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Nonopiate Analgesics and Adjuvants
Published in Gary W. Jay, Practical Guide to Chronic Pain Syndromes, 2016
Activation of PKC has been implicated in noted changes in pain perception. When activated by phorbol esters, PKC enhances thermal hyperalgesia in diabetic mice. Activated PKC also leads to enhancement of excitatory amino acids (EAAs) in dorsal horn neurons as well as trigeminal neurons. It is therefore possible that PKC may induce neuronal sensitization that produces hyperalgesia in diabetic neuropathy. Ruboxistaurin, a PKC inhibitor, may be a valid treatment for diabetic neuropathic pain (78-80).
Nonopiate Analgesics and Adjuvants
Published in Gary W. Jay, Clinician’s Guide to Chronic Headache and Facial Pain, 2016
Activation of PKC has been implicated in noted changes in pain perception. When activated by phorbol esters, PKC enhances thermal hyperalgesia in diabetic mice. Activated PKC also leads to enhancement of excitatory amino acids (EAAs) in dorsal horn neurons as well as trigeminal neurons. It is therefore possible that PKC may induce neuronal sensitization that produces hyperalgesia in diabetic neuropathy. Ruboxistaurin, a PKC inhibitor, may be a valid treatment for diabetic neuropathic pain (78-80).
Pharmacologic Treatment in Diabetic Macular Edema
Published in Glenn J. Jaffe, Paul Ashton, P. Andrew Pearson, Intraocular Drug Delivery, 2006
Zeshan A. Rana, P. Andrew Pearson
Inhibitors specific for PKC-b have a more favorable toxicity profile. In fact, in a study by Aiello et al. (52), the effect of VEGF on retinal vascular permeability appeared to be mediated predominantly by the b-isoform of PKC. There was >95% inhibition of VEGF-induced permeability after administration of a PKC b-isoform-selective inhibitor (50). Studies are currently being conducted with a new PKC-b inhibitor, known as ruboxistaurin mesylate. Thus far, based on animal studies, ruboxistaurin has shown to inhibit PKC-b formation and thereby normali-zing retinal vascular function (52).
The time to develop treatments for diabetic neuropathy
Published in Expert Opinion on Investigational Drugs, 2021
Protein kinase overactivation is one possible cause of microvascular dysfunction in diabetes. Ruboxistaurin is a selective protein kinase C inhibitor. An exploratory 6-month study in 20 patients with diabetic neuropathy showed a significant improvement in neuropathy symptom score (NTSS) and quality of life compared to 20 placebo patients [93]. These findings led to a one-year randomized placebo-controlled trial in 205 patients [94]. Overall, there was no overall change in symptom scores nor vibration perception. The lack of success of ruboxistaurin stimulated analysis of results in 262 placebo-treated patients in two one-year studies which showed positive improvements in symptom scores and vibration perception while nerve conduction velocities declined [95]. The authors concluded that longer-term studies would be necessary to show effects of agents compared to placebo in diabetic neuropathy trials.
Managing chronic kidney disease in diabetes patients with the latest chemical therapies
Published in Expert Review of Clinical Pharmacology, 2019
The selective PKC-β inhibitor ruboxistaurin (LY333531) developed by Eli Lilly can competitively interacts with the ATP binding site of PKC isoforms. It inhibitors PKC-βI and PKC-βII 76- and 61-fold selectively over PKC-α. In a pilot study, 123 subjects were randomized to receive 32 mg/day ruboxistaurin or placebo, and the result showed that the estimated glomerular filtration rate (eGFR) was maintained in ruboxistaurin group compared with deteriorating filtration rates in placebo group [43]. Phase III clinical trial (ClinicalTrials.gov identifier: NCT00297401) has been completed recently, but the result is still unavailable [44]. This is a pilot study with three parts, and 21 subjects with type 1 diabetes were randomized to receive ruboxistaurin or placebo in a 2:1 fashion. The impact of PKC inhibition on the renal and peripheral hemodynamic response to hyperglycemia was assessed in the part 1. The impact of PKC inhibition on the response to Angiotensin II was assessed in the part 2. The impact of PKC inhibition on proteinuria was assessed in the part 3.
Therapeutic targets for altering mitochondrial dysfunction associated with diabetic retinopathy
Published in Expert Opinion on Therapeutic Targets, 2018
Renu A. Kowluru, Manish Mishra
The hexosamine pathway, a relatively minor branch of glycolysis, usually accounts for only 2–5% of total glucose metabolism, but in diabetes, high circulating glucose increases flux through the hexosamine pathway, forming uridine diphosphate β-d-N-acetylglucosamine (UDP-GlcNAc), the donor for protein O-GlcNAcylation [18]. The O-GlcNAcylation process is a dynamic nutrient sensitive posttranslational modification, which can affect proteins by altering their activity, cellular localization, signaling, and transcription processes; in diabetes, hexosamine pathway is activated in the retina [18]. In addition, increase in glucose flux through glycolysis also increases de novo synthesis of diacylglycerol (DAG), a key activator of PKC. Activation of PKC in the retina is associated in many abnormalities seen in diabetes including disturbances in hemodynamics and endothelial permeability, leukostasis, and production of VEGF. PKC activation is also implicated in accelerated capillary cell apoptosis, and in reduction of the survival signaling pathway of platelet-derived growth factor [22]. Although an isoform-selective inhibitor of PKC-β, ruboxistaurin, which is not yet approved for diabetic retinopathy, has shown some promising results in reducing macular edema and sustained moderate visual loss [23], additional clinical trials are needed to investigate its effect on diabetic retinopathy.