Aqueous Humor Production Research Articles

Therapeutic potential of AAV-mediated MMP-3 secretion from corneal endothelium in treating glaucoma.

Intraocular pressure (IOP) is maintained as a result of the balance between production of aqueous humour (AH) by the ciliary processes and hydrodynamic resistance to its outflow through the conventional outflow pathway comprising the trabecular meshwork (TM) and Schlemm’s canal (SC). Elevated IOP, which can be caused by increased resistance to AH outflow, is a major risk factor for open-angle glaucoma. Matrix metalloproteinases (MMPs) contribute to conventional aqueous outflow homeostasis in their capacity to remodel extracellular matrices, which has a direct impact on aqueous outflow resistance and IOP. We observed decreased MMP-3 activity in human glaucomatous AH compared to age-matched normotensive control AH. Treatment with glaucomatous AH resulted in significantly increased transendothelial resistance of SC endothelial and TM cell monolayers and reduced monolayer permeability when compared to control AH, or supplemented treatment with exogenous MMP-3.Intracameral inoculation of AAV-2/9 containing a CMV-driven MMP-3 gene (AAV-MMP-3) into wild type mice resulted in efficient transduction of corneal endothelium and an increase in aqueous concentration and activity of MMP-3. Most importantly, AAV-mediated expression of MMP-3 increased outflow facility and decreased IOP, and controlled expression using an inducible promoter activated by topical administration of doxycycline achieved the same effect. Ultrastructural analysis of MMP-3 treated matrices by transmission electron microscopy revealed remodelling and degradation of core extracellular matrix components. These results indicate that periodic induction, via use of an eye drop, of AAV-mediated secretion of MMP-3 into AH could have therapeutic potential for those cases of glaucoma that are sub-optimally responsive to conventional pressure-reducing medications.

Rhegmatogenous Retinal Detachment Associated with Choroidal Detachment

Review describes the theme of rhegmatogenous retinal dеtаchment associated with choroidal separation. It is rare, but quite severe eye pathology. In most cases it has a very poor prognosis. Most authors consider the retinal detachment as a primary pathogenetic part, which decompensates the production of aqueous humor by increasing the absorptive surface of the retinal pigment epithelium. Dilatation of choroidal arterioles occurs in hypotension, it leads to extravasation of protein-rich fluid in the choroidal and the suprachoroidal space. This helps to further swelling and separation of the ciliary body and the choroid with reduced production of aqueous humor and progressive hypotension. There is a high risk of developing “retino-choroidal” separation in patients with macular rupture due to localization of retinal separation and rupture rear hyaloid membrane. The protein level in aqueous humor can be increased to 70 times. It may be a result of reflux of suprachoroidal proteins through uveoscleral route and / or venous proteins through the trabecular network. In addition, the diffusion of proteins from the posterior camera and vitreous cavity is possible. This creates favorable conditions for cell proliferation that can lead to postoperative proliferative vitreoretinopathy. Typically patients have a pronounced signs of inflammation, pain, and “red eye”, which is accompanied with vision decrement. Rhegmatogenous retinal reparationcan be associated with such clinical symptoms as severe panuveit, deepening of the anterior camera and the inflammatory response in the moisture, concentric wrinkles and sagging back of the iris, posterior synechia, iridofakodenez, blurred vitreous detachment of the ciliary body, hypotension, and choroidal and retinal detachment in addition. Debatableness of etiopathogenesis and a clinical picture, which is similar to other eye diseases create significant difficulties in early diagnosis and proper treatment of this pathology. Correct early diagnosis of “retino-choroidal dеtаchment” is complicated by several factors: sluggish pupil dilation, exacerbated by the presence of posterior synechiaes, clouding environments with the presence of cellular elements, choroidal dеtаchment, masking the retinal tears. Rhegmatogenous retino–choridal dеtаchment should be differentiated from a number of pathologies. The most obvious sign of “retinyl choroidal” dеtаchment is severe generalized inflammation leading to an erroneous diagnosis of uveitis. A particular problem is the differentiation with syndrome of uveal effusion, choroidal melanoma. Retino-choroidal dеtаchment is a rare pathology that requires timely and correct diagnosis of pathogenically based treatment.

