Out-of-plane arrivals recorded by drifting hydrophones during the Northern Ocean Rapid Surface Evolution Experiment.

This paper reports on an observation of three-dimensional (3D) arrivals for which the change in the direction of horizontally refracted sound is nearly 180°. The experimental site is Jan Mayen Channel (JMCh), which connects the Greenland and Norwegian Seas. During the experiment, signals from a moored source transmitting a 500-1500 Hz sweep every 4 h were recorded by three surface drifters equipped with hydrophone arrays. Over a 3-day period, the drifters moved north across JMCh toward the moored source. In each recording, an in-plane arrival is identified. In a subset of these recordings, a second arrival is observed, having travel time consistent with propagation from the moored source, turning at the ridge on the south side of the channel, and arriving at the drifters. In a smaller subset of recordings, a third arrival is also observed having travel time consistent with a turning point on the face of the bathymetric rise on the west end of the channel that forms the Jan Mayen volcano. A 3D ray trace is employed to show the change in direction results from repeated reflections from the seafloor such that it is classified as horizontal refraction and not a single-bounce reflection.

The Effect of Sodium Hyaluronate Eye Drops 2, 4 or 6 Times a Day on Signs and Symptoms of Dry Eye Disease.

Purpose: A randomized clinical trial was run to evaluate the effectiveness of a preservative-free 0.4% sodium hyaluronate eye drop (LOF) in different dosage schemes to alleviate signs and symptoms of dry eye disease (DED). Methods: A total of 116 subjects with mild-to-moderate DED were included, and 111 completed the study (from which 67.6% were female and 65.3% were users of oral contraceptives). Patients were randomly assigned to instill a drop of LOF either 2 (BID), 4 (QID) or 6 (6TD) times a day (at least 3 hours apart) for 30 days. The clinical parameters and symptom endpoints were Ocular Surface Disease Index (OSDI), tear break-up time (TBUT), ocular surface staining, and conjunctival hyperemia. Other parameters evaluated were chemosis, best corrected visual acuity, and the incidence of adverse events (AE). Results: There was a significant reduction in OSDI scores by day 30 in all groups. The recovery of the OSDI score back to normal values was observed in 51.4% of patients treated (50%, 48.6%, and 55.6% in BID, QID, and 6TD, respectively, p = 0.822). Similar improvement was observed for TBUT, 50.5% of patients increased this variable to >10 seconds (39.5%, 51.4%, and 61.1%, p = 0.175), and for ocular surface staining, ≥72% showed Grade 0. There were no significant differences among posology groups regarding ocular surface staining, conjunctival hyperemia, or any safety parameters. No overall improvement in OSDI and TBUT to normal values was noted for 31 patients (21 were female and 71.4% users of contraceptive drugs). Conclusion: The ophthalmic use of preservative free LOF, 2, 4 or 6 times a day, may alleviate clinical parameters and symptoms in 50% of patients with mild-to-moderate DED after a one-month treatment. This improvement seemed to be less ubiquitous in patients within reproductive age and using oral contraceptives. Trial Registration: This trial is registered at clinicaltrials.gov (NCT0704531).

Evaluation of the Relationship Between Diabetic Macular Edema and Renal Function in a Latino Population.

