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Lloyd Paul Aiello - One of the best experts on this subject based on the ideXlab platform.
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The effect of the oral PKC β inhibitor Ruboxistaurin on vision loss in two phase 3 studies.
Investigative ophthalmology & visual science, 2013Co-Authors: Matthew J. Sheetz, Lloyd Paul Aiello, Nazila Shahri, Matthew D. Davis, Ronald P. Danis, Toke Bek, José Cunha-vaz, Paul H. BergAbstract:PURPOSE To assess the effect of Ruboxistaurin (RBX) on vision loss through a prospectively defined combined analysis of two phase 3 trials (MBDL and MBCU). METHODS Patients in both of these 3-year randomized, placebo-controlled, double-masked trials had best-corrected Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) ≥ 75 letters (∼20/32 Snellen), ETDRS retinopathy level 20 to 47D (MBDL) or 35B to 53E (MBCU), and no prior panretinal or focal photocoagulation in at least one eye at baseline. Patients received oral placebo (N = 508 total from both studies) or RBX 32 mg/d (N = 520 total). Best-corrected ETDRS VA was measured at 6-month intervals for 3 years (MBDL) or for 18 to 48 months (MBCU). Sustained moderate visual loss (SMVL) was defined as a 15-letter or more reduction from baseline in VA sustained for a patient's last 6 months of study participation. RESULTS In the combined studies (N = 1028 total), SMVL occurred in 4.4% of placebo- versus 2.3% of RBX-treated patients (P = 0.069). In patients with a minimum of 2 years of follow-up (N = 825 total), there was less SMVL in the RBX group (4.4% placebo versus 2.1% RBX, P = 0.045). Other VA-related measures (mean VA, contrast sensitivity, Visual Functioning Questionnaire 25 [VFQ-25]) either trended toward a benefit for RBX or were also statistically significant in favor of RBX. In contrast, diabetic macular edema (DME) morphology-related measures (occurrence of significant center of macula involvement, optical coherence tomography [OCT]-determined center of macula thickness, application of focal photocoagulation) did not show a consistent trend in favor of or against RBX. CONCLUSIONS SMVL data in a prospectively defined combined analysis from these two phase 3 trials suggest a magnitude of effect of RBX on vision loss similar to that seen in two prior studies (approximately 50% reduction above standard care). However, event rates were low and statistical significance was not achieved. (ClinicalTrials.gov numbers, NCT00133952, NCT00090519.).
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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).
Retina (Philadelphia Pa.), 2011Co-Authors: Matthew J. Sheetz, Lloyd Paul Aiello, Keri A. Kles, Nazila Shahri, Matthew D. Davis, Ronald P. DanisAbstract: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. Ruboxi
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Ruboxistaurin: Review of Safety and Efficacy in the Treatment of Diabetic Retinopathy
2010Co-Authors: Golnaz Javey, Lloyd Paul Aiello, Stephen G. Schwartz, Harry W. Flynn, Matthew J. SheetzAbstract:Ruboxistaurin (Eli Lilly, Indianapolis, IN), an orally active inhibitor of the β isoform of protein kinase C (PKC), has been studied as a systemic treatment for diabetic retinopathy. PKC-β appears to be overactivated in response to hyperglycemia. This overactivation associates with various pathological effects within the retinal vascular system, including ischemia, vascular leakage, and angiogenesis. Several randomized clinical trials of Ruboxistaurin have been performed. In most trials, the primary outcomes were not achieved. Analysis of secondary outcomes data from these trials has demonstrated some evidence of safety and efficacy in the treatment of diabetic retinopathy. At this time, Ruboxistaurin has not received approval from the US Food and Drug Administration.
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Ruboxistaurin mesilate hydrate for diabetic retinopathy.
Drugs of today (Barcelona Spain : 1998), 2009Co-Authors: Stephen G. Schwartz, H.w. Jr. Flynn, Lloyd Paul AielloAbstract:Diabetic retinopathy remains a major worldwide cause of preventable blindness. The beta isoform of protein kinase C (PKC) may play an important role in the pathogenesis of this disorder. Ruboxistaurin mesylate hydrate is an orally bioavailable, highly-specific inhibitor of PKC beta, which has shown some efficacy in several large, multicenter, randomized clinical trials. The U.S. Food and Drug Administration issued an approvable letter for Ruboxistaurin in 2006, but at this time the medication is not available for routine clinical use.
