In Vivo Ocular Pharmacokinetics and Toxicity of Siponimod in Albino Rabbits.

Siponimod is a promising agent for the inhibition of ocular neovascularization in diabetic retinopathy and age-related macular degeneration. Siponimod's development for ophthalmological application is hindered by the limited information available on the drug's solubility, stability, ocular pharmacokinetics (PK), and toxicity in vivo. In this study, we investigated the aqueous stability of siponimod under stress conditions (up to 60 °C) and its degradation behavior in solution. Additionally, siponimod's ocular PK and toxicity were investigated using intravitreal injection of two different doses (either 1300 or 6500 ng) in an albino rabbit model. Siponimod concentration was quantified in the extracted vitreous, and the PK parameters were calculated. The drug half-life after administration of the low and high doses was 2.8 and 3.9 h, respectively. The data obtained in vivo was used to test the ability of published in silico models to predict siponimod's PK accurately. Two models that correlated siponimod's molecular descriptors with its elimination from the vitreous closely predicted the half-life. Furthermore, 24 h and 7 days after intravitreal injections, the retinas showed no signs of toxicity. This study provides important information necessary for the formulation and development of siponimod for ophthalmologic applications. The short half-life of siponimod necessitates the development of a sustained drug delivery system to maintain therapeutic concentrations over an extended period, while the lack of short-term ocular toxicity observed in the retinas of siponimod-treated rabbits supports possible clinical use.

Siponimod As a Novel Inhibitor of Retinal Angiogenesis: In Vitro and In Vivo Evidence of Therapeutic Efficacy.

Sphingosine-1-phosphate (S1P) receptors control endothelial cell proliferation, migration, and survival. Evidence of the ability of S1P receptor modulators to influence multiple endothelial cell functions suggests their potential use for antiangiogenic effect. The main purpose of our study was to investigate the potential of siponimod for the inhibition of ocular angiogenesis in vitro and in vivo. We investigated the effects of siponimod on the metabolic activity (thiazolyl blue tetrazolium bromide assay), cell toxicity (lactate dehydrogenase release), basal proliferation and growth factor-induced proliferation (bromodeoxyuridine assay), and migration (transwell migration assay) of human umbilical vein endothelial cells (HUVEC) and retinal microvascular endothelial cells (HRMEC). The effects of siponimod on HRMEC monolayer integrity, barrier function under basal conditions, and tumor necrosis factor alpha (TNF-α)-induced disruption were assessed using the transendothelial electrical resistance and fluorescein isothiocyanate-dextran permeability assays. Siponimod's effect on TNF-α-induced distribution of barrier proteins in HRMEC was investigated using immunofluorescence. Finally, the effect of siponimod on ocular neovascularization in vivo was assessed using suture-induced corneal neovascularization in albino rabbits. Our results show that siponimod did not affect endothelial cell proliferation or metabolic activity but significantly inhibited endothelial cell migration, increased HRMEC barrier integrity, and reduced TNF-α-induced barrier disruption. Siponimod also protected against TNF-α-induced disruption of claudin-5, zonula occludens-1, and vascular endothelial-cadherin in HRMEC. These actions are mainly mediated by sphingosine-1-phosphate receptor 1 modulation. Finally, siponimod prevented the progression of suture-induced corneal neovascularization in albino rabbits. In conclusion, the effects of siponimod on various processes known to be involved in angiogenesis support its therapeutic potential in disorders associated with ocular neovascularization. SIGNIFICANCE STATEMENT: Siponimod is an extensively characterized sphingosine-1-phosphate receptor modulator already approved for the treatment of multiple sclerosis. It inhibited retinal endothelial cell migration, potentiated endothelial barrier function, protected against tumor necrosis factor alpha-induced barrier disruption, and also inhibited suture-induced corneal neovascularization in rabbits. These results support its use for a novel therapeutic indication in the management of ocular neovascular diseases.

Angle Kappa agreement between Scheimpflug tomography, combined placido Scheimpflug and combined slit scanning placido systems.

PURPOSE: To compare the measured or calculated angle Kappa using Oculus pentacam HR, Sirius and Orbscan III devices. PATIENTS AND METHODS: A prospective randomized cohort study, conducted on 47 eyes of 47 healthy orthotropic individuals, with an age range of 18-50 years and a corrected Snellen's distance visual acuity (CDVA) of 0.8 decimal or better. Angle Kappa is assessed directly using Orbscan® III software version 1.8.165.1. (Bausch and Lomb Rochester, New York, United States), while Pentacam® HR 1.21r.65 (Oculus Optikgeräte GmbH, Wetzlar, Germany) and Sirius device (CSO, version 3.2.1.60, Costruzione Strumenti Oftalmici, Florence, Italy) were used to calculate angle kappa indirectly. RESULTS: Least mean difference of estimated angle Kappa was between Orbscan and Pentacam devices (- 0.18° ± 1.8), and it was statistically insignificant (p value = 0.1294). Differences between both Orbscan and Sirius, and Pentacam and Sirius were statistically significant (p value = 0.0004 and < 0.0001 consecutively). Bland Altman analysis showed a 95% confidence interval between Orbscan III and Pentacam of - 3.76 to 3.4 and between Orbscan III and Sirius of - 3.79 to 2.26. CONCLUSION: Pentacam parameters can be used as a reliable method to calculate angle kappa indirectly, without usage of any additional measurements from other machine. Sirius device parameters could also be used, but with less accurate results. A simple modification to those devices' software to calculate it, and incorporate it in the printout is possible, and highly recommended.