Ultrasound Cycloplasty in Glaucoma – Mechanisms of Action and their Possible Impact on Intraocular Pressure

Ultrasound cycloplasty (UCP) is a procedure based on high-intensity focused ultrasound (HIFU) for refractory and non-refractory glaucoma in cases for which surgery is not suitable. UCP may bring about a reduction in intraocular pressure (IOP) via multiple mechanisms of action that result in a decrease in aqueous humour production and increase in aqueous humour evacuation. UCP appears to have a favourable safety profile compared with cyclo-destructive methods, with no phthisis bulbi, no induced cataract, and no persistent hypotony. In 103 patients with refractory and non-refractory glaucoma who underwent UCP, 94 (91%) achieved an initial reduction in IOP, and in 65 patients (63.1%), treatment success was achieved whereby the IOP remained low. However, in 22 patients (21.4%), at 3 months, the IOP rose to near the original level, indicating treatment failure: ‘early failure’. In the remaining 7 patients (6.8%), a slow rise in IOP occurred over 6 months following the procedure: ‘late failure’. The differences in IOP changes in these 94 patients may be in part explained by: (i) a reduction in the uveoscleral–transscleral openings in some patients, leading to an eventual rise in the initially decreased IOP; (ii) a possible re-epithelialisation of the ciliary processes taking place in some cases; and/or (iii) that the circumference of 160° UCP treatment might not be sufficient for all patients. The first 3 months following the UCP procedure are therefore critical since treatment success or failure is determined within this timeframe.

Effects of black currants anthocyanins on hemodynamics of aqueous humor and peripheral blood circulation

Purpose: In our previous studies, we demonstrated the beneficial effects that black currant anthocyanins (BCACs) have on glaucomatous optic neuropathy (GON) through their possible mechanisms toward reactivity to endothelin-1 (ET-1). The purpose of the current study is to examine the influence of BCACs on peripheral blood circulation as well as aqueous humor (AH) circulation.Methods: In our examination of peripheral blood circulation, responses toward finger cooling stimulation were monitored by a thermography in 8 healthy subjects receiving one time administration of BCACs (130 mg) and 5 separate subjects receiving BCACs daily (50 mg/day) for one week. To examine aqueous humor (AH) circulation, AH outflow resistance or AH production was evaluated by means of a Weight on-off test at baseline and again at week 1, 2 or 3 of BCACs administration.Results: Compared to pre-administration, recovery of the surface temperature of the middle finger was achieved more rapidly after both the one time BCAC intake and when they were administered over 7 days. Upon administration of BCACs for three weeks, the IOP drop rate and IOP recovery time increased and shortened, respectively.Conclusions: Our present results indicate that BCACs intake effectively suppresses cold-induced vasospasms and modulates AH circulation by a possible ET-1 mediated mechanism.

Additive Intraocular Pressure-Lowering Effects of Ripasudil with Glaucoma Therapeutic Agents in Rabbits and Monkeys.

Ripasudil hydrochloride hydrate (K-115), a specific Rho-associated coiled-coil containing protein kinase (ROCK) inhibitor, is developed for the treatment of glaucoma and ocular hypertension. Topical administration of ripasudil decreases intraocular pressure (IOP) by increasing conventional outflow through the trabeculae to Schlemm's canal, which is different from existing agents that suppress aqueous humor production or promote uveoscleral outflow. In this study, we demonstrated that ripasudil significantly lowered IOP in combined regimens with other glaucoma therapeutic agents in rabbits and monkeys. Ripasudil showed additional effects on maximum IOP lowering or prolonged the duration of IOP-lowering effects with combined administration of timolol, nipradilol, brimonidine, brinzolamide, latanoprost, latanoprost/timolol fixed combination, and dorzolamide/timolol fixed combination. These results indicate that facilitation of conventional outflow by ripasudil provides additive IOP-lowering effect with other classes of antiglaucoma agents. Ripasudil is expected to have substantial utility in combined regimens with existing agents for glaucoma treatment.

Ophthalmology and mathematics: crossroad or scientific interface?

Ophthalmology and mathematics: crossroad or scientific interface?

