UNASSIGNED: To evaluate the safety, pharmacokinetics, and exploratory efficacy of tivozanib eye drops in healthy volunteers and patients with neovascular age-related macular degeneration (nAMD).
UNASSIGNED: This multicenter group-sequential dose escalation phase I study consisted of a placebo-controlled double-masked study of healthy volunteers (cohorts 1 and 2) and an open-label study of patients with nAMD (cohort 3).
UNASSIGNED: Healthy volunteers: Japanese or White men aged 20 to <50 years. Patients with nAMD with central subfield thickness (CST) ≥300 μm and best-corrected visual acuity score ≥23 letters in the study eye.
UNASSIGNED: In the single-dose cohort of healthy men (cohort 1: steps 1-5), 1 or 2 tivozanib eye drops (30 μL/drop, 5-minute interval; 0.5, 1.0, and 2.0 w/v%) or placebo were administered in 1 eye once. In the multiple-dose cohort of healthy men (cohort 2: steps 1-6), 1 or 2 tivozanib eye drops (0.5, 1.0, and 2.0 w/v%) or placebo were administered 3 times daily in 1 eye for 21 days. In the multiple-dose cohort of patients with nAMD (cohort 3, steps 1-3), 1 or 2 tivozanib eye drops (0.5 and 1.0 w/v%) were administered 3 times daily in 1 affected eye for 21 days.
UNASSIGNED: The safety outcome measures included adverse events (AEs). The pharmacokinetic outcome was serum tivozanib concentration. Among the exploratory efficacy outcomes, CST was evaluated.
UNASSIGNED: In total, 40, 48, and 28 participants were enrolled in cohorts 1, 2, and 3, respectively. Serious AEs did not occur in cohorts 1 to 3. The most frequent AE in multiple-dose cohorts was reversible punctate keratitis: placebo arm, 8.3% (healthy men, 1/12); tivozanib arm, 47.2% (healthy men, 17/36) and 14.3% (nAMD, 4/28). Serum tivozanib exposure increased dose-dependently and was similar in healthy men and patients with nAMD. In patients with nAMD, mean CST changes from baseline to day 22 were -27.6 ± 54.88 (0.5 w/v%; 1 drop, 3 times daily), -35.6 ± 49.64 (1.0 w/v%; 1 drop, 3 times daily), and -43.7 ± 55.19 μm (1.0 w/v%; 2 drops, 3 times daily).
UNASSIGNED: Tivozanib eye drops showed a favorable safety profile in healthy Japanese and White men and Japanese patients with nAMD.
UNASSIGNED: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

UNASSIGNED: Eye drops instillation in children is a fundamental part of accurately examining a child\'s eyes. Unfortunately eye drops can be a distressing experience for children, parents/guardians and orthoptists. The purpose of this research is to focus on the experiences of orthoptists and delve deeper into their views and explore if improvements can be made.
UNASSIGNED: This was a Qualitative study involving semi-structured interviews with 8 registered and currently practicing orthoptists in the UK. The interviews were undertaken online via Microsoft TEAMS. Thematic analysis was carried out for the purposes of data analysis.
UNASSIGNED: 3 major themes were identified (1) how orthoptist frame instilling eye drops, (2) techniques to address challenges, and (3) improvements to eye drops instillation process. Orthoptists were aware that instilling eye drops in children brought specific challenges such as distress and resistance; however they saw it as an essential part of their job. Orthoptists understood their role within a wider team which delivered eye care to children effectively and that there was a division of they believed that. Orthoptists were aware that the eye drops may cause some distress, however this did not affect compliance with treatment such as wearing glasses and/or a patch. Orthoptists believed verbal and non-verbal communication with the child was essential. Help was sought from parents or colleagues for physical restraint if required. Orthoptists suggested adapting to children with additional needs and giving out eye drops to parents/carers to instill at home if dilation in the eye clinic became difficult. They suggested improvements such as assistance from play specialists, developing a pre-procedural information video, practise as a student, the study of the medical exemptions module and the potential of using eye sprays instead of eye drops.
UNASSIGNED: The study reiterates the importance of verbal and non-verbal communication. The results may facilitate recommendations for change such as encouraging the study of medical exemptions and help support a case for play specialist support regularly, and the encouragement to develop a pre-procedural information video to improve quality of care. This is currently inconsistent across different Trusts in the UK. The study could result in improvements to current practise and influence other fields of medicine such as blood tests and MRI scans in children. The study also recommends further studies to investigate the parental perspective of instillation of eye drops in their child\'s eyes when they attend the eye clinic.