INTRODUCTION: Diabetic macular edema (DME) is one of the leading causes of vision impairment. The relationship between DME and estimated glomerular filtration rate (eGFR) has not been clearly evaluated in Hispanic or Latino populations. The objective of this study was to evaluate the eGFR in a Latino population with DME. METHODS: A cross-sectional, observational, and descriptive study was carried out on the basis of a multicenter phase III clinical trial. RESULTS: A total of 82 subjects diagnosed with DME (36 women and 46 men) were included in the study. The mean age was 61.93 ± 6.71 years. Mean values of the blood chemistry parameters glycated hemoglobin and eGFR were 7.20 ± 0.95% and 74.42 ± 26.82 mL/min/1.73 m2, respectively. The time elapsed since diagnosis of diabetes mellitus was 15.30 ± 7.35 years, while the duration of DME was 1.41 ± 1.75 years. Mean values for central macular thickness (CMT) and total macular volume (TMV) were 440.99 ± 132.22 µm and 11.97 ± 2.11 mm3, respectively. DME duration had a negative correlation with TMV (Rho - 0.26, p < 0.05) and a positive correlation with mean arterial pressure (Rho 0.26, p < 0.05). CMT was correlated with TMV (Rho 0.43, p < 0.0001) and visual acuity (Rho 0.26, p < 0.05). No significant correlations were observed between eGFR and CMT, TMV, or any demographic variable (p > 0.05). Chronic kidney disease (CKD) was associated with hypertension (OR 9.32, p = 0.035), elevated intraocular pressure (IOP) (OR 0.03, p = 0.011), and advanced age (OR 0.45, p = 0.011). CMT was significantly associated with TMV (ß = 27.69, p < 0.0001). CONCLUSIONS: We did not find a correlation between eGFR and DME. Our findings suggest that the presence of hypertension is associated with a decrease in the GFR < 60 mL/min/1.73 m2, and CKD may be associated with advanced age and elevated IOP which may increase the risk for the development of glaucoma. TRIAL REGISTRATION: NCT05217680 (clinicaltrials.gov).

Efficacy and Safety of an Ophthalmic DMPC-Based Nanoemulsion in Patients with Dry Eye Disease: A Phase I/II Randomized Clinical Trial.

Purpose: The goals of this study were to evaluate the safety and efficacy of an ophthalmic 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC)-based nanoemulsion (Nanodrop®) in patients with dry eye disease (DED). Methods: This was a randomized phase I/II multicentric, prospective, double-blind clinical trial. Patients (phase I: n = 25 and phase II: n = 101) were assigned to receive either PRO-176 (Nanodrop®) or Systane Balance® (control) for 29 days. Once the visits of the first 25 subjects were completed, if there were less than 20% of unexpected adverse events (AEs), related to PRO-176, recruitment was continued until the sample was completed for noninferiority (efficacy) analysis (phase II, n = 126). Efficacy endpoints were the ocular surface disease index (OSDI), tear break-up time (TBUT), epithelial defects, best corrected visual acuity (BCVA), and the incidence of expected AE. Results: For the phase I portion of the study, there were no differences between groups regarding the incidence of AE. All related-AE symptoms in both groups were mild and expected. For the phase II subset, there was a significant reduction in OSDI scores at day 29 and noninferiority between treatments was confirmed (p=0.650, CI 95% [-8.7, 5.5]). Similar improvement was observed for TBUT although no significant intergroup differences were found (p=0.518, CI 95% [-0.08, 1.6]). There were no significant differences between treatments for epithelial staining or safety parameters. Conclusions: Topical application of PRO-176 is as safe and effective as the controls. Both groups were clinically similar in terms of efficacy and safety. The results support the hypothesis that ophthalmic DMPC-based nanoemulsion may improve clinical parameters and symptoms in patients with DED. This trial is registered with NCT04111965.

Evaluation of the Rheological Properties, Preclinical Safety, and Clinical Effectiveness of a New Dispersive Ophthalmic Viscoelastic Device for Cataract Surgery.

Purpose: To evaluate the rheological properties of the ophthalmic viscoelastic device (OVD) PRO-149, its preclinical safety, and its effectiveness when used during cataract surgery in patients with age-related cataract. Material and Methods: Control (HEC) and test (PRO-149) OVDs were compared through rheological measures, by two preclinical safety studies in rabbits, and under normal-use conditions during cataract removal and lens implantation in a parallel randomized clinical trial. Results: Rheological properties were determined. Preclinical studies did not find any evidence of safety issues or toxicity. In the clinical trial, 36 subjects were included. After 29 days, there were no statistically significant differences in mean percentage of endothelial cell count change or in the postoperative intraocular pressure between groups. There were no significant differences between OVDs for any safety parameter studied. Finally, PRO-149 showed a statistically significant improvement in surgeon rating for ease of use during extraction (p < 0.05). Conclusion: PRO-149 is a dispersive OVD. The rabbit models did not find evidence of clinical alterations or toxicity. The results of the clinical study support that the two studied OVDs were clinically similar in terms of safety and effectiveness for cataract surgery. Trial Registration: The trial is registered at Clinical Trials.gov at NCT04702802 (21-01-11).