Mathematical modeling of aqueous humor flow and intraocular pressure under uncertainty: towards individualized glaucoma management

Purpose: The aim of the proposed analysis is to provide both a qualitative description and a quantitative assessment of how variations in aqueous humor (AH) flow parameters influence intraocular pressure (IOP) and the outcome of IOP-lowering medications.Methods: We developed a mathematical model that describes the steady-state value of IOP as the result of the balance between AH production and drainage. We performed stochastic simulations to assess the influence of different factors on the IOP distribution in ocular normotensive and ocular hypertensive subjects and on the IOP reduction following medications.Results: The distribution of the relative frequency of a given IOP value for ocular normotensive subjects fits a right-skewed Gaussian curve with a frequency peak of 25% at 15.13 mmHg and a skewness of 0.2, in very good agreement with the results from a population-based study on approximately 12,000 individuals. The model also shows that the outcomes of IOP-lowering treatments depend on the levels of pre-treatment IOP and blood pressure. The model predicts mean IOP reductions of 2.55 mmHg and 4.31 mmHg when the pre-treatment IOP mean values are 15.13 mmHg and 20.12 mmHg, respectively; these predictions are in qualitative and quantitative agreement with clinical findings.Conclusion: These findings may help identify patient-specific factors that influence the efficacy of IOP-lowering medications and aid the development of novel, effective, and individualized therapeutic approaches to glaucoma management.

Electro-fluid dynamics of aqueous humor production: simulations and new directions

Purpose: to theoretically investigate the role of bicarbonate ion (HCO−3 ) on the nonpigmented transepithelial potential dierence Vm, the sodium potassium pump (Na/K) and the active secretion of aqueous humor.Methods: a three-dimensional mathematical model is proposed to isolate the roles of HCO−3 and Na+, which are diicult to investigate experimentally. The model combines the velocity-extended Poisson-Nernst-Planck equations to describe ion electrodiusion and the Stokes equations to describe aqueous humor flow into the basolateral space adjacent to the nonpigmented ephitelial cells.Results: Computations showthat Vm is close to baseline experimental measurements (on monkeys) in the range [−2.7,−2.3]mVonly if HCO−3 is included in the simulation. The model is also capable of reproducing the flow of Na+ exiting the cell and the flow of K+ entering the cell, in accordance with the physiology of the Na/K pump. The simulated Na/K ratio is 1.53, which is in very good agreement with the theoretical value of 1.5.Conclusion: Model simulations suggest that HCO−3 inhibition may prevent physiologically correct baseline values of the nonpigmented transepithelial potential difference and Na/K ATPase function. This may provide useful indication in the design of medications that decrease the active secretion of aqueous humor, and supports the advantage of using mathematical models as a noninvasive complement of animal models.

Metabolomics of the human aqueous humor

The optical elements of the eye—cornea, lens, and vitreous humor—are avascular tissues, and their nutrition and waste removal are provided by aqueous humor (AH). The AH production occurs through the active secretion and the passive diffusion/ultrafiltration of blood plasma. The comparison of the metabolomic profiles of AH and plasma is important for understanding of the mechanisms of biochemical processes and metabolite transport taking place in vivo in ocular tissues. The work is aimed at the determination of concentrations of a wide range of most abundant metabolites in the human AH, the comparison of the metabolomic profiles of AH and serum, and the analysis of the post-mortem metabolomic changes in these two biological fluids. The quantitative metabolomic profiling was carried out with the use of two independent methods—high-frequency 1H NMR spectroscopy and HPLC with high-resolution ESI-MS detection. The concentrations of 71 most abundant metabolites in blood serum and AH from living patients and human cadavers have been measured. It has been found that the level of ascorbate in AH is by two orders of magnitude higher than that in serum; the levels of other metabolites are either similar to that in serum, or differ from that by a factor of 2–5. The post-mortem metabolomic composition of both serum and AH undergoes rapid and strong changes. The differences between the metabolomic profiles of AH and serum for majority of metabolites can be attributed to the metabolic activity of the ocular tissues leading to the lack or excess of some metabolites, while the high concentration of ascorbate in AH demonstrates the activity of ascorbate-specific pumps at the blood-aqueous border. The post-mortem metabolomic changes are caused by the disruption of the major biochemical cycles and cell lysis. These changes should be taken into account in the analysis of disease-induced changes in post-mortem samples of the ocular tissues.

Microstructure visualization of conventional outflow pathway and finite element modeling analysis of trabecular meshwork.