UNASSIGNED: Corneal ulcers are common lesions in both human and veterinary medicine. However, only a few studies have evaluated the efficacy of cross-linked hyaluronic acid (X-HA) eye drops on corneal wound healing. To our knowledge, this is the first study to demonstrate and compare the efficacy of amniotic membrane extract eye drops (AMEED) and X-HA for corneal wound healing in rats.
UNASSIGNED: A total of 15 male Wistar rats (30 eyes) were used in this study. Then, 10 eyes were treated with X-HA, AMEED, or 0.9% saline. After general and topical anesthesia, a superficial corneal ulcer was created using a corneal trephine. The defect was further polished with a diamond burr. Three groups of 10 eyes each were treated with either one drop of 0.75% X-HA or AMEED or 0.9% saline (control), administered every 12 h for a duration of 72 h. The median epithelial defect area (MEDA), expressed as a percentage of the total corneal surface, was measured at 0, 12, 24, 36, 48, and 72 h. Re-epithelization time scores were also evaluated. The Kruskal-Wallis test was used to compare median times for re-epithelization and histopathologic scores between groups, while the Friedman test (for paired data) was employed to compare results from the serial analysis of MEDA and vascularization scores between groups.
UNASSIGNED: MEDA was not significantly different between X-HA and AMEED. However, MEDA was significantly smaller in the X-HA group compared to the control group at 36 h (2.73 interquartile range (IQR) 5.52% x 9.95 IQR 9.10%, P=0.024) and 48 h (0.00 IQR 0.26% x 6.30 IQR 8.54%, P=0.030). The overall time for re-epithelization was significantly lower in the X-HA group (3.00 IQR 3.00) compared to the AMEED (6.5 IQR 3.00) and control (7.00 IQR 1.00) groups (P=0.035). Vascularization, hydropic degeneration, and epithelial-stromal separation were significantly less observed in samples in the X-HA-treated compared to samples in the AMEED- and saline-treated groups. Significantly more corneal epithelium cells were labeled for caspase3 in samples from the AMEED- and saline-treated groups compared to those from the X-HA-treated group.
UNASSIGNED: Topical X-HA has been shown to accelerate corneal epithelial healing. AMEED did not decrease corneal re-epithelialization time. X-HA may also potentially be used as an adjunct therapy for treating corneal ulcers in clinical situations.

The microbial contamination of eye drop tips and caps varies between 7.7% and 100%. In seeking patient protection and continuous improvement, the Pharmacy Department in the Sterile Ophthalmological and Oncological Preparations Unit at Cochin Hospital AP-HP, Paris, France, conducted a two-phase study to compare the antimicrobial efficiency and practical use of standard packaging and a marketed eye drop container incorporating a self-decontaminating antimicrobial green technology by Pylote SAS at the tip and cap sites. The first phase was conducted in situ to identify the microbial contaminants of eye drops used in the hospital and community settings. A total of 110 eye drops were included for testing. Staphylococcus species were the most prevalent bacteria. Candida parapsilosis was detected in only one residual content sample and, at the same time, on the cap and tip. The second phase was performed in vitro, according to JIS Z2801. Reductions above one log in Staphylococcus aureus and Pseudomonas aeruginosa counts were noted in Pylote SAS eye drop packaging after 24 h of contact. The practical tests showed satisfactory results. Pylote SAS antimicrobial mineral oxide technology exhibited promising effects that combined effectiveness, safety, and sustainability to protect the patient by preventing infections due to the contamination of eye drop containers.

