Abstract
Purpose :
Melanocortin receptor (MCR) agonists represent an innovative anti-inflammatory strategy based on augmenting natural processes that promote resolution of inflammation. The objective of a series of dose-ranging and duration-of-effect studies was to establish the effects of PL9588, a peptide with MC1R agonist activity, on intraocular pressure after administration in healthy rabbits.
Methods :
In different studies, male, experimentally naive Dutch belted rabbits (age 3–4 mo) were treated with different concentrations of PL9588 (0.005–1 mg/mL) in a vehicle of citrate buffer in saline with 0.1% (w/v) polysorbate 80. Latanoprost (0.005%) and timolol (0.5%) acted as positive controls. Administration was via Gilson pipette (50 µL) topically onto the globes of both eyes. For dose-ranging studies, each dose was separated by a ≥2-day washout. First dose was vehicle, followed by increasing PL9588 concentrations and finishing with the positive control (max 7 doses per animal). For the duration-of-effect studies, 2 groups of animals were dosed: group 1 (n = 6) in the early morning and group 2 (n = 6) in mid-afternoon. Intraocular pressure measurements (mm Hg) were taken by tonometry before dosing each formulation, and at 1, 2, 4, 8, 12 and 24 h (group 1) and at 1, 16, 20, and 24 h (group 2) after topical administration.
Results :
The most efficacious PL9588 dose was 0.001 mg/mL, which produced a 12%–18% reduction in ocular pressure beginning at approximately 1 h postdose, which persisted through the end of the experiment at 6 h postdose, This appeared more effective than timolol, which produced a ~5% reduction in ocular pressure at 1 h postdose with diminishing effect over time. Times postdose were extended in a subsequent experiment, which showed a ~10% decrease in ocular pressure from predose, approximately 2 h after administration, which was maintained for ~20 h. The positive control, latanoprost, reduced ocular pressure ~5% by 0.5 h postdose, and showed no reduction by 8 h.
Conclusions :
PL9588 at its lowest dose (0.001 mg/mL) showed reductions in intraocular pressure with magnitudes similar or greater to the positive controls latanoprost and timolol when administered into the eyes of rabbits. The effect of this single, low dose persists for ≥20 hours. This provides support for continued development of PL9588 with the aim of providing a new, once-daily treatment for glaucoma.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.