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Inhibition of PKC beta by oral administration of ruboxistaurin is well tolerated and ameliorates diabetes-induced retinal hemodynamic abnormalities in patients.
Invest Ophthalmol Vis Sci. 2006 Jan; 47(1):86-92.IO

Abstract

PURPOSE

To assess ocular and systemic safety and pharmacodynamic effects of the oral PKC beta selective inhibitor ruboxistaurin (RBX; LY333531) mesylate in patients with diabetes.

METHODS

This was a double-masked, placebo-controlled, parallel, randomized, single-center clinical study evaluating the effect of oral administration of RBX (8 mg twice a day, 16 mg per day, or 16 mg twice a day) or placebo for 28 days in patients with no or very mild diabetic retinopathy on mean retinal circulation time (RCT), retinal blood flow (RBF), treatment-emergent adverse events, and other safety parameters.

RESULTS

Twenty-nine persons aged 18 to 65 years with type 1 or 2 diabetes were evaluated. The only treatment-emergent adverse event with a statistically significant difference among treatment groups was abdominal pain, which was more common in placebo-treated subjects (P = 0.049). Statistically significant effects of RBX were observed on several hematologic and laboratory parameters, but values were within the normal reference range and none of the changes was deemed clinically meaningful. In patients receiving 16 mg RBX twice daily, the diabetes-induced increase in RCT was ameliorated, with a baseline-to-endpoint difference of -0.84 seconds (P = 0.046) relative to placebo. Increasing RBX dose was linearly associated with greater effect on RCT (P = 0.03). Similar results were observed with RBF.

CONCLUSIONS

RBX was well tolerated at doses up to 16 mg twice daily for 28 days in patients with diabetes. It ameliorated diabetes-induced RCT abnormalities. No serious safety problems were identified in this patient population. Compared with prior published data, these findings represent the first direct human evidence of both bioavailability of RBX to retinal vessels and amelioration of diabetes-induced retinal hemodynamic abnormalities by an oral PKC beta inhibitor.

Authors+Show Affiliations

Beetham Eye Institute and Eye Research Section, Joslin Diabetes Center, Boston, Massachusetts 02215, USA. laiello@joslin.harvard.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16384948

Citation

Aiello, Lloyd Paul, et al. "Inhibition of PKC Beta By Oral Administration of Ruboxistaurin Is Well Tolerated and Ameliorates Diabetes-induced Retinal Hemodynamic Abnormalities in Patients." Investigative Ophthalmology & Visual Science, vol. 47, no. 1, 2006, pp. 86-92.
Aiello LP, Clermont A, Arora V, et al. Inhibition of PKC beta by oral administration of ruboxistaurin is well tolerated and ameliorates diabetes-induced retinal hemodynamic abnormalities in patients. Invest Ophthalmol Vis Sci. 2006;47(1):86-92.
Aiello, L. P., Clermont, A., Arora, V., Davis, M. D., Sheetz, M. J., & Bursell, S. E. (2006). Inhibition of PKC beta by oral administration of ruboxistaurin is well tolerated and ameliorates diabetes-induced retinal hemodynamic abnormalities in patients. Investigative Ophthalmology & Visual Science, 47(1), 86-92.
Aiello LP, et al. Inhibition of PKC Beta By Oral Administration of Ruboxistaurin Is Well Tolerated and Ameliorates Diabetes-induced Retinal Hemodynamic Abnormalities in Patients. Invest Ophthalmol Vis Sci. 2006;47(1):86-92. PubMed PMID: 16384948.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of PKC beta by oral administration of ruboxistaurin is well tolerated and ameliorates diabetes-induced retinal hemodynamic abnormalities in patients. AU - Aiello,Lloyd Paul, AU - Clermont,Allen, AU - Arora,Vipin, AU - Davis,Matthew D, AU - Sheetz,Matthew J, AU - Bursell,Sven-Eric, PY - 2005/12/31/pubmed PY - 2006/2/10/medline PY - 2005/12/31/entrez SP - 86 EP - 92 JF - Investigative ophthalmology & visual science JO - Invest. Ophthalmol. Vis. Sci. VL - 47 IS - 1 N2 - PURPOSE: To assess ocular and systemic safety and pharmacodynamic effects of the oral PKC beta selective inhibitor ruboxistaurin (RBX; LY333531) mesylate in patients with diabetes. METHODS: This was a double-masked, placebo-controlled, parallel, randomized, single-center clinical study evaluating the effect of oral administration of RBX (8 mg twice a day, 16 mg per day, or 16 mg twice a day) or placebo for 28 days in patients with no or very mild diabetic retinopathy on mean retinal circulation time (RCT), retinal blood flow (RBF), treatment-emergent adverse events, and other safety parameters. RESULTS: Twenty-nine persons aged 18 to 65 years with type 1 or 2 diabetes were evaluated. The only treatment-emergent adverse event with a statistically significant difference among treatment groups was abdominal pain, which was more common in placebo-treated subjects (P = 0.049). Statistically significant effects of RBX were observed on several hematologic and laboratory parameters, but values were within the normal reference range and none of the changes was deemed clinically meaningful. In patients receiving 16 mg RBX twice daily, the diabetes-induced increase in RCT was ameliorated, with a baseline-to-endpoint difference of -0.84 seconds (P = 0.046) relative to placebo. Increasing RBX dose was linearly associated with greater effect on RCT (P = 0.03). Similar results were observed with RBF. CONCLUSIONS: RBX was well tolerated at doses up to 16 mg twice daily for 28 days in patients with diabetes. It ameliorated diabetes-induced RCT abnormalities. No serious safety problems were identified in this patient population. Compared with prior published data, these findings represent the first direct human evidence of both bioavailability of RBX to retinal vessels and amelioration of diabetes-induced retinal hemodynamic abnormalities by an oral PKC beta inhibitor. SN - 0146-0404 UR - https://www.unboundmedicine.com/medline/citation/16384948/Inhibition_of_PKC_beta_by_oral_administration_of_ruboxistaurin_is_well_tolerated_and_ameliorates_diabetes_induced_retinal_hemodynamic_abnormalities_in_patients_ L2 - http://iovs.arvojournals.org/article.aspx?doi=10.1167/iovs.05-0757 DB - PRIME DP - Unbound Medicine ER -