The Efficacy and Safety Associated with Switching from Concomitant Brimonidine and Ripasudil, or Brimonidine or Ripasudil Monotherapy to a Fixed Combination of Brimonidine and Ripasudil in Glaucoma Patients.

Objectives: The purpose of this study was to investigate switching from brimonidine and ripasudil, and brimonidine or ripasudil, to a fixed combination of brimonidine and ripasudil, and evaluate the associated efficacy and safety in glaucoma patients. Methods: Glaucoma patients undergoing treatment with at least brimonidine and ripasudil (n = 25) or treatment with at least brimonidine or ripasudil (n = 45) were evaluated in this retrospective study. After switching patients taking brimonidine and ripasudil, or brimonidine or ripasudil, to a ripasudil/brimonidine fixed-combination, ophthalmic suspension (RBFC), intra-ocular pressure (IOP), conjunctival hyperemia and superficial punctate keratopathy (SPK) were evaluated before and at 4, 12 and 24 weeks after switching to RBFC. Results: No significant differences in the IOPs were observed after switching from brimonidine and ripasudil to RBFC. However, a significant decrease was observed at 4, 12 and 24 weeks in the baseline IOP, from 17.0 ± 4.4 mmHg to 15.7 ± 3.2 mmHg (p < 0.01), 14.3 ± 3.4 mmHg (p < 0.01) and 14.4 ± 4.1 mmHg (p < 0.01), respectively, after switching from brimonidine or ripasudil to RBFC. No significant changes were noted for the SPK score or conjunctival hyperemia score at any of the visits after switching to RBFC. Conclusions: Throughout the 24-week evaluation period, the IOP was maintained after switching from brimonidine and ripasudil to RBFC. However, there was a significant decrease in the IOP after switching from brimonidine or ripasudil to RBFC. These results demonstrate that RBFC is safe for use in the treatment of glaucoma patients.

The anti-tumor effect of trifluridine via induction of aberrant mitosis is unaffected by mutations modulating p53 activity.

The fluorinated thymidine analog trifluridine (FTD) is a chemotherapeutic drug commonly used to treat cancer; however, the mechanism by which FTD induces cytotoxicity is not fully understood. In addition, the effect of gain-of-function (GOF) missense mutations of the TP53 gene (encoding p53), which promote cancer progression and chemotherapeutic drug resistance, on the chemotherapeutic efficacy of FTD is unclear. Here, we revealed the mechanisms by which FTD-induced aberrant mitosis and contributed to cytotoxicity in both p53-null and p53-GOF missense mutant cells. In p53-null mutant cells, FTD-induced DNA double-stranded breaks, single-stranded DNA accumulation, and the associated DNA damage responses during the G2 phase. Nevertheless, FTD-induced DNA damage and the related responses were not sufficient to trigger strict G2/M checkpoint arrest. Thus, these features were carried over into mitosis, resulting in chromosome breaks and bridges, and subsequent cytokinesis failure. Improper mitotic exit eventually led to cell apoptosis, caused by the accumulation of extensive DNA damage and the presence of micronuclei encapsulated in the disrupted nuclear envelope. Upon FTD treatment, the behavior of the p53-GOF-missense mutant, isogenic cell lines, generated by CRISPR/Cas9 genome editing, was similar to that of p53-null mutant cells. Thus, our data suggest that FTD treatment overrode the effect on gene expression induced by p53-GOF mutants and exerted its anti-tumor activity in a manner that was independent of the p53 function.