OBJECTIVE -Diabetes leads to protein kinase C (PKC)- overactivation and microvascular dysfunction, possibly resulting in disordered skin microvascular blood flow (SkBF) and other changes observed in diabetic peripheral neuropathy (DPN) patients. We investigate the effects of the isoform-selective PKC- inhibitor ruboxistaurin mesylate on neurovascular function and other measures of DPN.RESEARCH DESIGN AND METHODS -Endothelium-dependent and C fibermediated SkBF, sensory symptoms, neurological deficits, nerve fiber morphometry, quantitative sensory and autonomic function testing, nerve conduction studies, quality of life (using the Norfolk Quality-of-Life Questionnaire for Diabetic Neuropathy [QOL-DN]), and adverse events were evaluated for 20 placebo-and 20 ruboxistaurin-treated (32 mg/day) DPN patients (aged Ն18 years; with type 1 or type 2 diabetes and A1C Յ11%) during a randomized, doublemasked, single-site, 6-month study.RESULTS -Endothelium-dependent (ϩ78.2%, P Ͻ 0.03) and C fiber-mediated (ϩ56.4%, P Ͻ 0.03) SkBF at the distal calf increased from baseline to end point. Significant improvements from baseline within the ruboxistaurin group were also observed for the Neuropathy Total Symptom Score-6 (NTSS-6) (3 months Ϫ48.3%, P ϭ 0.01; end point Ϫ66.0%, P Ͻ 0.0006) and the Norfolk QOL-DN symptom subscore and total score (end point Ϫ41.2%, P ϭ 0.01, and Ϫ41.0, P ϭ 0.04, respectively). Between-group differences in baseline-to-end point change were observed for NTSS-6 total score (placebo Ϫ13.1%; ruboxistaurin Ϫ66.0%, P Ͻ 0.03) and the Norfolk QOL-DN symptom subscore (placebo Ϫ4.0%; ruboxistaurin Ϫ41.2%, P ϭ 0.041). No significant ruboxistaurin effects were demonstrated for the remaining efficacy measures. Adverse events were consistent with those observed in previous ruboxistaurin studies.CONCLUSIONS -In this cohort of DPN patients, ruboxistaurin enhanced SkBF at the distal calf, reduced sensory symptoms (NTSS-6), improved measures of Norfolk QOL-DN, and was well tolerated.
Diabetes Care 30:896 -902, 2007