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Effect of Ruboxistaurin on the visual acuity decline associated with long-standing diabetic macular edema.
Investigative ophthalmology & visual science, 2008Co-Authors: Matthew D. Davis, Lloyd Paul Aiello, Matthew J. Sheetz, Ronald P. Danis, Aniz Girach, Roy C Milton, Xin Zhi, Maria C. Jimenez, Louis VignatiAbstract:Purpose To compare relationships between severity and duration of diabetic macular edema (DME) and visual acuity (VA) observed in the PKC-DRS2 with those from the Early Treatment Diabetic Retinopathy Study (ETDRS) and to assess the effect of the orally administered PKC beta inhibitor Ruboxistaurin (RBX) on these parameters. Methods In the PKC-DRS2, patients with moderately severe to very severe nonproliferative diabetic retinopathy (n = 685) were randomly assigned to 32 mg/d RBX or placebo and followed up for 36 months with ETDRS VA measurements and fundus photographs (FP) every 3 to 6 months. Mean VA was calculated across all FP visits for eyes in each level of the ETDRS DME severity scale at those visits. For eyes with baseline VA > or = 20/40, relationships between change in VA from baseline to last visit and duration of severe DME were analyzed with linear regression. Results Mean VA decreased by approximately 22 letters between the mildest and most severe levels of the DME scale in the PKC-DRS2, compared with 27 letters in the ETDRS. In the placebo group, the rate of decrease in VA over time associated with duration of severe DME was 0.67 letters per month (24 letters over 36 months, compared with 20 letters over 28-36 months in the ETDRS). This rate was 30% less in the RBX group (0.47 letter per month, P = 0.022). Conclusions The VA decrease in the PKC-DRS2 associated with long-standing DME agrees well with estimates from the ETDRS. RBX appears to ameliorate this decrease, an effect that could be important clinically. (ClinicalTrials.gov number, NCT00604383.).
Matthew J. Sheetz - One of the best experts on this subject based on the ideXlab platform.
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The effect of the oral PKC β inhibitor Ruboxistaurin on vision loss in two phase 3 studies.
Investigative ophthalmology & visual science, 2013Co-Authors: Matthew J. Sheetz, Lloyd Paul Aiello, Nazila Shahri, Matthew D. Davis, Ronald P. Danis, Toke Bek, José Cunha-vaz, Paul H. BergAbstract:PURPOSE To assess the effect of Ruboxistaurin (RBX) on vision loss through a prospectively defined combined analysis of two phase 3 trials (MBDL and MBCU). METHODS Patients in both of these 3-year randomized, placebo-controlled, double-masked trials had best-corrected Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) ≥ 75 letters (∼20/32 Snellen), ETDRS retinopathy level 20 to 47D (MBDL) or 35B to 53E (MBCU), and no prior panretinal or focal photocoagulation in at least one eye at baseline. Patients received oral placebo (N = 508 total from both studies) or RBX 32 mg/d (N = 520 total). Best-corrected ETDRS VA was measured at 6-month intervals for 3 years (MBDL) or for 18 to 48 months (MBCU). Sustained moderate visual loss (SMVL) was defined as a 15-letter or more reduction from baseline in VA sustained for a patient's last 6 months of study participation. RESULTS In the combined studies (N = 1028 total), SMVL occurred in 4.4% of placebo- versus 2.3% of RBX-treated patients (P = 0.069). In patients with a minimum of 2 years of follow-up (N = 825 total), there was less SMVL in the RBX group (4.4% placebo versus 2.1% RBX, P = 0.045). Other VA-related measures (mean VA, contrast sensitivity, Visual Functioning Questionnaire 25 [VFQ-25]) either trended toward a benefit for RBX or were also statistically significant in favor of RBX. In contrast, diabetic macular edema (DME) morphology-related measures (occurrence of significant center of macula involvement, optical coherence tomography [OCT]-determined center of macula thickness, application of focal photocoagulation) did not show a consistent trend in favor of or against RBX. CONCLUSIONS SMVL data in a prospectively defined combined analysis from these two phase 3 trials suggest a magnitude of effect of RBX on vision loss similar to that seen in two prior studies (approximately 50% reduction above standard care). However, event rates were low and statistical significance was not achieved. (ClinicalTrials.gov numbers, NCT00133952, NCT00090519.).
