty acids in RJ. Using the stress-induced dry-eye model mice, it was confirmed that acetylcholine with three fatty acids (10-hydroxydecanoic acid, 8-hydroxyoctanoic acid, and (R)-3,10-dihydroxydecanoic acid) was essential for tear secretion. In ex vivo Ca2+ imaging, these three fatty acids suppressed the decrease in intracellular modulation of Ca2+ in the lacrimal gland by acetylcholine when treated with acetylcholinesterase, indicating that the specific type of RJ fatty acids contributed to the stability of acetylcholine. To our knowledge, this study is the first to confirm that a specific compound combination is important for the pharmacological activities of RJ. Our results elucidate the active molecules and efficacy mechanisms of RJ.

Effect of Withdrawing Chronic Topical Immune Modulating Treatment on Schirmer Tear Test Values in Dogs with Dry Eye Disease: Relevance to Dry Eye Studies.

Purpose: To determine the effect of discontinuing chronic topical immune modulating (IM) treatment on Schirmer tear test (STT) values in dogs with dry eye disease (DED). Methods: Serial measurements of STTs from 14 dogs (16 eyes) previously diagnosed with DED were obtained before and after discontinuation of topical IM agents. Dogs with moderate to severe DED that had been well controlled with a topical IM treatment were included. After initial assessment topical IM treatment was discontinued, but topical lubricant was continued, and STT values were obtained sequentially. A mixed-effects regression model was used to evaluate the effects of age, gender, breed, clinical score, frequency of treatment, baseline STT value, and drug type on final STT values after IM withdrawal. P < 0.05 was considered statistically significant. Results: During the follow-up period after the IM treatment had been discontinued (136 ± 29 days), 50% of the eyes (n = 8) exhibited STT values that never decreased to <10 mm/min. In the other 50% (n = 8), STT values decreased from 15.9 ± 4.7 mm/min to 6.1 ± 0.9 mm/min. In this group, the time it took to decrease the STT to <10 mm/min was 21.1 ± 9.5 days. Severe clinical signs of DED and low baseline STT pre-IM treatment significantly affected STT post-IM treatment withdrawal (P < 0.05). Conclusions: The duration that a residual effect of topical IM treatment persists needs to be taken into consideration when studies are designed utilizing dogs with previous IM treatment for DED.

A Pilot Study of Changes in the Level of Catecholamines and the Activity of α-2-Macroglobulin in the Tear Fluid of Patients with Parkinson's Disease and Parkinsonian Mice.

Development of differential and early (preclinical) diagnostics of Parkinson's disease (PD) is among the priorities in neuroscience. We searched for changes in the level of catecholamines and α-2-macroglobulin activity in the tear fluid (TF) in PD patients at an early clinical stage. It was shown that TF in patients is characterized by an increased level of noradrenaline mainly on the ipsilateral side of pronounced motor symptoms (72%, p = 0.049), a decreased level of adrenaline on both sides (ipsilateral-53%, p = 0.004; contralateral-42%, p = 0.02), and an increased α-2-macroglobulin activity on both sides (ipsilateral-53%, p = 0.03; contralateral-56%, p = 0.037) compared to controls. These changes are considered as potential biomarkers for differential diagnosis. Similar changes in the TF were found in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice when modeling clinical and preclinical stages of PD. These data show the adequacy of models to the pathogenesis of PD along the selected metabolic pathways, and also suggest that the found TF changes can be considered as potential biomarkers for preclinical diagnosis of PD. In Parkinsonian mice, the level of catecholamines also changes in the lacrimal glands, which makes it possible to consider them as one of the sources of catecholamines in the TF.

Astragalus â £ ameliorates the dry eye injury in rabbit model via MUC1-ErbB1 pathway.

