Effect of ruboxistaurin (RBX) On visual acuity decline over a 6-year period with cessation and reinstitution of therapy: results of an open-label extension of the Protein Kinase C Diabetic Retinopathy Study 2 (PKC-DRS2).

PURPOSE: The PKC-DRS2 was a Phase 3, randomized, double-masked, placebo (PBO)-controlled, 3-year study of the effect of 32 mg/day of ruboxistaurin (RBX), an orally administered protein kinase C inhibitor, on vision loss in patients with moderate to severe nonproliferative diabetic retinopathy. Ruboxistaurin reduced the occurrence of sustained moderate visual loss (SMVL; ≥15-letter decline in visual acuity sustained for the last 6 months of study participation) from 9.1% in the PBO group (N = 340) to 5.5% in the RBX group (N = 345, P = 0.034). This study evaluates the primary end point of SMVL in a 2-year open-label extension (OLE) of the PKC-DRS2, which began a median of 466 days (range, 263-1,296 days) after the conclusion of PKC-DRS2. METHODS: Visual acuity was measured by certified examiners using the Early Treatment Diabetic Retinopathy Study chart. RESULTS: Of the 514 patients who completed PKC-DRS2, 366 did so in the 32 study centers participating in the OLE, and of these, 203 (55%) enrolled in the OLE for treatment with 32 mg/day of RBX for 2 years. Of the 203 enrolled in the OLE, 100 had previously been treated with PBO (prior PBO subgroup) and 103 had been treated with RBX (prior RBX subgroup). PKC-DRS2 baseline patient and ocular characteristics were well matched between these two subgroups and were similar to the PKC-DRS2 patient population as a whole. Using the PKC-DRS2 baseline as the starting point, SMVL occurred in 6% of the prior PBO subgroup during the PKC-DRS2, increasing to 26% by the end of the OLE. However, in the prior RBX subgroup, SMVL occurred in only 4% and 8% during the PKC-DRS2 and by the end of the OLE, respectively (P < 0.001 for difference at the end of the OLE). In the prior PBO subgroup, mean visual acuity declined from 79.6 letters at PKC-DRS2 baseline to 73.1 letters at OLE end point (-6.5 letters). In the prior RBX subgroup, this loss was 2.7 letters (79.8 to 77.1) over the same period (P = 0.02). CONCLUSION: Over a 6-year study period incorporating 3 years of a rigorously placebo-controlled trial, approximately 1 year off treatment and 2-year OLE where all groups received therapy, those patients with greatest RBX exposure (∼5 years) experienced less SMVL compared with those in the original PBO group (∼2-year RBX exposure).

Effect of ruboxistaurin on visual loss in patients with diabetic retinopathy.

OBJECTIVE: To evaluate the effect of ruboxistaurin, an orally administered protein kinase C beta (PKC beta) isozyme-selective inhibitor, on vision loss in patients with diabetes. DESIGN: Thirty-six-month, randomized, double-masked, placebo-controlled, parallel, multicenter trial. PARTICIPANTS: Six hundred eighty-five patients randomized at 70 clinical sites. METHODS: Ophthalmologic examination was performed at screening and at each 3-month visit. Retinopathy status was assessed every 6 months with Early Treatment Diabetic Retinopathy Study (ETDRS) standard 7-field 30 degrees color stereoscopic fundus photography. Levels of diabetic retinopathy and diabetic macular edema were determined by 2 independent graders masked to site and treatment assignment, with additional independent adjudication as required. Eligible patients had a best-corrected visual acuity (VA) score of > or =45 letters, retinopathy level > or = 47A and < or = 53E, and no prior panretinal photocoagulation in at least one eye. MAIN OUTCOME MEASURE: Effect of oral ruboxistaurin (32 mg/day) on reduction of sustained moderate visual loss (> or =15-letter decrease in ETDRS VA score maintained > or = 6 months) in patients with moderately severe to very severe nonproliferative diabetic retinopathy. RESULTS: Sustained moderate visual loss occurred in 9.1% of placebo-treated patients versus 5.5% of ruboxistaurin-treated patients (40% risk reduction, P = 0.034). Mean VA was better in the ruboxistaurin-treated patients after 12 months. Baseline-to-end point visual improvement of > or =15 letters was more frequent (4.9% vs. 2.4%) and > or =15-letter worsening was less frequent (6.7% vs. 9.9%) in ruboxistaurin-treated patients relative to placebo (P = 0.005). When clinically significant macular edema was >100 microm from the center of the macula at baseline, ruboxistaurin treatment was associated with less frequent progression of edema to within 100 microm (68% vs. 50%, P = 0.003). Initial laser treatment for macular edema was 26% less frequent in eyes of ruboxistaurin-treated patients (P = 0.008). CONCLUSION: Oral ruboxistaurin treatment reduced vision loss, need for laser treatment, and macular edema progression, while increasing occurrence of visual improvement in patients with nonproliferative retinopathy.

Comparative analysis of the in vitro prosecretory effects of balsalazide, sulfasalazine, olsalazine, and mesalamine in rabbit distal ileum.

