PURPOSE:This study aimed to assess the long-term management and 5-year evolution of patients with neuropathic ocular pain (NOP) associated with chronic dry eye disease (DED). METHODS:Fourteen patients with NOP underwent a 5-year follow-up. Baseline and 5-year assessments included questionnaires on dry eye (Dry Eye Questionnaire 5 [DEQ-5] and Ocular Surface Disease Index), pain (Brief Pain Inventory [BPI]), anxiety/depression disorders (Hospital Anxiety and Depression Scale), and a dedicated questionnaire on NOP characteristics (Neuropathic Ocular Pain Questionnaire), which was developed for this study. Treatment tolerance and effectiveness were rated on a 0-5 scale. Clinical examination, meibography, tear film analysis, corneal nerve density, and inflammation assessment using in vivo confocal microscopy (IVCM) were performed at both time points. RESULTS:Patients were predominantly women (93%) with a mean age of 41 ± 17 years. High rates of comorbid anxiety/depressive disorders (85.7%) and diffuse chronic pain (35.7%) were observed, supporting the need for multimodal care. Over 5 years, significant improvements occurred in mean neuropathic pain scores (P = 0.005), BPI scores (P = 0.003), and DEQ-5 scores (P = 0.041). Clinical parameters remained unchanged, except for a significant decrease in IVCM inflammation score (P = 0.004). All patients received topical ophthalmic treatments; 78.6% were treated with systemic neuropathic pain relievers, and 64.3% received psychological care. The most effective treatments included artificial tears, cyclosporine eye drops, scleral lenses, oral therapies, and autologous serum eye drops. CONCLUSION:This study provides the first long-term overview of therapeutic strategies for NOP associated with DED. Findings support a multidisciplinary approach using specific questionnaires and personalized, long-term treatments. However, controlled prospective studies are needed to establish the efficacy of specific therapeutic strategies.
PURPOSE:Myopia, driven by pathological axial elongation, is a leading cause of visual impairment. This review synthesizes and critically evaluates the evidence for the "scleral hypoxia theory," focusing on the role of hypoxia-inducible factor-1α (HIF-1α) signaling in scleral remodeling during myopia progression. METHODS:A comprehensive literature search was conducted on PubMed to 2026, focusing on scleral hypoxia, HIF-1α signaling, extracellular matrix (ECM) remodeling, and their interplay with inflammatory and metabolic pathways. Evidence was categorized into 3 tiers: direct scleral/myopia evidence, indirect ocular evidence, and extrapolative evidence from other tissue systems. RESULTS:Converging evidence from human genetic studies, animal models, and cell-based experiments supports the scleral hypoxia theory. Reduced choroidal blood perfusion creates a hypoxic microenvironment in the sclera, stabilizing HIF-1α and activating downstream matrix metalloproteinases (MMPs), which promotes ECM degradation, scleral thinning, and biomechanical weakening, facilitating axial elongation. The HIF-1α pathway exhibits extensive crosstalk with transforming growth factor-β, AMP-activated protein kinase (AMPK)/Sirtuin 1 (SIRT1)/Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) metabolic signaling, oxidative stress, and inflammatory pathways. Emerging evidence suggests potential roles for macrophage polarization (M1/M2) in scleral remodeling. Notably, the majority of direct mechanistic evidence is derived from a limited number of landmark studies, and independent replication across diverse models is needed. CONCLUSIONS:The hypoxia-HIF-1α-MMP signaling axis is a promising candidate mechanism in myopic scleral remodeling, with translational implications for both pharmacological and nonpharmacological strategies. However, key gaps remain, including the need for independent replication, longitudinal human evidence, and direct experimental validation in scleral fibroblasts. Future multiomics and targeted interventional studies are required to establish causality and translate these findings into clinical applications.