BackgroundThe intraocular pressure (IOP) is maintained through a dynamic equilibrium between the production and drainage of aqueous humor. Elevation of intraocular pressure is mainly caused by the blocking of aqueous humor outflow pathway. Therefore, it is particularly important to study the structure of drainage pathway and the effect of ocular hypertension at the process of aqueous humor outflow.MethodsConventional drainage pathway of aqueous humor, including trabecular meshwork (TM), Schlemm’s canal (SC) and aqueous vein, were imaged by using trans-scleral imaging method with lateral resolution of 2 μm. For quantitative assessment, the morphological parameters of the TM were measured with different IOP levels via a combination of measurements and simulations.ResultsImages of the TM and the adjacent tissues were obtained. The porosity of TM with normal intraocular pressure varies from 0.63 to 0.74 as the depth increases, while in high IOP it is changed from 0.44 to 0.59. The diameter of aqueous vein varies from 32 to 43 μm, and is smaller than that of SC, which varies from 48 to 64.67 μm.ConclusionsOur research provides a non-contact method to visualize the microstructure of tissue for clinical examination associated with the blocking of the outflow pathway of aqueous humor in humans. The three-dimensional (3D) microstructures of limbus and the results of finite element modeling analysis of the TM model will serve for the future evaluation of new glaucoma surgical techniques.

Three-dimensional simulation of biological ion channels under mechanical, thermal and fluid forces

In this article we address the three-dimensional modeling and simulation of biological ion channels using a continuum-based approach. Our multi-physics formulation self-consistently combines, to the best of our knowledge for the first time, ion electrodiffusion, channel fluid motion, thermal self-heating and mechanical deformation. The resulting system of nonlinearly coupled partial differential equations in conservation form is discretized using the Galerkin Finite Element Method. The validation of the proposed computational model is carried out with the simulation of two ion nanochannels. The first is a voltage operated channel with K+ and Na+ ions, and the second is the sodium-potassium pump in which also chlorine (Cl−) and bicarbonate (HCO3−) ions are considered. In the first case study, we investigate the coupling between electrochemical and fluid-dynamical effects. Then, we enrich the modeling picture by investigating the influence of a thermal gradient. Finally, we add a mechanical stress responsible for channel deformation and investigate its effect on the functional response of the channel. Results show that fluid and thermal fields have no influence in absence of mechanical deformation whereas ion distributions and channel functional response are significantly modified if mechanical stress is included in the model. These predictions agree with biophysical conjectures on the importance of protein conformation in the modulation of channel electrochemical properties. In the second case study, we exploit our multiphysical mathematical formulation to investigate the effect of permanent surface charge on the function of the sodium-potassium pump. In particular, we consider the biophysical application in which the pump actively participates to the process of aqueous humor production across the transepithelial membrane in the ciliary body of the eye. In this study we are motivated by the fact that several data are available to verify the accuracy of model predictions and that the role of surface charge has not yet been mathematically analyzed in the specific context at hand. Results show that the model is able to predict in a very accurate manner the correct aqueous humor flow direction, the magnitude of aqueous velocity and the experimentally measured transepithelial membrane potential only if the (negative) surface permanent charge is larger than a limiting value, whereas if the charge is below this value, fluid inversion occurs.

Anterior segment optical coherence tomography changes with introduction and discontinuation of tamsulosin

PurposeThe aim of this study was to quantify changes and reversibility in pupil dilation and iris dilator muscle region thickness associated with introduction and subsequent discontinuation of tamsulosin in patients naïve to this drug with the aid of an anterior OCT system. MethodsThe study was carried out on 7 patients (14 eyes) naïve to tamsulosin and with benign prostatic hypertrophy (BHP). Measurements taken by Vistante OCT were done pre- and post-dilation of the following: pupil size, iris dilator muscle region (DMR) thickness, sphincter muscle region (SMR) thickness, and anterior chamber depth. These measurement were taken at Day 0 (tamsulosin naive), Day 30 (after one month of tamsulosin, the treatment period) and day 60 (after one month of no tamsulosin, the discontinuation period). ResultsPost-dilation pupil diameter significantly increased during the discontinuation period (P=0.047). Iris DMR thickness measurements post-dilation significantly decreased during treatment (P=0.00044), discontinuation (0.00011), and combined periods (P=0.000050). Anterior chamber depth measurements in post-dilation were significantly decreased during treatment (P=0.0016), discontinuation (P=0.017), and combined periods (P=0.00022). ConclusionTamsulosin discontinuation effectively increases dilated pupil size, a measure that has been inversely linked to IFIS incidence pre-operatively. Decreased DMR thickness in this short term likely illustrates changes aside from atrophy, such as vascular changes. Decreased anterior chamber depths suggest aqueous humor production is decreased as well.

