Microbial Dynamics in Ophthalmic Health: Exploring the Interplay between Human Microbiota and Glaucoma Pathogenesis.

The human microbiome has a crucial role in the homeostasis and health of the host. These microorganisms along with their genes are involved in various processes, among these are neurological signaling, the maturation of the immune system, and the inhibition of opportunistic pathogens. In this sense, it has been shown that a healthy ocular microbiota acts as a barrier against the entry of pathogens, contributing to the prevention of infections. In recent years, a relationship has been suggested between microbiota dysbiosis and the development of neurodegenerative diseases. In patients with glaucoma, it has been observed that the microbiota of the ocular surface, intraocular cavity, oral cavity, stomach, and gut differ from those observed in healthy patients, which may suggest a role in pathology development, although the evidence remains limited. The mechanisms involved in the relationship of the human microbiome and this neurodegenerative disease remain largely unknown. For this reason, the present review aims to show a broad overview of the influence of the structure and composition of the human oral and gut microbiota and relate its dysbiosis to neurodegenerative diseases, especially glaucoma.

Enhancing Ocular Surface in Dry Eye Disease Patients: A Clinical Evaluation of a Topical Formulation Containing Sesquiterpene Lactone Helenalin.

The aim of this work was to assess the tolerability, safety, and efficacy of an ophthalmic topical formulation containing helenalin from Arnica montana and hyaluronic acid 0.4% (HA) in patients with mild-to-moderate Dry Eye Disease (DED) exhibiting positive Matrix Metalloproteinase 9 (MMP-9) test results. Tolerability and safety were evaluated in 24 healthy subjects. Participants were instructed to apply one drop of the formulation three times a day in the study eye, for 2 weeks, followed by a clinical follow-up of 21 days. Efficacy was studied in 48 DED patients randomized into Study (Group 1/receiving the studied formulation) or Control (Group 2/Receiving HA 0.4% eye lubricant) groups for 1 month. Assessments included an MMP-9 positivity test, conjunctival impression cytology (CIC), Ocular Surface Disease Index (OSDI), non-invasive film tear breakup time (NIBUT), non-invasive average breakup time (NIAvg-BUT), ocular surface staining, Schirmer's test, and meibomiography. A crossover design with an additional 1-month follow-up was applied to both groups. Healthy subjects receiving the studied formulation exhibited good tolerability and no adverse events. Regarding the efficacy study, Group 1 exhibited a statistically significant reduction in the MMP-9 positivity rate compared to Group 2 (p < 0.001). Both Group 1 and Group 2 exhibited substantial improvements in OSDI and NIBUT scores (p < 0.001). However, Group 1 demonstrated a significant improvement in NI-Avg-BUT and Schirmer's test scores (p < 0.001), whereas Group 2 did not (p > 0.05). Finally, after the crossover, the proportion of MMP-9-positive subjects in Group 1 increased from 25% to 91.6%, while Group 2 showed a significant decrease from 87.5% to 20.8%. Overall, the topical formulation containing sesquiterpene helenalin from Arnica montana and hyaluronic acid was well tolerated and exhibited a favorable safety profile. Our formulation reduces DED symptomatology and modulates the ocular surface inflammatory process; this is evidenced by the enhancement of CIC, the improvement of DED-related tear film status, and the reduction of the MMP-9 positivity rate.

An insight on the eye bacterial microbiota and its role on dry eye disease.

The human ocular surface hosts a bacterial assemblage that integrates a diverse and complex microbiome. This bacterial microbiota is part of a healthy eye and plays a protective role in it. However, this ocular bacterial assemblage may alter the ocular surface inflammation response and can influence the development and progression of dry eye disease. For this reason, the present review describes the changes generated on the ocular surface by bacterial assemblages during the development of dry eye disease. Likewise, the interaction of this microbiota with the other inflammatory factors that influence the development of this disease is analyzed, as well as the use of treatments focused on modifying the bacteria on the ocular surface.

Nutraceuticals: A Promising Therapeutic Approach in Ophthalmology.

Oxidative stress represents one of the main factors driving the pathophysiology of multiple ophthalmic conditions including presbyopia, cataracts, dry eye disease (DED), glaucoma, age-related macular degeneration (AMD) and diabetic retinopathy (DR). Currently, different studies have demonstrated the role of orally administered nutraceuticals in these diseases. For instance, they have demonstrated to improve lens accommodation in presbyopia, reduce protein aggregation in cataracts, ameliorate tear film stability, break up time, and tear production in dry eye, and participate in the avoidance of retinal neuronal damage and a decrease in intraocular pressure in glaucoma, contribute to the delayed progression of AMD, or in the prevention or treatment of neuronal death in diabetic retinopathy. In this review, we summarized the nutraceuticals which have presented a positive impact in ocular disorders, emphasizing the clinical assays. The characteristics of the different types of nutraceuticals are specified along with the nutraceutical concentration used to achieve a therapeutic outcome in ocular diseases.

