Glaucoma is one of the most common blinding eye diseases worldwide. The limited ocular surface retention leading to a short duration of efficacy is the challenge in topical ocular drug delivery for glaucoma treatment. In this study, we developed a microsphere-in-situ gel composite drug delivery system (MPs-DSISG) containing Eudragit RS PO microspheres and a cation- and temperature-sensitive in situ gel, exhibiting dual-response properties. Precorneal fluorescence retention and tear elimination kinetics experiments confirmed that the ocular residence time of MPs-DSISG was longer than that of commercially available formulations and drug solutions. Besides prolonged retention time, the incorporated microspheres exhibited affinity for corneal epithelial cells and embedded themselves in the superficial layers of the conjunctiva, Tenon's capsule, episclera, and sclera. This enabled MPs-DSISG to achieve a 24 h intraocular pressure reduction, thus substantially reducing the dosing frequency. MPs-DSISG also demonstrated good biocompatibility‌ without ocular irritation and disturbing the tear film. In conclusion, this study demonstrates that incorporating microspheres into an in situ gel prolonged ocular retention and enhanced sustained drug efficacy, offering a promising improved treatment for anterior segment diseases.

Normal-tension glaucoma (NTG) is a progressive optic neuropathy in which intraocular pressure (IOP) reduction is important for limiting disease progression. Latanoprost is commonly used as first-line therapy, but treatment response varies. We investigated whether concomitant oral limaprost use was associated with the IOP response to latanoprost in patients with NTG. We retrospectively reviewed patients with NTG treated between January 2015 and August 2021 at the Veterans Health Service Medical Center. The final matched cohort included 446 patients: 223 patients receiving latanoprost with concomitant limaprost and 223 age- and sex-matched controls receiving latanoprost alone. Three-month IOP was analyzed at the patient level.Multivariable linear regression was performed with 3-month IOP as the outcome, adjusting for baseline IOP, age, sex, nonsteroidal anti-inflammatory drug use, systemic beta-blocker use, diabetes, and hypertension. Baseline IOP was similar between groups. The median IOP reduction at 3 months was 1.0 mm Hg [interquartile range (IQR), -0.5 to 2.5] in the limaprost group and 2.0 mm Hg [IQR, 0.5-3.0] in controls. In the adjusted analysis, concomitant limaprost use was associated with a 0.91-mm Hg higher IOP at 3 months (95% confidence interval, 0.54 to 1.27; P < .001). In a secondary exploratory subgroup of 63 patients who subsequently received add-on dorzolamide/timolol, 35 were in the limaprost group and 28 were controls; no statistically significant between-group difference in IOP reduction was detected. Concomitant limaprost use was associated with a modestly smaller observed IOP reduction after latanoprost treatment in patients with NTG. Because of the retrospective design and the modest magnitude of the association, prospective studies are needed to determine whether a clinically meaningful pharmacologic interaction exists.

Background and Objectives: Conjunctival hyperemia is common with netarsudil, but redness may not reflect the overall patient experience when treatment burden is reduced. We evaluated ocular surface symptoms, objective redness, tear-film parameters, intraocular pressure (IOP), and treatment preference after a routine-care switch from twice-daily fixed dorzolamide/timolol to once-daily netarsudil 0.02%, while continuing latanoprost. Materials and Methods: This prospective, single-center observational cohort included 30 consecutive adults with primary open-angle glaucoma or ocular hypertension and controlled IOP. Outcomes were assessed at baseline and months 1 and 2. The primary outcome was the Ocular Surface Disease Index (OSDI). Continuous eye-level outcomes were analyzed using mixed-effects models accounting for fellow-eye and repeated-measures correlation; grade ≥ 2 hyperemia was analyzed using participant-clustered logistic regression. Results: Twenty-seven participants (54 eyes) completed evaluable 2-month follow-up. Median OSDI decreased from 7.50 at baseline to 6.25 at month 1 and 5.00 at month 2 (Friedman p = 0.0015). The mean baseline-to-month 2 change was -2.95 points (95% CI, -4.80 to -1.10), and 6/27 participants (22.2%) improved by at least 7 points. Serle grade ≥ 2 hyperemia increased from 7.4% of eyes at baseline to 51.9% at month 1 and 44.4% at month 2. Estimated mean bulbar redness index increased from 1.57 to 2.14 (p < 0.0001), tear meniscus height increased modestly, and non-invasive keratograph break-up time showed no significant longitudinal change. Estimated mean IOP changed from 14.50 to 13.65 mmHg (p = 0.0083), with no eye showing an increase of at least 4 mmHg. Burning improved after multiplicity adjustment, and 17/27 participants with available month-2 preference data (63.0%) preferred netarsudil. Conclusions: The switch was associated with modest OSDI improvement and maintained short-term IOP control despite increased objective redness. Patient preference appeared to reflect factors beyond redness alone.