Optic nerve head perfusion changes in eyes with proliferative diabetic retinopathy treated with intravitreal ranibizumab or photocoagulation: a randomized controlled trial.

Background: Proliferative diabetic retinopathy (PDR) is a serious sight-threatening disease, and half of the patients with high-risk PDR can develop legal blindness within 5 years, if left untreated. This study was aimed at comparing panretinal photocoagulation (PRP) and intravitreal ranibizumab injections in terms of radial peripapillary capillary (RPC) density on optical coherence tomography angiography (OCTA) in patients with treatment-naive PDR. Methods: This open-label, prospective, randomized clinical trial included 50 patients with treatment-naive PDR with optic disc neovascularization and randomized them into two groups: group 1, with patients undergoing two sessions of PRP 2 weeks apart, and group 2, with patients received three intravitreal ranibizumab injections (0.5 mg) 1 month apart for 3 consecutive months. Patients underwent a full ophthalmological examination, including best-corrected distance visual acuity (BCDVA) measurement in the logarithm of minimal angle of resolution (logMAR) notation and OCTA before intervention and monthly after the last laser session or the first intravitreal ranibizumab injection for 3 months of follow-up. Visual field (VF) was tested at the beginning and end of 3 months. Results: Forty-two (84%) eyes completed the 3-month follow-up, including 22 eyes in the PRP group (88%) and 20 (80%) eyes in the ranibizumab group. The two groups were comparable in terms of demographic characteristics, diabetes duration, baseline BCDVA, glycated hemoglobin level, OCTA parameters, VF indices, and intraocular pressure (all P > 0.05). The RPC density change from baseline to the 3-month follow-up was significantly lower in the PRP group than in the ranibizumab group (mean difference in RPC density change: - 3.61%; 95% confidence interval: - 5.57% to - 1.60%; P = 0.001). The median (interquartile range) logMAR change from baseline to the 3-month follow-up (0.0 [0.2]) was significantly higher in the PRP group than in the ranibizumab group (- 0.15 [0.3]; P < 0.05). The median changes in central foveal thickness from baseline to the 3-month follow-up differed significantly between the two groups (P = 0.001). Conclusions: In eyes with PDR and neovascularization of the disc RPC density on OCTA increased in the ranibizumab group and decreased in the PRP group. Visual acuity gain was higher in the ranibizumab group than in the PRP group. Future multicenter trials addressing our limitations are required to verify the findings of this study.

Comparison of the Clinical Efficacy of Abobotulinumtoxin A (ABO) and Onabotulinumtoxin A (ONA) in the Treatment of Crow's Feet Wrinkles: A Split-Face Study.

PURPOSE: Comparing the clinical efficacy of Abobotulinumtoxin A (ABO) and Onabotulinumtoxin A(ONA) using a dosing ratio of 2.5U:1.0U in the treatment of crow's feet wrinkles. SUBJECTS AND METHODS: A single-blinded, randomized, split-face study, included 40 subjects, with moderate-to-severe crow's feet wrinkles. Patients were subjected to a dose equivalence of (ABO):(ONA); 2.5:1.0 U. Post treatment evaluation was done on 7, 30, and 120 days, comparing: Time, Duration, and Degree of Improvement; Patients Satisfaction. RESULTS: No significant difference was found between ABO & ONA regarding duration and time to improvement on static posture. While on dynamic posture, ABO showed significantly less time and longer duration. Both products produced highly significant improvement of the wrinkles' severity on both static and dynamic posture in comparison to the baseline severity. Satisfaction was more with ABO. CONCLUSION: ABO is a safe, effective alternative to ONA in treating crow's feet wrinkles.

Efficacy of Intravitreal injection of 2-Methoxyestradiol in regression of neovascularization of a retinopathy of prematurity rat model.