The therapeutic effects and potential mechanisms of astragaloside IV on a rabbits dry eye model induced by benzalkonium chloride (BAC) was examined. In our study, a BAC-induced dry eye rabbit model was treated with eye drops containing astragaloside IV (5, 10 µM) or solvent four times a day. The clinical evaluations, such as tear break-up time (BUT) and Schirmer tear test (STT), were performed on days 0, 7, 14, 21, and 28. On day 28, the cornea and bulbar conjunctiva tissues (left eye and right eye) were collected with histology, and immunofluorescent staining conducted. The levels of MUC1 and ErbB1in the corneas were determined by real-time quantitative PCR (qRT-PCR) and the proteins levels of MUC1 and ErbB1 were detected by Western blot. It was demonstrated that both astragaloside IV (5, 10 µM) treatments resulted in an increased STT and BUT on days 7, 14, 21 and 28. Additionally, the astragaloside IV (5, 10 µM)-treated group showed increasing PAS-positive goblet cells than model group (0 µM). Moreover, the MUC1 in model group (0 µM) was decreased, while the expression of MUC1 in astragaloside IV (5, 10 µM) group was increased. Furthermore, astragaloside IV had a protective effect on BAC-induced rabbits' dry eye and demonstrated clinical improvements, which indicated that astragaloside IV served as a potential protective agent in the clinical treatment of dry eye.

Cevimeline-induced anti-inflammatory effect through upregulations of mucins in the ocular surface of a dry eye mouse model.

This study aimed to investigate the effects of various concentrations of cevimelines (CVMs) and compare them with commercial drugs in a murine model of dry eye. The experimental mouse model used male and female NOD.B10.H2b mice over 12 weeks of age. Desiccation stress was performed at 30-40% ambient humidity, and subcutaneous injection of 0.5 mg/0.2 mL scopolamine hydrobromide was performed four times a day for 10 days. The efficacy of various concentrations of CVMs (seven experimental groups) was first evaluated, and then 2% CVM was compared with commercial drugs, such as cyclosporine A (CsA), diquafosol (DQS), and rebamipide (REB) (seven experimental groups). The clinical changes, including tear production, corneal irregularity, and fluorescein staining, were measured after the instillation of various concentrations of CVMs and commercial drugs for 0, 3, 5, 7, and 10 days. Histological changes, such as corneal detachment, conjunctival goblet cell and mucin density staining, were assessed by staining the cornea or conjunctiva with hematoxylin-eosin, periodic acid-Schiff, and alcian blue. The expression of inflammatory markers and mucin factors was detected by immunohistochemistry and immunofluorescence in the lacrimal gland, cornea, and conjunctiva. Tear production was significantly increased in the 2% CVM group and was similar to that in the DQS and REB groups (P < 0.05). The corneal smoothness and fluorescein staining score were significantly improved in the 2% CVM group and were similar to those in the REB group (P < 0.05). Corneal epithelial cells were significantly decreased in the 2% CVM group, with similar observations made in the DQS and REB groups (P < 0.05). The conjunctival goblet cells and mucin density recovered in the 2% CVM group were similar to those in the CsA and REB groups (P < 0.05). The 2% CVM group showed suppressed expression of inflammatory factors in the lacrimal gland and was comparable to that seen in the CsA and REB groups. The expression of mucin factors was upregulated in the cornea and conjunctiva of the 2% CVM group and was similar to that of the CsA and REB groups. In conclusion, administration of CVM resulted in recovery or clinical and histological improvement of the murine dry eye model, and all the observed parameters were comparable to those with commercial drugs.

Effects of Medetomidine, Dexmedetomidine and their combination with Acepromazine on the intraocular pressure (IOP), tear secretion and pupil diameter in dogs.

