1. A novel nitric oxide releasing prostaglandin analog, NCX 125, reduces intraocular pressure in rabbit, dog, and primate models of glaucoma.
- Author
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Borghi V, Bastia E, Guzzetta M, Chiroli V, Toris CB, Batugo MR, Carreiro ST, Chong WK, Gale DC, Kucera DJ, Jia L, Prasanna G, Ongini E, Krauss AH, and Impagnatiello F
- Subjects
- Animals, Aqueous Humor metabolism, Ciliary Body metabolism, Cyclic GMP metabolism, Dogs, Female, Glaucoma metabolism, Iris metabolism, Macaca fascicularis, Macrophages drug effects, Macrophages metabolism, Male, Nitric Oxide Synthase Type II antagonists & inhibitors, Ocular Hypertension drug therapy, Ocular Hypertension metabolism, Ophthalmic Solutions pharmacology, Prostaglandins F, Synthetic chemical synthesis, Rabbits, Tumor Cells, Cultured drug effects, Tumor Cells, Cultured metabolism, Antihypertensive Agents pharmacology, Disease Models, Animal, Glaucoma drug therapy, Intraocular Pressure drug effects, Nitric Oxide metabolism, Prostaglandins F, Synthetic pharmacology, Prostaglandins, Synthetic pharmacology
- Abstract
Purpose: Nitric oxide (NO) is involved in a variety of physiological processes including ocular aqueous humor dynamics by targeting mechanisms that are complementary to those of prostaglandins. Here, we have characterized a newly synthesized compound, NCX 125, comprising latanoprost acid and NO-donating moieties., Methods: NCX 125 was synthesized and tested in vitro for its ability to release functionally active NO and then compared with core latanoprost for its intraocular pressure (IOP)-lowering effects in rabbit, dog, and nonhuman primate models of glaucoma., Results: NCX 125 elicited cGMP formation (EC(50) = 3.8 + or - 1.0 microM) in PC12 cells and exerted NO-dependent iNOS inhibition (IC(50) = 55 + or - 11 microM) in RAW 264.7 macrophages. NCX 125 lowered IOP to a greater extent compared with equimolar latanoprost in: (a) rabbit model of transient ocular hypertension (0.030% latanoprost, not effective; 0.039% NCX 125, Delta(max) = -10.6 + or - 2.3 mm Hg), (b) ocular hypertensive glaucomatous dogs (0.030% latanoprost, Delta(max)= -6.7 + or - 1.2 mm Hg; 0.039% NCX 125, Delta(max) = -9.1 + or - 3.1 mm Hg), and (c) laser-induced ocular hypertensive non-human primates (0.10% latanoprost, Delta(max) = -11.9 + or - 3.7 mm Hg, 0.13% NCX 125, Delta(max) = -16.7 + or - 2.2 mm Hg). In pharmacokinetic studies, NCX 125 and latanoprost resulted in similar latanoprost-free acid exposure in anterior segment ocular tissues., Conclusions: NCX 125, a compound targeting 2 different mechanisms, is endowed with potent ocular hypotensive effects. This may lead to potential new perspectives in the treatment of patients at risk of glaucoma.
- Published
- 2010
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