NCX 470 Reduces Intraocular Pressure More Effectively Than Lumigan in Dogs and Enhances Conventional and Uveoscleral Outflow in Non-Human Primates and Human Trabecular Meshwork/Schlemm's Canal Constructs
JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS(2023)
摘要
Purpose: To determine NCX 470 (0.1%) and Lumigan (R) (bimatoprost ophthalmic solution, 0.01%-LUM) intraocular pressure (IOP)-lowering activity after single or repeated (5 days) dosing along with changes in aqueous humor (AH) dynamics.Methods: Ocular hypotensive activity of NCX 470 and LUM was compared with vehicle (VEH) in Beagle dogs using TonoVet (R). Non-human primates (NHP) and bioengineered three-dimensional (3D) human Trabecular Meshwork/Schlemm's Canal (HTM/HSC (TM)) constructs exposed to transforming growth factor-beta 2 (TGF beta 2) were used to monitor NCX 470 and LUM-induced changes in AH dynamics.Results: NCX 470 (30 mu L/eye) showed greater IOP reduction compared with LUM (30 mu L/eye) following single AM dosing [maximum change from baseline (CFBmax) = -1.39 +/- 0.52, -6.33 +/- 0.73, and -3.89 +/- 0.66 mmHg (mean +/- standard error of the mean) for VEH, NCX 470, and LUM, respectively]. Likewise, repeated 5 days daily dosing of NCX 470 resulted in lower IOP than LUM across the duration of the study (average IOP decrease across tests was -0.45 +/- 0.22, -6.06 +/- 0.15, and -3.60 +/- 0.22 mmHg for VEH, NCX 470, and LUM, respectively). NCX 470 increased outflow facility (Cfl) in vivo in NHP (CflVEH = 0.37 +/- 0.09 mu L/min/mmHg and CflNCX470 = 0.64 +/- 0.17 mu L/min/mmHg) as well as in vitro (CHTM/HSC) in HTM/HSC constructs (CHTM/HSC_VEH = 0.47 +/- 0.02 mu L/min/mm2/mmHg and CHTM/HSC_NCX470 = 0.76 +/- 0.03 mu L/min/mm2/mmHg). In addition, NCX 470 increased uveoscleral outflow (FuVEH = 0.62 +/- 0.26 mu L/min and FuNCX470 = 1.53 +/- 0.39 mu L/min with episcleral venous pressure of 15 mmHg) leaving unaltered aqueous flow (AHFVEH = 2.03 +/- 0.22 mu L/min and AHFNCX470 = 1.93 +/- 0.31 mu L/min) in NHP.Conclusions: NCX 470 elicits greater IOP reduction than LUM following single or repeated dosing. Data in NHP and 3D-HTM/HSC constructs suggest that changes in Cfl and Fu account for the robust IOP-lowering effect of NCX 470.
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关键词
aqueous humor dynamics,ocular hypertension,glaucoma,nitric oxide
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