PURPOSE:To investigate epidemiological factors and clinical manifestations associated with longitudinal treatment response to intense pulsed light in patients with meibomian gland dysfunction (MGD). METHODS:This study was conducted on 392 eyes (392 patients) undergoing 4 sessions of IPL. Treatment response was evaluated using measurements of meibomian gland expressibility (MGE) and meibum quality (MQ). A generalized estimating equation (GEE) was applied to evaluate associations between epidemiological factors, clinical parameters, and longitudinal changes in MGE and MQ. RESULTS:In adjusted GEE models, lower MGE and MQ grades indicated better meibomian gland function. Therefore, negative coefficients reflected improvement, whereas positive coefficients reflected a less favorable response. For MGE, worse baseline grade was associated with greater improvement after 4 sessions (B = -0.74, P < 0.001), although final MGE grades remained higher among eyes with higher baseline MGE grades. Telangiectasia across the meibomian gland orifice and keratinization were associated with less favorable MGE response (B = 0.52 and 0.30; P < 0.001 and 0.040, respectively). For MQ, worse baseline grade was associated with greater improvement (B = -0.85, P < 0.001), whereas telangiectasia across the orifice was associated with less favorable response (B = 1.45, P < 0.001). CONCLUSIONS:After 4 sessions of IPL, worse baseline MGE and MQ grades were associated with greater longitudinal improvement. However, residual dysfunction remained, particularly for MGE among eyes with more severe baseline disease. Meibomian gland orifice changes, particularly telangiectasia across the orifice and keratinization, were associated with less favorable longitudinal response and may help inform prognostication and individualized treatment planning.
PURPOSE:Antibody-drug conjugate (ADC)-associated ocular toxicity is an emerging, sometimes dose-limiting complication. Macropinocytosis has been implicated in off-target ADC uptake by corneal epithelial cells. This study evaluated whether ocular surface immunoglobulin (OSIG) inhibit macropinocytosis in human corneal epithelial cells (HCE-T) and characterized ocular biodistribution and tolerability following topical and subconjunctival administration. METHODS:Macropinocytosis was quantified in corneal epithelial cells after exposure to vehicle or increasing concentrations of OSIG. Ocular pharmacokinetics were evaluated in New Zealand White rabbits following single topical instillation or subconjunctival injection of 5% OSIG. OSIG concentrations were quantified in ocular tissues, ocular fluids, tears, serum, and submandibular lymph nodes using enzyme-linked immunosorbent assay (ELISA). Local tolerability was assessed after single and repeated subconjunctival injections using clinical observations, Draize scoring, and ophthalmic examinations. RESULTS:OSIG inhibited Dextran Texas Red uptake in a concentration-dependent manner, with near-complete inhibition at 5%. Topical OSIG produced only transient conjunctival exposure and did not achieve sustained corneal concentrations. In contrast, subconjunctival administration resulted in sustained ocular surface exposure, with peak corneal concentration of 11,200.8 ng/g on Day 14 and measurable conjunctival exposure through 28 days. Serum exposure was detectable but lower than ocular surface tissue exposure. Subconjunctival OSIG was generally well tolerated after single and repeated dosing, with findings limited mainly to transient conjunctival redness and chemosis. Two clinical cases of ADC-associated ocular toxicity treated with topical OSIG were also reviewed. CONCLUSIONS:OSIG inhibits macropinocytosis in HCE-T and achieves sustained corneal and conjunctival exposure following subconjunctival administration. These findings support further evaluation of subconjunctival OSIG as a local strategy to mitigate ADC-associated corneal toxicity.
Purpose: To review smart responsive hydrogels for dry eye disease (DED), focusing on pharmacological performance, disease relevance, safety, and translational feasibility. Methods: A narrative literature search was conducted in PubMed, Web of Science, Scopus, and Google Scholar up to June 11, 2026, using terms for DED, hydrogels, and ocular drug delivery. Studies were selected based on relevance to DED pathophysiology, hydrogel responsiveness, and translational safety. Results: Thermosensitive and ion-sensitive hydrogels are the most practical near-term options because they enable drop-like administration and rely on simple physiological triggers. ROS- and enzyme-responsive systems offer stronger mechanistic links to DED pathology but face challenges in trigger variability, safety, and manufacturing complexity. Photoresponsive platforms allow spatiotemporal control but require device-dependent activation. Multi-stimuli systems integrate retention and disease-triggered release, though their added complexity must be justified by measurable therapeutic benefit. Most DED-specific responsive hydrogels remain at the preclinical stage; human evidence mainly concerns familiar device formats, not the responsive formulations themselves. Conclusion: Smart responsive hydrogels can tailor drug delivery to ocular surface conditions, but evidence maturity varies across platforms. Thermosensitive and ion-sensitive gels are the most clinically plausible near-term candidates. ROS-responsive, enzyme-responsive, and multi-stimuli systems better engage DED biology but need stronger validation. Translation depends on direct comparator studies, phenotype-matched endpoints, long-term ocular safety, scalable sterile manufacturing, and appropriate regulatory strategies.
