Background
Risarestat (CT-112), an aldose reductase inhibitor, is developed for the treatment of diabetic complications.
Risarestat inhibits the accumulation of dulcitol in a dose-dependent manner, except for the 1.0% solution which has an activity comparable to the 0.25% solution[1]. Risarestat peaks in the corneal epithelium, stroma, endothelium and aqueous humor in 30 minutes following instillation, then gradually diminishes time-dependently over a period of 24 hours. Risarestat remains detectable in the lens up to 24 hours, with a peak concentration at 2 hours after instillation[2]. The anterior surface area of superficial cells in the group treated with Risarestat is significantly decreases from a mean value of 881 to 728 microns2. Corneal sensitivity significantly improves from 5.36 to 1.37 g/mm2[3]. Animals treated with Risarestat shows a significant increase in the mean blinkresponse compared to untreated galactose-fed rats and does not differ significantly from controls towards the completion of the 7 month study. Animals treated topically with Risarestat and untreated galactose-fed rats develop bilateral nuclear cataracts within 3 weeks[4].
[1]. Awata T, et al. Effect of an aldose reductase inhibitor, CT-112, on healing of the corneal epithelium in galactose-fed rats. J Ocul Pharmacol. 1988 Fall;4(3):195-201. [2]. Ohashi Y, et al. Intraocular penetration of CT-112, an aldose reductase inhibitor, following topical instillation. J Ocul Pharmacol. 1989 Winter;5(4):325-8. [3]. Hosotani H, et al. Reversal of abnormal corneal epithelial cell morphologic characteristics and reduced corneal sensitivity in diabetic patients by aldose reductase inhibitor, CT-112. Am J Ophthalmol. 1995 Mar;119(3):288-94. [4]. Jacot JL, et al. Diabetic-like corneal sensitivity loss in galactose-fed rats ameliorated with aldose reductase inhibitors. J Ocul Pharmacol Ther. 1998 Apr;14(2):169-80.
Protocol
Animal experiment: | Rats: The other 5 groups are fed on a 50% galactose diet, and 0.1, 0.25, 0.5 or 1.0% Risarestat ophthalmic solution or its vehicle is instilled in both eyes 4 times a day in each of the 5 treated groups. After 2 weeks, the corneal epithelium is scraped off in all rats and its dulcitol content is determined by gas chromatography[1]. Rabbits: Risarestat is prepared in acetate-buffered saline. 50 μL of 0.5% Risarestat in 7mM acetate-buffered saline (pH 5.2, 290 mOsm) containing 0.15% chlorbutanol as a preservative is instilled to both conjunctival sac of rabbits. This ophthalmic solution is proven to be untoxic to the external eye after 90 days' instillation to the rabbits 9 times a day. The rabbits are then sacrificed at, 15 and 30 minutes, 1, 2, 4, 8, and 24 hours after instillation[2]. |
参考文献: [1]. Awata T, et al. Effect of an aldose reductase inhibitor, CT-112, on healing of the corneal epithelium in galactose-fed rats. J Ocul Pharmacol. 1988 Fall;4(3):195-201.
[2]. Ohashi Y, et al. Intraocular penetration of CT-112, an aldose reductase inhibitor, following topical instillation. J Ocul Pharmacol. 1989 Winter;5(4):325-8.
[3]. Hosotani H, et al. Reversal of abnormal corneal epithelial cell morphologic characteristics and reduced corneal sensitivity in diabetic patients by aldose reductase inhibitor, CT-112. Am J Ophthalmol. 1995 Mar;119(3):288-94.
[4]. Jacot JL, et al. Diabetic-like corneal sensitivity loss in galactose-fed rats ameliorated with aldose reductase inhibitors. J Ocul Pharmacol Ther. 1998 Apr;14(2):169-80. |
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