Effect of Ruboxistaurin on the Visual Acuity Decline Associated with Long-standing Diabetic Macular Edema

Davis, Matthew D.; Sheetz, Matthew J.; Aiello, Lloyd Paul; Milton, Roy C.; Danis, Ronald P.; Zhi, Xu; Girach, Aniz; Jiménez, María Cristina Hernández; Vignati, Louis

doi:10.1167/iovs.08-2473

Cited by 80 publications

(51 citation statements)

References 14 publications

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“…Ruboxistaurin did however achieve significant reduction in diabetic macular oedema. 51 Another major pathway that modulates retinal vasoconstriction and decreased retinal blood flow during early diabetes is disruption of ion channel function. This dysfunction is largely concentrated at the level of the retinal arterioles as the main site for local blood flow regulation in the retina.…”

Section: Retinal Hypoperfusion In Diabetes: Links To Early Pathologymentioning

confidence: 99%

Microvascular lesions of diabetic retinopathy: clues towards understanding pathogenesis?

Curtis

Gardiner

Stitt

2009

Eye

318

231

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Retinopathy is a major complication of diabetes mellitus and this condition remains a leading cause of blindness in the working population of developed countries. As diabetic retinopathy progresses a range of neuroglial and microvascular abnormalities develop although it remains unclear how these pathologies relate to each other and their net contribution to retinal damage. From a haemodynamic perspective, evidence suggests that there is an early reduction in retinal perfusion before the onset of diabetic retinopathy followed by a gradual increase in blood flow as the complication progresses. The functional reduction in retinal blood flow observed during early diabetic retinopathy may be additive or synergistic to proinflammatory changes, leucostasis and vasoocclusion and thus be intimately linked to the progressive ischaemic hypoxia and increased blood flow associated with later stages of the disease. In the current review a unifying framework is presented that explains how arteriolar dysfunction and haemodynamic changes may contribute to late stage microvascular pathology and vision loss in human diabetic retinopathy.

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Section: Retinal Hypoperfusion In Diabetes: Links To Early Pathologymentioning

confidence: 99%

Microvascular lesions of diabetic retinopathy: clues towards understanding pathogenesis?

Curtis

Gardiner

Stitt

2009

Eye

318

231

View full text Add to dashboard Cite

show abstract

“…In 1996, the chemical characterization and in vivo pharmacological profile of orally active and highly selective PKC-inhibitor, ruboxistaurin mesylate (LY333531), were reported in science [95]. The highly selective activation of PKC and its inhibition by ruboxistaurin mesylate have been studied extensively [96] and demonstrated through clinical studies in the prevention of vision loss [97]. In 2009, Geraldes et al demonstrated that hyperglycemia persistently activated PKC and p38 MAPK to increase the expression of a novel target, SHP-1, leading to PDGF receptordephosphorylation and actions, and increased pericyte apoptosis, independent of NF-B [98].…”

Section: Pkc Inhibitors As Potentialmentioning

confidence: 99%

Molecular mechanisms of Diabetic Retinopathy, general preventive strategies and novel therapeutic targets

Safi¹,

Qvist²,

Kumar³

et al. 2013

Exp Clin Endocrinol Diabetes

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The growing number of people with diabetes worldwide suggests that diabetic retinopathy (DR) and diabetic macular edema (DME) will continue to be sight threatening factors. The pathogenesis of diabetic retinopathy is a widespread cause of visual impairment in the world and a range of hyperglycemia-linked pathways have been implicated in the initiation and progression of this condition. Despite understanding the polyol pathway flux, activation of protein kinase C (KPC) isoforms, increased hexosamine pathway flux, and increased advanced glycation end-product (AGE) formation, pathogenic mechanisms underlying diabetes induced vision loss are not fully understood. The purpose of this paper is to review molecular mechanisms that regulate cell survival and apoptosis of retinal cells and discuss new and exciting therapeutic targets with comparison to the old and inefficient preventive strategies. This review highlights the recent advancements in understanding hyperglycemia-induced biochemical and molecular alterations, systemic metabolic factors, and aberrant activation of signaling cascades that ultimately lead to activation of a number of transcription factors causing functional and structural damage to retinal cells. It also reviews the established interventions and emerging molecular targets to avert diabetic retinopathy and its associated risk factors.

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“…PKC-b inhibitor, ruboxistaurin, given orally, has been shown to delay progression of DME to a sight-threatening stage and may ameliorate edema-associated visual decline in patients with persisting severe DME (PKC-DMES Study Group 2007;Davis et al 2009). PKC-DRS2 group conducted a large multicenter randomized study in which they compared 32 mg of ruboxistaurin given orally to placebo over 36 months.…”

Section: Role Of Angiogenic Factors In Diabetic Macular Edemamentioning

confidence: 99%

Antiangiogenic Therapy for Ischemic Retinopathies

Al-Latayfeh¹,

Silva²,

Sun³

et al. 2012

Cold Spring Harbor Perspectives in Medicine

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Effect of Ruboxistaurin on the Visual Acuity Decline Associated with Long-standing Diabetic Macular Edema

Abstract: 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.).

Cited by 80 publications

References 14 publications

Microvascular lesions of diabetic retinopathy: clues towards understanding pathogenesis?

Microvascular lesions of diabetic retinopathy: clues towards understanding pathogenesis?

Molecular mechanisms of Diabetic Retinopathy, general preventive strategies and novel therapeutic targets

Antiangiogenic Therapy for Ischemic Retinopathies

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