Long-Term Clinical Outcome of Tacrolimus Skin Ointment (0.03%) for the Treatment of Vernal Keratoconjunctivitis: A Quasi-Experimental Study.

Background Vernal keratoconjunctivitis (VKC) is an allergic conjunctival inflammation with severe ocular complications if left untreated. The current management regimen is plagued with adverse effects, long-term problems, and clinical relapses. Tacrolimus offers an alternative treatment option, and long-term studies are needed to determine its efficacy. Methods A two-year follow-up based study was conducted on moderate to severe VKC patients, who were prescribed tacrolimus skin ointment. The 5-5-5 exacerbation scale was used for the monitoring and grading severity of the disease. Analysis of variance (ANOVA) and intergroup comparisons were conducted on exacerbation scale scores among follow-ups. Results A significant reduction was observed in the total score of severity from baseline (203.17±102.05) to three months' follow-up (69.94±70.54), and it kept reducing for 18 months post therapy. Similar results with statistically significant reduction were observed for all grades of the scale. The relapse rate was 5.71% within a month after therapy cessation, and none of the other patients showed relapse afterward. No significant ocular and systemic complications were observed during the study. Conclusion Tacrolimus is effective in the long-term management of VKC without the complications of conventional steroid-based therapy.

Rapamycin and FK506 derivative TH2849 could ameliorate neurodegenerative diseases through autophagy with low immunosuppressive effect.

Autophagy is an essential cellular process concern with cellular homeostasis down-regulated by mTOR, whose activity can be modulated by rapamycin, a kind of lipophilic macrolide antibiotic, through forming a complex with immunophilin FKBP12 essential for mTOR regulation to induce autophagy. Therefore, rapamycin is normally used as a neuron protective agent. The immunophilin FKBP12 binding ligand FK506 is well known as an immunosuppressive agent by inhibiting the calcineurin expression. In this study, we synthesized a series of modified compounds based on the FKBP12 binding moiety to as same as the binding structure of rapamycin and FK506 particularly. We removed the other binding regions of the complex that has the property of immunosuppression. We found that a novel small molecule named TH2849 from these derivative compounds has a significant binding connection with mTOR by comparing to calcineurin. The effects of TH2849 on calcineurin/NFAT were not as significant as FK506, and weak effects on IL2/p34cdc2 /cyclin signaling pathway were also found. Moreover, TH2849 also shows mitochondrial protective effect through stabilizing the mitochondrial structure and transmembrane potential (ΔΨm) and could rescue dopaminergic neurons in MPTP-treated zebrafishes as well as mice models with less immunosuppressive effect. Our present study shows that TH2849 works as a neuroprotective agent possibly by inducing autophagy and low immunosuppressive effect.