Inhibition of PKC beta by oral administration of ruboxistaurin is well tolerated and ameliorates diabetes-induced retinal hemodynamic abnormalities in patients.
OBJECTIVE
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.
Aiello
Lloyd Paul
LP
Beetham Eye Institute and Eye Research Section, Joslin Diabetes Center, Boston, Massachusetts 02215, USA. laiello@joslin.harvard.edu
Clermont
Allen
A
Arora
Vipin
V
Davis
Matthew D
MD
Sheetz
Matthew J
MJ
Bursell
Sven-Eric
SE
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D001783:Blood Flow Velocity / Q000187:drug effects; D001813:Blood-Retinal Barrier / Q000187:drug effects; D003922:Diabetes Mellitus, Type 1 / Q000150:complications* / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000503:physiopathology; D003930:Diabetic Retinopathy / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008301:Maleimides / Q000008:administration & dosage* / Q000009:adverse effects; D008875:Middle Aged; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D064546:Protein Kinase C beta; D012171:Retinal Vessels / Q000187:drug effects* / Q000502:physiology
D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; C099154:ruboxistaurin; D011493:Protein Kinase C; D064546:Protein Kinase C beta