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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).
Retina (Philadelphia Pa.), 2011Co-Authors: Matthew J. Sheetz, Lloyd Paul Aiello, Keri A. Kles, Nazila Shahri, Matthew D. Davis, Ronald P. DanisAbstract: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. Ruboxi
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Ruboxistaurin: Review of Safety and Efficacy in the Treatment of Diabetic Retinopathy
2010Co-Authors: Golnaz Javey, Lloyd Paul Aiello, Stephen G. Schwartz, Harry W. Flynn, Matthew J. SheetzAbstract:Ruboxistaurin (Eli Lilly, Indianapolis, IN), an orally active inhibitor of the β isoform of protein kinase C (PKC), has been studied as a systemic treatment for diabetic retinopathy. PKC-β appears to be overactivated in response to hyperglycemia. This overactivation associates with various pathological effects within the retinal vascular system, including ischemia, vascular leakage, and angiogenesis. Several randomized clinical trials of Ruboxistaurin have been performed. In most trials, the primary outcomes were not achieved. Analysis of secondary outcomes data from these trials has demonstrated some evidence of safety and efficacy in the treatment of diabetic retinopathy. At this time, Ruboxistaurin has not received approval from the US Food and Drug Administration.
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Ruboxistaurin: PKC-β inhibition for complications of diabetes
Expert opinion on pharmacotherapy, 2009Co-Authors: Ronald P. Danis, Matthew J. SheetzAbstract:Diabetes mellitus is the most common cause of blindness among working-age adults, with a prevalence of 7 – 8% of adults in the USA, and is one of the most common causes of renal failure requiring kidney transplant and the most common cause of non-traumatic lower limb amputation in developed nations . The role of the intracellular signaling enzyme protein kinase C (PKC) in the development of diabetic complications has become a field of intense research interest. An inhibitor of the PKC-β isoform Ruboxistaurin (RBX) has in vitro and in vivo benefits in ameliorating disturbances of cell regulation and blood flow related to hyperglycemia. The benefit of RBX for peripheral neuropathy has not been successfully demonstrated in Phase III trials. Although there was a beneficial effect of RBX on nephropathy in a pilot study, there has been no further clinical development for this indication. The major cause of visual disability – diabetic macular edema – seems to respond to RBX treatment with both anatomic and func...
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Selective PKC beta inhibition with Ruboxistaurin and endothelial function in type-2 diabetes mellitus.
Cardiovascular drugs and therapy, 2008Co-Authors: Nehal N. Mehta, Matthew J. Sheetz, Karen L. Price, Lynn Comiskey, Shirish Amrutia, Nayyar Iqbal, Emile R. Mohler, Muredach P. ReillyAbstract:Purpose Type-2 diabetes mellitus increases risk of atherosclerotic cardiovascular disease. However, the mechanisms linking hyperglycemia and atherosclerosis remain poorly understood. One proposed mechanism involves endothelial dysfunction via activation of protein kinase C beta (PKC beta). Prior studies demonstrate beneficial effects of PKC beta inhibition on microvascular parameters, but, to date, no study has examined the effect on macrovascular atherosclerotic readouts.
F. Ivy Carroll - One of the best experts on this subject based on the ideXlab platform.
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Synthesis and Characterization of the Selective, Reversible PKCβ Inhibitor (9 S)-9-[(Dimethylamino)methyl]-6,7,10,11-tetrahydro-9 H,18 H-5,21:12,17-dimethenodibenzo[ e,k]pyrrolo[3,4- h][1,4,13]oxadiazacyclohexadecine-18,20(19 H)-dione, Ruboxistaurin
ACS chemical neuroscience, 2018Co-Authors: Anita H. Lewin, Larry Brieaddy, Jeffrey R. Deschamps, Gregory H. Imler, S. Wayne Mascarella, P. Anantha Reddy, F. Ivy CarrollAbstract:The demonstrated role of PKCβ in mediating amphetamine-stimulated dopamine efflux, which regulates amphetamine-induced dopamine transporter trafficking and activity, has promoted the research use of the selective, reversible PKCβ inhibitor (9 S)-9-[(dimethylamino)methyl]-6,7,10,11-tetrahydro-9 H,18 H-5,21:12,17-dimethenodibenzo[ e,k]pyrrolo[3,4- h][1,4,13]oxadiazacyclohexadecine-18,20(19 H)-dione, Ruboxistaurin. Despite the interest in development of Ruboxistaurin as the mesylate monohydrate (Arxxant) for the treatment of diabetic retinopathy, macular edema, and nephoropathy, several crucial details in physicochemical characterization were erroneous or missing. This report describes the synthesis and full characterization of Ruboxistaurin free base (as a monohydrate), including X-ray crystallography to confirm the absolute configuration, and of the mesylate salt, isolated as a hydrate containing 1.5 mol of water per mole.
