Abstract
Purpose :
The nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling pathway plays a major role in aqueous humour drainage and intraocular pressure (IOP) homeostasis. The effects of this signaling pathway are silenced when cGMP is degraded by the phosphodiesterase type-5 enzyme (PDE-5). Here we investigated the IOP-lowering effects of NCX 1741, a novel NO-donating derivative of the PDE-5 inhibitor avanafil in rabbit and non-human primate models of ocular hypertension and glaucoma.
Methods :
Ocular normotensive New Zealand White rabbits (ONT-rabbits, n=8) and laser-induced ocular hypertensive non-human primates (OHT-monkeys, n=8) were used. Vehicle (phosphate buffer pH 6.0, Cremophor EL 5%, DMSO 0.3%, BAC 0.02%) or NCX 1741 in the vehicle were instilled (30 μL) in a masked fashion, and IOP was measured by pneumatonometry prior to (baseline) and periodically post-dosing for 5 hours (rabbits) or 24 hours (non-human primates). IOP comparisons were made between vehicle and drug treatments by two-tailed t-tests.
Results :
In ONT-rabbits, NCX 1741 (2.2%, 30 μL, n=8) decreased IOP by -2.4 ± 0.7 mmHg (p<0.01) at 60 min compared to vehicle treatment. In ocular OHT-monkeys NCX 1741 progressively lowered IOP over time reaching a maximum effect between 5 and 8 hours post-dosing (IOP changes were -5.3 ± 2 mmHg, p<0.05 and -6.0 ± 2.1 mmHg, p<0.01 compared to vehicle at 5 hours and 8 hours post-dosing, respectively). Interestingly, the IOP-lowering effect of NCX 1741 was still evident, albeit not significantly, at 24 hours after dosing (IOP change = -4.6 ± 2.4 mmHg).
Conclusions :
NCX 1741 effectively lowers IOP in ONT-rabbits and OHT-monkeys. Moreover, in OHT-monkeys, the IOP-lowering effects of NCX 1741 appear to persist for 24 hours post-dosing suggesting that NCX 1741 may represent a potent and effective IOP-lowering agent.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.