Novel therapeutic targets for reduction of intraocular pressure in primary open angle glaucoma

Glaucoma is a major cause of blindness in China and the world. Currently, all therapeutic means in treating open-angle glaucoma are limited to control the progression of optic neuropathy by lowering intraocular pressure (IOP). Clinically available medicines lower IOP by either enhancing the uveoscleral pathway or inhibiting aqueous humor production. Since the primary cause of IOP elevation in POAG is elevated outflow resistance in the trabecular outflow pathway, current medicines are not able to correct the underlying pathogenesis and pathophysiology of the disease. In this review article, we discuss a series of new therapeutic targets and therapeutic approaches that are designed to directly modify the pathological changes related to the reduction in trabecular outflow in glaucoma patients. Some of these targets and approaches may produce a significant breakthrough in the treatment of this devastating disease. (Chin J Ophthalmol, 2016, 52: 471-475).

Genetic association and stress mediated down-regulation in trabecular meshwork implicates MPP7 as a novel candidate gene in primary open angle glaucoma.

BackgroundGlaucoma is the largest cause of irreversible blindness affecting more than 60 million people globally. The disease is defined as a gradual loss of peripheral vision due to death of Retinal Ganglion Cells (RGC). The RGC death is largely influenced by the rate of aqueous humor production by ciliary processes and its passage through the trabecular meshwork (TM) in the anterior part of the eye. Primary open angle glaucoma (POAG), the most common subtype, is a genetically complex disease. Multiple genes and many loci have been reported to be involved in POAG but taken together they explain less than 10 % of the patients from a genetic perspective warranting more studies in different world populations. The purpose of this study was to perform genome-wide search for common variants associated with POAG in an east-Indian population.MethodsThe study recruited 746 POAG cases and 697 controls distributed into discovery and validation cohorts. In the discovery phase, genome-wide genotype data was generated on Illumina Infinium 660 W-Quad platform and the significant SNPs were genotyped using Illumina GGGT assay in the second phase. Logistic regression was used to test association in the discovery phase to adjust for population sub-structure and chi-square test was used for association analysis in validation phase. Publicly available expression dataset for trabecular meshwork was used to check for expression of the candidate gene under cyclic mechanical stress. Western blot and immunofluorescence experiments were performed in human TM cells and murine eye, respectively to check for expression of the candidate gene.ResultsMeta-analysis of discovery and validation phase data revealed the association of rs7916852 in MPP7 gene (p = 5.7x10−7) with POAG. We have shown abundant expression of MPP7 in the HTM cells. Expression analysis shows that upon cyclic mechanical stress MPP7 was significantly down-regulated in HTM (Fold change: 2.6; p = 0.018). MPP7 protein expression was also found to be enriched in the ciliary processes of the murine eye.ConclusionUsing a genome-wide approach we have identified MPP7 as a novel candidate gene for POAG with evidence of its expression in relevant ocular tissues and dysregulation under mechanical stress possibly mimicking the disease scenario.Electronic supplementary materialThe online version of this article (doi:10.1186/s12920-016-0177-6) contains supplementary material, which is available to authorized users.

Allometry and Scaling of the Intraocular Pressure and Aqueous Humour Flow Rate in Vertebrate Eyes.

In vertebrates, intraocular pressure (IOP) is required to maintain the eye into a shape allowing it to function as an optical instrument. It is sustained by the balance between the production of aqueous humour by the ciliary body and the resistance to its outflow from the eye. Dysregulation of the IOP is often pathological to vision. High IOP may lead to glaucoma, which is in man the second most prevalent cause of blindness. Here, we examine the importance of the IOP and rate of formation of aqueous humour in the development of vertebrate eyes by performing allometric and scaling analyses of the forces acting on the eye during head movement and the energy demands of the cornea, and testing the predictions of the models against a list of measurements in vertebrates collated through a systematic review. We show that the IOP has a weak dependence on body mass, and that in order to maintain the focal length of the eye, it needs to be an order of magnitude greater than the pressure drop across the eye resulting from gravity or head movement. This constitutes an evolutionary constraint that is common to all vertebrates. In animals with cornea-based optics, this constraint also represents a condition to maintain visual acuity. Estimated IOPs were found to increase with the evolution of terrestrial animals. The rate of formation of aqueous humour was found to be adjusted to the metabolic requirements of the cornea, scaling as , where Vac is the volume of the anterior chamber. The present work highlights an interdependence between IOP and aqueous flow rate crucial to ocular function that must be considered to understand the evolution of the dioptric apparatus. It should also be taken into consideration in the prevention and treatment of glaucoma.

