Inhibition of PKC β by oral administration of ruboxistaurin is well tolerated and ameliorates diabetes-induced retinal hemodynamic abnormalities in patients

被引:107
作者
Aiello, LP
Clermont, A
Arora, V
Davis, MD
Sheetz, MJ
Bursell, SE
机构
[1] Joslin Diabet Ctr, Beethman Eye Inst, Boston, MA 02215 USA
[2] Joslin Diabet Ctr, Eye Res Sect, Boston, MA 02215 USA
[3] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA 02115 USA
[4] Lilly Res Labs, Indianapolis, IN USA
[5] Univ Wisconsin, Fundus Photograph Reading Ctr, Madison, WI USA
关键词
D O I
10.1167/iovs.05-0757
中图分类号
R77 [眼科学];
学科分类号
100212 ;
摘要
PURPOSE. To assess ocular and systemic safety and pharmacodynamic effects of the oral PKC beta selective inhibitor ruboxistaurin (RBX; LY333531) mesylate in patients with diabetes. METHODS. This was a double-masked, placebo-controlled, parallel, randomized, single-center clinical study evaluating the effect of oral administration of RBX ( 8 mg twice a day, 16 mg per day, or 16 mg twice a day) or placebo for 28 days in patients with no or very mild diabetic retinopathy on mean retinal circulation time (RCT), retinal blood flow (RBF), treatment-emergent adverse events, and other safety parameters. RESULTS. Twenty-nine persons aged 18 to 65 years with type 1 or 2 diabetes were evaluated. The only treatment-emergent adverse event with a statistically significant difference among treatment groups was abdominal pain, which was more common in placebo-treated subjects ( P = 0.049). Statistically significant effects of RBX were observed on several hematologic and laboratory parameters, but values were within the normal reference range and none of the changes was deemed clinically meaningful. In patients receiving 16 mg RBX twice daily, the diabetes-induced increase in RCT was ameliorated, with a baseline-to-endpoint difference of - 0.84 seconds ( P = 0.046) relative to placebo. Increasing RBX dose was linearly associated with greater effect on RCT ( P = 0.03). Similar results were observed with RBF. CONCLUSIONS. RBX was well tolerated at doses up to 16 mg twice daily for 28 days in patients with diabetes. It ameliorated diabetes-induced RCT abnormalities. No serious safety problems were identified in this patient population. Compared with prior published data, these findings represent the first direct human evidence of both bioavailability of RBX to retinal vessels and amelioration of diabetes-induced retinal hemodynamic abnormalities by an oral PKC beta inhibitor.
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页码:86 / 92
页数:7
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