Topical Eye Drop Treatment Research Articles

Glaucoma treatment and deprivation: time-series analysis of general practice prescribing in England.

Despite advances in glaucoma management, topical eyedrop treatment has been paramount, with prostaglandin analogues (PGAs) being first-line agents. While late presentation is linked with deprivation, there is no recent research examining associations between deprivation and prescribing within primary care. To explore PGA prescribing in general practice over a 6-year timeline, assessing associations with deprivation. Analysis of NHS Business Services Authority (NHSBSA) data for general practice prescribing in England from April 2016-March 2022. Glaucoma treatments by GP prescribers were extracted, identifying ~9.11-9.58 million prescriptions/annum. Data were linked to Index of Multiple Deprivation (IMD) quintiles of GP practices. Crude rates per 1000 population were calculated using population data from NHS Digital. Time-series analyses facilitated comparison in prescribing nationally and in deprived areas. Autoregressive Integrated Moving Average (ARIMA) modelling facilitated measurement of synchrony between time series using cross correlation. PGAs and fixed combination eyedrops accounted for approximately two-thirds of glaucoma-related prescribing. Prescriptions per month increased slightly over a 6-year timeline, but rates per 1000 population reduced in 2020-2021 during the COVID-19 pandemic. The number of PGA prescriptions dispensed in deprived areas was lower than all other quintiles. Cross-correlation analysis indicates a lag of ~12 months between average PGA prescribing nationally versus more deprived areas. The rate of PGA prescribing in primary care was substantially lower in deprived versus affluent areas, with delayed uptake of PGAs in more deprived areas of ~12 months. Further research is needed to explore reasons for this discrepancy, permitting strategies to be developed to reduce unwarranted variation.

Salidroside alleviates oxidative stress in dry eye disease by activating autophagy through AMPK-Sirt1 pathway.

Dry eye disease (DED) is a multifactorial disease, and oxidative stress plays a crucial role in its pathogenesis. Recently, multiple studies have shown that upregulation of autophagy can protect the cornea from oxidative stress damage. The present study investigated the therapeutic effects of salidroside, the main component of Rhodiola crenulata, in both in vivo and in vitro dry eye models. The results showed that topical eye drop treatment with salidroside restored corneal epithelium damage, increased tear secretion, and reduced cornea inflammation in the DED mice. Salidroside activated autophagy through AMP-activated protein kinase (AMPK)-sirtuin-1 (Sirt1) signaling pathway, which promoted the nuclear translocation of nuclear factor erythroid-2-related factor 2 (Nrf2) and increased the expression of downstream antioxidant factors heme oxygenase-1 (HO-1) and NAD(P)H quinone dehydrogenase 1 (NQO1). This process restored antioxidant enzyme activity, reduced reactive oxygen species (ROS) accumulation, and alleviated oxidative stress. The application of autophagy inhibitor chloroquine and AMPK inhibitor Compound C reversed the therapeutic efficacy of salidroside, validating the above findings. In conclusion, our data suggest that salidroside is a promising candidate for DED treatment.

Time-dependent in situ structural and cellular aberrations in rabbit cornea in vivo after mustard gas exposure

An array of corneal pathologies collectively called mustard gas keratopathy (MGK) resulting from ocular exposure to sulfur mustard (SM) gas are the most prevalent chemical warfare injury. MGK involves chronic ocular discomfort that results in vision impairment. The etiology of MGK remains unclear and poorly understood primarily due to a lack of scientific data regarding structural and cellular changes in different layers of the cornea altered by mustard vapor exposure in vivo. The goals of this study were to (a) characterize time-dependent changes in different layers of corneal epithelium, stroma, and endothelium in live animals in situ by employing state-of-the-art multimodal clinical ophthalmic imaging techniques and (b) determine if SM-induced acute changes in corneal cells could be rescued by a topical eye drop (TED) treatment using in an established rabbit in vivo model. Forty-five New Zealand White Rabbit eyes were divided into four groups (Naïve, TED, SM, and SM + TED). Only one eye was exposed to SM (200 mg-min/m3 for 8 min), and each group had three time points with six eyes each (Table-1). TED was topically applied twice a day for seven days. Clinical eye examinations and imaging were performed in live rabbits with stereo, Slit-lamp, HRT-RCM3, and Spectralis microscopy system. Fantes grading, fluorescein staining, Schirmer's tests, and applanation tonometry were conducted to measure corneal haze, ocular surface aberrations, tears, and intraocular pressure respectively. H&E and PSR staining were used for histopathological cellular changes in the cornea. In vivo confocal and OCT imaging revealed significant changes in structural and morphological appearance of corneal epithelium, stroma, and endothelium in vivo in SM-exposed rabbit corneas in a time-dependent manner compared to naïve cornea. Also, SM-exposed eyes showed loss of corneal transparency characterized by increased stromal thickness and light-scattering myofibroblasts or activated keratocytes, representing haze formation in the cornea. Neither naive nor TED-alone treated eyes showed any structural, cellular, and functional abnormalities. Topical TED treatment significantly reduced SM-induced abnormalities in primary corneal layers. We conclude that structural and cellular changes in primary corneal layers are early pathological events contributing to MGK in vivo, and efficient targeting of them with suitable agents has the potential to mitigate SM ocular injury.

