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Abstract #25839 Published in IGR 12-2
A novel nitric oxide releasing prostaglandin analog, NCX 125, reduces intraocular pressure in rabbit, dog, and primate models of glaucoma
Borghi V; Bastia E; Guzzetta M; Chiroli V; Toris CB; Batugo MR; Carreiro ST; Chong WKM; Gale DC; Kucera DJJournal of Ocular Pharmacology and Therapeutics 2010; 26: 125-131
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 (plus or minus) 1.0 (mu)M) in PC12 cells and exerted NO-dependent iNOS inhibition (IC(50) = 55 (plus or minus) 11 (mu)M) 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 (plus or minus) 2.3 mm Hg), (b) ocular hypertensive glaucomatous dogs (0.030% latanoprost, (Delta)(max)=-6.7 (plus or minus) 1.2 mm Hg; 0.039% NCX 125, (Delta)(max) =-9.1 (plus or minus) 3.1 mm Hg), and (c) laser-induced ocular hypertensive non-human primates (0.10% latanoprost, (Delta)(max) =-11.9 (plus or minus) 3.7 mm Hg, 0.13% NCX 125, (Delta)(max) =-16.7 (plus or minus) 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.
F. Impagnatiello. NicOx Research Institute, Via Ariosto 21, Bresso, MI, 20091, Italy. impagnatiello@nicox.it
Classification:
11.14 Investigational drugs; pharmacological experiments (Part of: 11 Medical treatment)
5.2 Primates (Part of: 5 Experimental glaucoma; animal models)
5.3 Other (Part of: 5 Experimental glaucoma; animal models)
