Effect of Timolol on Aqueous Humor Outflow Facility in Healthy Human Eyes

Kazemi, Arash; McLaren, Jay W.; Trese, Matthew G.J.; Toris, Carol B.; Gulati, Vikas; Fan, Shan; Reed, David; Kristoff, Tyler; Gilbert, Jesse; Moroi, Sayoko E.; Sit, Arthur J.

doi:10.1016/j.ajo.2019.02.014

Cited by 19 publications

(12 citation statements)

References 48 publications

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“…After timolol treatment, the authors observed that the eye with a higher outflow facility had a larger posttreatment decrease in the outflow facility to achieve a stable IOP level. 35 Various explanations have been proposed for the mechanism by which outflow facility may modulate IOP and retain a stable pressure. Stamer et al 36 hypothesized that the outflow resistance within the conventional outflow pathway is constantly adjusted in response to the cell stretch caused by the fluctuating IOP; the mechanism might involve extracellular matrix turnover but would require hours and up to several days.…”

Section: Discussionmentioning

confidence: 99%

Acute Effects of Intraocular Pressure-Induced Changes in Schlemm's Canal Morphology on Outflow Facility in Healthy Human Eyes

Chen

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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Purpose To estimate the outflow facility coefficient (C) as a function of Schlemm's canal cross-sectional area (SCAR) in healthy subjects using noninvasive oculopression tonometry (OPT). Methods In 25 healthy volunteers, intraocular pressure (IOP) decay values were recorded by a ophthalmodynamometer, with a fixed external force (0.15 N) on the inferior-temporal eyelid, every 10 seconds, for four minutes, and again after a 30-minute rest. Schlemm's canal profile images and IOP were obtained pre-procedurally (baseline), immediately (T0), and at 1-minute intervals post-procedurally (T1, T2, T3, and T4). C was calculated for different IOPs. The SCAR, coronal, and the meridional diameter of Schlemm's canal were calculated. Results Mean C 0 for the maximum IOP was 0.020 ± 0.017 µL/min/mm Hg; mean C was 0.018 ± 0.0071 and 0.058 ± 0.0146 µL/min/mm Hg at 40 and 20 mm Hg, respectively. C was nonlinearly dependent on the IOP ( R 2 = 0.945). The SCAR was 5440 ± 3140.82, 3947.6 ± 2246.8, and 5375.7 ± 2662.7 µm 2 at baseline, T0, and T4, respectively. The coronal diameter of SC decreased significantly from the baseline (33.02 ± 11.3 µm) to T0 (26.6 ± 9.37 µm) and recovered at T4 (32.3 ± 9.53 µm). The SCAR and IOP correlated significantly throughout ( R 2 = 0.9944; P < 0.001). C0 significantly correlated with the SCAR at baseline and with changes in the SCAR and IOP from T0 to T4. Conclusions Schlemm's canal dimensions are responsible for the IOP-dependent mechanical forces, and these changes appear to directly affect outflow facility.

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Section: Discussionmentioning

confidence: 99%

Acute Effects of Intraocular Pressure-Induced Changes in Schlemm's Canal Morphology on Outflow Facility in Healthy Human Eyes

Chen

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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“…2 Therefore, the mode of action of current medications includes a decrease of AH production or increase of AH outflow by the TM or uveoscleral pathway or both. 3,4 Through our systems genetics investigations, we identified Cacna2d1, a subunit of the L-type calcium channel, as a gene modulator of IOP. Our previous study demonstrated that CACNA2D1 is localized to the CB (area of AH production) and TM (area of conventional AH drainage) in both mouse and human eyes leading us to predict that pregabalin (PRG), a gabapentinoid drug with high affinity and high selectivity for CACNA2D1, would lower IOP by decreasing the production or increasing the drainage of aqueous humor from the eye.…”

mentioning

confidence: 80%

“…Fortunately, IOP can be medically controlled; thus, IOP reduction is the first-line therapeutic option in glaucoma . Therefore, the mode of action of current medications includes a decrease of AH production or increase of AH outflow by the TM or uveoscleral pathway or both. , …”