Validation of a preclinical dry eye model in New Zealand white rabbits during and following topical instillation of 1% ophthalmic atropine sulfate.

BACKGROUND: The objective of this study was to validate an animal model for dry eye during and after the administration of 1% ophthalmic atropine sulfate (OAS) in New Zealand white (NZW) rabbits. METHODS: OAS (1%) was applied three times per day to 30 eyes of 15 healthy NZW rabbits. Sacrifice, enucleation, and lacrimal gland removal took place on days 15, 21, and 30 (OAS group). A second group (n = 5) was used as control. Clinical evaluations took place on days 3, 10, 15, 18, 21, 24 and 30. The primary endpoints were: Schirmer I test, tear break-up time (TBUT), and corneal fluorescein staining. As secondary endpoints, clinical changes including intraocular pressure, and histopathology were evaluated. RESULTS: While OAS was administered, the Schirmer I test showed a statistically significant reduction for OAS group versus control (p < 0.001), and versus basal production (p < 0.001). TBUT showed statistically significant differences between groups (days 3 and 10; p = 0.001) and versus basal values (day 3; p < 0.001). Fluorescein staining showed a statistically significant difference (day 3; p = 0.001). The most frequent clinical finding was conjunctival hyperemia (76.9% OAS vs. 20% control). For histopathology, all OAS subjects presented some degree of inflammation (86.7% minimal; 13.3% mild) whereas the control presented only 30% minimal inflammation. Goblet cell density showed no difference. CONCLUSIONS: The effectiveness of the OAS dry eye model in NZW rabbits as reported in previous studies was confirmed, provided that the application of the drug is maintained throughout the intervention; it is not a viable model after OAS administration is suspended.

Reexamining Ophthalmic Drugs, Safety and Tolerability in Phase 1 Clinical Trials.

PURPOSE: The purpose of this study was to evaluate the safety and tolerability profile of drugs used for treating common eye disorders when applied to normal healthy volunteers (NHVs) as explored in phase 1 trials. SUBJECTS AND METHODS: A total of 166 NHVs were identified in six phase 1 trials, examined in a retrospective analysis. The primary endpoints were visual comfort (by ocular comfort index, OCI) and safety (laboratory evaluations, vital signs (VS), visual acuity (VA), intraocular pressure (IOP), lissamine green and fluorescein staining, conjunctival hyperemia, chemosis, and adverse events' incidence (AE)). RESULTS: Compared to baseline, 75.9%, 40.4% and 73.7% of NHV (for lubricant, hypotensive and antibiotic treatments, respectively) improved their OCI score by their final visit. Laboratory evaluations and VS were within normal ranges in 88% of NHV. Similar results were found for VA, corneal and conjunctival staining, and chemosis. IOP decreased significantly in the hypotensive agents' group, trace to mild hyperemia was reported in 32.1%, 27.1%, and 6.8%, respectively. Additionally, lubricant and hypotensive investigational drugs (ID) had a lower risk of incidence of AE than approved drugs (OR 0.856, 95% CI [0.365, 1.999] and 0.636, 95% CI [0.096, 4.197], respectively). Meanwhile, on antibiotic drugs, the risk for ID-related AE was higher (OR 1.313, 95% CI [0.309, 5.583]). CONCLUSION: Phase 1 trials are important in order to ensure the safety and tolerability of ophthalmic medications. This study demonstrates that NHVs do not face a significant risk of harm in these studies, since 98% of the reported AE were mild, and all AE were resolved by the end of the study in which they appeared. TRIAL REGISTRATION: This is a retrospective study of six previously conducted clinical trials, registered on clinicaltrials.gov with the following registration IDs: NCT04081610, NCT03524157, NCT03520348, NCT03966365, NCT03965052 and, NCT03519516.