PURPOSE:To evaluate the efficacy and safety of sustained-release intracameral prostaglandin analog implants, including bimatoprost (Durysta) and travoprost (iDose TR), in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT). METHODS:A systematic review and pooled quantitative analysis were performed according to PRISMA guidelines. PubMed, Scopus, Embase, and Google Scholar were searched for studies published between 2020 and 2025 evaluating sustained-release intracameral prostaglandin implants. Randomized and nonrandomized studies reporting intraocular pressure (IOP) and safety outcomes were included. RESULTS:Six studies comprising 1,047 eyes met inclusion criteria. Bimatoprost implants (10 µg and 15 µg) achieved mean IOP reductions of 6.1-6.7 mmHg at 12 months, whereas pooled slow-eluting travoprost implant data demonstrated reductions ranging from 5.5 to 7.75 mmHg depending on study design and follow-up duration. Subgroup analysis demonstrated comparable efficacy between travoprost and bimatoprost implants at 3 months; however, at 12 months, travoprost efficacy was lower than the 15 µg bimatoprost implant while remaining comparable to the 10 µg implant. Most adverse events were mild and transient. Corneal endothelial cell loss occurred in a dose-dependent manner with repeated bimatoprost administrations, particularly with the 15 µg implant, whereas no significant endothelial cell loss was reported with travoprost implants. Both implants substantially reduced topical medication burden. CONCLUSIONS:Sustained-release intracameral prostaglandin implants provide durable IOP reduction while decreasing dependence on topical therapy. Although efficacy differences between travoprost and bimatoprost implants appear modest, their safety profiles differ, particularly regarding corneal endothelial effects. Further long-term comparative studies are warranted.
PURPOSE:Proliferative vitreoretinopathy (PVR) is driven by the epithelial-mesenchymal transition (EMT) of retinal pigment epithelial (RPE) cells. While palmitic acid (PA) represents a potent metabolic stressor in the subretinal microenvironment, its impact on the microRNA (miRNA) landscape remains poorly defined. This study investigated the role of miR-129-5p in PA-induced transdifferentiation and evaluated the protective potential of ectopic miR-129-5p mimicry in ARPE-19 cells. METHODS:Low-passage ARPE-19 cells were challenged with sublethal PA to induce lipotoxic stress. miR-129-5p levels were modulated using synthetic mimics under basal and stressed conditions. EMT progression was tracked using immunofluorescence for tight junction topology and transcription factor nuclear localization, Phalloidin-FITC cytoskeletal F-actin staining, and immunoblotting for hallmark epithelial (E-cadherin) and mesenchymal (α-smooth muscle actin, fibronectin) effectors. Functional shifts were evaluated via wound healing and paracellular macromolecular permeability assays. RESULTS:PA exposure triggered a myofibroblastic phenotype and significantly depleted the intracellular miR-129-5p pool, accompanied by parallel vesicle-independent extracellular efflux. Under unchallenged baseline, mimic delivery directly suppressed endogenous ZEB1/2 expression. Under lipid stress, miR-129-5p mimicry neutralized transdifferentiation, successfully restoring E-cadherin and counteracting core transcription factor upregulation (ZEB1, ZEB2, and Snail). Morphologically, mimicry prevented pericellular ZO-1 dissolution, suppressed ZEB2 nuclear translocation, and blocked contractile stress fiber assembly. Functionally, maintaining this miRNA node significantly attenuated PA-enhanced cell migration and rescued outer blood-retinal barrier homeostasis by suppressing paracellular macromolecular flux. CONCLUSIONS:miR-129-5p functions as an essential cell-autonomous posttranscriptional gatekeeper of RPE identity, cytoskeletal architecture, and barrier homeostasis. Targeted modulation of this posttranscriptional network offers a promising pharmacological framework for mitigating lipotoxicity-associated subretinal fibrosis in PVR.