Different adverse effects of air pollutants on dry eye disease: Ozone, PM2.5, and PM10

To date, there have been no well-organized clinical studies evaluating which air pollutants affect dry eye disease (DED). In this study, we investigated changes in the clinical parameters of DED according to exposure to outdoor air pollutants, including PM2.5 (particulate matter with an aerodynamic diameter of less than 2.5 μm), PM10 (less than 10 μm), and ozone. A prospective observational study was conducted on 43 DED patients who had used the same topical eye drop treatment between 2016 and 2018 in South Korea. Ocular surface discomfort index (OSDI) score, tear film break-up time (TBUT), corneal fluorescein staining score (CFSS), and tear secretion were measured during each visit. Air pollution data of ambient PM10, PM2.5, and ozone, based on the patients’ address, were obtained, and mean concentrations were computed for one day, one week, and one month before the examination. The relationships between air pollutants and DED were analyzed in single- and multi-pollutant models adjusted for demographic and clinical factors. In the multi-pollutant model, the OSDI score was positively correlated with ozone and PM2.5 exposure [ozone: β(exposure for 1 day/1 week) = 0.328 (95% CI: 0.161–0.494)/0.494 (0.286–0.702), p < 0.001/<0.001, per 1 ppb increase; PM2.5: β(1 day/1 week) = 0.378 (0.055–0.699)/0.397 (0.092–0.703), p = 0.022/ = 0.011, per 1 μg/m3 increase], and tear secretion decreased with increased ozone exposure [ozone: β(1 week/1 month) = −0.144 (−0.238 to −0.049)/-0.164 (−0.298 to −0.029), p = 0.003/ = 0.017, per 1 ppb increase]. Interestingly, increased PM10 exposure was only associated with decreased TBUT [β(1 day/1 week/1 month) = −0.028(-0.045 to −0.011)/-0.029(-0.046 to −0.012)/-0.023(-0.034 to −0.006), p = 0.001/ = 0.001/ = 0.018, per 1 μg/m3 increase]. Tear secretion and CFSS were not associated with PM10 exposure. Increased ozone and PM2.5 exposure led to aggravated ocular discomfort, and increased PM10 concentration aggravated tear film stability in patients with DED. Thus, each air pollutant may aggravate DED via different mechanisms of action.

The SRPK1 inhibitor SPHINX31 prevents increased retinal permeability in a rodent model of diabetes