Pharmacokinetics and Safety of an Intravitreal Humanized Anti-VEGF-A Monoclonal Antibody (PRO-169), a Biosimilar Candidate to Bevacizumab.

BACKGROUND: PRO-169 is a biosimilar candidate to bevacizumab (BEV), a monoclonal antibody (mAb) that inhibits vascular endothelial growth factor-A (VEGF-A) developed for intravitreal use. The current study demonstrates the intraocular pharmacokinetics (PK) of PRO-169 and its safety using New Zealand white (NZW) rabbits. METHODS: Intraocular concentration was evaluated in thirty-six rabbits at 1h, 1, 2, 5, 14 and 30 days after a single bilateral injection of PRO-169 or BEV (1.25 mg/0.05 mL). In a secondary experiment, safety was evaluated after three consecutive unilateral injections at 30-day intervals in twenty-four rabbits (PRO-169: 1.25 mg/0.05 mL or ranibizumab [RZB]: 0.5 mg/0.05 mL), by liver-associated enzymes (LAE), ophthalmological examination and adverse event (AE) incidence. Primary endpoints were vitreous maximum concentration (Cmax), time to attain maximum concentration (tmax), area under curve (AUC0-t), half-life (t1/2) and LAE. Secondary endpoints included aqueous humor (AH) and plasma pharmacokinetics, clinical examination and AEs. RESULTS: The Cmax in the vitreous was 593.75 ± 45.63 (PRO-169) vs 644.79 ± 62.65 µg/mL (BEV) (p= 0.136). Tmax was 0.53 ± 0.82 vs 0.85 ± 0.73 days (p= 0.330). The AUC0-t was 3837.72 ± 465.91 vs 4247.31 ± 93.99 days*µg/mL (p= 0.052) and the half-life was 4.99 ± 0.89 vs 5.18 ± 0.88 days (p= 0.711). LAEs were normal in 92% of NZW rabbits; no differences between groups were observed (p>0.05). The AH and plasma PKs were also similar. Finally, clinical examinations found no alterations. AEs were observed in 25% of PRO-169 rabbits, without differences vs RZB (p=0.399). CONCLUSION: PRO-169 can be efficiently diffused and distributed in ocular compartments, showing vitreous pharmacokinetics analogous to BEV. The safety experiment did not find evidence of clinical alterations from a repeated injection of PRO-169. These results provide scientific justification supporting that PRO-169 should be evaluated in future clinical trials to confirm its safety and efficacy.

Safety and tolerability evaluation after repeated intravitreal injections of a humanized anti-VEGF-A monoclonal antibody (PRO-169) versus ranibizumab in New Zealand white rabbits.

BACKGROUND: To evaluate the retinal toxicity after repeated intravitreal injections of a humanized anti-VEGF-A monoclonal antibody (PRO-169) versus ranibizumab in New Zealand white (NZW) rabbit eyes. METHODS: NZW rabbits were injected intravitreally with PRO-169 (n = 12), 1.25 mg/0.05 ml or ranibizumab (n = 12), 0.5 mg/0.05 ml into the right eye (OD), whereas the left eye (OS) of each rabbit was used as control. Three consecutive injections were administered at 30-days intervals. An electroretinogram (ERG) was recorded 30 days after each injection. Clinical examination was conducted before and after injections, including intraocular pressure determination and eye fundus exploration. Eyes were enucleated and retina, cornea, conjunctiva, ciliary body and optic nerve were prepared for histopathology assessment. RESULTS: ERG of the experimental and control eyes in PRO-169 and ranibizumab groups were similar in amplitude and pattern throughout the follow-up period. Clinical examination found no alterations of intraocular pressure (IOP). No retinal damage was observed in both, the experimental and control eyes, of all the rabbits. The histopathologic studies showed similar results in both groups, showing no signs of structural damage. CONCLUSIONS: Our study did not find evidence of retinal toxicity from a repeated intravitreal injection of PRO-169 or ranibizumab (Lucentis®) in NZW rabbits. These findings support intravitreal PRO-169 as a safe candidate to develop as a future alternative for the treatment of retinal neovascularization diseases.