Enhanced Oxygen Saturation in Optic Nerve Head of Non-Human Primate Eyes Following the Intravitreal Injection of NCX 434, an Innovative Nitric Oxide-Donating Glucocorticoid

Abstract

Purpose: Hypoxia of the retina and optic nerve head (ONH) is believed to be pivotal in the development of ocular vascular disorders, including diabetic macular edema (DME). Glucocorticoids are among the most effective agents for the treatment of back of the eye diseases. However, this class of compounds is highly liable to increase intraocular pressure (IOP) and does not improve ocular perfusion or tissue oxygenation. Nitric oxide (NO) has vasodilating properties and lowers IOP in experimental models and humans, suggesting that its properties might complement those of glucocorticoids. NCX 434 is an NO-donating triamcinolone acetonide (TA) that is less likely to increase IOP while targeting both the vascular and inflammatory components of DME. Methods: NCX 434 was studied in vitro with respect to its NO-releasing properties in isolated methoxamineprecontracted rabbit aortic rings and glucocorticoid-like activity in recombinant human glucocorticoid receptors. IOP and oxygen saturation in the ONH and overlaying arteries and veins were studied in the anesthetized cynomolgus monkey. Measurements were taken using, respectively, an applanation tonometer and a hyperspectral imaging system before and 7, 14, 21, 31 and 41 days after the intravitreal injection of NCX 434 (5.8 mg/ eye) or TA equimolar doses (4.0 mg/eye). Results: NCX 434 inhibited 3 H-dexamethasone-specific binding (IC 50 = 34 -5 nM) on human glucocorticoid receptors and elicited NO-dependent aortic ring relaxation (EC 50 of 0.5 -0.1 mM, E max 98.9%). In monkey eyes, NCX 434 enhanced, whereas TA did not, oxygen saturation in various ONH areas (*P < 0.05 vs. basal), decreased it in veins, and did not affect it in the overlaying arteries. Neither NCX 434 nor TA altered IOP significantly at all time points. However, at 31 days post-treatment TA appeared to start increasing IOP (D IOP = + 3.31 -0.51 mmHg, 30.8%, over baseline, NS). Conclusions: NCX 434 enhances ocular tissue oxygenation. This feature appears to depend on its NO-donating properties; thus, the compound deserves to be further investigated for the treatment of DME and other ocular disorders with impaired ocular perfusion.

The nitric oxide donating triamcinolone acetonide NCX 434 does not increase intraocular pressure and reduces endothelin-1 induced biochemical and functional changes in the rabbit eye

“…The compound has been shown to lack IOP raising effects, unlike TA alone, and to enhance oxygen saturation of the ONH in non-human primate eyes,13 suggesting potential retinal protective activity. We have now tested this hypothesis by comparing NCX 434 with TA on changes occurring in rabbit eyes exposed to retinal and ONH ischaemia/reperfusion caused by repeated injections of ET-1.…”

“…The glucocorticoid moiety is expected to provide ocular anti-inflammatory effects while NO is expected to have multiple additional effects: regulating intraocular pressure (IOP),10 promoting vasodilation in the eye11 and inhibiting proinflammatory cytokine via modulation of transcription factor nuclear factor kappa-B 12. Consistent with its dual mechanism of action, this compound has been shown to differentiate from TA in that it retains glucocorticoid binding affinity in recombinant human glucocorticoid receptors and enhances oxygen saturation in areas of the ONH of non-human primate eyes while not increasing IOP 13. Based on these and other observations, we hypothesise that NCX 434 could exert neuroprotective activities in pathological conditions where vasogenic alterations account for progressive retinal ganglion cell (RGC) loss, for example, in diabetic retinopathy 2…”

High Intraocular Pressure Following Anti-Vascular Endothelial Growth Factor Therapy: Proposed Pathophysiology due to Altered Nitric Oxide Metabolism

“…6,28 Retinal and optic nerve head oxygenation has also been shown to be increased by NO donor therapies in monkeys through vasodilation. 3 Additionally, the role of NO in anterior segment and TM physiology has been extensively evaluated.…”

“…76 It is possible that any ganglion cell and RNFL damage due to elevated IOP could be magnified due to the ability of anti-VEGF agents to negatively affect retinal and optic nerve head blood flow. 3 Horsley et al retrospectively investigated this concept and found that long-term anti-VEGF therapy did not result in RNFL loss. 78 This, however, was not corroborated by Martinez-de-la-casa et al They conducted a prospective investigation and determined that long-term anti-VEGF therapy resulted in a statistically significant decrease in RNFL thickness from baseline.…”

“…1 Many studies have been conducted concerning the role of NO in normal physiology, and specifically how it relates to the eye. [2][3][4][5][6] These studies have outlined the intraocular presence of components of the NO signaling pathway and demonstrated multiple roles in various ocular functions and vascular homeostasis.…”