PURPOSE:Antisense oligonucleotide (AON)-mediated exon skipping is a potential therapeutic approach to certain inherited retinal diseases, including Usher's Syndrome Type 2 A. Heteroduplex AONs (HAONs) have been reported to enhance RNA-modulating activity in vivo; this study evaluated whether the HAON strategy improves Ush2a exon skipping activity in the mouse retina. METHODS:AONs of different chemical makeup targeting Ush2a exon 12 were formulated as HAONs with and without lipid conjugation. Activity was evaluated in 2D and 3D cell models and in the mouse eye following intravitreal administration. RESULTS:Lipid conjugation was required to increase activity in the mouse retina. However, exon-skipping effects observed for cholesterol (Chol)-conjugated HAONs in vivo were not reflected in cell models. A single dose of HAONs bearing a Chol on either strand or the Chol-AON conjugate produced up to a 4.6-fold increase in Ush2a exon 12 skipping in mouse retina over AON alone, with effects lasting at least 28 days without major tolerability findings. CONCLUSION:Chol conjugation-either to a HAON construct or directly to the AON-can substantially enhance the potency of retina-targeted exon-skipping AON therapies in vivo.
PURPOSE:Recurrent corneal erosion (RCE) is an ocular surface disease with poor epithelial-stromal adhesion and limited therapies. This study aimed to elucidate the role of necroptosis, a pro-inflammatory form of programmed cell death, in the pathogenesis of corneal erosion. METHODS:An in vitro UVB injury model was established in human corneal epithelial cells (HCEpiCs), followed by unbiased LC-MS/MS proteomics and pathway enrichment analysis. In parallel, a UVB-induced corneal erosion model was generated in C57BL/6 mice. To test therapeutic relevance, mice received a topical neutralizing anti-IFN-γ antibody or vehicle after injury. Corneal epithelial integrity and stromal architecture were assessed histologically, while activation of IFN-γ-JAK/STAT signaling, RIPK1/RIPK3/MLKL necroptosis, DAMP release, NLRP3 inflammasome assembly, and IL-1β maturation were examined using immunofluorescence, qRT-PCR, and Western blotting. RESULTS:Proteomic profiling showed significant enrichment of necroptosis-related proteins following UVB exposure. UVB-treated corneal epithelium exhibited increased IFN-γ signaling and JAK/STAT activation, accompanied by elevated expression and activation of RIPK1, RIPK3, and MLKL. Necroptosis was associated with increased release of DAMPs, heightened NLRP3 inflammasome activation, and increased maturation/secretion of IL-1β. In vivo, topical anti-IFN-γ treatment reduced corneal epithelial defects, improved epithelial-stromal attachment, and decreased activation markers of the RIPK-MLKL and NLRP3-IL-1β pathways. CONCLUSIONS:Our findings unveil a novel and critical pathogenic axis in corneal erosion, where IFN-γ signaling drives a necroptotic-inflammatory loop. This work provides a new molecular framework for understanding corneal epithelial injury and identifies the IFN-γ-necroptosis axis as a promising therapeutic target for RCE.
Benzalkonium chloride (BAK), a common preservative in multi-dose ophthalmic products, is often studied under acute high-dose exposure, which highlights overt damage to corneal epithelial cells. These studies tend to exaggerate the maximum cytotoxic effects and do not accurately reflect the gradual, cumulative damage seen during long-term use. By reviewing clinical, animal, and cellular data, we argue that repeated low-dose BAK exposure leads to barrier dysfunction, energy depletion, priming of inflammation, and impaired regeneration before significant cell death occurs. We suggest a repair-exhaustion model: minor injuries from repeated exposure are initially managed by membrane resealing and epithelial renewal, but over time, repair capacity becomes exhausted. This has two main implications: (i) long-term toxicity should be evaluated using functional measures such as barrier integrity, mitochondrial health, inflammation, and repair ability, and not cell viability alone; (ii) there may be a window during which reducing preservative levels or adding barrier-supporting and mitochondrial-protective agents can minimize cumulative damage. Instead of simply using or avoiding the preservative, this approach encourages formulation and clinical strategies that maintain antimicrobial effects while strengthening tissue resilience.
