Abstract
Fingolimod (FTY720), a novel class of sphingosine 1-phosphate receptor modulators, has received special interest among ophthalmologists, particularly given that oral administration of FTY720 has proven to effectively treat corneal graft rejection in animal models. However, no studies have examined the performance of FTY720 as an ophthalmic solution in reducing corneal rejection in high-risk corneal rejection models, and the stability and ocular irritation profile of FTY720 ophthalmic solution are also unknown. Thus, we developed 0.1%, 0.2% and 0.5% FTY720 ophthalmic solutions and evaluated their chemical stabilities under various storage conditions with high- performance liquid chromatography. To investigate the ocular irritancy of the FTY720 ophthalmic solution, New Zealand albino rabbits were subjected to the Draize test. Furthermore, classic, well-established rat allogenic penetrating keratoplasty models were used to investigate the anti-rejection efficacy of the tested FTY720 ophthalmic solutions. We found that the non-irritating 0.5% FTY720 ophthalmic solution could prolong corneal allograft survival in rats with significant efficacy for about one month. Furthermore, no significant concentration changes occurred in any of the types of FTY720 ophthalmic solutions within three months. These results revealed crucial profiles of FTY720 ophthalmic solutions and warrant further investigation and optimization of FTY720 in the anti-rejection therapy after keratoplasty.
Highlights
Types of tautomers in aqueous solution[12]
After it is phosphorylated in vivo, FTY720 acts as an agonist analog by binding to and decreasing the expression of sphingosine 1-phosphate receptor 1, which is normally required for T-cell egress from secondary lymphoid tissue; this decrease in expression causes the sequestration of lymphocytes from the peripheral circulation to the lymph nodes, preventing lymphocyte migration to the inflammatory sites and grafted organs[21,22,23,24,25]
FTY720 Ophthalmic Solution is Stable under Various Preservation Conditions
Summary
Types of tautomers in aqueous solution[12]. Because of these shortcomings, the currently available immunosuppressants are still unsatisfactory for anti-rejection management after keratoplasty. As a metabolite of the ascomycete Isaria sinclairii, FTY720 is remarkably potent in effectively suppressing Th1-mediated allograft rejection in various experimental animal models and in humans[16,17,18,19,20] After it is phosphorylated in vivo, FTY720 acts as an agonist analog by binding to and decreasing the expression of sphingosine 1-phosphate receptor 1, which is normally required for T-cell egress from secondary lymphoid tissue; this decrease in expression causes the sequestration of lymphocytes from the peripheral circulation to the lymph nodes, preventing lymphocyte migration to the inflammatory sites and grafted organs[21,22,23,24,25]. The efficacy of the FTY720 ophthalmic solutions at overcoming rejection was investigated in the rat allogenic high-risk keratoplasty model
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