An Oral Polyphenol Formulation to Modulate the Ocular Surface Inflammatory Process and to Improve the Symptomatology Associated with Dry Eye Disease.

Due to their antioxidant, anti-inflammatory, neuroprotective, and anti-angiogenic effects, polyphenols are first-rate candidates to prevent or treat chronic diseases in which oxidative stress-induced inflammation plays a role in disease pathogenesis. Dry eye disease (DED) is a common pathology, on which novel phenolic compound formulations have been tested as an adjuvant therapeutic approach. However, polyphenols are characterized by limited stability and solubility, insolubility in water, very rapid metabolism, and a very short half-life. Thus, they show poor bioavailability. To overcome these limitations and improve their stability and bioavailability, we evaluated the safety and efficacy of an oral formulation containing among other compounds, polyphenols and omega-3 fatty acids, with the addition of a surfactant in patients with DED. Subjects were randomly assigned to one of four study groups including the study formulation (A), placebo (P), the study formulation + eye lubricant (A + L), and placebo + eye lubricant (P + L). Patients from the A and P groups were instructed to take two capsules every 24 h, while patients in the L groups also added one drop of lubricant twice a day for 12 weeks as well. Regarding safety, non-ocular abnormalities were observed during study formulation therapy. Liver function tests did not show any statistically significant difference (baseline vs. week 4). Concerning efficacy, there was a statistically significant difference between baseline, month 1, and month 3 in the OSDI (Ocular Surface Disease Index) test results in both treatment groups (group A and group A + L). Furthermore, both groups showed statistically significant differences between baseline and month 3 regarding the non-invasive film tear breakup time (NIF-BUT) score and a positive trend related to Shirmer's test at month 3. The non-invasive average breakup time (NIAvg-BUT) score showed a statistically significant difference at month 3 when compared with baseline in the A + L group. The P + L group showed a statistically significant difference in terms of the OSDI questionary between baseline and month 3. Regarding the lissamine green staining, the A + L group showed a statistical difference between baseline and month 3 (p = 0.0367). The placebo + lubricant group did not show statistically significant differences. Finally, the placebo group did not show any data with statistically significant differences. Consequently, this polyphenol formulation as a primary treatment outperformed the placebo alone, and the polyphenol oral formulation used as an adjuvant to artificial tears was superior to the combination of the placebo and the artificial tears. Thus, our data strongly suggest that this polyphenol oral formulation improves visual strain symptoms and tear film status in patients with mild to moderate DED.

Safety and Tolerability of Topical Ophthalmic Triamcinolone Acetonide-Loaded Liposomes Formulation and Evaluation of Its Biologic Activity in Patients with Diabetic Macular Edema.

Intravitreal injections (IVTs) of corticosteroids as triamcinolone acetonide (TA) are frequently used for the treatment of many vitreous and retinal disorders. However, IVTs are related to severe ocular complications. Lately, a topical ophthalmic TA-loaded liposomes formulation (TALF) was designed to transport TA into the posterior segment of the eye when instilled on the ocular surface. To evaluate the safety, tolerability, and biological activity of TALF, an animal study and a phase I clinical assay were performed. Moreover, four patients with diabetic macular edema (DME) were treated with TALF in order to explore the biological activity of the formulation. No inflammation, lens opacity, swelling, or increase in intraocular pressure were recorded after the instillation of TALF in any of the animal or clinical studies. Mainly, mild and transient adverse events such as dry eye and burning were reported. TALF significantly improves visual acuity and diminishes central foveal thickness in patients with DME. The current data demonstrate the safety, tolerability, and biological activity of TALF. It seems that TALF can be used topically to treat vitreous and retinal diseases that respond to TA such as DME, avoiding the use of corticosteroid IVTs and their associated hazards.

Topical Triamcinolone Acetonide-Loaded Liposomes as Primary Therapy for Macular Edema Secondary to Branch Retinal Vein Occlusion: A Pilot Study.