BACKGROUND: The aminosalicylates remain foundation therapy for mild-to-moderate ulcerative colitis. Pro-drug 5-aminosalicylic acid (5-ASA; mesalamine) formulations have been developed to prevent 5-ASA from the proximal absorption and release of mesalamine, to decrease inflammation, and to improve colonic absorption. Clinically, pro-drugs such as olsalazine have been associated with dose-dependent diarrhea, which was likely secondary to ileal secretion induced by the azo linkages, in 17% of patients. The present study tested the hypothesis that the use of all compounds with azo linkages leads to increased secretion. METHODS: Intestinal tissue was randomly assigned to serve as controls or to receive brush border addition of equimolar concentrations of the compounds, and the change in short-circuit current was measured. RESULTS: Mesalamine did not induce secretion at any dose. Mean equivalent doses (0.1 to 10 mM) of balsalazide (range, 6.3 +/- 1.5 to 16.7 +/- 1.3 microA/cm2), olsalazine (range, 2.0 +/- 1.0 to 7.0 +/- 2.1 microA/cm2), and sulfasalazine (3.2 +/- 1.1 to 6.2 +/- 1.5 microA/cm2) significantly stimulated (P < 0.001) secretion. The values for the effective dose that is half the maximal dose for secretion induced by sulfasalazine, olsalazine, and balsalazide were 0.4, 0.7, and 0.9 mM, respectively. CONCLUSIONS: This study is the first to demonstrate that the use of pro-drugs with azo bonds leads to increased ileal secretion at equimolar concentrations of 5-ASA. Physicians should use caution when providing higher doses of the pro-drug forms of 5-ASA to their patients, as this could lead to increased diarrhea.

Role of protein kinase C inhibition in the development of diabetic microvascular complications.

Diabetes mellitus affects millions of people in the USA and throughout the world. The global epidemic may be attributed to both the increasing age of the population and the increasing rates of obesity. Diabetes is associated with chronic microvascular (diabetic neuropathy, retinopathy and nephropathy) and macrovascular complications (heart disease, stroke and peripheral vascular disease). Patients with diabetes benefit from a comprehensive approach to prevent complications, including weight loss, smoking cessation, antiplatelet agents, and glycemic and blood pressure control. However, all of these are difficult for patients to achieve and maintain on a daily basis and there is still a risk of developing vascular complications. Specific therapies for diabetic complications targeting molecules that are activated by hyperglycemia are emerging. The aim of this review is to highlight the role of protein kinase Cß in the development of diabetic microvascular complications while briefly describing clinical experience with the protein kinase Cß inhibitor ruboxistaurin.

How the diabetic eye loses vision.

The objective is to review the most common causes of vision loss in patients with diabetes with the goal of better managing patients with diabetic eye disease. In this review, the causes of vision loss, and the clinical evaluation and management of diabetic retinopathy (DR) and diabetic macular edema (DME) are outlined. Patients with diabetes mellitus have an increased risk of vision loss and blindness. In patients with diabetes, the primary mechanism responsible for vision loss is centrally involved DME or clinically significant macular edema (CSME), defined as vascular leakage resulting in fluid accumulation that affects the center of the macula. DR and DME are thought to result from the effects of excessive blood glucose on the vessels that produces microvascular damage. The progression of DR can be slowed by intensive glycemic and blood pressure control. Severe visual loss from proliferative DR and moderate visual loss from DME can be reduced by laser photocoagulation. DR and DME are diagnosed on dilated retinal examination and confirmed with diagnostic testing. Many experts and associations recommend that patients with diabetes have an yearly, thorough, dilated eye exam. This manuscript describes the case history of a patient with diabetes and vision loss.

Factors that impact symptomatic diabetic peripheral neuropathy in placebo-administered patients from two 1-year clinical trials.

OBJECTIVE: The purpose of this study was to evaluate the change in neuropathy symptoms and disease progression in placebo-administered patients from two 1-year studies in which the impact of ruboxistaurin (RBX) in mild diabetic peripheral neuropathy (DPN) was tested. RESEARCH DESIGN AND METHODS: Data from 262 placebo-administered patients from two identical phase 3, randomized, double-blind trials were combined and analyzed. RESULTS: After 1 year, change in the neuropathy impairment score of lower limbs [NIS(LL)] (-0.63 points; P = 0.005), vibration detection threshold (VDT) (-0.42 just noticeable difference units; P = 0.003), and Neuropathy Total Symptom Score-6 (NTSS-6) questionnaire (-3.73 points; P < 0.001) improved, whereas some electrophysiology measures and heart rate deep breathing (HRDB) (-0.78 beats; P = 0.003) worsened compared with baseline values. There was a small but significant worsening of A1C (0.28%; P < 0.001), and a greater percentage of patients were using analgesics at the end of the trials (33.6%; P = 0.003). At 1 year, the change in NTSS-6 directly correlated with changes in NIS(LL) and VDT and inversely correlated with the peroneal nerve conduction velocity. On logistic regression analyses, a > or = 50% reduction in NTSS-6 score was less likely in patients who used antihypertensive or chronic symptom medication at baseline. CONCLUSIONS: In placebo-administered patients with mild symptomatic DPN, there was a progressive improvement in symptoms over 12 months, whereas nerve conduction studies and HRDB declined, and clinically significant worsening of DPN would require > 1 year of observation.

fMLP induces Hsp27 expression, attenuates NF-kappaB activation, and confers intestinal epithelial cell protection.