Anita H. Lewin - One of the best experts on this subject based on the ideXlab platform.
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Synthesis and Characterization of the Selective, Reversible PKCβ Inhibitor (9 S)-9-[(Dimethylamino)methyl]-6,7,10,11-tetrahydro-9 H,18 H-5,21:12,17-dimethenodibenzo[ e,k]pyrrolo[3,4- h][1,4,13]oxadiazacyclohexadecine-18,20(19 H)-dione, Ruboxistaurin
ACS chemical neuroscience, 2018Co-Authors: Anita H. Lewin, Larry Brieaddy, Jeffrey R. Deschamps, Gregory H. Imler, S. Wayne Mascarella, P. Anantha Reddy, F. Ivy CarrollAbstract:The demonstrated role of PKCβ in mediating amphetamine-stimulated dopamine efflux, which regulates amphetamine-induced dopamine transporter trafficking and activity, has promoted the research use of the selective, reversible PKCβ inhibitor (9 S)-9-[(dimethylamino)methyl]-6,7,10,11-tetrahydro-9 H,18 H-5,21:12,17-dimethenodibenzo[ e,k]pyrrolo[3,4- h][1,4,13]oxadiazacyclohexadecine-18,20(19 H)-dione, Ruboxistaurin. Despite the interest in development of Ruboxistaurin as the mesylate monohydrate (Arxxant) for the treatment of diabetic retinopathy, macular edema, and nephoropathy, several crucial details in physicochemical characterization were erroneous or missing. This report describes the synthesis and full characterization of Ruboxistaurin free base (as a monohydrate), including X-ray crystallography to confirm the absolute configuration, and of the mesylate salt, isolated as a hydrate containing 1.5 mol of water per mole.
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Synthesis and Characterization of the Selective, Reversible PKCβ Inhibitor (9S)‑9-[(Dimethylamino)methyl]-6,7,10,11-tetrahydro‑9H,18H‑5,21:12,17-dimethenodibenzo[e,k]pyrrolo[3,4‑h][1,4,13]oxadiazacyclohexadecine-18,20(19H)‑dione, Ruboxistaurin (LY333
2018Co-Authors: Anita H. Lewin, Larry Brieaddy, Jeffrey R. Deschamps, Gregory H. Imler, Wayne S. Mascarella, Anantha P. Reddy, Ivy F. CarrollAbstract:The demonstrated role of PKCβ in mediating amphetamine-stimulated dopamine efflux, which regulates amphetamine-induced dopamine transporter trafficking and activity, has promoted the research use of the selective, reversible PKCβ inhibitor (9S)-9-[(dimethylamino)methyl]-6,7,10,11-tetrahydro-9H,18H-5,21:12,17-dimethenodibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexadecine-18,20(19H)-dione, Ruboxistaurin. Despite the interest in development of Ruboxistaurin as the mesylate monohydrate (Arxxant) for the treatment of diabetic retinopathy, macular edema, and nephoropathy, several crucial details in physicochemical characterization were erroneous or missing. This report describes the synthesis and full characterization of Ruboxistaurin free base (as a monohydrate), including X-ray crystallography to confirm the absolute configuration, and of the mesylate salt, isolated as a hydrate containing 1.5 mol of water per mole
Aaron I. Vinik - One of the best experts on this subject based on the ideXlab platform.
