OMDI, a novel IOP-lowering compound, reduced IOP by increasing outflow facility and uveoscleral outflow in nonhuman primates.

The Hydrus Microstent provided an effective way to increase outflow facility in human eyes ex vivo.

Axonopathy is a hallmark of many neurodegenerative diseases including glaucoma, where elevated intraocular pressure (ocular hypertension, OHT) stresses retinal ganglion cell (RGC) axons as they exit the eye and form the optic nerve. OHT causes early changes in the optic nerve such as axon atrophy, transport inhibition, and gliosis. Importantly, many of these changes appear to occur prior to irreversible neuronal loss, making them promising points for early diagnosis of glaucoma. It is unknown whether OHT has similarly early effects on the function of RGC output to the brain. To test this possibility, we elevated eye pressure in mice by anterior chamber injection of polystyrene microbeads. Five weeks post-injection, bead-injected eyes showed a modest RGC loss in the peripheral retina, as evidenced by RBPMS antibody staining. Additionally, we observed reduced dendritic complexity and lower spontaneous spike rate of On-αRGCs, targeted for patch clamp recording and dye filling using a Opn4-Cre reporter mouse line. To determine the influence of OHT on retinal projections to the brain, we expressed Channelrhodopsin-2 (ChR2) in melanopsin-expressing RGCs by crossing the Opn4-Cre mouse line with a ChR2-reporter mouse line and recorded post-synaptic responses in thalamocortical relay neurons in the dorsal lateral geniculate nucleus (dLGN) of the thalamus evoked by stimulation with 460 nm light. The use of a Opn4-Cre reporter system allowed for expression of ChR2 in a narrow subset of RGCs responsible for image-forming vision in mice. Five weeks following OHT induction, paired pulse and high-frequency stimulus train experiments revealed that presynaptic vesicle release probability at retinogeniculate synapses was elevated. Additionally, miniature synaptic current frequency was slightly reduced in brain slices from OHT mice and proximal dendrites of post-synaptic dLGN relay neurons, assessed using a Sholl analysis, showed a reduced complexity. Strikingly, these changes occurred prior to major loss of RGCs labeled with the Opn4-Cre mouse, as indicated by immunofluorescence staining of ChR2-expressing retinal neurons. Thus, OHT leads to pre- and post-synaptic functional and structural changes at retinogeniculate synapses. Along with RGC dendritic remodeling and optic nerve transport changes, these retinogeniculate synaptic changes are among the earliest signs of glaucoma.

To investigate the daytime vs nighttime differences in intraocular pressure (IOP), aqueous humor dynamics, central cornea thickness, and blood pressure among a cohort of healthy volunteers. Methods: Thirty healthy volunteers (mean [SD] age, 57.0 [8.6] years) were enrolled in the study. Individuals underwent 1 daytime visit and 1 nighttime visit for the measurement of aqueous humor dynamics. Measurements included IOP by pneumatonometry, aqueous flow by fluorophotometry, outflow facility by fluorophotometry and tonography, uveoscleral outflow by mathematical calculation, central cornea thickness by pachymetry, and blood pressure by sphygmomanometry. Results between visits were compared by appropriate t test. Dependence of the pneumatonometer probe results on position was tested in enucleated rabbit eyes at set pressures and probe positions. Results: Compared with daytime seated IOP, nighttime seated IOP was reduced by 16%, whereas nighttime supine IOP was increased by 17% (PϽ.001 for both).

PURPOSE.To study the effect on outflow facility and outflow resistance of a nitinol microstent implanted into Schlemm's canal.METHODS. Using a constant pressure perfusion method, outflow facility and outflow resistance were measured in 26 pairs of dissected anterior segments from donated human eyes. Measurements were made at perfusion pressures of 10, 20, 30 and 40 mm Hg. The Hydrus Microstent was placed in Schlemm's canal of one eye and the contralateral eye underwent a sham procedure. Outflow facility and outflow resistance were measured again after the microstent implantation or sham procedure.RESULTS. The Hydrus Microstent significantly increased outflow facility from 0.33 6 0.17 lL/min/mm Hg to 0.52 6 0.19 lL/ min/mm Hg (P < 0.001). Outflow resistance was significantly reduced from 4.38 6 3.03 mm Hg/lL/min at baseline to 2.34 6 1.04 mm Hg/lL/min (P < 0.001) with the microstent. There was a linear correlation between outflow resistance at baseline and decrease in outflow resistance with the microstent (R 2 ¼ 0.89, P < 0.0001).CONCLUSIONS. The increase in outflow facility and decrease in resistance supports the potential use of the Hydrus Microstent as a surgical option to reduce intraocular pressure (IOP). The IOP-lowering effect may be higher in eyes with higher outflow resistance (and IOP) as compared with eyes with lower outflow resistance (and IOP). (Invest Ophthalmol Vis Sci.

To evaluate the interaction of intraocular pressure (IOP)-lowering medications with physiologic day and night changes in aqueous humor dynamics in participants with ocular hypertension.Methods: Thirty participants were enrolled in this double-masked, randomized, crossover study. Each participant underwent aqueous humor dynamics measurements at baseline and at 2 weeks of dosing in random order with latanoprost in the evening and placebo in the morning, timolol maleate twice daily, and dorzolamide hydrochloride twice daily. Measurements included central corneal thickness by ultrasound pachymetry, anterior chamber depth by A-scan, seated and habitual IOP by pneumatonometry, blood pressure by sphygmomanometry, episcleral venous pressure by venomanometry, and aqueous flow by fluorophotometry. Outflow facility was assessed by fluorophotometry and by tonography. Uveoscleral outflow was mathematically calculated using the Goldmann equation.Results: Latanoprost use significantly decreased IOP during the day and night. It increased daytime uveoscleral outflow by a mean (SD) of 0.90 (1.46) µL/min (P=.048), but a nighttime increase of 0.26 (1.10) µL/min (P=.47) did not reach statistical significance. Timolol use decreased IOP during the day by reducing aqueous flow by 25%. Dorzolamide use lowered IOP only at the noon measurement and reduced daytime aqueous flow by 16%. Neither dorzolamide nor timolol use added to the physiologic 47% reduction in nighttime aqueous flow. Conclusions:The daytime IOP-lowering effects of latanoprost are mediated by an increase in uveoscleral outflow, and those of timolol and dorzolamide are mediated by aqueous flow suppression. Nighttime physiologic changes in uveoscleral outflow limit the nighttime pharmacodynamic efficacy of latanoprost. Aqueous flow suppression with timolol and dorzolamide was ineffective in obtaining IOP lowering at night.

Rebound tonometry can be used to obtain accurate IOP measurements in conscious, restrained mice while avoiding the rapid and profound ocular hypotensive effects of general anesthesia. Small changes in IOP with an aqueous-flow suppressant are readily detectable with conscious restraint that may be missed with chemical restraint.

Administration of ketamine/xylazine anesthesia for 120 min did not alter outflow facility or lessen the effect of latanoprost on outflow facility in mice as determined by a new analysis system. Accurate IOP measurements must be made within minutes of anesthesia administration but outflow facility measurements can be made with less haste.