PurposeIn diabetic retinopathy (DR) microvascular damage results from ischaemia driven production of pro‐angiogenic vascular endothelial growth factor (VEGF) inducing angiogenesis and increased permeability in the retina. Small molecule inhibitors of serine‐rich protein kinase‐1 (SRPK1), with good penetration properties to the retina, have been shown to inhibit choroidal neovascularisation in mice as eye drops by decreasing pro‐angiogenic and increasing anti‐angiogenic VEGF isoforms. SRPK1 inhibitors such as SPHINX31 may therefore switch splicing in DR and prevent increased vascular permeability.MethodsFFA was performed in Norway Brown rats on day 0 and 7, using the Micron IV retinal microscope (Phoenix Research). Animals received twice daily topical eye drops with eye formulation only control buffer (n = 5) or SPHINX31 (200 μg/ml, n = 6). On day 1 animals received a single dose of streptozotocin (50 mg/kg, i.p.) to induce type I diabetes and maintained for 1 week without insulin. The ratio of interstitial to vascular fluorescence was calculated and plotted against time to determine an estimate of permeability.ResultsRetinal permeability (12.67 ± 1.09 × 10−4 cms−1) was shown to significantly increase (p &lt; 0.01) in diabetics compared to before diabetes (8.85 ± 1.29 × 10−4 cms−1) in the eye formulation control group. Following a weekly regimen of twice daily topical eye drop treatment with SPHINX31 retinal permeability was no greater in the diabetics than (7.92 ± 1.65 × 10−4 cms−1) than before induction of diabetes, (8.15 ± 2.33 × 10−4 cms−1) and in the control group.ConclusionsSPHINX31 protected the retinal endothelial permeability barrier from diabetes‐associated loss of integrity. SPHINX31 may therefore be a potential alternative and more specific topical therapeutic for DR.

A novel rare sugar inhibitor of murine herpes simplex keratitis

PurposeTo determine the therapeutic efficacy of a novel rare sugar, l-psicose, for the treatment of HSV-1 induced herpetic stromal keratitis (HSK) in a mouse eye model. MethodsOne rare sugar l-psicose was assayed for HSV-1 inhibition of in vitro virus adsorption. The IC50 and IC90 values of l-psicose were determined using plaque reduction assay (PRA) in CV-1 cell. Female Balb/c mice were corneally infected with HSV-1, strain KOS-GFP; A topical eye drop treatment of l-psicose was started 24 h after infection and continued four times daily for ten consecutive days. The severity of HSK was monitored by slit lamp examination in a masked fashion and Infectious HSV-1 shedding was determined by PRA. Resultsl-psicose was found to have anti-viral activity in vitro at an IC50 dose of 99.5 mM and an IC90 dose of 160 mM. Topical eye drop treatment with 200 mM l-psicose in PBS solution significantly reduced the severity of HSK compared to the mock treatment group. The in vivo mouse ocular model results of l-psicose therapy correlated with accelerated clearance of virus from eye swabs. ConclusionThe results suggest that topical treatment with rare sugar l-psicose has efficacy against HSK through inhibition of HSV-1.

Preliminary report of improved sleep quality in patients with dry eye disease after initiation of topical therapy.

PurposeDry eye disease (DED) is potentially associated with sleep and mood disorders. This study evaluated sleep quality in patients with DED using a questionnaire-based survey before and after topical eyedrop treatment. The effectiveness of sleep and ophthalmic services in assisting with sleep problems in patients with eye disease was also assessed.MethodsSeventy-one consecutive patients with DED visiting eight general eye clinics in various locations answered a questionnaire containing the Pittsburgh Sleep Quality Index and Hospital Anxiety and Depression Scale. Photophobia and chronotype (morningness/eveningness) were also evaluated with two representative questions from established questionnaires (National Eye Institute Visual Function Questionnaire-25 and Morningness/Eveningness questionnaire). Follow-up evaluation was conducted by interview or mail 3–10 months after the initial evaluation. A sleep service was established in two eye clinics to identify possible ocular diseases related to sleep and mood disorders; it comprised a questionnaire, sleep diary, actigram, medical interviews, visual field testing, retinal ganglion cell layer thickness measurement, and DED examination.ResultsPatients with newly diagnosed DED exhibited a greater improvement in sleep after DED treatment compared with patients with established DED. Improvement in Pittsburgh Sleep Quality Index was significant (P<0.05) and strongly correlated with improvement in Hospital Anxiety and Depression Scale (P<0.05) for new patients, but not for patients with established DED. Ten eye clinic patients visited the sleep service and nine of them had DED. They were successfully treated with eyedrops and sleep services, which included blue-light-shield eyewear and wearable blue-light therapy lamps according to their problem.ConclusionSleep quality improved in patients with DED after topical treatment with or without the sleep service. Psychiatric treatment focusing on sleep disorders could be beneficial for patients with DED.

Ocular drug delivery nanowafer with enhanced therapeutic efficacy.