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confidence: 99%

Once Daily Pregabalin Eye Drops for Management of Glaucoma

et al. 2019

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Elevated intraocular pressure (IOP) is the most significant risk factor contributing to visual field loss in glaucoma. Unfortunately, the deficiencies associated with current therapies have resulted in reduced efficacy, several daily dosings, and poor patient compliance. Previously, we identified the calcium voltage-gated channel auxiliary subunit alpha2delta 1 gene (Cacna2d1) as a modulator of IOP and demonstrated that pregabalin, a drug with high affinity and selectivity for CACNA2D1, lowered IOP in a dose-dependent manner. Unfortunately, IOP returned to baseline at 6 h after dosing. In the current study, we develop a once daily topical pregabalin-loaded multiple water-inoil-in-water microemulsion formulation to improve drug efficacy. We characterize our formulations using multiple in vitro and in vivo evaluations. Our lead formulation provides continuous release of pregabalin for up to 24 h. Because of its miniscule droplet size (<20 nm), our microemulsion has a transparent appearance and should not blur vision. It is also stable at one month of storage at temperatures ranging from 5 to 40 °C. Our formulation is nontoxic, as illustrated by a cell toxicity study and slit-lamp biomicroscopic exams. CACNA2D1 is highly expressed in both the ciliary body and the trabecular meshwork, where it functions to modulate IOP. A single drop of our lead pregabalin formulation reduces IOP by greater than 40%, which does not return to baseline until >30 h post-application. Although there were no significant differences in the amplitude of IOP reduction between the formulations we tested, a significant difference was clearly observed in their duration of action. Our multilayered microemulsion is a promising carrier that sustains the release and prolongs the duration of action of pregabalin, a proposed glaucoma therapeutic.

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“…For example, Timolol was a first-line drug for lowering IOP by blocking the beta-adrenergic receptors in the ciliary body 20 to decrease aqueous humor flow 21 . More recently, timolol has been shown to have an effect on outflow facility 22 , which also impacts IOP. The other five genes are targets in many clinical trials involving razuprotafib, ataluren, ELX-02, MT-3724, roxadustat, daprodustat, vadadustat, and perhexiline, which provide candidates for drug repurposing for possible glaucoma treatment.…”

Section: Discussionmentioning

confidence: 99%

Whole-exome sequencing study identifies novel rare variants and genes associated with intraocular pressure and glaucoma

Gao

Chiariglione

Arch

2022

Preprint

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Elevated intraocular pressure (IOP) is a major risk factor for glaucoma, the leading cause of irreversible blindness worldwide. IOP is also the only modifiable risk factor for glaucoma. Previous genome-wide association studies have established the contribution of common genetic variants to IOP. The role of rare variants for IOP was unknown. Using whole exome sequencing data from 454,756 participants in the UK Biobank (UKB), we conducted the largest exome-wide association study of IOP to date. In addition to confirming known IOP genes, we identified 40 novel rare-variant genes for IOP, such as BOD1L1, ACAD10 and HLA-B, demonstrating the power of including and aggregating rare variants in gene discovery. Many of these IOP genes are also associated with glaucoma phenotypes in UKB and the FinnGen cohort. Six of these genes, i.e. ADRB1, PTPRB, RPL26, RPL10A, EGLN2, and MTOR, are drug targets that are either established for clinical treatment or are in clinical trials. Furthermore, we constructed a rare-variant polygenic risk score and showed its significant association with glaucoma in independent subjects. We demonstrated the value of rare variants to enhance our understanding of the biological mechanisms regulating IOP, and uncovered potential novel therapeutic targets for glaucoma.

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Effect of Timolol on Aqueous Humor Outflow Facility in Healthy Human Eyes

Cited by 19 publications

References 48 publications

Acute Effects of Intraocular Pressure-Induced Changes in Schlemm's Canal Morphology on Outflow Facility in Healthy Human Eyes

Acute Effects of Intraocular Pressure-Induced Changes in Schlemm's Canal Morphology on Outflow Facility in Healthy Human Eyes

Once Daily Pregabalin Eye Drops for Management of Glaucoma

Whole-exome sequencing study identifies novel rare variants and genes associated with intraocular pressure and glaucoma

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