BACKGROUND: A great number of sedatives and anaesthetics have been used to perform surgeries or routine ophthalmologic examinations in animals and sometimes the combination of these medicines has more suitable effects than each one alone. OBJECTIVES: This paper aims to explore the main effects of Medetomidine + Acepromazine, Dexmedetomidine + Acepromazine on intraocular pressure, tear secretion and pupil diameter. METHODS: To accomplish the aforementioned aim, 32 adult dogs (aged one-to-three-years-old) were clinically examined. Dogs were divided into four groups consisting of group DA, Dexmedetomidine (5 µg/kg) + Acepromazine (0.05 mg/kg); Group D, Dexmedetomidine (5 µg/kg); Group M, Medetomidine (10 µg/kg); Group MA, Medetomidine (10 µg/kg) + Acepromazine (0.05 mg/kg). The ocular factors including tear production, pupil diameter and intraocular pressure of both right and left eyes were first measured and then recorded in each dog at time T0 (-15 min). Afterwards, the drugs were administered intramuscularly, based on which the ocular factors were re-measured at T1 (+5 min), T2 (+15 min) and T3 (+20 min). All four groups showed a reduction in intraocular pressure, which was significant in DA, D and M groups. RESULTS: Furthermore, there was a fluctuation in the amount of tear secretion in DA and D groups (increase and then decrease), as well as a significant reduction in M and MA groups. Decreasing in pupil diameter also occurred in all four groups, but the reduction was significant only in DA and MA groups. CONCLUSION: According to the results obtained, as the changes caused by the systemic administration of the above drug compounds did not exceed the physiological range, it can be concluded that these combinations could be utilized as suitable sedatives or pre-anaesthetic compounds in the eye surgeries.

Lactobacillus plantarum and Bifidobacterium bifidum alleviate dry eye in mice with exorbital lacrimal gland excision by modulating gut inflammation and microbiota.

In order to understand the efficacy of probiotics against dry eye syndrome, we selected anti-inflammatory probiotics Lactobacillus plantarum NK151 and Bifidobacterium bifidum NK175, which increased the ratio of IL-10 to TNF-α expression, from the human gut bacteria collection and examined their effects on tear secretion and cornea/conjunctiva inflammation in mice with excision of the unilateral exorbital lacrimal gland and 1% atropine and 0.1% benzalkonium chloride solution (ELA)-induced dry eye. Exposure to ELA significantly reduced tear secretion in mice, assessed by the phenol red thread tear test. However, oral gavage of NK151 and/or NK175 significantly increased ELA-suppressed tear secretion, IL-10 expression, and goblet cell population and decreased the ELA-induced corneal fluorescein-staining score, IL-1ß and TNF-α expression in the conjunctiva. They also suppressed ELA-induced myeloperoxidase, IL-1ß, and TNF-α expression. In particular, they increased the ratio of IL-10 to TNF-α expression in the colon. Their treatments increased ELA-induced α-diversity reduction to that of the control group and partially restored ELA-shifted ß-diversity to that of the control group. Oral gavage of NK151 and/or NK175 reduced ELA-induced Verrucomicrobia and Actinobacteria populations at the phylum level. Furthermore, they reduced ELA-induced Bacteroidaceae, Akkemansiaceae, and AC160630_f populations and increased ELA-suppressed Lactobacillaceae and Muribaculaceae populations at the family level. These gut bacteria populations exhibited significant correlation with the tear secretion volume. In conclusion, NK151 and/or NK175 alleviated dry eye by modulating the expression ratio of pro-inflammatory cytokines such as TNF-α and anti-inflammatory cytokines such as IL-10 and gut microbiota composition.

Efficacy of 0.05% cyclosporine A on the lipid layer and meibomian glands after cataract surgery: A randomized, double-masked study.