PURPOSE:This study investigated the effects of silver nitrate (AgNO3), a preservative in ophthalmic solution, alone and in combination with latanoprost (LP), on corneal epithelial barrier function and zonula occludens-1 (ZO-1) distribution in the corneal epithelium of rabbits. METHODS:Twelve adult male albino New Zealand white rabbits (weighing 3.0-3.5 kg) were the subjects in this study. These mature rabbits received five instillations at 5-min intervals of AgNO3 (0.01, 0.1, or 1%), benzalkonium chloride (BAK 0.02%), LP (0.005%) alone, or LP combined with AgNO3 (0.01 or 1%). Corneal resistance (CR) was measured, and histological analyses were performed. RESULTS:AgNO3 1% increased CR (108.2%); however, CR significantly decreased when combined with LP (P < 0.05). Marked CR reduction was observed in the eyes administered BAK and LP + AgNO3 1%. Immunostaining showed preserved ZO-1 in the eyes that received AgNO3 1% and LP + AgNO3 0.01%, whereas those that received BAK, LP alone, and LP + AgNO3 1% demonstrated disrupted ZO-1. CONCLUSIONS:A high concentration of AgNO3 with LP exacerbated corneal epithelial barrier impairment, which highlights the importance of preservative concentration control in ophthalmic formulations.
Purpose: To categorize preexisting fundus findings in a large group of healthy young adult cynomolgus macaques [nonhuman primates (NHPs)] and to compare them to similar conditions in young human retinas.Methods: During the past 30 years, more than 20,000 young purpose-bred cynomolgus macaques were screened prior to enrollment in nonclinical pharmaceutical development studies at a single contract research organization. The fundus findings were documented by clinical examinations, various retinal imaging modalities, and/or visual electrophysiological testing.Results: Sheen from the internal limiting membrane (ILM) was common in these young adult NHPs as it is in young humans. Infrequent in both NHPs and humans were cilioretinal arteries. Small patches of retinal pigment epithelial (RPE) depigmentation were common, for which there is no human correlate. Likewise, there is no exact human correlate for foveal drusen-like spots in the young NHPs. Also common in NHPs but uncommon in humans were remnants of the fetal vasculature. Conditions rare in both NHPs and humans included myelinated nerve fiber layer, astrocytic hamartoma, coloboma, and congenital hypertrophy of the RPE. Notable rare abnormal findings included a white dot condition, a large macular tumor, and idiopathic optic atrophy, all of which were of unknown etiology.Discussion: Preexisting abnormalities, when taken together, are common in NHPs and can occasionally complicate the assessment of toxicity from test articles subsequently administered, impacting the clinical development of test articles. As such, it is critical that NHPs be prescreened and, ideally, the fundus appearance be documented with fundus imaging when enrolled in preclinical studies.
PURPOSE:5-Fluorouracil (5-FU) is a commonly used antimetabolite in cancer therapy. Patients (25% to 38%) undergoing chronic systemic 5-FU chemotherapy are affected by ocular toxicity and require cessation of therapy to manage ocular complications. However, the mechanism by which 5-FU crosses the blood-tear barrier is not well understood. The current study investigates the role of organic anion transporters (OAT2 and 3) in the blood-tear barrier of the lacrimal gland, in trafficking 5-FU into the ocular surface. METHOD:Computer simulations were performed to determine the substrate specificity of 5-FU for OAT isoforms. Tear pharmacokinetic studies of intravenous 5-FU were conducted in rabbits (n = 3 per group), with and without OAT blockade. The ocular adverse effect of 5-FU was assessed in vitro using human corneal epithelial cells (HCEC). Furthermore, the potential of artificial tears to reduce ocular accumulation of 5-FU was evaluated. RESULTS:Computational studies indicated that 5-FU is a substrate for OAT2. 5-FU was detected in the tear from systemic circulation (Cmax = 16.7 µg/mL) within five minutes of administration. The concentration of 5-FU reaching the ocular surface reduced HCEC viability in a concentration-dependent manner. Furthermore, topical pretreatment with OAT2 blockers reduced 5-FU exposure in tears by 1.53 to 2.96-fold, and prophylactic artificial tears containing polyethylene glycol 400 and propylene glycol achieved a 1.68-fold reduction in 5-FU exposure in tears. CONCLUSION:Blocking OAT-2 with eye drops (OAT2 blockers and artificial tears) reduced the tear concentration of 5-FU, suggesting a potential to minimize ocular toxicity of 5-FU in patients undergoing chemotherapy.
