Ruboxistaurin Research Articles

The Effect of Ruboxistaurin on Visual Loss in Patients With Moderately Severe to Very Severe Nonproliferative Diabetic Retinopathy

The purpose of this study was to evaluate the Safety and efficacy of the orally administered protein kinase C (PKC) beta isoform-selective inhibitor ruboxistaurin (RBX) in subjects with moderately severe to very severe nonproliferative diabetic retinopathy (NPDR). In this multicenter, double-masked, randomized, placebo-controlled study, 252 subjects received placebo or RBX (8, 16, or 32 mg/day) for 36-46 months. Patients had an Early Treatment Diabetic Retinopathy Study (ETDRS) retinopathy severity level between 47B and 53E inclusive, an ETDRS visual acuity of 20/125 or better, and no history of scatter (panretinal) photocoagulation. Efficacy measures included progression of DR, moderate visual loss (MVL) (doubling of the visual angle), and sustained MVL (SMVL). RBX was well tolerated without significant adverse effects but had no significant effect on the progression of DR. Compared with placebo, 32 mg/day RBX was associated with a delayed occurrence of MVL (log rank, P = 0.038) and of SMVL (P = 0.226). RBX reduction of SMVL was evident only in eyes with definite diabetic macular edema at baseline (10% 32 mg/day RBX vs. 25% placebo, P = 0.017). In multivariable Cox proportional hazard analysis, 32 mg/day RBX significantly reduced the risk of MVL compared with placebo (hazard ratio 0.37 [95% CI 0.17-0.80], P = 0.012). In this clinical trial, RBX was well tolerated and reduced the risk of visual loss but did not prevent DR progression.

Inhibition of PKC ? by ruboxistaurin (RBX) does not enhance the blood pressure (BP) response to glyceryl trinitrate (GTN)

Background Activation of PKC β by hyperglycemia impairs endothelial- and nitric oxide (NO)-dependent vasodilation. RBX, a specific inhibitor of PKC β undergoing clinical testing for the treatment of diabetic microvascular complications, normalizes NO signaling in diabetic animals and restores vascular function. This study assessed a possible interaction between RBX and the exogenous NO donor, GTN, on BP. Methods A randomized, double masked, placebo (PL)-controlled, 2 period crossover study was performed in 21 stable angina pectoris subjects. RBX (96 mg/d; 3x the therapeutic dose) or PL was given orally to steady state. Graded GTN was then infused with dose escalation until discontinued for hypotension or when 120 mcg/min was achieved. Primary treatment comparison was the slope of the change in standing systolic BP from predose (ΔSSBP)/ ln(GTN dose) curve. Treatment difference in ΔSSBP at a GTN rate producing a 10 mmHg fall with PL treatment (GTN*) was also assessed. Results RBX did not alter the slope of ΔSSBP/ ln(GTN dose) curve (p=0.272 ANCOVA) or affect the ΔSSBP at the 8.44 mcg/min GTN* rate (mean −0.9 mmHg; 95% CI −3.3, 1.5). Conclusion Ruboxistaurin can be coadministered with organic nitrates as it does not potentiate their BP lowering effect. Clinical Pharmacology & Therapeutics (2005) 77, P15–P15; doi: 10.1016/j.clpt.2004.11.060