A digoxin derivative that potently reduces intraocular pressure: efficacy and mechanism of action in different animal models.

Glaucoma is a blinding disease. Reduction of intraocular pressure (IOP) is the mainstay of treatment, but current drugs show side effects or become progressively ineffective, highlighting the need for novel compounds. We have synthesized a family of perhydro-1,4-oxazepine derivatives of digoxin, the selective inhibitor of Na,K-ATPase. The cyclobutyl derivative (DcB) displays strong selectivity for the human α2 isoform and potently reduces IOP in rabbits. These observations appeared consistent with a hypothesis that in ciliary epithelium DcB inhibits the α2 isoform of Na,K-ATPase, which is expressed strongly in nonpigmented cells, reducing aqueous humor (AH) inflow. This paper extends assessment of efficacy and mechanism of action of DcB using an ocular hypertensive nonhuman primate model (OHT-NHP) (Macaca fascicularis). In OHT-NHP, DcB potently lowers IOP, in both acute (24 h) and extended (7-10 days) settings, accompanied by increased aqueous humor flow rate (AFR). By contrast, ocular normotensive animals (ONT-NHP) are poorly responsive to DcB, if at all. The mechanism of action of DcB has been analyzed using isolated porcine ciliary epithelium and perfused enucleated eyes to study AH inflow and AH outflow facility, respectively. 1) DcB significantly stimulates AH inflow although prior addition of 8-Br-cAMP, which raises AH inflow, precludes additional effects of DcB. 2) DcB significantly increases AH outflow facility via the trabecular meshwork (TM). Taken together, the data indicate that the original hypothesis on the mechanism of action must be revised. In the OHT-NHP, and presumably other species, DcB lowers IOP by increasing AH outflow facility rather than by decreasing AH inflow.NEW & NOTEWORTHY When applied topically, a cyclobutyl derivative of digoxin (DcB) potently reduces intraocular pressure in an ocular hypertensive nonhuman primate model (Macaca fascicularis), associated with increased aqueous humor (AH) flow rate (AFR). The mechanism of action of DcB involves increased AH outflow facility as detected in enucleated perfused porcine eyes and, in parallel, increased (AH) inflow as detected in isolated porcine ciliary epithelium. DcB might have potential as a drug for the treatment of open-angle human glaucoma.

Peripapillary retinal nerve fiber layer assessment of spectral domain optical coherence tomography and scanning laser polarimetry to diagnose preperimetric glaucoma.

PURPOSE: To compare the abilities of peripapillary retinal nerve fiber layer (RNFL) parameters of spectral domain optical coherence tomograph (SDOCT) and scanning laser polarimeter (GDx enhanced corneal compensation; ECC) in detecting preperimetric glaucoma. METHODS: In a cross-sectional study, 35 preperimetric glaucoma eyes (32 subjects) and 94 control eyes (74 subjects) underwent digital optic disc photography and RNFL imaging with SDOCT and GDx ECC. Ability of RNFL parameters of SDOCT and GDx ECC to discriminate preperimetric glaucoma eyes from control eyes was compared using area under receiver operating characteristic curves (AUC), sensitivities at fixed specificities and likelihood ratios (LR). RESULTS: AUC of the global average RNFL thickness of SDOCT (0.786) was significantly greater (p<0.001) than that of GDx ECC (0.627). Sensitivities at 95% specificity of the corresponding parameters were 20% and 8.6% respectively. AUCs of the inferior, superior and temporal quadrant RNFL thickness parameters of SDOCT were also significantly (p<0.05) greater than the respective RNFL parameters of GDx ECC. LRs of outside normal limits category of SDOCT parameters ranged between 3.3 and 4.0 while the same of GDx ECC parameters ranged between 1.2 and 2.1. LRs of within normal limits category of SDOCT parameters ranged between 0.4 and 0.7 while the same of GDx ECC parameters ranged between 0.7 and 1.0. CONCLUSIONS: Abilities of the RNFL parameters of SDOCT and GDx ECC to diagnose preperimetric glaucoma were only moderate. Diagnostic abilities of the RNFL parameters of SDOCT were significantly better than that of GDx ECC in preperimetric glaucoma.

Ability of different scanning protocols of spectral domain optical coherence tomography to diagnose preperimetric glaucoma.

PURPOSE: To evaluate the ability of the optic nerve head (ONH), retinal nerve fiber layer (RNFL), and ganglion cell complex (GCC) parameters of spectral domain optical coherence tomograph (SDOCT) in detecting preperimetric glaucoma. METHODS: In a cross-sectional study, 34 preperimetric glaucoma eyes (34 patients) and 72 control eyes (72 subjects) with large physiologic optic disc cupping underwent ONH, RNFL, and GCC imaging with SDOCT. Preperimetric glaucoma was diagnosed in the presence of glaucomatous optic neuropathy on masked evaluation of optic disc photographs by two glaucoma experts and normal visual fields. The ability of SDOCT parameters to discriminate preperimetric glaucoma eyes from eyes with large physiologic cups was evaluated by areas under the receiver operating characteristic curves (AUC), sensitivities at fixed specificities, and likelihood ratios (LR). RESULTS: All SDOCT parameters were significantly different (P < 0.05) between the two groups. The ONH, RNFL, and GCC parameters with best AUCs to differentiate preperimetric glaucoma from eyes with large physiologic cups were vertical cup to disc ratio (0.76), inferior quadrant RNFL thickness (0.76), and inferior quadrant GCC thickness (0.75), respectively. Sensitivities at 95% specificity of SDOCT parameters ranged between 15% and 29%. Likelihood ratios of outside normal limits category of parameters ranged between 3 and 11, and within normal limits category between 0.5 and 0.8. CONCLUSIONS: Diagnostic abilities of ONH, RNFL, and GCC parameters of SDOCT to differentiate preperimetric glaucoma eyes from control eyes with large physiologic cupping were only moderate.