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A 6-month, randomized, double-masked, placebo-controlled study evaluating the effects of the protein kinase C-beta inhibitor Ruboxistaurin on skin microvascular blood flow and other measures of diabetic peripheral neuropathy
2015Co-Authors: Carolina M. Casellini, Patricia M. Barlow, Amanda L. Rice, Gary Pittenger, Edward J. Bastyr, Anne M. Wolka, Aaron I. VinikAbstract: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 fiber– mediated 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 18 years; with type 1 or type 2 diabetes and A1C 11%) during a randomized, double-masked, single-site, 6-month study. RESULTS — Endothelium-dependent (78.2%, P 0.03) and C fiber–mediated (56.4%, P 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 months48.3%, P 0.01; end point66.0%, P 0.0006) and the Norfolk QOL-DN symptom subscore and total score (end point 41.2%, P 0.01, and 41.0, P 0.04, respectively). Between-group differences in baseline–to–end point change were observed for NTSS-6 total score (placebo13.1%; Ruboxistaurin66.0%, P 0.03) and the Norfolk QOL-DN symptom subscore (placebo4.0%; Ruboxistaurin41.2%, P 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
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Quality of life and objective measures of diabetic neuropathy in a prospective placebo-controlled trial of Ruboxistaurin and topiramate.
Journal of diabetes science and technology, 2011Co-Authors: Amanda L Boyd, Carolina Casselini, Etta J. Vinik, Aaron I. VinikAbstract:Background:The Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QOL-DN) is a validated comprehensive questionnaire designed to capture the entire spectrum of DN related to large fiber, small fiber, and autonomic neuropathy not captured in existing instruments. We aimed to determine if the Norfolk QOL-DN could be used to capture changes in QOL that correlate with nerve fiber-specific objective measures in a placebo-controlled trial of two agents that affect different nerve fibers.Methods:Sixty patients with DN were allocated to treatment on Ruboxistaurin (RBX) (n = 18), topiramate (TPX) (n = 18), or placebo (n = 18). QOL-DN was administered and objective measures of nerve function were performed at entry and end of the study period.Results:Total QOL scores improved significantly in the active treatment groups (RBX −9.56 ± 4.13; TPX −12.22 ± 2.76) but not in placebo (−5.56 ± 3.49). There were differences in nerve function improvement between treatments. Neurological symptom scores (NSS) im...
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a 6 month randomized double masked placebo controlled study evaluating the effects of the protein kinase c β inhibitor Ruboxistaurin on skin microvascular blood flow and other measures of diabetic peripheral neuropathy
Diabetes Care, 2007Co-Authors: Carolina M. Casellini, Patricia M. Barlow, Amanda L. Rice, Gary Pittenger, Edward J. Bastyr, Anne M. Wolka, Melissa Casey, Kathryn Simmons, Aaron I. VinikAbstract:OBJECTIVE—Diabetes leads to protein kinase C (PKC)-β 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-β inhibitor Ruboxistaurin mesylate on neurovascular function and other measures of DPN. RESEARCH DESIGN AND METHODS—Endothelium-dependent and C fiber–mediated 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 ≥18 years; with type 1 or type 2 diabetes and A1C ≤11%) during a randomized, double-masked, single-site, 6-month study. RESULTS—Endothelium-dependent (+78.2%, P 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.
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the protein kinase c beta inhibitor Ruboxistaurin for the treatment of diabetic microvascular complications
Expert Opinion on Investigational Drugs, 2005Co-Authors: Aaron I. VinikAbstract:The potential for addressing the underlying biological abnormalities in diabetes has eluded most investigators because of the complex mechanisms underlying the effects of diabetes on the pathogenesis of the complications. Although macrovascular complications, such as myocardial infarction, stroke and gangrene, are only partially attributable to hyperglycaemia and its attendant effects, the microvascular complications including retinopathy, nephropathy and neuropathy are directly related to the degree of hyperglycaemia. In controlled trials, a 22-34% reduction in one of these side effects was achieved for every 1% reduction in glycosylated haemoglobin. Theoretically, it should be feasible to eliminate these complications in a perfect world. However, achieving euglycaemia is nearly impossible and there is increasing data to suggest that it may be an elusive target with ever lower levels being implicated in the pathogenesis of microvascular disease and there is a price to be paid of hypoglycaemia if further intensification is pursued. A logical argument would be to block pathways that are activated by hyperglycaemia. A major pathway implicated is the activation of protein kinase C-beta in all of the targeted tissues, and there is animal data to support the notion that blocking this pathway can reverse or abrogate the untoward effects of diabetes. The possible role of the protein kinase C-beta inhibitor, Ruboxistaurin, in animal studies and the recently reported clinical studies to place in perspective a possible addition to the therapeutic armamentarium of the imperfect world of diabetes control will be reviewed.