PURPOSE: To quantitatively evaluate the effects of 0.05% cyclosporine A (CsA) on lipid layer thickness (LLT) and meibomian glands after cataract surgery using the LipiView® ocular surface interferometer. METHODS: This study was a prospective randomized double-masked clinical trial conducted by Pusan National University Yangsan Hospital between April 04, 2019, and November 31, 2019. Sixty-two participants were recruited, and 12 of them were not enrolled because they had undergone previous treatments for ocular surface diseases. The participants were adult patients with cataract, exhibiting normal lid position; they did not present any other ocular disease and did not meet the exclusion criteria of the clinical trial. Fifty subjects were enrolled in the study. The randomized subjects received treatment with 0.05% CsA (group A) or 0.5% carboxymethyl cellulose (CMC) (group B) over the 3 months following the cataract surgery. Subjective and objective assessments were performed at preoperative and postoperative visits. Ocular Surface Disease Index (OSDI), tear breakup time (TBUT), and Schirmer's I test were performed by the same surgeon, and LLT and meiboscore were determined using the LipiView® interferometer. RESULTS: Fifty subjects subjects enrolled consisted of men (50%) and women (50%), with a mean (SD) age of 65.94 (10.35) years. Four subjects in group A and five in group B were excluded from the analysis as they were lost to follow-up within 1 month after cataract surgery. Thus, the study comprised 41 eyes of 41 subjects; 21 subjects were treated with CsA and 20 subjects with CMC. Comparing the clinical measurements between groups A and B taken at the last visit, while controlling the effects of the preoperative values, TBUT and LLT showed significant differences (p = 0.035 and p = 0.047, respectively, by ANCOVA). The TBUT between the subjects using CsA and those using CMC after cataract surgery showed a significant difference during follow up (p = 0.003 by repeated measures ANOVA). In the multivariate analysis, preoperative LLT and the use of CsA were found to be independent parameters for postoperative LLT (R2 = 0.303; p = 0.008 and p = 0.045, respectively), whereas the follow-up duration exhibited a positive correlation with the difference between the preoperative and postoperative values of LLT in the group treated with CsA (R2 = 0.738 and p < 0.001). CONCLUSION: Treatment with 0.05% CsA following cataract surgery is effective in improving TBUT and LLT in comparison with 0.5% CMC. A higher preoperative value of LLT and the postoperative use of CsA could be significant determinants of a higher postoperative LLT value. TRIAL REGISTRATION: ISRCTN registry with ISRCTN 10173448.

A combination of CMC and α-MSH inhibited ROS activated NLRP3 inflammasome in hyperosmolarity stressed HCECs and scopolamine-induced dry eye rats.

An important mechanism involved in dry eye (DE) is the association between tear hyperosmolarity and inflammation severity. Inflammation in DE might be mediated by the NLRP3 inflammasome, which activated by exposure to reactive oxygen species (ROS). A combination of carboxymethylcellulose (CMC) and α-melanocyte stimulating hormone (α-MSH) may influence DE through this mechanism, thus avoiding defects of signal drug. In this study, we assessed whether treatment comprising CMC combined with α-MSH could ameliorate ocular surface function; we found that it promoted tear secretion, reduced the density of fluorescein sodium staining, enhanced the number of conjunctival goblet cells, and reduced the number of corneal apoptotic cells. Investigation of the underlying mechanism suggested that the synergistic effect of combined treatment alleviated DE inflammation through reduction of ROS level and inhibition of the NLRP3 inflammasome in human corneal epithelial cells. These findings indicate that combined CMC + α-MSH treatment could ameliorate lesions and restore ocular surface function in patients with DE through reduction of ROS level and inhibition of NLRP3 signalling.

Influence of Different Antidepressants on Ocular Surface in Patients With Major Depressive Disorder.

PURPOSE: Several studies have previously reported the association between dry eye and depression along with the treatment of depression. The aim of this study was to investigate the effects of different antidepressant drugs on tear parameters in patients with major depressive disorder. METHODS: We recruited 132 patients who were using different antidepressants and 58 healthy controls. Venlafaxine, duloxetine, escitalopram, and sertraline were used by 34, 28, 36, and 34 patients, respectively. The participants filled out and completed the Beck Depression Scale. We recorded Schirmer test, tear breakup time (TBUT) and corneal staining values of the participants. The Ocular Surface Disease Index was completed by the participants. In addition, we evaluated the tear meniscus parameters by using anterior segment optical coherence tomography. RESULTS: All conventional dry eye tests and tear meniscus parameters were significantly lesser in the depression group than in the control group (Schirmer test, 11.41 ± 6.73 mm and 22.53 ± 4.98 mm; TBUT, 5.29 ± 2.92 seconds and 13.38 ± 1.72; Corneal staining, tear meniscus area, 0.026 ± 0.012 mm2 and 0.11 ± 0.025 mm2; tear meniscus depth, 182.75 ± 78.79 µm and 257.48 ± 90.1 µm; tear meniscus height, 290.3 ± 133.63 µm and 459.78 ± 180.26 µm, in patients and controls, respectively). The tear parameters of the duloxetine group were lowest among the drug groups and Schirmer test, and TBUT of the venlafaxine group was statistically significantly different from the duloxetine group (P = 0.028 and P = 0.017, respectively). Ocular Surface Disease Index score of the depression group was significantly higher than the control group (31.12 ± 21.15 and 17.43 ± 11.75 in depression and control group, respectively.). CONCLUSIONS: We found that the usage of selective serotonin reuptake inhibitors and serotonin noradrenaline reuptake inhibitors affects the ocular surface by a mechanism other than the anticholinergic system. Besides serotonin blockage, the noradrenaline blockade of serotonin noradrenaline reuptake inhibitors may increase the dry eye findings on the ocular surface.

