Abstract
Purpose :
To test ocular toxicity and long-term analgesic efficacy of two novel ocular formulations of Substance P receptor antagonist Aprepitant in comparison with Diclofenac and Oxybuprocaine.
Methods :
7/8-week-old male C57BL/6N mice received topical (eye) treatment as follows: formulation A vehicle (n=18), formulation A 0.005% (n=7), 0.05% (n=7), and 0.5% (n=7); formulation B vehicle (n=18), formulation B 0.05% (n=7), and 0.5% (n=7); 0.4% Oxybuprocaine (n=7), 0.1% Diclofenac (n=7), and saline (n=6). Eye-drops were applied 3 times/day for 90 days. The animals were monitored by in vivo slit-lamp microscopy imaging. At days 0, 45, and 90 the eye-wiping test and corneal sensitivity measure were performed immediately after the last treatment to evaluate corneal nociception and sensitivity. At day 90, mice were euthanized and corneas were dissected to assess nerve density and leukocyte infiltration by immunofluorescence and to evaluate inflammation/pain-associated markers (TNF-α, IL-6, IL-1β, and Neurokinin-1 receptor) by RT-PCR.
Results :
We found that both formulations A and B did not induce any significant epithelial damage or change in corneal transparency and nerve density. However, the Diclofenac group displayed a significant reduction in corneal nerve density after 90 days of treatment (p<0.01). Formulation A groups showed increased CD45+ infiltration (p<0.01) and up-regulation of inflammatory markers (p<0.05), which was not observed in formulation B groups. Both formulation B groups significantly reduced nociception (p<0.05) and corneal sensitivity (p<0.01) after 45 and 90 days. Similarly, Diclofenac significantly decreased nociception only after the first administration (day 0) (p<0.05) and sensitivity at all time points (p<0.001). As expected, the anesthetic medication Oxybuprocaine was the most effective in preventing pain (p<0.001) and in reducing corneal sensitivity (p<0.0001) at all time points. Finally, formulation A candidates were effective only at day 90 (p<0.05).
Conclusions :
Both formulations B (0.05% and 0.5%) exhibit analgesic efficacy at day 45 and 90, differently from 0.1% Diclofenac, which is effective only at day 0. Differently from Diclofenac, both formulation B groups are not toxic for corneal nerves even after long-term (90 days) administration.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.