Purpose: To explore safety and therapeutic efficacy of a topical ophthalmic triamcinolone acetonide-loaded liposome formulation (TA-LF) as primary therapy in patients with macular edema (ME) secondary to branch retinal vein occlusion (BRVO). Methods: Twelve eyes of 12 patients with ME secondary to BRVO were exposed to a topical instillation of 1 drop of TA-LF (TA 0.2%) 6 times a day for 12 weeks to evaluate safety and efficacy. Best corrected visual acuity (BCVA) intraocular pressure (IOP), slit lamp examination, and central foveal thickness (CFT) were analyzed at every visit. In addition, the morphology of TA-LF was analyzed using scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Results: Patients presented a significant improvement of BCVA and CFT without significant IOP modification (P = 0.94). Treated eyes showed BCVA improvement from 40 ± 12.05 to 64.83 ± 15.97 letters and CFT reduction from 682.91 ± 278.60 to 271.58 ± 57.66 µm after 12 weeks of TA-LF therapy (P < 0.001). No adverse events, including IOP rising, were registered. SEM analysis of liposomal formulations showed that liposome (LP) size depends on its concentration. As the concentration of TA increased, the average size of LPs and the number of larger particles increased as well. TEM study displayed that LP formulation efficiently solubilizes TA crystals in nanoparticles and encapsulates them. Conclusion: LPs can function as nanocarriers of TA and they could be used as topical ophthalmic primary therapy instead of intravitreal drugs in patients with ME secondary to BRVO.

Novel Triamcinolone Acetonide-Loaded Liposomal Topical Formulation Improves Contrast Sensitivity Outcome After Femtosecond Laser-Assisted Cataract Surgery.

Purpose: To assess visual results, macular modifications, and the incidence of clinically significant macular edema (CSME) in patients using a topical triamcinolone acetonide-loaded liposomal formulation (TA-LF) after femtosecond laser-assisted cataract surgery (FLACS). Methods: Fifty-six eyes after FLACS were selected. Twenty-eight eyes in the combined therapy group (P + N) were treated with prednisolone 1% and nepafenac 0.1% for 21 days postoperatively, whereas 28 eyes in the TA-LF group received a liposomal formulation containing 2 mg/mL of TA (0.2%) for the same period of time. Follow-up visits at 1 day, 6 weeks, and 12 weeks after surgery consisted of visual acuity, contrast sensitivity (CS), central foveal thickness (CFT), total macular volume (TMV) measurements, and the detection of CSME. Results: CS improved in the TA-LF group (basal value: 1.087 ± 0.339 vs. 1.276 ± 0.147 at week 12, P = 0.0346), whereas in the P + N group, CS was not different from the baseline (basal value: 1.130 ± 0.331 vs. 1.274 ± 0.133 at week 12, P = 0.1276). There were similar increases in postoperative CFT and TMV in both groups. CFT and TMV significantly correlate with CS only in the TA-LF group. The r2 for CFT and CS was 0.1963 (P = 0.0206), whereas the r2 for TMV and CS was 0.3615 (P = 0.0007) at 12 weeks. No difference was observed in the incidence of CSME between the groups. Conclusion: TA-LF is associated with better CS outcomes compared to combined therapy after FLACS.

Novel Triamcinolone Acetonide-Loaded Liposomes Topical Formulation for the Treatment of Cystoid Macular Edema After Cataract Surgery: A Pilot Study.

PURPOSE: To report tolerability, safety, and efficacy of a topical triamcinolone acetonide-loaded liposomes formulation (TA-LF) in targeting the macular area in patients with refractory pseudophakic cystoid macular edema (PCME). METHODS: For tolerability, safety and efficacy evaluation, 12 eyes of 12 patients with refractory PCME were exposed to one drop of TA-LF (TA at 0.2%) every 2 h for 90 days or until best-corrected visual acuity (BCVA) was achieved. Intraocular pressure (IOP), slit lamp examination, and central foveal thickness (CFT) were analyzed at every visit. RESULTS: Patients with refractory PCME under TA-LF therapy showed a significant improvement in BVCA and CFT without significant IOP modification (P = 0.94). On average CFT decreased to 206.75 ± 135.72 µm and BCVA improved to 20.08 ± 10.35 letters (P < 0.0005). BCVA was achieved at 10.58 ± 6.70 weeks (range 2-18). TA-LF was well tolerated in all cases. Neither ocular surface abnormalities nor adverse events were recorded. CONCLUSION: TA-LF was well tolerated and improved BCVA and CFT on patients with refractory PCME.

Feasibility and safety of vitrectomy under topical anesthesia in an office-based setting.

