IOP-lowering effects of NCX 667 in combination with travoprost in ocular normotensive and transient hypertensive rabbits

Abstract

Purpose : NCX 667 is a novel stand-alone nitric oxide (NO)-donor previously shown to potently and effectively lowers intraocular pressure (IOP) in preclinical animal models of ocular hypertension and glaucoma; however, the IOP-lowering potential of NCX 667 was not investigated in concomitant administration with existing therapeutics. Here we report on the IOP-lowering effects of NCX 667 alone and combined with clinically relevant doses of the prostaglandin F2α (PGF2α) analogue travoprost in rabbits.

Methods : New Zealand white (NZW) rabbits with transient hypertonic saline-induced IOP elevation (tOHT-rabbits) and ocular normotensive NZW rabbits were used. In tOHT-rabbits, 0.1 ml of saline solution (5%) was injected into the vitreous humor of both eyes. IOP was measured prior to (baseline) and during the following 5hrs post-dosing. In both animal models two treatment schedules were followed: dosing NCX 667 10 min before travoprost; and dosing NCX 667 10 min after travoprost.

Results : As expected in ocular normotensive rabbits, travoprost (0.004%, 30μl) showed minimal IOP lowering (E_max= -1.6±1.6 mmHg at 30 min) whereas 0.1% of NCX 667 was selected as the minimal effective dose (E_max= -2.1±0.4 mmHg at 60 min). NCX 667 (0.1%, 30μl) combined with travoprost (0.004%, 30μl) resulted in superior efficacy (E_max= -3.9±0.8, -2.1±0.4 and -1.6±1.6 mmHg for NCX 667+travoprost, NCX 667 and travoprost, respectively). Surprisingly, the combination of NCX 667 and travoprost resulted in steady IOP-lowering up to 5hrs post-dosing not otherwise recorded for the compounds administered alone (E_5hrs= -2.6±0.7, 1.1±0.8 and -0.6±0.1 mmHg for NCX 667+travoprost, NCX 667 and travoprost, respectively). Similar results were obtained when NCX 667 was administered after travoprost. In tOHT-rabbits, NCX 667 (0.3%, 30μl) combined with travoprost (0.004%, 30μl) resulted in superior IOP-lowering efficacy compared to each drug given alone. Due to the transient nature of the in tOHT-rabbit model the duration of the IOP-lowering activity could not be assessed.

Conclusions : NCX 667 is an effective IOP-lowering agent whose efficacy is not only strengthened but also prolonged when combined with the PGF2α agonist travoprost. Additional investigations are needed to better understand the mechanism of action involved.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.