BACKGROUND: Retinopathy of prematurity (ROP) is one of the targets for early detection and treatment to prevent childhood blindness in world health organization programs. The purpose of study was to evaluate the efficacy of intravitreal injection of 2-Methoxyestradiol (2-ME) nanoemulsion in regressing neovascularization of a ROP rat model. METHODS: A prospective comparative case - control animal study conducted on 56 eyes of 28 healthy new born Sprague Dawley male albino rat. ROP was induced in 21 rats then two concentrations of 2-ME nanoparticles were injected in right eyes of 14 rats (low dose; study group I, high dose; study group II). A blank nanoemulsion was injected in the right eyes of seven rats (control positive group I). No injections performed in contralateral left eyes (control positive group II). Seven rats (14 eyes) were kept in room air (control negative group). On postnatal day 17, eyeballs were enucleated. Histological structure of the retina was examined using Hematoxylin and eosin staining. Vascular endothelial growth factor (VEGF) and glial fibrillary acidic protein (GFAP) expressions were detected by immunohistochemical studies. RESULTS: Intravitreal injection of 2-ME (in the two concentrations) caused marked regression of the new vascular tufts on the vitreal side with normal organization and thickness of the retina especially in study group II, which also show negative VEGF immunoreaction. Positive GFAP expression was detected in the control positive groups and study group (I). CONCLUSION: Intravitreal injection of 2-Methoxyestradiol nanoemulsion is a promising effective method in reduction of neovascularization of a ROP rat model.

Safety and efficacy of photodynamic therapy using BCECF-AM compared to mitomycin C in controlling post-operative fibrosis in a rabbit model of subscleral trabeculectomy.

AIM: To evaluate the safety and efficacy of cellular photoablation using BCECF-AM [2', 7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein, acetoxymethyl ester mixed isomers] as a method to control postoperative fibrosis in subscleral trabeculectomy (SST) compared to mitomycin C (MMC) in a rabbit model. METHODS: A comparative prospective case-control animal study was conducted. Fourteen rabbits were subjected to SST with intraoperative use of wound modulating agents (MMC or BCECF-AM) of the right eye (study groups I and II respectively) and SST without use of intraoperative wound modulating agents for the left eye (control group II). Two rabbits 4 eyes were considered as control group I with no surgical intervention. BCECF-AM was injected subconjunctivally 30min before surgery followed by intraoperative illumination with diffuse blue light for 10min. Antifibrotic efficacy was established by clinical response and histological examination. Clinical response was assessed by measuring intraocular pressure (IOP) at day 1, 3, 5, 7, 14, 21 postoperatively. Success was defined by >20.0% reduction in IOP from the preoperative values without anti-glaucoma medications. RESULTS: The mean percentage of reduction was 35.0% in the study group I with only one eye (14.3%) had 12.5% reduction. The mean percentage of reduction was 28.0 % in the study group II with two eyes (28.6%) in study group II had 14.2% reduction each. Regarding the control group II, the mean percentage of reduction was 14.3 % with 64.3% eyes had <20.0% reduction. There was a highly statistically significant difference between each of the study groups (right eyes) and the corresponding control group II (left eyes) as regards the mean postoperative IOP values started from day 5 in both study groups and this highly significant difference remained so till the end of the follow up period. Histologically, MMC treated blebs showed thinning of conjunctival epithelium with marked reduction of the goblet cells relative to control. Marked sub-epithelial edema was seen along with variable collagen dispersion. Mild cellularity was noted in sub-epithelial tissue. BCECF-AM treated blebs showed normal conjunctival epithelial thickness with abundant goblet cells. Mild sub-epithelial edema was noted along with moderate collagen dispersion. No histological abnormality was noted in the ciliary body or the cornea in any of the studied groups. CONCLUSION: Cellular photoablation using BCECF-AM is a safe and effective wound modulating agent to control postoperative fibrosis in trabeculectomy. However MMC considered as a more potent adjuvant to trabeculectomy than BCECF-AM in promoting IOP reduction.

Forensic analysis of ocular injuries during the 2011 revolution in Egypt.

INTRODUCTION: During the year 2011 the Egyptian revolution arose with a change in the trend of eye trauma in Egypt. AIM OF WORK: This study aims at reviewing the epidemiology of ocular trauma presenting to Ain Shams University teaching hospital during the year 2011 and comparing it with epidemiology during the previous 5 years. PATIENTS AND METHODS: This is a retrospective epidemiological and clinical study of patients admitted to Ain Shams University Hospital with ocular trauma from 2006 till 2011. Cases were analyzed with respect to age, sex, occupation, admission interval, type, mode, time and place of injury, causative instrument, diagnosis and examination findings, investigations, management and visual outcomes. RESULTS: Total numbers of cases presenting during the year 2011 was 237 cases. The mean age was 22.5 years. Students (47.2%) and jobless people (21.9%) constituted the majority of the sample. During the year 2011 there was a significant increase in the percentage of injuries occurring in the street. There was also a significant rise in the percentage of homicidal ocular injuries specially those caused from non-rifled weapons. Fourteen cases of endophthalmitis were associated with non-rifled fire arm missiles while 7 were associated with glass intra-ocular foreign body. This indicated that the probability of occurrence of endophthalmitis with metal intraocular foreign bodies was 2:3 i.e. 66.6% where as in glass intra ocular foreign body was 7:9 i.e. 77.7%. CONCLUSION: The majority of ocular trauma in our population during the year 2011 was due to homicidal street injuries occurring mainly in males of young age group, which is consistent with the events occurring in Egypt in this year. The findings indicate that ocular trauma is a significant cause of visual loss in this population.