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P.–P. Elena, T. Amar, T. Caillaud, M. Wong, J.–C. Bizec; PKC412 Content in Retina, Choroid and Plasma of Pup Mice with Retinal Neovascularization Induced by Hypoxic Stimuli . Invest. Ophthalmol. Vis. Sci. 2004;45(13):4053.
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Purpose: The aim of this study was to investigate the distribution of CGP41251 (PKC412), a selective inhibitor of protein kinase C, in retina, choroid and plasma following topical applications of PKC412 ointments in pup mice induced with retinopathy of prematurity (ROP). Methods: Oxygen–induced retinopathy was induced by exposing C57BL/6J 7–day old mice to a 75% oxygen atmosphere for 5 consecutive days. Then, in a normal oxygen atmosphere, pup mice were treated in both eyes with 2–µl ocular applications of 0%, 0.25%, 0.5% or 1% PKC412 ointment twice a day for 6 consecutive days. Since the eyes were still closed at that age, the lids were gently mechanically opened before each administration. A positive control group (75% oxygen, untreated) was also added. Each treatment group consisted of 6 different litters totalizing 30 pups (2 litters per time–point). Animals were sacrificed 0.5 h, 2 h or 7 h after the last administration. PKC412 content was determined for each pup in plasma, and in pooled retinas and choroids using a validated HPLC–MS method. Results: PKC412 was still found in both eyes pooled retinas and choroids and in plasma 7 h after the last administration. No PKC412 was detected on untreated animals and on animals treated with placebo. In retina, Cmax was attained 2 h, 0.5 h and 0.5 h after the last administration at 0.27, 0.73 and 1.34 µg/g for the 0.25%; 0.5% and 1% PKC412 ointment treated groups, respectively. In choroid, Cmax was attained 0.5 h after the last administration at 0.60, 1.66 and 2.70 µg/g for the 0.25%; 0.5% and 1% PKC412 ointment treated groups, respectively. In plasma, Cmax was attained 2 h, 2 h, and 0.5 h after the last administration at 8.4, 29.3 and 23.6 ng/ml for the 0.25%; 0.5% and 1% PKC412 ointment treated groups, respectively. Conclusions: In this study, we demonstrated that CGP41251 (PKC412), administered topically as an ointment twice a day for 6 consecutive days after hyperoxia, was found in retina and in choroid of the pup mice. These results showed that PKC412 was found in an amount twice higher in choroid than in retina (when considering Cmax values) whatever the concentration. The amount detected in plasma was low and no difference could be found between the 0.5% and the 1% PKC412 concentrations. These kinetic results could be related to the efficacy of the 1% ointment to reduce the number of neovessel nuclei in this model (see abstract: Caillaud T. et al. "PKC412 reduces retinal neovascularization induced by hypoxic stimuli in pup mice.").
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