Background and Objectives: Pseudoexfoliative glaucoma (PEXG) is a secondary glaucoma caused by the deposition of abnormal flaky protein-like material inside the eye, leading to blockage of the drainage system, increased intraocular pressure (IOP), and optic nerve damage. This study aimed to evaluate the effects of latanoprost and timolol-dorzolamide therapy on the concentrations of interleukin (IL)-1β, IL-6, IL-8, IL-10, IL-12p70, and tumor necrosis factor-alpha (TNF-α) in the aqueous humor and serum samples of patients with PEXG. Materials and Methods: This prospective observational study included 60 patients allocated to three age-matched groups (n = 20 per group). Group 1 received latanoprost therapy, Group 2 received timolol-dorzolamide therapy, and Group 3 comprised patients with cataracts without PEXG who were not receiving antiglaucoma medication (control group). All participants underwent a comprehensive ophthalmological examination, including visual acuity assessment, specular microscopy, IOP measurement, and intraocular lens (IOL) measurement. Peripheral venous blood was taken from each patient before the surgical procedure and aqueous humor samples were collected during cataract surgery. Concentrations of IL-1β, IL-6, IL-8, IL-10, IL-12p70, and TNF-α were determined using a Cytometric Bead Array and flow cytometry. Results: No significant differences were observed in the aqueous humor and serum concentrations of IL-6 and IL-8 between the treatment groups, while IL-1β, IL-10, IL-12p70, and TNF-α did not reach detection. A significant positive correlation was found between IOL and aqueous humor IL-6 concentration in group 1 and between IL-6 and IL-8 serum concentration and IOP in controls. Conclusions: Latanoprost and timolol-dorzolamide therapy were not associated with significant differences in aqueous humor or serum IL-6 and IL-8 concentrations in patients with PEXG. IL-1β, IL-10, IL-12p70, and TNF-α were not detectable in the analyzed samples. These findings support the presence of low-grade inflammation in patients with PEXG that does not differ according to the therapy administered. Corneal endothelial alterations are disease-related rather than treatment-induced.

Infantile hemangiomas (IH) are the most common childhood vascular tumors, potentially complicated by ulceration and permanent functional or aesthetic sequelae. Current treatments include corticosteroids, β-blockers, and lasers, among others, existing evidence relies predominantly on direct pairwise comparisons. Consequently, the relative benefits and risks across these modalities remain inadequately defined. We conducted a systematic review and network meta-analysis (NMA) evaluating pharmacologic, laser, and combination therapies for IH to establish treatment hierarchies and inform clinical practice and future guidelines.

Although timolol ophthalmic solutions or hospital-compounded formulations have been used off-label for the treatment of superficial infantile hemangioma (IH), no topical timolol formulation has been developed specifically for this indication. This study was the first to develop a population pharmacokinetic (popPK) model for topical timolol maleate gel and to perform exploratory exposure-safety analyses. Data from Phase I-III clinical trials in healthy adults and infants with proliferative superficial IH were used to develop the popPK model. Potential covariate effects on the pharmacokinetics were investigated, and exploratory relationships between timolol exposure and safety outcomes were assessed. A total of 810 plasma concentration measurements from 138 subjects (24 healthy adults and 114 infants) were included in the popPK analysis. Timolol pharmacokinetics were well described by a one-compartment model with first-order absorption and elimination. No significant covariates influencing clearance were identified. No apparent associations were identified between timolol exposure and the evaluated safety outcomes. Overall, systemic exposure following administration of this topical timolol maleate gel formulation was limited, supporting its favorable safety profile in infants with superficial IH. These quantitative findings may help guide its rational clinical use.

Glaucoma, a leading cause of irreversible blindness, is commonly treated with topical eye drops that reduce intraocular pressure (IOP), but their efficacy is limited by rapid precorneal clearance. To address this, we developed a dynamic hydrogel (CSFP) via Schiff base bonding between carboxymethyl chitosan (CMCS) and 4-formylphenylboronic acid (FPBA) as an advanced delivery vehicle for brimonidine (BRI) and timolol (TIM), two common IOP-lowering agents. The mechanical properties were tunable by adjusting CMCS and FPBA concentrations. The optimized hydrogel exhibited a storage modulus of ∼38.8 Pa (at 1 Hz, 1% strain), excellent self-healing ability, and shear-thinning behavior, facilitating easy administration and resistance to blink-induced clearance. It also achieved near 100% transmittance and a refractive index of 1.339, ensuring optical clarity. Notably, the incorporated phenylboronic acid (PBA) groups enabled selective binding to sialic acid residues on ocular mucins via dynamic phenylboronic ester bonding, prolonging precorneal retention beyond 30 min compared to less than 5 min for the solution control. In a magnetic bead-induced ocular hypertensive rat model, CSFP hydrogel loaded with either BRI or TIM induced greater and long-lasting IOP reduction than the free drug solutions. This work highlights the potential of mucoadhesive dynamic covalent hydrogels for advanced ocular drug delivery.