Effects of 1% Topical Brinzolamide on Intraocular Pressure in Healthy Dogs

Background: Glaucoma is one of the most common causes of blindness in dogs, and is generally characterized by death of the retinal ganglion cells associated with a rapid loss of vision. Increased intraocular pressure (IOP) occurs in patients with primary glaucoma, due to genetic abnormalities in pectinal ligaments and the trabeculae of the iridocorneal angle, producing inadequate drainage of aqueous humor. IOP is the result of the dynamic equilibrium between the production and drainage of aqueous humor. Intraocular surgery, anterior lens luxation, systemic diseases, immune-mediated, neoplastic and infectious diseases lead to the breakdown of the blood-aqueous barrier and increase the amount of protein and cells in aqueous humor, which can block this drainage pathway. Under these conditions, becomes indispensable the pharmacological control of IOP by reducing aqueous humor production. The main objective of the present study was to evaluate the effects of topical 1% brinzolamide on intraocular pressure (IOP) in twelve healthy dogs.Materials, Methods & Results: The age range of affected dogs was 1-5 years, with a mean age of 2.5 years. Twelve dogs were included in this study. All animals were healthy based on clinical, ophthalmic and hematological examinations. Selected animals were kept in a room with 500 lux luminosity, 56.8% relative humidity, 20°C temperature, exposed to 12 h of light/dark cycle, were fed twice daily and water ad libitum. All animals were adaptation to the procedures and examiners and IOP was measured by applanation tonometry at 08:00 a.m., 11:00 a.m., 02:00 p.m., 05:00 p.m., and 08:00 p.m., for 7 days and 2 days of baseline. Subsequently, one eye of each dog was randomly assigned, the eye received one drop of 1% brinzolamide at 08:30 a.m., 02:30 p.m., and 08:30 p.m. during four consecutive days and adelfo eyes received one drop of sterile saline solution and were considered control eyes. During the treatment phase and on the day after the treatment had finished, all parameters were evaluated in a blind fashion at the same pre-established time points. The value for IOP during the baseline of the treated eye were 16.77 ± 0.22 mmHg. The baseline period, values did not differ significantly between treated and control eyes. Comparison between the first day of brinzolamide-treated eyes with the average daily values of the two days of the baseline period showed that IOP decreased significantly 8.88%. IOP after four days of daily instillations of brinzolamide was able to decrease overall IOP by 1.42 mmHg (8.47%) when compared with the baseline period. Overall IOP values in the brinzolamide-treated eyes decreased 1.02 mmHg (6.24%) when compared to the control eyes. There were no statistically significant differences when compared control eye to baseline. Three times daily instillations of 1% brinzolamide in healthy dogs significantly decrease 8.47% IOP. During the post-treatment period, the average daily values of the brinzolamide-treated eyes remained 1.52 mmHg below the average daily values observed at baseline period.Discussion: The present research showed that, the average daily IOP values in the brinzolamide-treated eyes decreased 1.49 mmHg (8.88%) at the end of the first day, 1.69 mmHg (10.07%) at the end of the fourth day, and the cumulative IOP values after four days of treatment, were able to decrease by 1.42 mmHg (8.53%). Three times daily instillations of 1% brinzolamide in healthy dogs significantly decrease IOP, and therefore may be indicated to management of intraocular hypertension and glaucoma.

Effect of a Preservative-free Dorzolamide/Timolol Fixed Combination on Elevated Intraocular Pressure after Vitrectomy

