Abstract
Purpose :
Recent evidences indicate that (R)-DOI, a 5-HT2R agonist, can modulate inflammatory processes and prevent allergic asthma in mice. In addition, (R)-DOI reduced complications from Herpes Simplex Virus-associated ocular disease. Given the foreseen applications in ophthalmology for a new immuno-modulatory drug class, we set out to investigate the therapeutic viability of topical eye drops (R)-DOI for ocular inflammatory diseases.
Methods :
1/ Ocular and plasma pharmacokinetics of a single topical administration of (R)-DOI 0.1% were determined using LC-MS/MS (LLOQ of 0.1ng/g) in DB rabbits.
2/ Compound 48/80 was used to induce an anaphylactic response, pruritis, and inflammation modeling allergic conjunctivitis in NZW rabbits. Animal groups were pretreated with topical (R)-DOI 0.05%, 0.01% or 0.001%.
3/ Topical (R)-DOI 0.01% was applied TID subsequent to disease induction in the antigen TB-induced recurrent intermediate uveitis model in NZW rabbits.
Results :
1/ The observed C (ng/mL-ng) values were: cornea-10900, iris-ciliary body-7810, conjunctiva-5680, choroid-1240, aqueous humor-297, retina-195, vitreous humor-3.47 and plasma-1.82. The terminal half-life ranged from 35 to 11 hrs in ocular tissues and was 1.9 in plasma. A follow up study established the ability of R-DOI to interact with melanin pigments.
2/ (R)-DOI 0.01% demonstrated the most significant inhibition of the allergic response (64% mean inhibition of total clinical score).
3/ R)-DOI treatment prevented worsening of vitreous haze (VH) in eyes presenting a mild uveitis disease at treatment initiation. Treatment improved time to resolution (VH) in moderate to severely graded eyes by 35% on the primary induction and by ~50% following re-induction. Histopathology assessments at Day 35 revealed decreased intensity of inflammatory cell infiltrates involving the choroid and retina in treated animals as well as a reduced frequency of retinal degeneration.
Conclusions :
Topical ophthalmic (R)-DOI is readily absorbed into the rabbit eye and effectively reaches both anterior and posterior segments at therapeutically relevant concentrations.(R)-DOI demonstrated antiinflammatory efficacy and protection in both anterior and posterior ocular tissues against acute and chronic disease states in allergic conjunctivitis and intermediate uveitis models in rabbits.
This is a 2021 ARVO Annual Meeting abstract.