Purpose: The purpose of this study was to evaluate the feasibility and safety of office-based vitreoretinal procedures. Methods: Patients undergoing primary elective pars plana vitrectomy were elected for surgery in an office-based setting (performed in a minor procedure room under topical anesthesia [TA] and oral anxiolysis). Rates of surgical objective achievement, surgical timing, and comfort were recorded to evaluate feasibility. Intraoperative and postoperative adverse events were assessed to evaluate safety. Results: Office-based vitrectomy surgery was performed in 34 eyes of 30 patients. The mean surgical time was 12.351 ± 8.21 min. Surgical objectives were achieved in 100% of cases. The mean best-corrected visual acuity improvement was 9.08 letters (P < 0.0001). During most parts of the procedure, no patient reported pain or discomfort. Neither intraoperative nor postoperative adverse events were reported until the final follow-up visit. Conclusion: Office-based vitreoretinal procedures under TA could be as feasible and as safe as vitreoretinal procedures under conventional anesthesia.

Characterization and Pharmacokinetics of Triamcinolone Acetonide-Loaded Liposomes Topical Formulations for Vitreoretinal Drug Delivery.

PURPOSE: To achieve a safer alternative to intravitreal injection of corticosteroids, we developed and characterized triamcinolone acetonide-loaded liposomes formulations (TA-LFs) to be used topically for vitreoretinal drug delivery. METHODS: Four different 0.2% TA-LFs (TA-LF1 to TA-LF4) were generated and submitted to physicochemical characterization. Posteriorly, an ex vivo diffusion assay was performed using rabbit corneas as membranes. Finally, concentrations of triamcinolone acetonide (TA) were determined by high-performance liquid chromatography in ocular tissues from New Zealand white rabbits after multiple topical doses of TA-LF2 (6 times per day, 14 days). In addition, toxicity and tolerability of TA-LF2 was evaluated by cell viability assay and eye examination of study animals, respectively. RESULTS: TA-LF2 was the most stable formulation maintaining a stable hidrogenion potential (pH) at 30 and 40°C and even improving encapsulation with higher temperature. TA-LF2 and TA-LF3 presented the best diffusion performance in vitro reaching the highest TA concentrations after 8 h of follow-up. In vivo diffusion and pharmacokinetics analysis showed that concentrations of TA in retina and vitreous reached the highest peak at 12 h after topical administration of TA-LF2 (252.10 ± 90.00 ng/g and 32.6 ± 10.27 ng/g, respectively) and subsequently decline to 24.0 ± 11.72 ng/g and 19.5 ± 13.14 ng/g, respectively, at 14 days of follow-up. Finally, cell viability was unaffected by TA-LF2, and no increase in intraocular pressure nor ocular alterations were observed after topical administration of this formulation in rabbits. CONCLUSION: TA-loaded liposomes, administered topically, can deliver TA in the vitreous cavity and reach the retina efficiently.

Surgical Results in Ocriplasmin Candidates With Symptomatic Vitreomacular Traction Syndrome.

PURPOSE: To report surgical outcomes in a series of cases with symptomatic vitreomacular traction that met MIVI-TRUST (Microplasmin for intravitreous injection-traction release without surgical treatment) criteria for ocriplasmin use who underwent primary 25-gauge vitrectomy. MATERIALS AND METHODS: A single-center retrospective chart review study was performed in patients who underwent primary 25-gauge vitrectomy for symptomatic vitreomacular traction (VTM) from January 2013 through January 2016. Pre- and postoperative visual acuity (measured by the early treatment diabetic retinopathy acuity test), and posterior hyaloid focal attachment to the macula (demonstrated by high-definition optical coherence tomography) were analyzed. In addition, intra- and postoperative complications were obtained from medical records. RESULTS: Fifteen consecutive cases of symptomatic VMT traction that underwent primary 25-gauge vitrectomy were included. All met the MIVI-TRUST criteria for ocriplasmin use. In all cases, VMT resolution, macular hole closure, and improvement in best corrected visual acuity (BCVA) were observed. Mean visual acuity improved from 56.53 ± 16.04 letters at baseline to 73.13 ± 7.46 letters at 24 weeks of follow-up. The mean BCVA improvement from baseline was 16.60 letters (range 6-44), which was statistically significant (P < 0.0001). Ten of fifteen patients (66.6%) showed significant improvement of their BCVA to 20/40 or better (70 or more in ETDRS visual acuity test). No significant intra- or postoperative complications were documented. CONCLUSIONS: Primary 25-gauge pars plana vitrectomy in eyes with symptomatic vitreomacular traction is able to efficiently resolve VMT and macular holes, improving vision in candidates for intravitreal injection of ocriplasmin. This well-tolerated surgical procedure may be a reliable and predictable alternative for resolving VMT pathology.