Timolol maleate (TM) is a nonselective β-blocker commonly used to treat ocular hypertension and glaucoma. Traditional formulations, such as eye drops and gel-forming solutions, often require frequent administration and may lead to systemic side effects and poor patient compliance. To address these challenges, this study investigated the fabrication and characterization of TM-loaded ocular implants via vat-polymerization 3D printing. The implants were fabricated using polyethylene glycol diacrylate (PEGDA) alone or in combination with polylactic acid/polyurethane acrylate (PLA/PUA) or poly(lactic-co-glycolic acid) (PLGA). The implants were characterized for their thermal properties, drug-release profiles, and biocompatibility. Fourier transform infrared (FTIR) spectroscopy confirmed the absence of significant chemical interactions between the TM and the polymers. Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) revealed the thermal stability of the TM-loaded implants, with drug loading influencing the thermal properties. In vitro release studies over 180 days showed that drug release was proportional to the surface area-to-volume (SA/V) ratio of the implant. The release kinetics followed a diffusion-controlled mechanism, as described by the Korsmeyer-Peppas model. The biocompatibility study showed no significant cytotoxicity, with fibroblast viability exceeding 80%. These findings suggest that TM-loaded implants could provide a more effective, sustained-release alternative for glaucoma treatment.

Objective: To evaluate the efficacy and safety of a preservative-free tafluprost/timolol maleate fixed-dose combination compared with preservative-free tafluprost monotherapy in Chinese patients with open-angle glaucoma (OAG) or ocular hypertension (OHT). Methods: This was a multicenter, randomized, double-blind, parallel-controlled clinical trial conducted across 25 centers, including the Eye & ENT Hospital of Fudan University, from January 2019 to November 2022. Patients diagnosed with OAG or OHT who required enhanced intraocular pressure (IOP) reduction after a 4-week washout period were enrolled. Participants were randomized 1∶1 to receive either tafluprost/timolol or tafluprost once daily for 3 months. The primary endpoint was the change from baseline in mean diurnal IOP (the average of measurements at 8:00, 10:00, and 16:00) at Month 3. Secondary endpoints included IOP changes at individual time points and the proportion of responders achieving predefined IOP reduction thresholds. Safety was assessed via the incidence of adverse events (AEs). Analysis of covariance (ANCOVA) using the Markov Chain Monte Carlo (MCMC) method was employed for the primary endpoint; superiority was established if the upper limit of the 95% confidence interval (CI) was<0 mmHg (1 mmHg=0.133 kPa). Continuous variables in secondary endpoints were compared using ANCOVA, and responder rates were analyzed using Fisher's exact test. Results: A total of 219 patients were enrolled (tafluprost/timolol group: n=110; tafluprost group: n=109). The primary efficacy analysis set included 215 patients (tafluprost/timolol: n=107; tafluprost: n=108). Baseline characteristics were well-balanced between the two groups. The majority of patients were male [127 (59.1%)] with a mean age of (44.80±15.71) years at screening. At Month 3, the mean diurnal IOP reduction from baseline was (6.56±3.44) mmHg in the tafluprost/timolol group and (5.36±2.94) mmHg in the tafluprost group. After adjusting for baseline IOP, the between-group difference was -1.312 mmHg (95%CI: -2.010 to -0.696); as the upper limit was<0 mmHg, tafluprost/timolol demonstrated superior IOP-lowering efficacy to tafluprost. Responder rates for IOP reductions of≥15%,≥25%, and≥30% were significantly higher in the tafluprost/timolol group (P=0.016, 0.028, and 0.032, respectively). The incidence of ocular AEs was 20.0% (22/110) in the tafluprost/timolol group and 26.6% (29/109) in the tafluprost group. The most common AE was conjunctival hyperemia, occurring in 2.7% (3/110) and 8.3% (9/109) of the groups, respectively. Conclusion: Compared with preservative-free tafluprost monotherapy, the tafluprost/timolol combination provides significantly greater IOP reduction in patients with OAG and OHT, while maintaining a favorable safety profile.

Infantile hemangioma (IH) is a benign tumor that appears in the first year of life and typically involutes within 3 to 4 years. Ulcerative IH, the most common complication, poses a significant burden to patients. Early referral of high-risk cases reduces morbidity. Current literature on risk factors and prognosis is limited. Segmental and mixed IH in urogenital, head, neck, and lip areas show higher ulceration risk. Diagnosis is typically clinical; histopathology is rarely performed. Atypical cases require positive glucose transporter-1 immunohistochemistry. Larger lesions, delayed intervention, and bacterial infection worsen prognosis, prolong healing, and increase recurrence. Condition-dependent treatments, including oral propranolol (starting at 1 mg/kg or less daily, maintenance at 2 to 3 mg/kg daily), timolol prophylaxis, and wound management care combined with laser therapy, shorten therapy duration and minimize recurrence. Empiric antibiotics are indicated for infected ulcerative IH. Surgery is indicated for life-threatening cases (eg, chest wall hemangiomas requiring transfusion or airway obstruction) and high-morbidity cases (eg, lip lesions affecting speech or periorbital lesions impairing vision). The Infantile Hemangioma Referral Score helps clinicians identify high-risk patients who require prompt referral, thereby preventing delayed treatment.