OBJECTIVE: To assess the safety and efficacy of ripasudil for retinopathy of prematurity (ROP).
METHODS: Phase 1/2, multicenter, open-label, single-arm, 12-week clinical trial.
METHODS: Infants born with gestational age (GA) of ≤ 32 weeks or weight of ≤ 1500 g with zone I or II, ≥ stage 1, ROP in both eyes were enrolled. Ripasudil eye drops were administered to patients in both eyes. Phase 1 was a dose-escalation study (once daily for 1 week, then twice daily for 2 weeks); an additional dosing up to 9 weeks was allowed if no safety issues occurred. In phase 2, ripasudil was administered twice daily for up to 12 weeks. Adverse events were assessed. The proportion of patients with type 1 ROP progression, number of days for type 1 ROP progression, and progression to the most advanced ROP stage were estimated.
RESULTS: Twenty-four infants were enrolled (phase 1, n = 3; phase 2, n = 21). Nineteen and four patients experienced systemic and ocular adverse events, respectively. Efficacy endpoints were not different between the ripasudil and historical control groups. However, in the GA ≤ 27 weeks subgroup, fewer patients progressed to type 1 ROP in the ripasudil than in the historical control group (P = 0.09). In the GA ≤ 27 weeks subgroups, the 25th percentile for the number of days for type 1 ROP progression was 22 days in the historical control group and 44 days in the ripasudil group.
CONCLUSIONS: Ripasudil was safe and inhibited/delayed type 1 ROP progression, especially in infants with short GA.

Accidental poisonings by ingesting conjunctival fluid mixed with eye drops commonly involve alpha-2 adrenergic receptor agonists and tetrahydrozoline. These substances are recognized in commonly reported ingestions. Victims of all ages, otherwise in good health, often present as pale and lethargic to the emergency department (ED) after unintentionally ingesting topical eye medication. While eye drop poisoning cases in childhood include accidents during the play and poisonings in adults mean either suicide attempts or side effects caused by the systemic absorption of the substance, fluid of the ocular surface is a risk to all age groups. With this in mind, this study aimed to summarize data in the literature on tetrahydrozoline and alpha-2 adrenergic receptor agonists as dangerous medications, even when administered in low-bioavailability forms, such as eye drops. With this aim, a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-compliant systematic review of relevant studies was conducted. A search of PubMed, Scopus, Web of Science, and EBSCOhost yielded nine studies that met the rigorous inclusion criteria. The primary studies were subject to a meta-analysis once a quality appraisal of the studies and a narrative synthesis of the extracted data had been conducted. The author hopes that this information will provide observations that will lead to better designs for over-the-counter eye drops, off-label drug usage policies, and parental attention.

The literature reveals gaps in the availability of green analytical methods for assessing products containing gatifloxacin (GFX), a fluoroquinolone. Presently, method development is supported by tools such as the National Environmental Methods Index (NEMI) and Eco-Scale Assessment (ESA), which offer objective insights into the environmental friendliness of analytical procedures. The objective of this work was to develop and validate a green method by the NEMI and ESA to quantify GFX in eye drops using HPLC. The method utilized a C8 column (4.6 × 150 mm, 5 μm), with a mobile phase of purified water containing 2% acetic acid and ethanol (70:30, v/v). The injection volume was 10 μL and the flow rate was 0.7 mL/min in isocratic mode at 25°C, with detection performed at 292 nm. The method demonstrated linearity in the range of 2-20 μg/mL, and precision at intra-day (relative standard deviation [RSD] 1.44%), inter-day (RSD 3.45%), and inter-analyst (RSD 2.04%) levels. It was selective regarding the adjuvants of the final product (eye drops) and under forced degradation conditions. The method was accurate (recovery 101.07%) and robust. The retention time for GFX was approximately 3.5 min. The greenness of the method, as evaluated by the NEMI, showed four green quadrants, and by ESA, it achieved a score of 88.

Compounded insulin eye drops were prepared at 1 IU/mL from commercially available subcutaneous insulin by dilution in saline solution or artificial tears. Physicochemical characterization and in vitro tolerance testing in human and conjunctival cells were followed by a 28-day short-term stability study under various conditions. The formulations were isotonic (280-300 mOsm/L), had a pH close to neutral (7-8), medium surface-tension values (<56 MN/m-1), and low (≈1 mPa·s) and medium (≈5 mPa·s) viscosities (compounded normal saline solution and artificial tear-based preparation, respectively). These values remained stable for 28 days under refrigeration. Microbiological stability was also excellent. Insulin potency remained in the 90-110% range in the compounded formulations containing normal saline solution when stored at 2-8 °C for 28 days, while it decreased in those based on artificial tears. Although both formulations were well tolerated in vitro, the compounded insulin diluted in a normal saline solution exhibited better cell tolerance. Preliminary data in humans showed that insulin in saline solution was an effective and safe treatment for persistent corneal epithelial defects. Compounded insulin eye drops diluted in normal saline solution could, therefore, constitute an emergent therapy for the treatment of persistent corneal epithelial defects.