Purpose: To verify the effect of preservative-free Dorzolamide/Timolol fixed combination (PFDTC) on intraocular pressure (IOP) elevation after vitrectomy. Methods: We retrospectively reviewed medical records of 33 patients who used PFDTC after pars plana vitrectomy. All patients’ visual acuity and IOP was measured and symptoms of conjunctival irritation were investigated through survey and slit lamp examination. Results: Before vitrectomy, the mean IOP was 13.6 ± 4.4 mm Hg which was elevated to 31.7 ± 5.4 mm Hg after vitrectomy (p < 0.001) and applying eyedrop lowered the mean IOP to 17.2 ± 7.0 mm Hg (p < 0.001). Regardless of tamponade material type, all elevated IOP decreased (p < 0.001) and the IOP of all 33 eyes did not rise to over 30 mm Hg again. No additional surgery for IOP control was needed during two-month follow-up period. Of the 33 patients using PFDTC, patients who felt discomfort were five (15.2%) and no patients showed side effects severe enough to stop use of eyedrop. Conclusions: PFDTC is an anti-glaucomatic agent which can reduce the IOP by inhibiting aqueous humor production. Without need for additional surgery, the eyedrop can effectively lower elevated post-vitrectomy IOP, with expectation of good patient compliance due to low risk of conjunctival irritation. J Korean Ophthalmol Soc 2016;57(9):1386-1391

New drugs and preparations for open-angle glaucoma in adults

Primary (or chronic) open-angle glaucoma (POAG or COAG) may be asymptomatic but causes progressive optic nerve damage with significant loss of visual field.1–3 Treatments aim to lower intraocular pressure (IOP)...

Involvement of ZEB1 and Snail1 in excessive production of extracellular matrix in Fuchs endothelial corneal dystrophy

Fuchs endothelial corneal dystrophy (FECD) due to corneal endothelial cell degeneration is a major cause of corneal transplantation. It is characterized by abnormal deposition of extracellular matrix (ECM), such as corneal guttae, accompanied by a loss of endothelial cells. Although recent studies have revealed several genomic factors, the molecular pathophysiology of FECD has not yet been revealed. In this study, we establish a cellular in vitro model by using immortalized corneal endothelial cells obtained from late-onset FECD and control patients and examined the involvement of epithelial mesenchymal transition (EMT) on excessive ECM production. We demonstrate that the EMT-inducing genes ZEB1 and SNAI1 were highly expressed in corneal endothelial cells in FECD and were involved in excessive production of ECM proteins, such as type I collagen and fibronectin through the transforming growth factor (TGF)-β signaling pathway. Furthermore, we found that SB431542, a specific inhibitor of TGF-β type I ALK receptors, suppressed the expression of ZEB1 and Snail1 followed by reduced production of ECM. These findings suggest that increased expression levels of ZEB1 and Snail1 in FECD cells were responsible for an increased responsiveness to TGF-β present in the aqueous humor and excessive production of ECM. In addition, these results suggest that the regulation of EMT-related genes by blocking the TGF-β signaling pathway may be a feasible therapeutic strategy for FECD.

Digoxin derivatives with selectivity for the α2β3 isoform of Na,K-ATPase potently reduce intraocular pressure

The ciliary epithelium in the eye consists of pigmented epithelial cells that express the α1β1 isoform of Na,K-ATPase and nonpigmented epithelial cells that express mainly the α2β3 isoform. In principle, a Na,K-ATPase inhibitor with selectivity for α2β3 that penetrates the cornea could effectively reduce intraocular pressure, with minimal systemic or local toxicity. We have recently synthesized perhydro-1,4-oxazepine derivatives of digoxin by NaIO4 oxidation of the third digitoxose and reductive amination with various R-NH2 substituents and identified derivatives with significant selectivity for human α2β1 over α1β1 (up to 7.5-fold). When applied topically, the most α2-selective derivatives effectively prevented or reversed pharmacologically raised intraocular pressure in rabbits. A recent structure of Na,K-ATPase, with bound digoxin, shows the third digitoxose approaching one residue in the β1 subunit, Gln84, suggesting a role for β in digoxin binding. Gln84 in β1 is replaced by Val88 in β3. Assuming that alkyl substituents might interact with β3Val88, we synthesized perhydro-1,4-oxazepine derivatives of digoxin with diverse alkyl substituents. The methylcyclopropyl and cyclobutyl derivatives are strongly selective for α2β3 over α1β1 (22-33-fold respectively), as determined either with purified human isoform proteins or intact bovine nonpigmented epithelium cells. When applied topically on rabbit eyes, these derivatives potently reduce both pharmacologically raised and basal intraocular pressure. The cyclobutyl derivative is more efficient than Latanoprost, the most widely used glaucoma drug. Thus, the conclusion is that α2β3-selective digoxin derivatives effectively penetrate the cornea and inhibit the Na,K-ATPase, hence reducing aqueous humor production. The new digoxin derivatives may have potential for glaucoma drug therapy.