PURPOSE:To evaluate whether vatinoxan, a peripherally selective alpha2-adrenoceptor antagonist, prevents the acute, medetomidine-associated ophthalmic changes in rats. METHODS:Adult male Wistar rats (n = 9 in each group) were randomly allocated to receive subcutaneous medetomidine 0.4 mg/kg and midazolam 2 mg/kg (MM), MM with vatinoxan 8 mg/kg (MM-V), or MM with regular insulin 1 IU/kg (MM-I). Macroscopic photography (to assess globe position) and slit-lamp biomicroscopy were performed, and blood glucose (BG) concentration, intraocular pressure (IOP), and central corneal thickness (CCT) were measured at intervals until 50 min post-treatment. Surgical anesthesia was then induced, and aqueous humor glucose (AHG) concentration was measured prior to euthanasia. RESULTS:In MM and MM-I, exophthalmos worsened over time (P < 0.05) and compared to MM-V (P ≤ 0.04 for both). BG increased significantly over time (P < 0.001) only in MM, and AHG was significantly higher in MM than in MM-V and MM-I (P < 0.001). Lens clarity was decreased at 50 min in both MM (P = 0.002) and MM-I (P = 0.048), compared to MM-V. CCT was greater in MM-V than in MM at 50 min (P = 0.02). Corneal clarity remained unchanged. IOP declined in all groups but remained significantly higher in MM-V 10 min versus 50 min post-treatment (P = 0.02). CONCLUSIONS:Vatinoxan prevented pathological exophthalmos, lens opacification, the acute decline in IOP, hyperglycemia, and increased AHG in rats sedated with medetomidine-midazolam. Insulin similarly prevented hyperglycemia, but none of the ophthalmic changes. Acute alpha2-adrenoceptor agonist-mediated ophthalmic pathologies are independent from glycemic control.
Crystalline opacities appearing after intravitreal antibiotic injections can closely mimic worsening endophthalmitis, potentially prompting unnecessary surgical or pharmacologic interventions. This underrecognized phenomenon, most commonly seen after sequential intravitreal administration of vancomycin and ceftazidime, results from physicochemical incompatibility leading to intraocular precipitation. Despite their alarming appearance, these crystalline deposits are benign, self-limited, and retain antimicrobial activity. Review of the few published human cases reveals favorable outcomes with conservative management once infection is excluded. Recognizing this entity is crucial to avoid misdiagnosis, overtreatment, and medicolegal implications. Awareness of preventive measures-such as using separate syringes, staggered injections, and warmed solutions-can further minimize risk. Ultimately, differentiating true infectious progression from sterile drug precipitation preserves both vision and clinical judgment.