The artemisinin analog SM934 alleviates dry eye disease in rodent models by regulating TLR4/NF-κB/NLRP3 signaling.

Dry eye disease (DED) is a multifactorial disorder of the tears and ocular surface characterized by manifestations of dryness and irritation. Although the pathogenesis is not fully illuminated, it is recognized that inflammation has a prominent role in the development and deterioration of DED. ß-aminoarteether maleate (SM934) is a water-soluble artemisinin derivative with anti-inflammatory and immunosuppressive activities. In this study, we established scopolamine hydrobromide (SCOP)-induced rodent model as well as benzalkonium chloride (BAC)-induced rat model to investigate the therapeutic potential of SM934 for DED. We showed that topical application of SM934 (0.1%, 0.5%) significantly increased tear secretion, maintained the number of conjunctival goblet cells, reduced corneal damage, and decreased the levels of inflammatory mediators (TNF-α, IL-6, IL-10, or IL-1ß) in conjunctiva in SCOP-induced and BAC-induced DED models. Moreover, SM934 treatment reduced the accumulation of TLR4-expressing macrophages in conjunctiva, and suppressed the expression of inflammasome components, i.e., myeloid differentiation factor88 (MyD88), Nod-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein containing CARD (ASC), and cleaved caspase 1. In LPS-treated RAW 264.7 cells, we demonstrated that pretreatment with SM934 (10 µM) impeded the upregulation of TLR4 and downstream NF-κB/NLRP3 signaling proteins. Collectively, artemisinin analog SM934 exerts therapeutic benefits on DED by simultaneously reserving the structural integrity of ocular surface and preventing the corneal and conjunctival inflammation, suggested a further application of SM934 in ophthalmic therapy, especially for DED.

Alpha-Adrenergic Agonists Stimulate Fluid Secretion in Lacrimal Gland Ducts.

Purpose: The role of adrenergic innervation in the regulation of lacrimal gland (LG) ductal fluid secretion is unknown. The Aim of the present study was to investigate the effect of adrenergic stimulation on fluid secretion in isolated LG duct segments and to study the underlying intracellular mechanisms. Methods: Fluid secretion of isolated mouse LG ducts was measured using video-microscopy. Effect of various adrenergic agonists (norepinephrine, phenylephrine, and isoproterenol) on fluid secretion as well as inhibitory effects of specific antagonists on adrenergic agonist-stimulated secretory response were analyzed. Changes in intracellular Ca2+ level [Ca2+i] were investigated with microfluorometry. Results: Both norepinephrine and phenylephrine initiated a rapid and robust fluid secretory response, whereas isoproterenol did not cause any secretion. Phenylephrine-induced secretion was completely blocked by α1D-adrenergic receptor blocker BMY-7378. The endothelial nitric oxide synthase (eNOS) inhibitor L-NAME or guanylyl cyclase inhibitor ODQ reduced but not completely abolished the phenylephrine-induced fluid secretion, whereas co-administration of Ca2+-chelator BAPTA-AM resulted in a complete blockade. Phenylephrine stimulation induced a small, but statistically significant elevation in [\(Ca_i^{2 + }\)]. Conclusions: Our results prove the direct role of α1-adrenergic stimulation on LG ductal fluid secretion. Lack of isoproterenol-induced fluid secretory response suggests the absence of ß-receptor mediated pathway in mouse LG ducts. Complete blockade of phenylephrine-induced fluid secretion by BMY-7378 and predominant inhibition of the secretory response either by L-NAME or ODQ suggest that α-adrenergic agonists use the NO/cGMP pathway through α1D receptor. Ca2+ signaling independent from NO/cGMP pathway may also play an at least partial role in α-adrenergic induced ductal fluid secretion.