Sustained expression of cytoprotective intestinal epithelial heat shock proteins (Hsps), particularly Hsp27, depends on stimuli derived from bacterial flora. In this study, we examined the role of the bacterial chemotactic peptide fMLP in stimulating colonic epithelial Hsp expression at concentrations encountered in a physiological milieu. Treatment of the polarized human intestinal epithelial cell line Caco2bbe with physiological concentrations of fMLP (10-100 nM) induced expression of Hsp27, but not Hsp72, in a time- and concentration-dependent manner. Induction of Hsp27 by fMLP was specific since the fMLP analogs MRP and MLP were not effective. Hsp27 induction by fMLP was blocked by the fMLP-receptor antagonist BOC-FLFLF and was blocked when the dipeptide transporter PepT1, an entry pathway for fMLP, was silenced. fMLP activated both the p38 and ERK1/2 MAP kinase pathways in Caco2bbe cells, but not the SAPK/JNK pathway. The p38 inhibitor SB203580, but not the MEK-1 inhibitor PD98059, blocked Hsp27 induction by fMLP. fMLP treatment inhibited actin depolymerization and decreased transepithelial resistance caused by the oxidant monochloramine, and this inhibition was reversed by silencing Hsp27 expression. fMLP pretreatment also inhibited activation of proinflammatory transcription factor NF-kappaB by TNF-alpha in Caco2bbe cells, reducing induction of NF-kappaB target genes by TNF-alpha both in human intestinal biopsies and Caco2bbe cells. In conclusion, fMLP may contribute to the maintenance of intestinal homeostasis by mediating physiological expression of Hsp27, enhancing cellular protection, and negatively regulating the inflammatory response.

Diagnostic tools for diabetic sensorimotor polyneuropathy.

Diabetes and its complications are major causes of mortality in the United States, with increasing rates of morbidity and increasing health care costs. Patients diagnosed with diabetes attempt to control cholesterol levels, blood pressure, and blood glucose levels to decrease the risk of diabetic microvascular complications (DMC), such as diabetic sensorimotor polyneuropathy (DSP) [also known as diabetic peripheral neuropathy (DPN)]. Despite control of these risk factors for vascular disease, many patients still develop DSP. Research investigating diabetic neuropathy holds promise for specific treatment of diabetic complications. Intrinsic to the success of new therapies is the accurate diagnosis and evaluation of DSP. Symptom scores, quantitative sensory testing and electrophysiology are some of the diagnostic tools to identify the signs and symptoms of DSP. Early detection of neuropathy enables clinicians to prevent long-term complications like ulcers and amputations in patients with diabetes. The focus of this review is to describe the composite of tools necessary for diagnosis of DSP.

Pathophysiology and treatment of diabetic peripheral neuropathy: the case for diabetic neurovascular function as an essential component.

Worldwide, diabetes and its complications are major causes of morbidity, decreased quality of life, mortality and increasing health care costs. Patients with diabetes attempt to control blood pressure, lipids and blood glucose levels to decrease their risk of macrovascular and microvascular complications, such as diabetic peripheral neuropathy (DPN). Even with control of these risk factors for vascular disease, many patients still develop complications. Targeted therapies to the underlying mechanisms of diabetic neuropathy are essential to slow the progression of the disease. This review describes the signs, symptoms and diagnosis of DPN. Additionally, new therapies and the complex etiology that contributes to the development of diabetic neuropathy are described (oxidative stress, hyperglycemia, advanced glycated end products, autoimmunity, neurotrophic factors and protein kinase C beta).

Clinical safety of the selective PKC-beta inhibitor, ruboxistaurin.

The aim of this manuscript is to report the safety profile of patients treated with ruboxistaurin mesylate (RBX; LY333531), a selective protein kinase C-beta (PKC-beta) inhibitor, for up to 4 years. Data from patients with diabetes (1396 RBX 32 mg/day; 1408 placebo) were combined from 11 placebo-controlled, double-masked studies. The proportion of patients who reported one or more serious adverse events was greater in the placebo group than in the RBX-treated group (23.2 versus 20.8%, respectively). There were 51 deaths (21 RBX; 30 placebo) reported in this patient cohort; none of the deaths was attributed to study drug by the investigators. Common adverse drug reactions (> or = 1/100 - < 1/10 patients) that were reported in the RBX-treated patients were dyspepsia and increased blood creatine phosphokinase. In controlled, randomised clinical trials, RBX had an adverse event profile comparable to placebo, and was well tolerated.