Presently, eye injuries are treated by topical eye drop therapy. Because of the ocular surface barriers, topical eye drops must be applied several times in a day, causing side effects such as glaucoma, cataract, and poor patient compliance. This article presents the development of a nanowafer drug delivery system in which the polymer and the drug work synergistically to elicit an enhanced therapeutic efficacy with negligible adverse immune responses. The nanowafer is a small transparent circular disc that contains arrays of drug-loaded nanoreservoirs. The slow drug release from the nanowafer increases the drug residence time on the ocular surface and its subsequent absorption into the surrounding ocular tissue. At the end of the stipulated period of drug release, the nanowafer will dissolve and fade away. The in vivo efficacy of the axitinib-loaded nanowafer was demonstrated in treating corneal neovascularization (CNV) in a murine ocular burn model. The laser scanning confocal imaging and RT-PCR study revealed that once a day administered axitinib nanowafer was therapeutically twice as effective, compared to axitinib delivered twice a day by topical eye drop therapy. The axitinib nanowafer is nontoxic and did not affect the wound healing and epithelial recovery of the ocular burn induced corneas. These results confirmed that drug release from the axitinib nanowafer is more effective in inhibiting CNV compared to the topical eye drop treatment even at a lower dosing frequency.

Anti-angiogenic effects of the receptor tyrosine kinase inhibitor, pazopanib, on choroidal neovascularization in rats

Neovascularization in the eye is a major cause of irreversible vision loss. The present study was undertaken to determine mechanisms through which pazopanib, a drug that targets multiple receptor tyrosine kinases such as VEGF receptors, inhibits angiogenesis and experimental choroidal neovascularization (CNV). Pazopanib inhibited VEGF expression by retinal pigment epithelium (RPE) cells and choroidal endothelial cells (CEC), decreased VEGF-induced cellular migration in a dose-dependent manner and suppressed extracellular signal-regulated kinase (ERK)-1/-2 phosphorylation. To assess the impact of pazopanib in vivo, CNV was induced in rats by rupturing the Bruch's membrane by laser coagulation. These experiments demonstrated that twice-daily topical eye drop treatment significantly ( P < 0.001) decreased leakage from photocoagulated lesions by 89.5%. Furthermore, the thickness of the developed CNV lesions was significantly inhibited by 71.7% ( P < 0.001) in pazopanib-treated eyes, and immunoreactivity of VEGF was lower than in control eyes. Our data suggest that pazopanib is a promising inhibitor of angiogenesis leading to an effective inhibition of CNV development in vivo. This activity can be largely ascribed to the down-regulation of VEGF release in the retina as well as to impaired VEGF-induced signaling and chemotaxis. Using a convenient topical dosing regimen, pazopanib may prove useful for treating a variety of ocular neovascular diseases such as neovascular age-related macular degeneration.

Novel Molecular Imaging Approach for Subclinical Detection of Iritis and Evaluation of Therapeutic Success

There is an urgent need for early diagnosis in medicine, whereupon effective treatments could prevent irreversible tissue damage. Acute anterior chamber inflammation is the most common form of uveitis and a major cause of vision loss. The proximity of the iris vasculature to the light-permeable cornea and its involvement in ocular inflammation make it an ideal target for noninvasive molecular imaging. To accomplish this, carboxylated fluorescent microspheres (MSs) were conjugated with recombinant P-selectin glycoprotein ligand-1 and systemically injected in endotoxin-induced uveitic animals. MS adhesion in the microcirculation of the anterior and posterior chamber was visualized by intravital microscopy and scanning laser ophthalmoscopy. In iritic animals, significantly higher numbers of recombinant P-selectin glycoprotein ligand-1-conjugated MSs adhered to the endothelium (P = 0.03) matching the increase in leukocyte adhesion. Conjugated MSs specifically interacted with firmly adhering leukocytes, allowing quantification of the endogenous immune response. Topical eye drop treatment with dexamethasone (P < 0.01) or cyclosporine A (P < 0.01) significantly lowered MS adhesion in iris vessels. Surprisingly, topical dexamethasone significantly reduced MS interaction in the fundus vessels (P < 0.01), while cyclosporine A did not. In vivo MS accumulation preceded clinical signs of anterior uveitis and leukocyte adhesion in iris vasculature. This work introduces noninvasive subclinical detection of endothelial injury in the iris vasculature, providing a unique opportunity for quantifying vascular injury and immune response in vivo.