Gabapentin (GBP) was originally developed as a potential agonist for Gamma-Amino-Butyric-Acid (GABA) receptors, aiming to inhibit the activation of pain-signaling neurons. Contrary to initial expectations, it does not bind to GABA receptors. Instead, it exhibits several distinct pharmacological activities, including: (1) binding to the alpha-2-delta protein subunit of voltage-gated calcium channels in the central nervous system, thereby blocking the excitatory influx of calcium; (2) reducing the expression and phosphorylation of CaMKII via modulation of ERK1/2 phosphorylation; (3) inhibiting glutamate release and interfering with the activation of NMDA receptors; (4) enhancing GABA synthesis; (5) increasing cell-surface expression of δGABA_A receptors, contributing to its antinociceptive, anticonvulsant, and anxiolytic-like effects. Additionally, GBP displays (6) inhibition of NF-kB activation and subsequent production of inflammatory cytokines, and (7) stimulation of the purinergic adenosine A1 receptor, which supports its anti-inflammatory and wound-healing properties. Initially approved for treating seizures and postherpetic neuralgia, GBP is now broadly used for various conditions, including psychiatric disorders, acute and chronic neuropathic pain, and sleep disturbances. Recently, as an eye drop formulation, it has also been explored as a therapeutic option for ocular surface discomfort in conditions such as dry eye, neurotrophic keratitis, corneal ulcers, and neuropathic ocular pain. This review aims to summarize the evidence supporting the molecular effects of GBP, with a special emphasis on its applications in ocular surface diseases.

BACKGROUND: Glaucoma-related dry eye disease (DED) is often underestimated, but it is an important comorbidity affecting 40% to 59% of glaucoma patients. It may be an exacerbation of a pre-existing condition or a novel disease starting after the initiation of topical medication. The cumulative effect of medication, preservatives and excipients leads to an alteration in tear film composition and ocular surface stability. The main purpose of this investigation was to study a group of Portuguese glaucoma patients regarding the presence of DED symptoms and correlate the severity of the symptoms with the usage of different types of glaucoma topical medications.
METHODS: This is a cross-sectional observational study of patients diagnosed with primary and secondary open-angle glaucoma. The questionnaire Standardized Patient Evaluation of Eye Dryness (SPEED) translated to Portuguese (SPEED-Vp) was taken by patients followed in the Glaucoma Department of Unidade Local de Saúde Entre Douro e Vouga, Santa Maria da Feira, Portugal. Data was collected regarding their age, gender, type of topical medication in use as well as frequency and duration of usage. A statistical analysis was performed.
RESULTS: A total of 75 patients answered the SPEED-Vp questionnaire. The mean age was 72 ± 7 years old. Fifty-two percent (n=39) were male, and 48% (n=36) were female patients. About 49.33% (n=37) had been on intraocular pressure (IOP)-lowering eyedrops for more than five years. About 61.43% (n=43) of patients used IOP-lowering eyedrops with preservatives. Most of the patients used prostaglandin analogs (75.71%, n=53) and beta-blockers (72.86%, n=51). SPEED score average was 2.75. About 25.33% (n=19) had no DED symptoms, 58.67% (n=44) had mild symptoms, 8% (n=6) had moderate symptoms and 8% (n=6) had severe symptoms. No statistically significant correlation was found between SPEED score and age, gender, number of eyedrop containers, number of active principles, application frequency, presence of preservatives, number of eyedrop containers with preservatives, duration of eyedrops usage or any of the medication groups.
CONCLUSIONS: Although a high percentage of patients were on eyedrops with preservatives, this low rate of symptoms might be because patients tended to devalue these symptoms; were already on treatment with artificial tears; or have an underestimation of the sensation of dry eye due to decreased neuronal corneal nerve responses and density. These results were surprisingly positive. This might also be the result of the healthcare provider\'s sensibilization to this issue (early diagnosis, early prescription of artificial tears and change from preservative to preservative-free medication).