PURPOSE:To evaluate whether bioimpedance-derived body composition parameters are associated with adalimumab exposure and immunogenicity in noninfectious uveitis (NIU) and whether they provide information complementary to body mass index (BMI). METHODS:Forty-five patients with NIU receiving adalimumab monotherapy (40 mg every 2 weeks) for at least 12 months were enrolled in this single-center cross-sectional study. Body composition was assessed by use of multifrequency bioimpedance analysis (InBody 770). Serum adalimumab trough concentrations and anti-adalimumab antibodies (AAA) were measured. Associations were evaluated using Pearson correlations, multivariable linear regression, and receiver operating characteristic (ROC) analyses. RESULTS:Adalimumab trough concentrations were moderately inversely correlated with BMI (r = -0.51, P = 0.0004), body fat mass (r = -0.51, P = 0.0004), percent body fat (r = -0.48, P = 0.001), and visceral fat area (r = -0.53, P = 0.0002), but not with lean-mass parameters. In separate multivariable models adjusted for age and sex, each adiposity measure was independently associated with trough concentrations (adjusted R2 0.18-0.25). ROC analysis showed comparable discrimination of low drug exposure for BMI (area under the curve [AUC] 0.69) and body composition metrics (AUC 0.70-0.74; DeLong P > 0.5). BMI showed the strongest correlation with AAA levels (r = 0.58, P < 0.0001). CONCLUSIONS:Bioimpedance-derived adiposity measures and BMI showed similar associations with adalimumab exposure in NIU. Body composition may offer complementary biological context for interpreting pharmacokinetic variability and immunogenicity. Future studies are warranted to determine whether body composition data improve therapeutic drug monitoring in uveitis.
The clinical tolerability profiles of cyclosporine A (CsA) ophthalmic emulsions differ markedly between anionic (Restasis®, 0.05% CsA) and cationic (Ikervis®, 0.1% CsA) formulations, despite delivering the same active compound. Anionic emulsions are more frequently associated with transient blurred vision, whereas cationic emulsions are more frequently associated with instillation-site pain. The mechanistic basis for this divergence has not been clearly defined, and conventional evaluation has relied on animal-based irritation assays or large clinical trials. This Commentary proposes a two-phase physicochemical interpretive framework, aligned with New Approach Methodologies (NAMs) and Integrated Approaches to Testing and Assessment (IATA), in which rotational rheometry is used to characterize early instillation-phase behavior (0-5 min) and gas chromatography-mass spectrometry (GC-MS) is used to characterize sustained post-instillation-phase features (5-30 min). Preliminary observations on Restasis, Ikervis, and a 0.5% carboxymethylcellulose-sodium artificial-tear reference (a nonionic, nonsurfactant, low-nociceptive physicochemical control) are presented as supporting context. Restasis exhibited substantially higher viscosity than Ikervis across all shear rates, whereas Ikervis and the CMC reference showed comparable high-shear viscosity despite markedly different reported tolerability-a viscosity-discomfort dissociation. GC-MS putatively identified a long-chain tertiary amine signal exclusively in Ikervis (retention time ≈13.0 min), which was absent in Restasis and the CMC reference. The proposed framework is hypothesis-generating rather than mechanistically conclusive; it is intended to support future targeted validation studies rather than replace clinical evaluation. GC-MS may serve as a useful complementary fingerprinting tool within NAM/IATA-aligned ophthalmic formulation assessment.
PURPOSE:Demodex blepharitis is caused by Demodex mite infestation of the eyelash follicles and associated sebaceous glands (the glands of Zeis) and is often associated with tear film instability and dry eye disease (DED). Information on the role of Zeis glands is limited. This study used surrogate Zeis gland secretions in healthy volunteers to evaluate whether Zeis gland secretions could potentially contribute to the tear film lipid layer. METHODS:The blinking status of each eye (partial or complete blinker) was assessed with interferometry. A surrogate Zeis gland secretion was applied with a moistened ophthalmic fluorescein strip across the center of the lower eyelid near the eyelash base. The presence of fluorescent dye in the tear film was evaluated at 2 and 5 min using a fluorescein angiography image acquisition system. RESULTS:Forty eyes (20 subjects) were enrolled; 31 (77.5%) partial blinkers, 4 (10.0%) complete blinkers, and 5 (12.5%) nonblinkers that did not blink during the interferometry assessment. Fluorescent dye was detected in the tear film of 18 (45.0%) eyes at 2 min and 24 (60.0%) eyes at 5 min, with similar proportions of partial blinker, complete blinker, and nonblinker eyes demonstrating a fluorescent signal. CONCLUSION:A surrogate Zeis gland secretion accessed the tear film in most eyes, suggesting that Zeis gland secretions may contribute to the tear film. In Demodex blepharitis, abnormal or reduced lipid production from the Zeis and/or meibomian glands may contribute to DED. Further research is needed to clarify the underlying mechanisms of DED in patients with Demodex blepharitis.
