James tweeten opthamalogist in boise1/3/2024 ![]() RBX is more effective at preventing diabetes-induced retinal vascular leakage in these models than in preventing retinal neovascularization. RBX prevents diabetes- and VEGF-induced retinal vascular leakage in animals. In addition, VEGF is a potent vasopermeability factor that may be involved in DME, the intracellular signaling pathway of which involves activation of PKC β. Diabetes-induced de novo synthesis of diacylglycerol activates PKC β in the retina, which increases vascular permeability through various mechanisms including phosphorylation of junctional proteins and dissolution of tight junctions. The broad range of baseline DME severity in study eyes ( Table 2 ) makes it difficult to detect an effect of RBX on change in distance of edema from the center of the macula.ĭME results from increased leakage of plasma components from the retinal vasculature and has been postulated to occur via two different PKC β-mediated mechanisms. This study was not designed to demonstrate an effect of RBX on DME or visual function, and patients were enrolled regardless of their DME status at baseline. The rate of SMVL was higher in eyes with definite DME at baseline, and it was among these eyes that there was a trend for a beneficial effect of 32 mg/day RBX (Fig. In the PKC-DRS, 79% of patients had DME in at least one study eye at baseline and 34% had DME involving the center of the macula in at least one study eye at baseline. SMVL and MVL are often caused by DME involving the center of the macula. Thus, these findings are consistent with a beneficial effect of RBX on the occurrence of SMVL. However, reduction of SMVL by RBX in eyes with DME at baseline did achieve statistical significance ( P = 0.017, Fig. Since SMVL occurs less frequently than MVL, there is less chance of observing a statistical difference in SMVL in this study. Although reduction in SMVL by RBX treatment did not reach statistical significance, the relative risk reductions for SMVL and MVL were in the same direction and generally of similar magnitude (0.62 vs. MVL, defined as a loss of 15 letters or more of best-corrected visual acuity on the ETDRS visual acuity chart, and SMVL, defined as MVL at each of two consecutive visits 6 or more months apart, are clinically meaningful end points equivalent to a doubling of the visual angle (e.g., deterioration from 20/20 to 20/40). However, there did appear to be a beneficial effect of RBX on the secondary study outcomes of MVL and SMVL (Figs. In addition, it is possible that PKC β activation is not critical for the progression of DR to the proliferative stage in humans. Over time, different growth factors or other molecules, including different isoforms of PKC, could be compensating any potential beneficial effects of PKC β inhibition. Although activation of PKC β is involved in mediating VEGF-induced intracellular signaling, RBX is not primarily a VEGF inhibitor, and in cellular and animal models, its antiproliferative effect is weaker than its antipermeability activity. It is also known that the majority of the neovascular response in the retina is mediated by VEGF. Alternatively, RBX may not be potent enough to overcome these effects. Thus, in our study participants, significant biochemical and pathologic retinal changes that are no longer amenable to PKC β inhibition may have already occurred before enrollment. It has been well established that PKC β is activated very early in diabetes, well before clinically apparent retinopathy. Study patients had moderately severe to very severe NPDR at baseline. The apparent lack of efficacy of RBX in preventing progression of retinopathy to the proliferative stage could occur for several reasons. There are cellular and animal data suggesting that the β-isoform of PKC may be involved in mediating diabetes-induced retinopathy, retinal vascular permeability, and retinal neovascularization.
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